CN111072571B - Dithiocarbamates as FAK inhibitors - Google Patents
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- C07—ORGANIC CHEMISTRY
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention aims to provide a dithiocarbamate compound serving as a FAK inhibitor, a pharmaceutical composition, a preparation method and application thereof. The compound has a structure shown in the following general formula (I).
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and relates to a novel compound, a method for preparing the compound, a medicinal composition and application thereof, in particular to a novel aminodithioformate compound serving as a FAK inhibitor and application of the compound in preparing medicaments for treating and preventing cancers.
Background
The research and development of the antitumor drugs are one of the most popular drug research and development fields in the world, and although the research and development of the antitumor drugs are greatly improved in recent years, the antitumor drugs with high efficiency and small toxic and side effects are still lacking clinically. The difference of the expression levels of certain key proteins of normal cells and tumor cells is utilized to develop a targeting drug which can selectively kill the tumor cells and reduce the toxic and side effects on the normal cells. Local adhesion kinase (FAK) is a protein which is low in expression level in normal cells and is over-expressed in many tumor cells, such as colon cancer, cervical cancer, prostate cancer, head and neck squamous cell carcinoma, breast cancer and the like. Research shows that FAK kinase can phosphorylate downstream protein to activate downstream pathway, such as activating ERK pathway to induce cell cycle process, acting on PI3K/Akt pathway to inhibit apoptosis of cell, etc. it plays important role in proliferation, metabolism, survival of tumor, tumor-related blood vessel and tumor microenvironment. A study conducted in 2015 found that nuclear FAK also recruits regulatory T cells by promoting Transcription of several cytokine genes to play an immunosuppressive role (Alan Serrles, Tom Lund, Bryan Serrles, Adam Byron et al, nucleic FAK Controls Chemokine Transcription, Tregs, and Evasion of Anti-tumor immunity. cell.2015,163, 160-173). Based on the important role of FAK in tumor occurrence and development and the difference of expression level of FAK in normal cells and tumor cells, a new targeted anti-tumor drug is possibly researched by taking FAK as a target, and the target also draws wide attention of pharmaceutical chemists and pharmaceutical companies in recent years.
FAK inhibitor Defectinib (code VS-6063) developed by Verastem corporation for treating KRAS-mutated non-small cell lung cancer has completed phase II clinical trials. The experimental results show that the tolerance and adaptability of patients after long-term administration are good, however, researchers also find that the FAK inhibitor alone does not show obvious effects, and indicate that the FAK inhibitor can be tried to be combined with other medicines (an immune checkpoint inhibitor, a MEK inhibitor, a chemotherapeutic medicine and the like). FAK inhibitor developed by Kurarian Stecke company, with the code of GSK2256089, is currently combined with small molecule inhibitor Vismodegib participating in hedgehog pathway repair for phase II clinical experiments on treating advanced meningiomas. Meanwhile, many small molecule inhibitors are in phase i clinical or preclinical studies. TAE226 is a derivative of bisaminopyrimidine, can inhibit phosphorylation of FAK and a signal path mediated by FAK, can prolong survival rate of mice in a breast cancer bone metastasis model, and cannot enter clinical experiments due to large side effects.
Although there are many FAK inhibitors in clinical and preclinical studies, there is no one drug on the market, and for these reasons, the development of novel FAK-targeting antitumor drugs with proprietary intellectual property rights is still of great importance.
The invention relates to a high-activity FAK inhibitor with a novel structure, and enzyme activity and cell activity tests prove that the FAK inhibitor has obvious effects on inhibition of FAK kinase and proliferation inhibition of tumor cells.
Disclosure of Invention
In the research process, the inventor finds a compound shown as a general formula (I) or pharmaceutically acceptable salt or solvate thereof, wherein the compound has FAK inhibitory activity and can be used for treating related cancers positive to FAK.
In a first aspect the present invention provides a compound having the general formula (i):
wherein:
r is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl; the heteroaryl group contains 1-3 heteroatoms selected from N, O or S; the substituents are independently selected from C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylsulfonyl, oxo, ester, hydroxy, cyano, cycloalkyl, amino;
x is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl.
In a preferred embodiment of the first aspect of the invention, R is selected from C1-4Substituted or unsubstituted alkyl, allyl, 2-butenyl, thienyl, phenyl, benzyl, phenylethyl, phenylpropyl, picolyl, furylmethyl, thienylethyl; the substituents are independently selected from methyl, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, oxo, ester, hydroxy, cyano, 1, 3-dioxolane, tetrahydropyran, dimethylaminoethyl, dimethylaminopropyl, methylaminoethyl, pyrrolylethyl, piperidinylethylMethyl piperazinyl ethyl;
x is independently selected from hydrogen, methyl, methoxy, fluoro, trifluoromethyl.
According to an embodiment of the present invention, the compound of formula I according to the present invention may be at least one selected from the group consisting of:
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (4-pyridine) methylene ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-pyridine) methylene ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-pyridine) methylene ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 2-carbonitrile ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-phenethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 3-oxobutyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-benzyl ester;
4- (2-methoxy) ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 4-tetrahydropyranylidene;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-ethoxy-2-oxo) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 2-hydroxyethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-ethoxy-2, 3-dioxo) propyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-methanesulfonyl) ethyl ester;
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1, 3-dioxolane));
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-carbodithioic acid-allyl ester;
4- (2-hydroxy) propyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid methyl ester;
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1-pyrrolidinyl));
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1-piperidine));
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1- (4-methyl) piperazine));
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-morpholinyl) ethyl ester;
4- (2-methyl) propyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-ethoxy) ethyl ester;
4- (2-butene) 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithio-carboxylate;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-cyano) propyl ester;
4- (4-hydroxy) butyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (ethylsulfonyl));
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 1-oxoethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 2-oxopropyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-methylamino) ethyl ester;
4- (3- (N, N-dimethylamino)) propyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 2-thiazole ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-phenyl ester;
ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (2-thienyl));
4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-furan) methylene ester;
4- (3-phenyl) propyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate;
4- (4- ((4- (2-methylcarbamoyl) anilino-pyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-fluoropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-methylpyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-methoxypyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester;
4- (4- ((4- (2-methylcarbamoyl) anilino-5-trifluoromethylpyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-dimethylamino) ethyl ester.
