CN114957216A - Target inhibitor, preparation method, application and pharmaceutical composition thereof - Google Patents

Target inhibitor, preparation method, application and pharmaceutical composition thereof Download PDF

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CN114957216A
CN114957216A CN202210583078.5A CN202210583078A CN114957216A CN 114957216 A CN114957216 A CN 114957216A CN 202210583078 A CN202210583078 A CN 202210583078A CN 114957216 A CN114957216 A CN 114957216A
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CN114957216B (en
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师健友
钟磊
童荣生
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Sichuan Peoples Hospital of Sichuan Academy of Medical Sciences
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    • 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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Abstract

The invention disclosesA target inhibitor, a preparation method, application and a pharmaceutical composition thereof, the target inhibitor is used for inhibiting at least one of ALK and EGFR and comprises a compound shown in a formula 1:
Figure DDA0003662436260000011
wherein R is 1 、R 2 Each independently selected from any one of substituted or unsubstituted benzene ring, substituted or unsubstituted benzo heterocycle, substituted or unsubstituted condensed ring, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, halogen, cyano, ester group, aldehyde group, alkoxy, carbonyl, acyl, amino, azo group, sulfonic group, mercapto, nitro and hydroxyl. The novel compound is obtained by taking 2, 4-diamino-5-chloropyrimidine as a mother nucleus, has better activity on at least one mutant of ALK and EGFR, breaks through the drug resistance defect of the existing ALK inhibitor and EGFR inhibitor, and has good prospect in the field of tumor treatment.

Description

Target inhibitor, preparation method, application and pharmaceutical composition thereof
Technical Field
The invention relates to the technical field of molecular targeted drugs, and particularly relates to a target inhibitor, and a preparation method, application and a pharmaceutical composition thereof.
Background
The anaplastic lymphoma kinase ALK and the epidermal growth factor receptor EGFR are recognized as effective targets for the treatment of non-small cell lung cancer. The life quality of cancer patients can be effectively improved and the life time of the patients can be prolonged by targeting the ALK target and the EGFR target, but the generation of drug resistance influences the treatment effect of the existing ALK inhibitor and EGFR inhibitor to different degrees.
The development of ALK kinase resistance is mainly caused by secondary mutations in the kinase and by re-induction of kinase activation and signaling. These resistance mutations can directly block the binding of ALK inhibitors to target kinases, alter the conformation of the kinases, and alter the ATP binding affinity of the kinases. The drug resistance of ALK inhibitors mainly includes ALK L1196M, C1156Y, G1202R, 1174L, F1198F, and the like. In 2011, the FDA in the united states approved Crizotinib for first-line treatment of ALK-positive NSCLC, which can occupy the tyrosine kinase pocket of ALK and block ATP binding to ALK, but resistance mutations at L1196M and C1156Y typically occur 1 year after patient treatment. The amino acid residue L1196 can control the entrance of small molecule ALK inhibitor into the hydrophobic pocket in the catalytic site, and when the amino acid residue L1196 is mutated, the stability of the hydrogen bond network in the ALK structure domain is destroyed, thereby affecting the combination between ALK and Criztinib. In contrast, C1156Y is resistant by a different mechanism, C1156 is close to the catalytic α C-helix, promoting Atp binding when the cysteine is replaced by tyrosine or preventing inhibitor binding by stabilizing ALK activity. In view of the above mutations, researchers developed second generation ALK inhibitors Certinib and Alectinib, which can effectively overcome the mutations that confer resistance to Crizotinib, including L1196M, G1269A, and S1206Y; alectinib showed activity in vitro against C1156Y and F1174C/L; this gives a different drug resistance spectrum for Certinib and Alectinib. However, like Crizotinib, patients eventually develop resistance to Certinib and Alectinib. G1202R is the most common resistance mutation found in patients receiving second generation ALK inhibitor therapy. G1202R would introduce steric hindrance at the drug binding pocket, thereby affecting the binding between ALK and second generation ALK inhibitors. In order to overcome G1202R mutation, researchers design and synthesize a third-generation ALK inhibitor Loratinib, which is an ATP competitive macrocyclic double-target (ALK and ROS1) inhibitor, has the characteristics of oral administration and capability of passing through a blood brain barrier, can effectively treat ALK positive metastatic NSCLC, but after the treatment of Loratinib lasts for 8 months, gene detection finds that a patient has a new ALK L1198F hinge region mutation.
The drug resistance mechanism of the EGFR targeting drug mainly comprises EGFR amplification, gene mutation, alternative activation and the like of an EGFR kinase structural domain. Among all possible mechanisms, the secondary and tertiary mutations of EGFR are the most intractable, mainly including EGFR T790M, C797S mutations, and the like. Gefitinib and Erlotinib are the first generation EGFR inhibitors approved by the FDA in the united states for the treatment of NSCLC in 2009 and 20013, respectively, which achieve significant benefit in patients carrying so-called sensitizing mutations (e.g., L858R and exon 19 deletion) by inhibiting the kinase domain of EGFR and interfering with oncogenic cell signaling. However, in about 50% of patients with EGFR changes, T790M resistance mutations occur, greatly limiting the efficacy of these drugs in clinical applications. In the mutated methionine residues, their bulky side chains are thought to sterically hinder the binding of these reversible inhibitors and disrupt hydrogen bond formation between the inhibitor and the amino acid residues of EGFR. In another proposed mechanism, researchers believe that the T790M-containing mutant has an increased affinity for ATP, resulting in a decrease in the cellular potency of EGFR inhibitors. Second-generation EGFR inhibitors were used for the T790M mutation, but the clinical therapeutic effects of Dacomitinib and Neratinib were not significant in the second-generation EGFR inhibitors, and the therapeutic dose window of Afatinib was too narrow. The reasons for this may be: the therapeutic dose of the drug is far greater than the tolerance of the patient; lack of selectivity for different EGFR mutations. To overcome the above problems, researchers have designed and synthesized third generation inhibitors. The third generation EGFR TKI has an acrylamide warhead and reacts with Cys797 in the EGFR binding domain to form a covalent bond, inhibiting the kinase activity of EGFR. However, the inability of third-generation EGFR inhibitors to form covalent bonds with EGFR (C797S) has led to the development of resistance by third-generation EGFR inhibitors. Although patients with trans-EGFR mutations, in which the T790M and C797S mutations are located on different alleles, can be treated by first and third generation EGFR inhibitors in combination, resistance mediated by 85% of cis-EGFR mutations (the T790M and C797S mutations are located on the same allele) remains an unmet clinical need.