As used herein, the term "pharmaceutically acceptable salts" refers to the conventional non-toxic salts formed by the reaction of a compound of formula I with an inorganic or organic acid. For example, the conventional non-toxic salts can be prepared by reacting a compound of formula I with an inorganic or organic acid. Wherein, the inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, and the organic acid can be citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like.
It is also understood that hydrates, solvates (e.g., methanolate, ethanolate, ethylacetate) of the compounds of formula I of the present invention are also within the scope of the present invention. Methods of solvation are well known in the art.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof.
In a third aspect, the invention provides the use of a compound as described above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition for the manufacture of a medicament for modulating the catalytic activity of a protein kinase, wherein the protein kinase is selected from the group consisting of locally attached kinases.
In a fourth aspect, the present invention provides the use of a compound as described above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition for the manufacture of a medicament for the treatment or prevention of cancer.
In a preferred embodiment of the fourth aspect of the invention, the cancer is preferably colon cancer, breast cancer, prostate cancer or brain glioma.
A fifth aspect of the invention provides a process for the preparation of a compound according to the first aspect of the invention, said process comprising the steps of:
(1) taking 2-nitrobenzoyl chloride as a raw material, obtaining a compound 2 through methylamine nucleophilic substitution and nitro reduction reaction, and carrying out nucleophilic substitution reaction on the compound 2 and various 5-substituted or unsubstituted 2, 4-dichloropyrimidines under alkaline conditions to obtain a compound 3.
Wherein X is selected from hydrogen, fluorine, chlorine, methyl and methoxy;
(2) 4-nitrobenzoyl chloride is used as a raw material, and a compound 5 is obtained through nucleophilic substitution and nitro reduction reaction.
(3) Carrying out C-N coupling reaction on the compounds 3 and 5 in the steps (1) and (2)(palladium acetate as catalyst, Xantphos as ligand) to obtain compounds 6a-6e, reacting compounds 6a-6e with CS after removing Boc protection by trifluoroacetic acid2And different halogenated hydrocarbons or olefins are subjected to nucleophilic substitution or Michael addition reaction to obtain corresponding target compounds;
wherein X is selected from hydrogen, fluorine, chlorine, methyl and methoxy;
(4) when X is selected from trifluoromethyl, the synthesis method comprises the following steps: firstly, 2, 4-dichloro-5-trifluoromethylpyrimidine reacts with the compound 5 in the step (2) to obtain a compound 7, the compound 7 reacts with the compound 2 in the step (1) under an alkaline condition to obtain a compound 8, the compound 8 is subjected to Boc removal protection by trifluoroacetic acid and then reacts with CS2And different halogenated hydrocarbons or olefins are subjected to nucleophilic substitution or Michael addition reaction to obtain corresponding target compounds;
r in the step (3) and the step (4) is selected from C1-4Substituted or unsubstituted alkyl, allyl, 2-butenyl, thienyl, phenyl, benzyl, phenylethyl, phenylpropyl, picolyl, furylmethyl, thienylethyl; the substituents are independently selected from methyl, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, oxo, ester, hydroxy, cyano, 1, 3-dioxolane, tetrahydropyran, dimethylaminoethyl, dimethylaminopropyl, methylaminoethyl, pyrrolylethyl, piperidinylethyl, methylpiperazinylethyl;
Detailed Description
The term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is connected to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and various isomers thereof, n-octyl and various isomers thereof, n-nonyl and various isomers thereof, and n-decyl and various isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system consisting of at least 3 carbon atoms, which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; and fused, bridged or spiro ring groups formed from two or more of the above-mentioned monocyclic rings via a common side and a common carbon atom.
The term "alkoxy" as used herein refers to a group having an oxygen atom attached to the alkyl group and a single bond through the oxygen atom to the rest of the molecule, and encompasses a wide variety of possible geometric and stereoisomeric groups. By way of non-limiting examples of alkoxy radicals, mention may be made of the following linear or branched radicals: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and its other seven isomers, n-hexoxy and its other sixteen isomers, n-heptoxy and its various isomers, n-octoxy and its various isomers, n-nonoxy and its various isomers, n-decoxy and its various isomers.
The term "aryl" as used herein refers to an aromatic ring system consisting of at least 6 carbon atoms, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or by fusion. As non-limiting examples of aryl groups, the following groups may be cited: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, perylenyl, azulenyl, pentalenyl, heptalenyl, acenaphthenyl, fluorenyl, phenalenyl, fluoranthenyl, acephenanthrenyl, benzoacenaphthenyl, triphenylene, tetracenyl, picene, pentalenyl, pentacenyl, tetrapentaphenylene, hexylenyl, hexacenyl, coronenyl, trinaphthyl, heptenyl, heptacenyl, pyranthryl, egg phenyl, biphenyl, binaphthyl.
The term "heteroaryl" as used herein refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or fused. As non-limiting examples of heteroaryl groups, the following groups may be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarinyl, pyrazolopyridinyl, pyridopyridazinyl, pyrrolopyridyl, imidazopyridinyl, pyrazolopyridazinyl; and a group formed by the above-mentioned heteroaryl group by a single bond connection or a fusion connection.
The term "arylalkyl" as used herein, refers to an alkyl group having one or more hydrogen atoms independently replaced by an aryl group, wherein the aryl and alkyl groups are as defined above.
The term "heteroarylalkyl" as used herein refers to an alkyl group wherein one or more hydrogen atoms are independently replaced by a heteroaryl group, wherein the heteroaryl and alkyl groups are as defined above.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.
The pharmaceutical composition of the present invention contains a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, including but not limited to: water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar-agar, pectin, acacia, stearic acid or cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preservatives, tonicity adjusting agents, buffering agents, sweetening agents, flavoring agents, coloring agents or any combination of the foregoing.
The pharmaceutical composition of the present invention can be formulated into any form of preparations, such as capsules, tablets, aerosols, solutions, suspensions, dragees, syrups, emulsions, ointments, pastes, injections, powders, granules, pastes, sustained-release preparations, foams. The drug of the present invention may be formulated into an oral administration preparation, a nasal administration preparation, a pulmonary administration preparation, an buccal preparation, a subcutaneous administration preparation, an intradermal administration preparation, a transdermal administration preparation, a parenteral administration preparation, a rectal administration preparation, a depot administration preparation, an intravenous administration preparation, an intraurethral administration preparation, an intramuscular administration preparation, an intranasal administration preparation, an ophthalmic administration preparation, an epidural administration preparation or a topical administration preparation, according to the administration route.
The "cancer" in the present invention includes various cancers known in the art, including but not limited to: lung cancer, liver cancer, stomach cancer, cervical cancer, colon cancer, breast cancer, leukemia, non-small cell cancer, prostate cancer or repigmoma, brain cancer, skin cancer, bone cancer, lymph cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, duodenal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, renal cancer, genital cancer, and thyroid cancer.
Examples
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples.
In one exemplary embodiment, the compounds of the present invention are synthesized by the following method, wherein each substituent is as defined in formula (i).
Example 1: preparation of 2-nitro-N-methylbenzamide
Methylamine hydrochloride (3g, 45mmol) and sodium bicarbonate (12.6g, 150mmol) were dissolved in 30ml acetonitrile, 2-nitrobenzoyl chloride (3.9ml, 30mmol) was added, stirred and heated at reflux for 4h with the evolution of a large amount of gas. After removing unreacted salts by filtration, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to separation and purification with a silica gel column (petroleum ether/ethyl acetate elution) to obtain 4.55g of a white solid in a yield of 84%.1H NMR(400MHz，DMSO-d6)：2.76(d,3H)，7.60(dd,1H),7.68(td,1H),7.77(td,1H),7.97-8.05(m,1H),8.59(d,1H).13CNMR(100MHz，DMSO-d6)：δ＝26.10，124.03，128.98，130.65，132.52，133.50，147.16，165.78.
Example 2: preparation of 2-amino-N-methylbenzamide
Dissolving 2-nitro-N-methylbenzamide (4.80g,27mmol) in a mixed solvent of 24ml ethanol and 8ml water, adding ammonium chloride (2.25g,42mmol) and iron powder (6.70g,120mmol), heating and refluxing for 2h, filtering out the solid with kieselguhr, and separating and purifying the liquid with a silica gel column (petroleum ether/ethyl acetate elution) to obtain 3.73g of light pink solid with the yield of 92%.1H NMR(400MHz，CDCl3)：δ＝2.92(d,3H)，5.51(s,2H),6.30(s,1H),6.57-6.63(m,1H),6.66(dd,1H),7.14-7.20(m,1H),7.29(dt,1H).13C NMR(100MHz，CDCl3):δ＝26.60，116.41，116.77，117.37，127.33，132.26，148.63，170.22.
Example 3 a: preparation of 2- (2-chloropyrimidinyl) amino-N-methylbenzamide
2-amino-N-methylbenzamide (0.79g, 5.25mmol) and 2, 4-dichloropyrimidine (0.74g, 5mmol) were dissolved in 30-isopropanol, DIPEA (1.05ml, 6mmol) was added, and the mixture was heated under reflux for 24 h. After completion of the reaction, the solvent was distilled off under reduced pressure, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified by a silica gel column (elution with ethyl acetate/petroleum ether) to obtain 0.85g of a yellow solid in 65% yield.1H NMR(400MHz，DMSO-d6)：δ＝2.79(d,3H)，6.87(d,1H),7.13-7.26(m,1H),7.46-7.57(m,1H),7.69(dd,1H),8.11(d,1H),8.20(d,1H),8.65(d,1H),10.96(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.12,106.52,122.10,123.23,124.19,128.27,131.31,137.70,157.58,159.28,161.13,168.43.
Example 3 b: preparation of 2- (2, 5-dichloropyrimidinyl) amino-N-methylbenzamide
The synthesis method is the same as example 3a and the yield is 82% by taking 2, 4-dichloro-5-fluoro-pyrimidine as a raw material.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H).7.22(dd,1H),7.55-7.64(m,1H),7.82(dd,1H),8.46(s,1H),8.55(d,1H),8.88(d,1H),12.27(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.36,114.93,120.77,120.92,123.06,128.11,131.84,138.33,155.25,156.12,156.63,168.71.
Example 3 c: preparation of 2- (2-chloro-5-fluoropyrimidinyl) amino-N-methylbenzamide
The synthesis method of 2,4, 5-trichloropyrimidine used as a raw material is the same as that of the example 3a, and the product is obtainedThe rate was 80%.1H NMR(400MHz，DMSO-d6)：2.82(d,3H)，7.11-7.28(m,1H),7.51–7.65(m,1H),7.82(dd,1H),8.39(d，1H),8.53(d,1H),8.86(d,1H),12.27(d,1H).13C NMR(100MHz，DMSO-d6):δ＝26.27,120.49(d,J＝15.9Hz),122.85,128.13,132.03,138.41,141.45(d,J＝20.9Hz),144.36,146.93,150.37(d,J＝10.8Hz),152.72(d,J＝3.6Hz),168.79.
Example 3 d: preparation of 2- (2-chloro-5-methylpyrimidinyl) amino-N-methylbenzamide
2-amino-N-methylbenzamide (1.26g, 8.4mmol) and 2, 4-dichloro-5-methylpyrimidine (0.93ml, 8mmol) were dissolved in anhydrous DMF (6ml), 60% NaH (0.38g, 9.6mmol) was added under ice bath, and the mixture was stirred at room temperature for 24 h. After the reaction, water was added dropwise to terminate the reaction, and the reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column (elution with ethyl acetate/petroleum ether) to obtain 0.88g of a yellow solid with a yield of 40%.1H NMR(400MHz，DMSO-d6)：δ＝2.18(s,3H)，2.83(d,3H),7.10-7.19(m,1H),7.54-7.62(m,1H),7.80(dd,1H),8.14(s,1H),8.64(d,1H),8.83(d,1H),11.74(s,1H).13C NMR(100MHz，DMSO-d6):δ＝12.98,26.31,115.40,120.17,120.45,122.09,128.05,131.89,139.51,156.19,156.63,159.46,169.07.