Therefore, it is necessary to develop a target inhibitor which can break through the drug-resistant mutation of the ALK existing inhibitor and can effectively inhibit the EGFR T790M/C797s mutation.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a target inhibitor, a preparation method, application and a pharmaceutical composition thereof, so as to improve the technical problems.
The invention is realized by the following steps:
in a first aspect, the present invention provides a target inhibitor, primarily for inhibiting at least one of ALK and EGFR, comprising a compound represented by formula 1:
Figure RE-GDA0003757929780000021
wherein R is 1 、R 2 Each independently selected from substituted or unsubstituted benzene ring, substituted or unsubstituted benzo heterocycle, substituted or unsubstituted condensed ring, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyl, substituted or unsubstituted alkyneAny one of a group, halogen, cyano group, ester group, aldehyde group, alkoxy group, carbonyl group, acyl group, amino group, azo group, sulfonic group, mercapto group, nitro group and hydroxyl group.
Alternatively, R 1 、R 2 Each independently selected from any one of a substituted or unsubstituted benzene ring, a substituted or unsubstituted benzo heterocycle, a substituted or unsubstituted condensed ring, a substituted or unsubstituted heterocycle, a substituted or unsubstituted cycloalkyl and a substituted or unsubstituted straight-chain alkyl.
Alternatively, R 1 、R 2 Each independently selected from any one of benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted linear alkyl.
Alternatively, R 1 The halogen-free substituted benzene ring is one of substituted benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted straight-chain alkyl, when the benzene ring is mono-substituted, the substituent group is selected from any one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, when the benzene ring is multi-substituted, the substituent groups are independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxyl; r 2 Is selected from substituted benzene ring, the benzene ring has para-position substitution gene, and the para-position substitution group is tertiary amino group or nitrogen-containing heterocycle; or, R 1 Selected from substituted benzene ring, the benzene ring has para-position substitution gene, the para-position substitution group is tertiary amino group or nitrogen-containing heterocycle, R 2 The halogen-free substituted benzene ring is one of substituted benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted straight-chain alkyl, when the benzene ring is mono-substituted, the substituent group is one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, and when the benzene ring is multi-substituted, the substituent groups are independently one of halogen, methyl, carboxyl, hydroxyl and methoxyl. Alternatively, R 1 、R 2 The alkyl selected from the group consisting of C1-C10 alkyl.
In a second aspect, the present invention also provides a preparation method of the above target inhibitor, and the synthetic route is as follows:
Figure RE-GDA0003757929780000031
optionally, the preparation method of the target inhibitor comprises the following steps: in correspondence with a group containing R 1 Adding 2, 4, 5-trichloropyrimidine solution dropwise into the amine solution to carry out first reaction, extracting and separating to obtain an intermediate, dissolving again, and adding the intermediate containing R correspondingly 2 The amine of (a) is subjected to a second reaction. Optionally, the reaction temperature of the first reaction and the reaction temperature of the second reaction are both 75-90 ℃, and preferably 80 ℃.
In a fourth aspect, the invention also provides an application of the target inhibitor in preparing a medicament for treating tumors, wherein optionally the tumors have ALK fusion mutation and/or EGFR mutation, and optionally the tumors are lung cancer.
In a fifth aspect, the present invention also provides a pharmaceutical composition comprising the target inhibitor described above.
The invention has the following beneficial effects: the novel compound with different side chain functional groups is obtained by taking 2, 4-diamino-5-chloropyrimidine as a mother nucleus, can have better activity on ALK third-generation mutants and EGFR third-generation mutations, can break through the drug resistance defect of the existing ALK inhibitor and EGFR inhibitor, and has good research value and application prospect in the fields of tumor treatment and research.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following describes a target inhibitor, its preparation method, application and pharmaceutical composition.
In the terms of the present invention, "substituted" means that a hydrogen atom bonded to a carbon atom of a compound becomes an additional substituent, and the position of substitution is not limited as long as the position is a position at which the hydrogen atom is substituted (i.e., a position at which the substituent may be substituted), and when two or more substituents are substituted, the two or more substituents may be the same as or different from each other.
In the terminology of the invention, the term "substituted or unsubstituted" means substituted with one, two or more substituents selected from the group consisting of the following. For example, "a substituent in which two or more substituents are linked" may include a biphenyl group. In other words, biphenyl can be an aryl group, or can be interpreted as a substituent with two phenyl groups attached.
The term "independently selected" as used in the terms of the present invention means that the same or different structures may be selected for multiple instances of a given variable in a single compound.
The term "comprising" as used in the present terminology means "including (but not limited to)".
Unless otherwise indicated, structures shown herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention except for replacement of a hydrogen atom with deuterium or tritium or replacement of a carbon atom with 13C or 14C enriched carbon are within the scope of the present invention.
Some embodiments of the present invention provide a target inhibitor for inhibiting at least one of ALK and EGFR, comprising a compound represented by formula 1:
Figure RE-GDA0003757929780000041
wherein R is 1 、R 2 Each independently selected from substituted or unsubstituted benzene ring, substituted or unsubstituted benzo heterocycle, substituted or unsubstituted condensed ring, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, halogen, cyano, ester group, aldehyde group, alkoxy, carbonyl, acyl, amino, azo group, sulfonic acidAny one of a group, a mercapto group, a nitro group and a hydroxyl group.
It should be noted that R is the same as R in the above parent nucleus 1 、R 2 Compounds that specifically inhibit ALK or EGFR or both are subject to radical changes are within the scope of the invention.
Further, in some embodiments, for R 1 、R 2 The optional groups are further screened, i.e. R 1 、R 2 Each of which may be independently selected from any one of a substituted or unsubstituted benzene ring, a substituted or unsubstituted benzo-heterocycle, a substituted or unsubstituted condensed ring, a substituted or unsubstituted heterocycle, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted straight-chain alkyl.
Further, in some embodiments, R 1 、R 2 Each of the substituents may be independently selected from any one of a benzene ring, a benzo heterocycle, a substituted condensed ring, a substituted or unsubstituted heterocycle, a cycloalkyl group and a substituted straight-chain alkyl group.
The heterocyclic ring in the above embodiment may be a three-membered heterocyclic ring, a four-membered heterocyclic ring, a five-membered heterocyclic ring, a six-membered heterocyclic ring, or may be other forms of heterocyclic compounds such as fused ring heterocyclic compounds, including but not limited to ethylene oxide, thiirane, furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, indole, quinoline, and the like. The heterocyclic ring in the benzo heterocycle includes, but is not limited to, three-membered ring, four-membered ring, five-membered ring or six-membered ring, etc., the doped elements include, but are not limited to, oxygen, sulfur, nitrogen, etc., and the number of doping includes, but is not limited to, 1, 2, etc. When the benzene ring is substituted, the substitution includes, but is not limited to, 1 or 2 substitution positions, and further substitution may be performed on the basis of the substituent group. The alkyl group includes, but is not limited to, cycloalkyl, straight-chain alkyl, iso-alkyl, etc., and the number of C atoms thereof is not limited, and may be, for example, C1-C20, or C2-C10, C1-C5, etc.
Dual-target inhibitors can affect two different pathways of disease progression, often producing synergistic or enhanced effects, and reducing the development of disease resistance. Accordingly, some embodiments of the inventionIn the formula, by reacting with R 1 And R 2 The group is further screened to obtain a series of double-target inhibitors taking ALK and EGFR as targets, which can simultaneously play a role in inhibiting ALK and EGFR, have better activity on ALK third-generation mutants and EGFR third-generation mutations, and overcome the drug resistance of the existing drugs.
Specifically, R 1 The substituted benzene ring is selected from any one of substituted benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted straight-chain alkyl, when the benzene ring is mono-substituted, the substituent group is selected from any one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, when the benzene ring is multi-substituted, the substituent groups are respectively and independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxyl; r 2 Is selected from substituted benzene ring, the benzene ring has para-position substitution gene, and the para-position substitution group is tertiary amino group or nitrogen-containing heterocycle.
Or, R 1 Selected from substituted benzene ring, the benzene ring has para-position substitution gene, the para-position substitution group is tertiary amino group or nitrogen-containing heterocycle, R 2 The substituted benzene ring is selected from any one of substituted benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted straight-chain alkyl, when the benzene ring is mono-substituted, the substituent group is selected from any one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, when the benzene ring is multi-substituted, the substituent groups are independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxyl. R 1 、R 2 The alkyl selected from the group consisting of C1-C10 alkyl.
Further, in some embodiments, R 1 Is selected from any one of substituted benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted straight-chain alkyl, when the benzene ring is monosubstituted, the substituent group is selected from any one of halogen, C1-C5 alkyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, when the benzene ring is polysubstituted, a plurality of substituent groups are respectively and independently selected from halogen, methyl and carboxylAny one of a group, a hydroxyl group and a methoxy group; C1-C5 alkyl is preferably methyl or ethyl. R is 2 Is selected from substituted benzene ring, the benzene ring has para-position substitution gene, and the para-position substitution group is tertiary amino group or nitrogen-containing heterocycle.
Further, in some embodiments, when R is 1 When the substituted benzene ring is selected, the benzene ring is mono-substituted, di-substituted or tri-substituted benzene ring; alternatively, when the phenyl ring is trisubstituted, the substituents are all methoxy groups. The benzo heterocycle is a benzodioxole, preferably the benzo heterocycle is benzodioxole.
In some embodiments, the substituent group of the fused ring can be a hydroxyl group. The heterocyclic ring is a five-membered heterocyclic ring, preferably the heterocyclic ring is selected from any one of thiazole, imidazole, pyrazole and oxazole, further preferably the heterocyclic ring is selected from thiazole or pyrazole; when the heterocycle is substituted heterocycle, the substituent group is selected from any one of methyl and nitro, and preferably, the heterocycle is mono-substituted.
In some embodiments, the cycloalkane to which the cycloalkyl group corresponds is cyclopropane or cyclopentane. The linear alkyl is C2-C4 alkyl, preferably, the linear alkyl is ethyl, preferably, the substituent group of the linear alkyl is amino or heterocycle, preferably, the substituent group of the linear alkyl is selected from any one of substituted or non-substituted nitrogen heterocycle, oxygen nitrogen heterocycle and isopropylamino.
In some embodiments, R 2 Wherein the tertiary amino group is selected from any one of dimethyl tertiary amino, piperazine group and nitrogen-oxygen heterocycle; preferably, the benzene ring also has an ortho substituent, and the ortho substituent is methoxy.
Specifically, in some embodiments, R 1 Any one selected from the following groups:
Figure RE-GDA0003757929780000051
Figure RE-GDA0003757929780000061
R 2 any one selected from the following groups:
Figure RE-GDA0003757929780000062
further, by the screening test, in some embodiments, the target inhibitor is selected from at least one of the following compounds:
Figure RE-GDA0003757929780000071
Figure RE-GDA0003757929780000081
Figure RE-GDA0003757929780000091
Figure RE-GDA0003757929780000101
Figure RE-GDA0003757929780000111
Figure RE-GDA0003757929780000121
some embodiments of the present invention further provide a method for preparing the target inhibitor, which is characterized in that the synthetic route is as follows:
Figure RE-GDA0003757929780000122
the above synthetic route firstly substitutes 2, 4, 5-trichloro-benzene with different amines4-amino on the mother nucleus of pyrimidine reacts at a certain temperature to obtain an intermediate a, then 2-amino on the mother nucleus is substituted by different substituted amines to finally obtain AE series compounds, R 1 And R 2 Representing different branches. Different substituted anilines include, but are not limited to: 4-ethylaniline, 4- (4-ethylpiperazin-1-yl) aniline, 4-fluoroaniline, 3-bromo-4-methylaniline, 6-amino-1-naphthol, m-bromoaniline, 5-aminoisophthalic acid dimethyl ester, aniline, 4-amino-3-fluorobenzoic acid, N-isopropylethylenediamine, 4-aminobenzoic acid methyl ester, 3-methoxyaniline, 2- (3, 4-dimethoxyphenyl) ethylamine, 3-methylaniline, 4- (4-methylpiperazin) aniline, 2-methoxy-4- (4-methylpiperazin-1-yl) aniline, cyclopropylamine, N, N-dimethyl-p-phenylenediamine, 3- (4-methylpiperazin-1-yl) aniline, 4-piperidinoaniline, N, N-diethyl-p-phenylenediamine, 3, 4, 5-trimethoxyaniline, 2-methoxy-5-methylaniline, 4-bromo-3-methoxyaniline, 4-amino-2-methylbenzoic acid, 2-aminoacetophenone, 4-aminoacetophenone, 2, 5-dimethoxyaniline, and the like.