Example 3 e: preparation of 2- (2-chloro-5-methoxypyrimidinyl) amino-N-methylbenzamide
The synthesis method was the same as example 3d, using 2, 4-dichloro-5-methoxypyrimidine as the starting material, with a yield of 41%.1H NMR(400MHz，DMSO-d6)：δ＝2.83(d,3H).3.99(s,3H),7.16(t,1H),7.58(t,1H),7.78(d,1H),8.02(s,1H),8.67(d,1H),8.77(d,1H),11.83(s,1H).13C NMR(100MHz，DMSO-d6):26.29,56.82,120.14,120.61,122.11,128.10,131.78,135.80,138.84,140.24,149.16,151.66,168.71.
Example 4: preparation of 1-Boc-4- ((4-nitro) benzoyl) piperazine
The synthesis method is the same as example 1 with 4-nitrobenzoyl chloride and 1-boc piperazine as raw materials, and the yield is 90%.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H)，3.19-3.71(m,8H),7.71(d,2H),8.30(d,2H).13C NMR(100MHz，DMSO-d6):δ＝27.95，42.81，43.11，79.20，123.71，128.31，142.02，147.80，153.76，167.25.
Example 5: preparation of 1-Boc-4- ((4-amino) benzoyl) piperazine
The synthesis method was the same as example 2, using 1-Boc-4- ((4-nitro) benzoyl) piperazine as a reactant, with a yield of 93%.1H NMR(400MHz，CDCl3)：δ＝1.47(s,9H),3.52(d,8H),3.94(s,2H),6.65(d,2H),7.25(d,2H).13C NMR(100MHz，CDCl3):δ＝28.52,44.24,80.38,114.33,124.67,129.49,148.59,154.77,171.25.
Example 6 a: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilinopyrimidine
1-Boc-4- ((4-amino) benzoyl) piperazine (1.04g,3.4mmol) and 2- ((2-chloropyrimidin-4-yl) amino) -N-methylbenzamide (0.85g,3.24mmol), potassium phosphate (1.40g,6.48mmol), Xantphos (0.28g,0.5mmol), Pd (OAc)2(0.11g,0.5mmol) was dissolved in DMF (8ml) and heated under reflux under argon and the reaction stirred for 22 h. Filtering the insoluble solid with diatomaceous earth, and filtering the liquid with dichloromethaneExtraction, washing with saturated brine, drying over anhydrous sodium sulfate, and separation and purification with silica gel column (dichloromethane/acetone elution) gave 1.02g of yellow solid in 60% yield.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H),2.82(d,3H),3.46(d,8H),6.37(d,1H),7.12(t,1H),7.37(d,2H),7.51(t,1H),7.72(d,1H),7.85(d,2H),8.13(d,1H),8.47(d,1H),8.68(d,1H),9.55(s,1H),10.80(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.24,28.03,42.98,43.73,79.17,99.85,118.15,121.62,121.90,127.54,128.03,128.11,131.33,139.59,142.34,153.86,156.68,159.28,168.97,169.47.
Example 6 b: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-fluoropyrimidine
The synthesis method is the same as 6a by taking 2- ((2-chloro-5-fluoropyrimidinyl-4-yl) amino) -N-methylbenzamide as a raw material, and the yield is 62%.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H)，2.82(d,3H),3.33-3.54(m，8H),7.07-7.19(m,1H)，7.36(d,2H),7.49-7.59(m,1H),7.73-7.86(m,3H),8.22(d,1H),8.82(t,2H),9.61(s,1H),11.80(d,1H).13C NMR(100MHz，DMSO-d6):δ＝26.30,28.03,79.17,117.87,120.08,120.78,121.82,127.63,128.06,131.80,139.47,140.00-140.57(m),142.39(d,J＝25.4Hz),149.07(d,J＝3.4Hz),153.84,155.08(d,J＝3.4Hz),169.06,169.41.
Example 6 c: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-chloropyrimidine
The synthesis method is the same as 6a by taking 2- ((2-chloro-5-chloropyrimidinyl-4-yl) amino) -N-methylbenzamide as a raw material, and the yield is 62%.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H),2.83(d,3H),3.34-3.56(m,8H),7.17(t,1H),7.36(d,2H),7.48-7.58(m,1H),7.78(d,3H),8.28(s,1H),8.76(dd,2H),9.73(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.31，28.02，42.90，43.56，79.16，105.80，118.47，121.01，121.58，122.13，127.99，131.45，139.15，141.78，153.83，154.53，155.07，157.39，168.87，169.32.
Example 6 d: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-methylpyrimidine
The synthesis method is the same as 6a by taking 2- ((2-chloro-5-methylpyrimidinyl-4-yl) amino) -N-methylbenzamide as a raw material, and the yield is 58%.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H)，2.09(s,3H),2.83(d,3H),3.44(d,8H),7.10(t,1H),7.34(d,2H),7.52(t,1H),7.77(d,1H),7.82(d,2H),8.02(s,1H),8.76(d,1H),8.87(d,1H),9.41(s,1H),11.26(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.33,28.03,30.68,42.93,43.58,79.16,107.34,117.75,119.95,121.10,127.09,128.07,131.58,140.50,142.65,153.84,155.53,157.85,158.47,169.32,169.49.