Any method that can synthesize the compounds according to the above embodiments of the present invention by conventional organic chemical synthesis methods can be used to prepare the target inhibitors protected by the present invention.
In some embodiments, the above preparation method specifically comprises: in correspondence with a group containing R 1 Adding 2, 4, 5-trichloropyrimidine solution dropwise into the amine solution to carry out first reaction, extracting and separating to obtain an intermediate, dissolving again, and adding the intermediate containing R correspondingly 2 The amine of (2) is subjected to a second reaction. The solvent can be selected from isopropanol or other solvent capable of dissolving reactant.
In some embodiments, the reaction temperature of the first reaction and the second reaction is 75-90 ℃, preferably 80 ℃. The progress of the reaction can be determined by TLC detection. The reaction time of the first reaction is about 5 to 8 hours.
After the first reaction is finished, taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing the reaction product by using saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying the intermediate for later use.
And (3) after the second reaction is finished, standing at room temperature, precipitating after a period of time, filtering to obtain a precipitate, adding water to dissolve the precipitate, adding a NaOH solution after the precipitate is dissolved, adjusting the pH value to 12, filtering to collect a solid, washing with water, washing for 2-3 times, and drying to obtain the target compound.
Some embodiments of the invention also provide application of the target inhibitor in preparing a medicament for treating tumors. Tumors include, but are not limited to, hematologic malignancies, brain tumors, head/neck cancer, esophageal cancer, gastric cancer, appendiceal cancer, colon cancer, anal cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, gastrointestinal stromal tumors, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, uterine body cancer, cervical cancer, ovarian cancer, osteosarcoma, soft tissue sarcoma, kaposi's sarcoma, myosarcoma, bladder cancer, or testicular cancer.
Preferably, the tumor has an ALK fusion mutation and/or an EGFR mutation, more preferably, the tumor is lung cancer.
Some embodiments of the invention also provide a pharmaceutical composition comprising the target inhibitor described above. That is, the pharmaceutical composition may further include other pharmaceutically acceptable salts and pharmaceutically acceptable carriers, and may be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection or by various methods such as oral administration or transdermal administration. A pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material (e.g., excipients, diluents, additives, and solvents) involved in the transport of the compound of the invention or a composition containing the compound of the invention from a given organ to another organ.
The preparation can be prepared by selecting an appropriate preparation form (e.g., oral preparation or injection) according to the administration method and using various methods conventionally used for preparing preparations. Examples of oral formulations may include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions and oily or aqueous suspensions. In oral administration, the free compound or salt form may be used. Aqueous formulations may be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by forming an alkali metal salt such as a sodium salt. As the injection, a stabilizer, a preservative, a dissolution aid, and the like can be used in the preparation. After a solution that may contain these auxiliaries and the like is filled in a container, a preparation for use may be prepared as a solid preparation by lyophilization and the like. Further, one dose may be filled in one container, or two or more doses may be filled in one container.
Examples of solid preparations include tablets, powders, granules, capsules, pills and lozenges. These solid preparations may contain pharmaceutically acceptable additives as well as the compounds of the present invention. Examples of additives include fillers, extenders, binders, disintegrants, dissolution promoters, skin moisturizers, and lubricants. These additives may be selected and mixed as necessary to prepare a formulation. Examples of liquid preparations include solutions, syrups, elixirs, emulsions and suspensions. Examples of additives include suspending agents and emulsifying agents. These additives may be selected and mixed as necessary to prepare a formulation.
The features and properties of the present invention are described in further detail below with reference to examples. The target compound of the specific AE number in the foregoing embodiment was synthesized by the following examples.
Example 1
The embodiment provides a method for synthesizing a target compound AE-6, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, precipitating after a period of time, filtering to obtain a precipitate, adding 5mL of water to dissolve the precipitate, adding a NaOH solution after the precipitate is dissolved, adjusting the pH value to 12, filtering to collect a solid, washing with water (3 mL/time), washing for 3 times, and drying to obtain the target compound AE-6.
Example 2
The embodiment provides a method for synthesizing a target compound AE-9, which specifically comprises the following steps:
adding 1mmol of 4-fluoroaniline into a 25mL round-bottom flask, dissolving the 4-fluoroaniline with 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-9.
Example 3
The embodiment provides a method for synthesizing a target compound AE-19, which specifically comprises the following steps:
adding 1mmol of 3-bromo-4-methylaniline into a 25mL round-bottom flask, dissolving the mixture in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-19.
Example 4
The embodiment provides a method for synthesizing a target compound AE-20, which specifically comprises the following steps:
adding 1mmol of 6-amino-1-naphthol into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-20 as described in the synthesis of the target compound AE-6.
Example 5
The embodiment provides a method for synthesizing a target compound AE-21, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-21 as described in the synthesis of the target compound AE-6.
Example 6
The embodiment provides a method for synthesizing a target compound AE-22, which specifically comprises the following steps:
adding 1mmol of 3-methyl aminobenzoate into a 25mL round-bottom flask, dissolving the methyl aminobenzoate by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-22.
Example 7
The embodiment provides a method for synthesizing a target compound AE-24, which specifically comprises the following steps:
adding 1mmol of 4-aminodiphenyl ether into a 25mL round-bottom flask, dissolving the 4-aminodiphenyl ether in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-24.
Example 8
The embodiment provides a method for synthesizing a target compound AE-25, which specifically comprises the following steps:
adding 1mmol of aniline into a 25mL round-bottom flask, dissolving the aniline with 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-25.
Example 9
The embodiment provides a method for synthesizing a target compound AE-37, which specifically comprises the following steps:
adding 1mmol of 4-amino-3-fluorobenzoic acid into a 25mL round-bottom flask, dissolving the 4-amino-3-fluorobenzoic acid with 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, and directly adding NaOH until the Ph is 12 after no precipitate is separated out after a period of time, filtering and collecting the precipitate, and performing silica gel column chromatography to obtain the target compound AE-37.
Example 10
The embodiment provides a method for synthesizing a target compound AE-40, which specifically comprises the following steps:
adding 1mmol of N-isopropyl ethylenediamine into a 25mL round-bottom flask, dissolving the N-isopropyl ethylenediamine in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-40.
Example 11
The embodiment provides a method for synthesizing a target compound AE-41, which specifically comprises the following steps:
adding 1mmol of 4-methyl aminobenzoate into a 25mL round-bottom flask, dissolving the methyl aminobenzoate by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-41.
Example 12
The embodiment provides a method for synthesizing a target compound AE-42, which specifically comprises the following steps:
adding 1mmol of 3-methoxyaniline into a 25mL round-bottom flask, dissolving the 3mmol of 3-methoxyaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-42.
Example 13
The embodiment provides a method for synthesizing a target compound AE-50, which specifically comprises the following steps:
1mmol of 2- (3, 4-dimethoxyphenyl) ethylamine was added into a 25mL round-bottom flask, dissolved in 10mL of isopropanol, then 3mmol of acid-binding agent N, N diisopropylethylamine was added, the mixture was heated at 80 ℃ and stirred uniformly, 1mL of isopropanol solution containing 1.15mmol of 2, 4, 5 trichloropyrimidine was slowly added dropwise, and after the dropwise addition was completed, the reaction was detected by TCL. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, collecting the precipitate as described in the synthesis of the target compound AE-6, and drying to obtain the target compound AE-50.
Example 14
The embodiment provides a method for synthesizing a target compound AE-61, which specifically comprises the following steps:
adding 1mmol of 3-methylaniline into a 25mL round-bottom flask, dissolving the 3mmol of acid-binding agent N, N diisopropylethylamine by using 10mL of isopropanol, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-61.
Example 15
The embodiment provides a method for synthesizing a target compound AE-64, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 4- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the 'synthesis of the target compound AE-6' to obtain the target compound AE-64.
Example 16
The embodiment provides a method for synthesizing a target compound AE-65, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 2-methoxy-4- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (4) TLC detection, standing at room temperature after the reaction is completed, and after a period of time, no precipitate is separated out, and the post-treatment of the reaction is the same as that described in the 'synthesis of the target compound AE-37', so that the target compound AE-65 is obtained.
Example 17
The embodiment provides a method for synthesizing a target compound AE-69, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 4- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-69 as described in the 'synthesis of the target compound AE-6'.
Example 18
The embodiment provides a method for synthesizing a target compound AE-70, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 2-methoxy-4- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, and standing for a period of time to obtain no precipitate, wherein the post-treatment of the reaction is the same as that described in the description of synthesis of the target compound AE-37, so as to obtain the target compound AE-70.
Example 19
The embodiment provides a method for synthesizing a target compound AE-72, which specifically comprises the following steps:
adding 1mmol of cyclopropylamine into a 25mL round-bottom flask, dissolving the cyclopropylamine in 10mL of isopropanol, adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 ℃ with stirring, and 0.1mL 37% concentrated hydrochloric acid was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-72 as described in the synthesis of the target compound AE-6.
Example 20
The embodiment provides a method for synthesizing a target compound AE-141, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol N, N-dimethyl-p-phenylenediamine, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the assay reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-141.
Example 21
The embodiment provides a method for synthesizing a target compound AE-142, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 3- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-142.
Example 22
The embodiment provides a method for synthesizing a target compound AE-145, which specifically comprises the following steps:
adding 1mmol of m-bromoaniline into a 25mL round-bottom flask, dissolving the m-bromoaniline in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol N, N-diethyl-p-phenylenediamine, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the assay reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, and standing for a period of time to obtain no precipitate, wherein the post-treatment and purification of the reaction are the same as those described in the synthesis of the target compound AE-37, so as to obtain the target compound AE-145.
Example 23
The embodiment provides a method for synthesizing a target compound AE-146, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol N, N-dimethyl-p-phenylenediamine, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the assay reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-146.
Example 24
The embodiment provides a method for synthesizing a target compound AE-147, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol of 3- (4-methylpiperazine) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-147 as described in the 'synthesis of the target compound AE-6'.
Example 25
The embodiment provides a method for synthesizing a target compound AE-148, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate each time for extraction, after three times of extraction, washing the reaction product by using saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying the intermediate for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol N- (4-aminophenyl) piperidine, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the assay reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-148.
Example 26
The embodiment provides a method for synthesizing a target compound AE-149, which specifically comprises the following steps:
adding 1mmol of 4-ethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol N, N-diethyl-p-phenylenediamine, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the assay reaction. TLC detection, standing at room temperature after the reaction is completed, no precipitate is separated out after a period of time, and the post-treatment and purification of the reaction are the same as those described in the synthesis of the target compound AE-6 to obtain the target compound AE-149
Example 27
The embodiment provides a method for synthesizing a target compound AE-150, which specifically comprises the following steps:
adding 1mmol of N, N-diethyl-p-phenylenediamine into a 25mL round-bottom flask, dissolving the N, N-diethyl-p-phenylenediamine in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 ℃ with stirring, and 0.1mL 37% concentrated hydrochloric acid was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-150.
Example 28
The embodiment provides a method for synthesizing a target compound AE-151, which specifically comprises the following steps:
adding 1mmol of N, N-dimethyl-p-phenylenediamine into a 25mL round-bottom flask, dissolving the N, N-dimethyl-p-phenylenediamine in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-151.