Example 6 e: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-methoxypyrimidine
The synthesis method is the same as 6a by taking 2- ((2-chloro-5-methoxy pyrimidyl-4-yl) amino) -N-methylbenzamide as a raw material, and the yield is 59%.1H NMR(400MHz，DMSO-d6)：δ＝1.43(s,9H)，2.84(d,3H),3.33-3.55(m,8H),3.92(s,3H)，7.11(t,1H)，7.36(d,2H),7.48-7.57(m,1H),7.76(d,1H),7.84(d,2H),7.95(s,1H),8.70(d,1H),8.93(d,1H),9.34(s,1H),11.43(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.29，28.01，42.94，43.55，56.89，79.14，117.12，120.51，121.19，126.66，128.13，131.49，135.50，136.13，139.74，143.01，150.95，153.04，153.84，168.93，169.57
Example 7: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4-chloro-5-trifluoromethylpyrimidine
2, 4-dichloro-5-trifluoromethylpyrimidine (0.46ml,3.4mmol) was dissolved in 1, 2-dichloroethane: tert-butanol is 1: 1(24ml), a zinc chloride solution (4ml) dissolved in 1M diethyl ether was added dropwise to the mixture under ice-bath, and the mixture was stirred for 1 hour in ice-bath. Adding dichloroethane dropwise: tert-butanol is 1: 1(3ml) dissolved 1-Boc-4- ((4-amino) benzoyl) piperazine (1.04g,3.4mmol) and stirred for 1.5h on ice bath. The solvent was distilled off under reduced pressure, and the extract was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to separation and purification with silica gel column (elution with ethyl acetate/petroleum ether) to obtain 0.76g of a white solid in a yield of 46%.1H NMR(400MHz，DMSO-d6)：δ＝1.42(s,9H)，3.40(s,8H),7.45(d,2H),7.82(d,2H)，8.85(s,1H)，10.90(s,1H).13C NMR(100MHz，DMSO-d6):δ＝27.99,42.90,43.49,79.14,111.82(q,J＝33.3Hz),119.55,128.07,130.26,139.80,153.81,157.73,158.08(d,J＝4.7Hz),160.37,168.97.
Example 8: preparation of 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-trifluoromethylpyrimidine
With 2-amino-N-methylbenzamide and: 2- (4- (N-Boc-piperazinyl) formyl) anilino-4-chloro-5-trifluoromethylpyrimidine serving as a reactant is synthesized according to the same method as in example 3. After the reaction, the solvent was evaporated under reduced pressure, extracted with dichloromethane, and purified by silica gel column separation to obtain a yellow solid with a yield of 55%.1H NMR(400MHz，DMSO-d6):δ＝1.42(s,9H)，2.80(d,3H),3.29–3.59(m,8H),7.20(d,1H),7.34(d,2H),7.53(t,1H),7.75(d,3H),8.50(s,2H),8.76(d,1H),10.07(s,1H),11.34(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.21,28.01,39.94,40.15,79.16,119.43,122.24-122.62(m),123.24(d,J＝17.4Hz),125.83,127.85,129.08,131.12,138.44,140.89,153.83,155.94,156.24,160.59,168.73,169.16.
Example 9: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (4-pyridine) methylene ester
The compound 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-chloropyrimidine (0.85g,1.5mmol) was dissolved in 3ml of dichloromethane, and 3ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure, the product was dissolved in 6ml of DMF, 1ml of triethylamine was added, and stirring was continued at room temperature for 1 hour. After the reaction was completed, carbon disulfide was directly added without any treatment, and stirred at room temperature for 0.5h, and then 4-chloromethylpyridine (0.25g, 1.5mmol) was added, and stirred at 50 ℃ for 12 h. After the reaction, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and separated and purified with a silica gel column (dichloromethane/acetone elution) to obtain 0.78g of a yellow solid, which showed a total reaction yield of 82%.1H NMR(400MHz，DMSO-d6)：δ＝2.82(d,3H).3.68(s,4H),4.04(s,2H),4.32(s,2H),4.64(s,2H),7.17(t,1H),7.41(t,4H),7.54(t,1H),7.79(d,3H),8.28(s,1H),8.51(d,2H),8.75(dd,2H),9.75(s,1H),11.63(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.34,35.79,49.35,51.07,105.92,118.40,121.00,121.59,122.13,124.11,127.64,128.03,128.22,131.47,139.18,142.05,146.01,149.57,154.50,155.08,157.36,168.90,169.41,194.49.
Example 10: preparation of methylene 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-pyridine)
The synthesis method was the same as in example 9, using 2-chloromethylpyridine as the starting material. The total reaction yield was 78%.1H NMR(400MHz，DMSO-d6)：δ＝2.83(d,3H),3.69(s,4H),3.97-4.10(m,2H),4.34(s,2H),4.69(s,2H),7.17(t,1H),7.29(dd,1H),7.42(d,2H),7.48-7.59(m,2H),7.73-7.84(m,4H),8.28(s,1H),8.52(d,1H),8.77(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.34,42.70,49.29,50.78,105.92,118.41,120.99,121.60,122.09,122.43,127.63,128.02,128.20,136.71,139.19,142.05,149.21,155.07,156.03,157.35,168.90,169.42,195.09.
Example 11: preparation of methylene 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (3-pyridine)
The synthesis method was the same as in example 9, using 3-chloromethylpyridine as the starting material. The total reaction yield is 80%.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H)，3.69(s,4H),4.03(s,2H),4.34(s,2H),4.62(s,2H),7.17(t,1H),7.35(dd,1H),7.42(d,2H),7.55(t,1H),7.80(t,4H),8.27(s,1H),8.47(d,1H),8.64(s,1H),8.77(dd,2H),9.75(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.31,37.46,49.36,50.76,105.88,118.39,121.01,121.58,122.10,123.42,127.64,128.00,131.43,132.67,136.68,139.15,142.01,148.35,150.08,154.48,155.06,157.35,168.87,169.38,194.65.
Example 12: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithioformate-2-carbonitrile
The synthesis method is the same as that of example 9, using bromopropionitrile as a raw material. Total yield of the reaction 76％。1H NMR(400MHz，DMSO-d6):2.83(d,3H),2.97(t,2H),3.57(t,2H),3.70(s,4H),4.04(s,2H),4.33(s,2H),7.18(t,1H),7.42(d,2H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.77(dd,2H),9.76(s,1H),11.64(s,1H)。13C NMR(100MHz，DMSO-d6):δ＝17.28，26.34，31.41，49.40,50.84,105.87,118.40,119.19,121.04,121.61,122.17,127.66,128.04,128.21,131.48,139.14,142.01,154.54,155.08,157.37,168.88,169.38,193.92.