Example 29
The embodiment provides a method for synthesizing a target compound AE-153, which specifically comprises the following steps:
adding 1mmol of 3, 4, 5-trimethoxyaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 ℃ with stirring, and 0.1mL 37% concentrated hydrochloric acid was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-153.
Example 30
The embodiment provides a method for synthesizing a target compound AE-154, which specifically comprises the following steps:
adding 1mmol of 2-methoxy-5-methylaniline into a 25mL round-bottom flask, dissolving the mixture by 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate each time for extraction, after three times of extraction, washing the reaction product by using saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying the intermediate for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 ℃ with stirring, and 0.1mL 37% concentrated hydrochloric acid was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-154.
Example 31
The embodiment provides a method for synthesizing a target compound AE-155, which specifically comprises the following steps:
adding 1mmol of 4-bromo-3-methoxyaniline into a 25mL round-bottom flask, dissolving the mixture in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 3mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-155.
Example 32
The embodiment provides a method for synthesizing a target compound AE-158, which specifically comprises the following steps:
adding 1mmol of 4-amino-2-methylbenzoic acid into a 25mL round-bottom flask, dissolving the 4-amino-2-methylbenzoic acid in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, and standing for a period of time to obtain no precipitate, wherein the post-treatment and purification of the reaction are the same as those described in the synthesis of the target compound AE-37, so as to obtain the target compound AE-158.
Example 33
The embodiment provides a method for synthesizing a target compound AE-161, which specifically comprises the following steps:
adding 1mmol of 2-aminoacetophenone into a 25mL round-bottom flask, dissolving the 2-aminoacetophenone in 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating the mixture at 80 ℃, stirring the mixture evenly, slowly dropwise adding 1mL of isopropanol solution in which 1.15mmol of 2, 4, 5 trichloropyrimidine is dissolved, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-161.
Example 34
The embodiment provides a method for synthesizing a target compound AE-166, which specifically comprises the following steps:
adding 1mmol of 4-aminoacetophenone into a 25mL round-bottom flask, dissolving the 4-aminoacetophenone with 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N-diisopropylethylamine, heating at 80 ℃, stirring uniformly, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after dropwise adding. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mol of 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate as described in the synthesis of the target compound AE-6 to obtain the target compound AE-166.
Example 35
The embodiment provides a method for synthesizing a target compound AE-167, which specifically comprises the following steps:
adding 1mmol of 2, 5-dimethylaniline into a 25mL round-bottom flask, dissolving the mixture by using 10mL of isopropanol, then adding 3mmol of acid-binding agent N, N diisopropylethylamine, heating the mixture at 80 ℃, uniformly stirring the mixture, slowly dropwise adding 1mL of isopropanol solution dissolved with 1.15mmol of 2, 4, 5 trichloropyrimidine, and detecting the reaction by using TCL after the dropwise adding is finished. The reaction was complete after about 5-8 h. And taking out a reaction product, adding 30mL of ethyl acetate for extraction each time, after three times of extraction, washing with saturated saline solution, adding 50g of anhydrous sodium sulfate to remove water in the ethyl acetate, then performing suction filtration to obtain an organic layer containing a compound, performing reduced pressure concentration to obtain a substance, namely an intermediate, and drying for later use. To a 25mL round bottom flask was added the intermediate, 7.5mL isopropanol was added followed by 2mmol 4- (4-ethylpiperazin-1-yl) aniline, heated to 80 deg.C with stirring, and 0.1mL 37% concentrated HCl was added to start the detection reaction. And (3) TLC detection, standing at room temperature after the reaction is completed, separating out a precipitate after a period of time, filtering to obtain a precipitate, and collecting the precipitate to obtain the target compound AE-167 as described in the synthesis of the target compound AE-6.
Experimental example 1
ALK kinase Activity assay
The specific experimental method is as follows:
1. compounds were diluted with DMSO to 50 x of the final reaction concentration and 100 μ Ι _ of the mother liquor was transferred to a 96-well plate.
2. In the same 96-well plate, 100 μ L DMSO was added as a no-compound control and a no-enzyme control, respectively, and the plate was labeled as a master plate.
3. Preparation of intermediate plates 10. mu.L of compound stock was transferred from the original plate to a new 96-well plate as an intermediate plate, to which 90. mu.L of 1 Xkinase buffer was added per well and shaken for 10 minutes.
4. 2.5-fold enzyme solution was prepared: ALK (G1202R) kinase was added to the 1 Xkinase buffer.
5. Preparation of 2.5 fold polypeptide solution: FAM-labeled polypeptide and ATP were added to 1 × kinase buffer.
6. mu.L of a test compound solution was added to each well of a 384-well test plate, and 10. mu.L of a 2.5 Xenzyme solution was added to each well, followed by incubation at room temperature for 10 minutes.
7. mu.L of 2.5 Xpolypeptide solution was added to each well of 384-well assay plates, and after incubation at 28 ℃ for 1 hour, 25. mu.L of stop solution was added to stop the reaction.
8. Data were collected using Caliper with an enzyme inhibition ratio (% Inh) (max-conversion)/(max-min) × 100.
The results of the experiment are shown in table 1.
ALK inhibitory Rate of the Compounds of Table 1 at a concentration of 10 μ
Figure RE-GDA0003757929780000251
Figure RE-GDA0003757929780000261
Experimental example 2
EGFR kinase Activity assay
The specific experimental method is as follows:
1. compounds were diluted with DMSO to 50 x of the final reaction concentration and 100 μ Ι _ of the mother liquor was transferred to a 96-well plate.
2. In the same 96-well plate, 100 μ L DMSO was added as a no-compound control and a no-enzyme control, respectively, and the plate was labeled as a master plate.
3. Preparation of intermediate plate 10. mu.L of compound stock was transferred from the original plate to a new 96-well plate as an intermediate plate, 90. mu.L of 1 Xkinase buffer was added to each well of the intermediate plate, and the plate was shaken for 10 minutes.
4. 2.5-fold enzyme solution was prepared: EGFR (T790M/C797S/L858R) kinase was added to the 1 Xkinase buffer.
5. Preparation of 2.5 fold polypeptide solution: FAM-labeled polypeptide and ATP were added to 1 × kinase buffer.
6. mu.L of a test compound solution was added to each well of a 384-well test plate, and 10. mu.L of a 2.5 Xenzyme solution was added to each well, followed by incubation at room temperature for 10 minutes.
7. mu.L of 2.5 Xpolypeptide solution was added to each well of 384-well assay plates, and after incubation at 28 ℃ for 1 hour, 25. mu.L of stop solution was added to stop the reaction.
8. Data were collected using Caliper with an enzyme inhibition ratio (% Inh) (max-conversion)/(max-min) × 100.
The results of the experiment are shown in table 2.
TABLE 2 inhibition of EGFR by compounds at a concentration of 10. mu.M
Figure RE-GDA0003757929780000262
Figure RE-GDA0003757929780000271
Experimental example 3
In vitro determination of antitumor Activity
1. Preparation of compound mother liquor
The preparation of mother liquor of Brigatinib and AE series compounds is shown in Table 3.
TABLE 3 preparation of mother liquors of the compounds
Figure RE-GDA0003757929780000272
Figure RE-GDA0003757929780000281
2. Manipulation of cell experiments
The cells selected in the experiment are constructed PC-9-LRTM cells-human non-small cell lung cancer (cells which are constructed by taking PC-9 as a parent cell and carry EGFR L858R/T790M/C797S mutation), Karpas-299 cells-human anaplastic large cell lymphoma cell lines (NPM-ALK positive), NCI-H1975 cells-human lung adenocarcinoma cells. Among the three cells, PC-9-LRTM is a semi-suspension cell, Karpas-299 is a suspension cell, and NCI-H1975 is an adherent cell. The cell passaging procedure for the three cells was slightly different. The operation of the PC-9-LRTM is as follows: adding the PC-9-LRTM suspension cell liquid into a centrifuge tube in a biological safety cabinet, adding 2-3mL PBS into a culture dish, shaking the culture dish to enable PBS to uniformly cover the bottom of the culture dish, repeating the process for multiple times, transferring the PBS into the centrifuge tube, repeating the process for two to three times, then adding 1.5mL pancreatin, digesting for 2-4min, adding 4mL culture medium, stopping digestion, blowing and beating the cells gently, after blowing and beating, putting the cells into the centrifuge tube, centrifuging for 5min at 1200rpm, removing the culture medium containing the pancreatin, adding 3mL culture medium, blowing and beating uniformly, adding 1mL cell suspension into the culture dish filled with 9mL culture medium, transferring into an incubator and continuing culture. Karpas-299 operates as follows: in a biological safety cabinet, adding karpas-299 suspension cell liquid into a centrifuge tube, centrifuging at 1200rpm for 5min, removing a culture medium containing pancreatin, adding 3mL of the culture medium, uniformly blowing, adding 1mL of cell suspension into a culture dish containing 9mL, and transferring to an incubator for continuous culture. NCI-H1975 operates as follows: and (3) in an ultraclean workbench, discarding the supernatant, adding 2-3mL PBS, shaking the culture dish to enable the PBS to uniformly cover the bottom of the culture dish, repeating the steps for multiple times, discarding the PBS, repeating the steps for two to three times, then adding 1mL pancreatin, digesting for 2-4min, adding 4mL culture medium, stopping digestion, blowing off the cells on the bottom of the culture dish, sucking out the cell suspension, transferring the cell suspension into a centrifuge tube, centrifuging at 1200rpm for 3min, discarding the supernatant, adding 5mL culture medium to resuspend the cells, adding 1mL cell suspension into the culture dish filled with 9mL culture medium, and continuing culture.
Diluting the prepared mother liquor of Brigatinib and AE series compounds to the concentration required by the experiment by using an RPMI 1640 complete culture medium, wherein the concentration of the medicament in the experiment is 10 mu M/L, each medicament is provided with three holes, and each medicament is provided with 10 mu L. Meanwhile, a control group (without medicine under the same condition) and a blank control group (without medicine and cells under the same condition) are set. After the medicine is added, the culture is continued for 48 hours. And selecting compounds with the inhibition rate of not less than 50% according to the primary screening result during secondary screening. The drug concentration of the rescreen was reduced from 10. mu.M/L to one third of the previous concentration. The compounds which do not enter the secondary screening are primarily screened, the concentration re-detection activity is improved, and the initial concentration is set to be 20 mu M/L and 40 mu M/L respectively. After 48h of treatment of the cells with the compound, 10 μ LCCK8 solution was added per well. The absorbance (OD450nm value) was measured after 2-6h of incubation, and the average of 3 duplicate wells was taken as the final experimental result. Growth inhibition (% Inh) ═ 1- [ OD experimental group-OD blank group ]/[ OD control group-OD blank group ] × 100%
The CCK8 method is adopted to determine the anti-cell proliferation activity of AE series compounds, and the experimental results are shown in Table 4.
TABLE 4 in vitro antiproliferative Activity of AE series of Compounds
Figure RE-GDA0003757929780000282
Figure RE-GDA0003757929780000291
In conclusion, specific compounds prepared in the above embodiments of the invention have higher inhibition effects on ALK G1202R and EGFR T790M/C797S/L858R kinase at a level of 10 μ M; the compounds have better inhibition effect in ALK-dependent cells and EGFR-dependent cells, and show that the compounds can be used as good double-target inhibitors of ALK and EGFR. The compound can break through the drug resistance defects of the existing ALK inhibitor and EGFR inhibitor, and has good research value and application prospect in the fields of tumor treatment and research.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A target inhibitor for inhibiting at least one mutant of ALK and EGFR, comprising a compound of formula 1:
Figure RE-FDA0003757929770000011
wherein R is 1 、R 2 Each independently selected from any one of substituted or unsubstituted benzene ring, substituted or unsubstituted benzo heterocycle, substituted or unsubstituted condensed ring, substituted or unsubstituted heterocycle, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, halogen, cyano, ester group, aldehyde group, alkoxy, carbonyl, acyl, amino, azo group, sulfonic group, mercapto, nitro and hydroxyl.