Example 13: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-phenethyl ester
(2-bromoethyl) benzene was used as a raw material, and the synthesis method was the same as in example 9. The total reaction yield was 79%.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H),2.91-3.01(m,2H),3.56-3.45(m,2H),3.68(s,4H),4.01(s,2H),4.35(s,2H),7.13-7.25(m,2H),7.31(q,4H),7.41(t,2H),7.55(t,1H),7.81(t,3H),8.28(s,1H),8.78(dd,2H),9.77(s,1H),11.67(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.32，34.46，49.29，50.58，105.89，118.39，120.99，121.59，122.12，126.35，127.67，128.02，128.19，128.40，128.46，131.46，139.17，139.99,142.01,154.51,155.07,157.36,168.87,169.36,195.60.
Example 14: preparation of 3-oxobutyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate
The synthesis method was the same as in example 9, using methyl acrylate as a raw material. The total reaction yield was 83%.1H NMR(400MHz，DMSO-d6)：δ＝2.85-2.75(m,5H),3.48(t,2H),3.65(d,7H),4.00(s,2H),4.31(s,2H)，7.13-7.21(m,1H),7.40(d,2H),7.51-7.58(m,1H),7.73-7.78(m,3H),8.28(s,1H),8.75(dd,2H),9.74(s,1H),11.62(s,1H)。13C NMR(100MHz，DMSO-d6):δ＝32.02，34.19，42.48，49.48，50.48，105.87，118.38，121.01，121.60，122.15，127.70，128.04，128.20，131.48，139.15，142.00，154.55，155.08，157.37，168.88，169.36,195.86.
Example 15: preparation of benzyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate
Benzyl bromide was used as a raw material, and the synthesis method was the same as in example 9. The total reaction yield was 79%.1H NMR(400MHz，DMSO-d6)：δ＝2.83(d,3H),3.68(s,4H),4.03(dd,2H),4.34(s,2H),4.56(s,2H),7.17(t,1H),7.30(dt,3H),7.41(d,4H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.76(dd,2H),9.76(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.33,40.78,49.19,50.59,105.86,118.39,121.02,121.60,122.15,127.40,127.68,128.03,128.19,128.49,129.25,131.48,136.13,139.15,142.00,154.53,155.07,157.37,168.88,169.37,195.20.
Example 16: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-methoxy) ester
The synthesis method is the same as example 9 with 2-bromoethyl methyl ether as the raw material. The total reaction yield is 82%.1H NMR(400MHz，DMSO-d6)：δ＝2.83(d,3H)，3.27(s,3H)，3.50(t,2H),3.57(dd,2H),3.68(s,4H),3.94-4.12(m,2H),4.33(s,2H),7.18(t,1H),7.42(d,2H)，7.55(t,1H)，7.79(dd,3H),8.28(s,1H),8.70-8.84(m,2H),9.76(s,1H)11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.34，35.82，49.18，50.70，57.90，69.86，105.92，118.40，120.99，121.60，122.10，127.64，128.02，128.20，131.45，139.19，142.04，154.49，155.08，157.36，168.89，169.40，195.54.
Example 17: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 4-tetrahydropyranylidene
The synthesis method was the same as in example 9 using 4-bromomethyl tetrahydropyran as a raw material. The total reaction yield is 82%.1H NMR(400MHz，DMSO-d6)：δ＝1.27(ddd,2H)，1.66(d,2H),1.76-1.92(m,1H),2.82(d,3H),3.17-3.31(m,4H),3.67(s,4H),3.79-3.89(m,2H),4.03(d,2H),4.32(s,2H),7.17(t,1H),7.41(d,2H),7.55(t,1H),7.78(t,3H),8.28(s,1H),8.76(dd,2H),9.75(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):26.31，32.02，34.18，42.51，49.21，50.59，66.76，105.90.118.37，120.97，121.58，122.11，127.66，128.03，128.21，131.46，139.18，142.02，154.50，155.07，157.36，168.87，169.37，195.87.
Example 18: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-ethoxy-2-oxo) ester
The synthesis method is the same as that of example 9, using ethyl bromoacetate as a raw material. The total yield of the reaction is 83 percent1H NMR(400MHz，DMSO-d6)：δ＝1.22(t,3H),2.84(d,3H),3.71(s,4H),4.08(dq,4H),4.22(s,2H),4.31(s,2H),7.18(t,1H),7.43(d,2H),7.56(t,1H),7.80(t,3H),8.28(s,1H),8.72-8.83(m,2H),9.76(s,1H),11.66(s,1H).13C NMR(100MHz，DMSO-d6):δ＝14.06,26.34,38.27,49.36,51.02,61.11,105.88,118.40,121.02,121.61,122.15,127.66,128.03,128.21,131.48,139.16,142.03,154.53,155.08,157.37,168.00,168.89,169.40,194.63.
Example 19: preparation of 2-hydroxyethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithioate
The synthesis method is the same as that of example 9, using bromoethanol as a raw material. The total yield of the reaction was 77%.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H),3.42(t,2H),3.60-3.77(m,6H),3.98-4.15(m,2H),4.34(s,2H),5.02(t,1H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.77(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.37，30.71，49.24，50.75，59.31，105.92，118.46，121.06，121.65，122.19，127.71，128.05，128.24，131.50，139.18，142.04，154.54，155.11，157.40，168.93，169.45，195.96.
Example 20: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-ethoxy-2, 3-dioxo) propyl ester
The synthesis method is the same as that of example 9, using ethyl 3-bromopyruvate as a raw material. The total reaction yield is 76%.1H NMR(400MHz，DMSO-d6)：δ＝1.12-1.34(m,4H)，2.82(d,3H),3.70(s,4H),3.95-4.40(m,6H),4.60(s,1H),7.18(t,1H),7.41(d,2H),7.55(t,1H),7.79(t,3H)，8.28(s,1H),8.75(dd,2H),9.74(s,1H),11.62(s,1H)。13C NMR(100MHz，DMSO-d6):δ＝13.86,26.33,50.04,51.21,61.47,62.05,105.85,118.39,121.05,121.61,122.19,127.66,128.04,128.21,131.50,139.12,142.01,154.56,155.08,157.38,168.88,169.36,186.73,190.19,194.37.
Example 21: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-methanesulfonyl) ester
The synthesis method was the same as in example 9, using 1-chloro-2 (methylsulfonyl) ethane as the starting material. The total reaction yield is 76%.1H NMR(400MHz，DMSO-d6)：2.84(d,3H),3.09(s,3H),3.46-3.55(m,2H),
3.60-3.78(m,6H),4.03(s,2H),4.34(s,2H),7.18(t,1H),7.42(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.76(dd,2H),9.74(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.32,28.59,40.57,49.33,50.65,52.78,105.88,118.40,121.01,121.58,122.13,127.63,128.01,128.18,131.44,139.13,142.00,154.50,155.07,157.35,168.86,169.38,194.22.
Example 22: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1, 3-dioxolane))
The synthesis method was the same as in example 9, using 2- (2-bromoethyl) -1, 3-dioxane as a starting material. The total reaction yield was 81%.1H NMR(400MHz，DMSO-d6):δ＝1.90-2.03(m,2H)，2.82(d,3H),3.25-3.36(m,2H),3.67(s,4H),3.76-3.94(m,4H),4.16(d,4H),4.89(t,1H),7.17(t,1H),7.40(d,2H),7.55(t,1H),7.78(dd,3H),8.28(s,1H),8.75(dd,2H),9.74(s,1H),11.62(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.28，30.97，32.45，49.15，50.48，54.87，64.33，102.32，105.84，118.39，121.02，121.57，122.10，127.69，127.98，128.13，131.42，139.12，141.96，154.49，155.06，157.35，168.84，169.34，195.57.
Example 23: preparation of allyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate
The synthesis method is the same as that of example 9, using bromopropene as a raw material. The total reaction yield is 84%.1H NMR(400MHz，DMSO-d6)：δ＝2.85(d,3H)，3.70(s,4H),4.11(t,6H),5.16(d,1H),5.34(d,1H),5.91(ddt,1H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.81(dd,3H),8.27(s,1H),8.77(t,2H),9.75(s,1H),11.67(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.30，49.52，50.53，54.87，105.89，118.39，120.99，121.57，122.06，127.63，127.98,128.15，131.40，139.16，142.00，154.45，155.05，157.34，168.86，169.37,195.05.
Example 24: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-hydroxy) propyl ester
The synthesis method is the same as that of example 9, using methyl oxirane as a raw material. The total reaction yield was 78%.1H NMR(400MHz，DMSO-d6)：2.51(s,1H),2.60(s,3H),2.83(d,3H),3.38(s,2H),3.68(s,5H),4.03(s,2H),4.33(s,2H),7.18(t,1H),7.41(d,2H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.77(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝19.49,26.34,30.70,49.16,50.56,54.93,105.87,118.40,121.03,121.61,122.17,127.71,128.04,128.20,131.29,139.14,141.99,154.54,155.08,157.37,168.88,169.38,196.89.
Example 25: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The synthesis method is the same as that of example 9, using N, N-dimethylamino ethyl bromide as a raw material. The total reaction yield was 78%.1H NMR(400MHz，DMSO-d6)：δ＝2.19(s,6H)，2.53(dd,2H),2.85(d,3H),3.40(t,2H),3.69(s,4H),4.04(dd,2H),4.34(s,2H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.81(t,3H),8.28(s,1H),8.72–8.84(m,2H),9.76(s,1H),11.68(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.33，34.46，44.77，49.20，50.46，57.30，105.9，118.39，120.97，121.58，122.09，127.65，128.02，128.20，131.44，139.19，142.02，154.48，155.07，157.36，168.88，169.38，196.08.
Example 26: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid methyl ester
The synthesis method was the same as in example 9, using methyl iodide as the starting material. The total yield of the reaction was 77%.1H NMR(400MHz，DMSO-d6)：δ＝2.64(s,3H),2.81(d,3H),3.69(s,4H),4.04(dd,2H),4.33(s,2H),7.17(t,1H),7.42(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.77(dd,2H),9.78(s,1H),11.68(s,1H).13C NMR(100MHz，DMSO-d6):δ＝20.16,26.34,49.21,50.56,105.69,118.40,120.68,121.35,122.08,127.34,127.99,128.16,131.33,139.15,142.00,154.43,155.10,157.36,168.88,169.34,196.01.
Example 27: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1-pyrrolidinyl)) -ester
The synthesis method is the same as example 9 with N-chloroethyl pyrrolidine as the raw material. The total reaction yield was 74%.1H NMR(400MHz，DMSO-d6)：δ＝1.67(s,4H),2.50(d,4H),2.68(t,2H),2.84(d,3H),3.41(t,2H),3.68(s,4H),4.03(s,2H),4.33(s,2H),7.18(t,1H),7.42(d,2H),7.55(t,1H),7.80(t,3H)，8.28(s，1H),8.77(dd,2H),9.75(s,1H),11.67(s,1H).13C NMR(100MHz，DMSO-d6):δ＝23.13,26.32,49.19,50.52,53.31,54.06,105.88,118.39,120.99,121.58,122.12,127.67,128.01,128.19,131.45,139.17,142.01,154.50,155.07,157.36,168.87,169.37,196.12.
Example 28: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1-piperidine)) ester
The synthesis method of 1- (2-chloroethyl) piperidine used as a raw material is the same as that of example 9. The total reaction yield is 84%.1H NMR(400MHz，DMSO-d6)：δ＝1.40-1.54(m,4H),2.38(s,4H),2.46-2.53(m,3H),2.83(d,3H),3.39(dd,3H),3.67(s,4H),4.03(dd,2H),4.31(s,2H),7.17(t,1H),7.41(d,2H)7.55(t,1H),7.79(t,3H),8.28(s,1H),8.76(dd,2H),9.74(s,1H),11.64(s,1H)。13C NMR(100MHz，DMSO-d6):δ＝23.96，25.47，26.28，33.78，49.33，50.42，53.72，57.03，105.83，118.37，121.01，121.56，122.10，127.69，127.98，128.13，131.42，139.12，141.95，154.49，155.05，157.35，168.83，169.32，196.08.