2. The target inhibitor of claim 1, wherein R is 1 、R 2 Each independently selected from any one of a substituted or unsubstituted benzene ring, a substituted or unsubstituted benzo heterocycle, a substituted or unsubstituted condensed ring, a substituted or unsubstituted heterocycle, a substituted or unsubstituted cycloalkyl and a substituted or unsubstituted straight-chain alkyl;
preferably, R 1 、R 2 Each independently selected from any one of benzene ring, benzo heterocycle, substituted condensed ring, substituted or unsubstituted heterocycle, cycloalkyl and substituted linear alkyl;
more preferably, R 1 The substituted benzene ring is selected from any one of a substituted benzene ring, a benzo heterocyclic ring, a substituted condensed ring, a substituted or unsubstituted heterocyclic ring, a cycloalkyl and a substituted straight-chain alkyl, when the benzene ring is mono-substituted, a substituent group is selected from any one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxy, ester group, hydroxyl and carboxyl, when the benzene ring is multi-substituted, a plurality of substituent groups are respectively and independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxy; r 2 Is selected from substituted benzene ring, the benzene ring has para-position substituted gene, and the para-position substituted group isTertiary amino groups or nitrogen-containing heterocycles; or, R 1 Selected from substituted benzene rings, the benzene rings have para-substituted genes, the para-substituted groups are tertiary amino groups or nitrogen-containing heterocycles, R 2 The aromatic heterocyclic ring is characterized by comprising a benzene ring, a substituted condensed ring, a substituted or unsubstituted heterocyclic ring, a naphthenic group and a substituted straight-chain alkyl group, wherein when the benzene ring is monosubstituted, a substituent group is selected from any one of halogen, methyl, ethyl, nitro, sulfydryl, methylthio, methoxyl, ester group, hydroxyl and carboxyl, and when the benzene ring is polysubstituted, a plurality of substituent groups are independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxyl;
preferably, R 1 、R 2 The alkyl selected from the group consisting of C1-C10 alkyl.
3. The target inhibitor of claim 2, wherein R is 1 The compound is selected from any one of a substituted benzene ring, a benzo heterocyclic ring, a substituted condensed ring, a substituted or unsubstituted heterocyclic ring, a cycloalkyl and a substituted straight-chain alkyl, when the benzene ring is mono-substituted, a substituent group is selected from any one of halogen, C1-C5 alkyl, nitro, mercapto, methylthio, methoxy, ester group, hydroxyl and carboxyl, when the benzene ring is multi-substituted, a plurality of substituent groups are independently selected from any one of halogen, methyl, carboxyl, hydroxyl and methoxy; the C1-C5 alkyl is preferably methyl or ethyl;
R 2 is selected from substituted benzene rings, the benzene rings have para-position substituted genes, and the para-position substituted groups are tertiary amino groups or nitrogen-containing heterocycles.
4. The target inhibitor of any one of claims 1-3, wherein R is 1 When the compound is selected from substituted benzene rings, the benzene ring is a mono-substituted, di-substituted or tri-substituted benzene ring; preferably, when the benzene ring is trisubstituted, the substituent groups are all methoxy;
preferably, the benzo heterocycle is a benzodioxole, more preferably, the benzo heterocycle is a benzodioxole;
preferably, the substituent group of the fused ring is hydroxyl;
preferably, the heterocyclic ring is a five-membered heterocyclic ring, more preferably, the heterocyclic ring is selected from any one of thiazole, imidazole, pyrazole and oxazole, further preferably, the heterocyclic ring is selected from thiazole or pyrazole; when the heterocycle is substituted heterocycle, the substituent group is selected from any one of methyl and nitro, preferably, the heterocycle is mono-substituted;
preferably, the cycloalkane corresponding to said cycloalkyl group is cyclopropane or cyclopentane;
preferably, the straight-chain alkyl group is a C2-C4 alkyl group, preferably the straight-chain alkyl group is an ethyl group, preferably the substituent of the straight-chain alkyl group is an amino group or a heterocycle, preferably the substituent of the straight-chain alkyl group is selected from any one of a substituted or unsubstituted nitrogen heterocycle, oxygen-nitrogen heterocycle and isopropylamino;
preferably, R 2 Wherein the tertiary amino group is selected from any one of a dimethyl tertiary amino group, a piperazine group and a nitrogen-oxygen heterocycle; preferably, the benzene ring further has an ortho substituent group, and the ortho substituent group is methoxy.
5. The target inhibitor of claim 1, wherein R is 1 Any one selected from the following groups: a
Figure RE-FDA0003757929770000021
Figure RE-FDA0003757929770000022
Figure RE-FDA0003757929770000031
6. The target inhibitor of claim 5, wherein R is 2 Any one selected from the following groups:
Figure RE-FDA0003757929770000032
7. the target inhibitor of claim 6, wherein the target inhibitor is selected from at least one of the following compounds:
Figure RE-FDA0003757929770000033
Figure RE-FDA0003757929770000041
Figure RE-FDA0003757929770000051
Figure RE-FDA0003757929770000061
Figure RE-FDA0003757929770000071
Figure RE-FDA0003757929770000081
Figure RE-FDA0003757929770000091
8. a process for preparing a target inhibitor according to any one of claims 1 to 7, wherein the synthesis route is as follows:
Figure RE-FDA0003757929770000092
preferably, the preparation method comprises: in correspondence with a group containing R 1 The amine solution is added with 2, 4, 5-trichloropyrimidine solution dropwise for the first reaction, an intermediate is obtained by extraction and separation, and after the intermediate is dissolved again, the intermediate is added with the compound containing R 2 The amine of (a) is subjected to a second reaction;
preferably, the reaction temperature of the first reaction and the second reaction is 25-90 ℃, and preferably 80 ℃.
9. Use of a target inhibitor according to any one of claims 1-7 for the preparation of a medicament for the treatment of a tumor, preferably a tumor having an ALK fusion mutation and/or an EGFR mutation, more preferably a lung cancer.
10. A pharmaceutical composition comprising the target inhibitor of any one of claims 1-7.
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