Example 29: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (1- (4-methyl) piperazine))
The synthesis method was the same as in example 9, using 1- (2-bromoethyl) -4-methylpiperazine as a raw material. The total reaction yield is 80%.1H NMR(400MHz，DMSO-d6)：δ＝2.18(s,3H)，2.46(dd,8H),2.56(dd,2H),2.83(d，3H),3.35-3.45(m,2H),3.67(s,4H),4.03(dd,2H),4.32(s,2H),7.12-7.21(m,1H),7.42(d,2H),7.54(dd,1H),7.71-7.84(m,3H),8.27(d,1H),8.76(dd,2H),9.74(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.28,33.69,45.43,49.19,50.55,52.14,54.44,56.22,105.83,118.38,121.01,121.56,122.11,127.69,127.99,128.14,131.42,139.11,141.96,154.49,155.05,157.34,168.84,169.33,195.98.
Example 30: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-morpholinyl) carboxylate
The synthesis method is the same as example 9 with 4- (2-bromoethyl) morpholine as the raw material. The total reaction yield is 80%.1H NMR(400MHz，DMSO-d6)：δ＝2.42(s,3H)，2.58(t,1H),2.83(d,4H)3.33-3.51(m,3H),3.52-3.59(m,3H),3.65(d,5H),4.03(d,2H),4.32(s,2H),7.18(t,1H),7.41(d,2H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.76(dd,2H),9.74(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.29,49.14,50.66,51.57,53.01,56.75,66.10,105.85,118.38,121.01,121.57,122.11,127.69,127.99,128.16,131.44,139.13,141.97,154.50,155.06,157.35,168.85,169.33,195.92.
Example 31: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-methyl) propyl ester
The synthesis method was the same as in example 9 using 1-bromo-2-methylpropane as a starting material. The total reaction yield is 85%.1H NMR(400MHz，DMSO-d6)：δ＝1.21(d,6H),1.86(m,1H),2.79(d,2H),2.81(d,3H),3.56(s,4H),4.03(dd,2H),4.34(s,2H),7.17(t,1H),7.42(d,2H),7.55(t,1H),7.78(t,3H),8.28(s,1H),8.77(dd,2H),9.75(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝14.86,26.71,31.60,44.62,49.36,50.64,105.67,118.40,121.46,121.78,122.36,127.64,127.96,128.15,131.68,139.42,141.97,154.38,155.23,157.35,168.93,169.47,195.63.
Example 32: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-ethoxy) ester
The synthesis method was the same as in example 9, using 1-bromo-2-ethoxyethane as the starting material. The total reaction yield was 79%.1H NMR(400MHz，DMSO-d6)：δ＝2.03(t,3H),2.84(d,3H),3.46(dd,2H),3.51(t,2H),3.60(dd,2H),3.68(s,4H),4.02(dd,2H),4.33(s,2H),7.18(t,1H),7.41(d,2H),7.55(t,1H)，7.79(t,3H),8.28(s,1H),8.76(dd,2H),9.76(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝15.98,26.35,49.20,50.69,54.63,57.82,70.03,105.87,118.65,121.06,121.79,122.24,127.87,128.02,128.21,131.50,139.20,142.01,154.40,155.12,157.34,168.95,169.30,195.52.
Example 33: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (2-butene) ester
The synthesis method was the same as in example 9 using 1-bromo-2-butene as the starting material. The total reaction yield was 83%.1H NMR(400MHz，DMSO-d6)：δ＝2.16(d,3H),2.85(d,3H),3.76(s,4H),3.98(d,2H),4.12(dd,2H),4.35(s,2H),5.51(dd,1H),5.84(ddt,1H),7.18(t,1H),7.43(d,2H),7.56(t,1H),7.80(dd,3H),8.27(s,1H),8.77(t,2H),9.75(s,1H),11.66(s,1H).13C NMR(100MHz，DMSO-d6):δ＝14.78,26.35,39.74,49.53,50.64,55.76,105.76,118.35,121.02,121.57,122.25,127.89,128.01,128.20,131.42,139.15,142.00,154.46,155.10,157.35,168.79,169.40,195.10.
Example 34: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-cyano) propyl ester
The synthesis method is the same as example 9 with 4-bromobutyronitrile as a raw material. The total reaction yield is 76%.1H NMR(400MHz，DMSO-d6)：δ＝2.43-2.56(m,2H),2.83(d,3H),2.86(t,2H),3.54(t,2H),3.75(s,4H),4.04(s,2H),4.33(s,2H),7.18(t,1H),7.42(d,2H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.78(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝18.28,22.35,26.34,32.47,49.81,50.63,105.36,118.96,119.20,121.01,121.51,122.15,127.63,128.05,128.30,131.46,139.15,142.02,154.68,155.09,157.40,168.89,169.32,195.21.
Example 35: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (4-hydroxy) butyl ester
The synthesis method was the same as in example 9 using 4-bromo-1-butanol as the starting material. The total yield of the reaction is 75%.1H NMR(400MHz，DMSO-d6)：δ＝2.01-2.13(m,2H),2.22-2.36(m,2H),2.82(d,3H)，3.40(t,2H),3.62-3.84(m,6H),4.10(s,2H),4.34(s,2H),5.26(5,1H),7.18(t,1H),7.41(d,2H),7.55(t,1H),7.79(dd,3H),8.28(s,1H),8.76(dd,2H),9.75(s,1H),11.68(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.37,28.29,30.80,35.60,49.25,50.76,59.59,105.82,118.42,121.10,121.65,122.21,127.68,128.06,128.21,131.41,139.20,142.03,154.54,155.12,157.36,168.85,169.35,195.92.
Example 36: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (ethylsulfonyl)) ester
The synthesis method was the same as in example 9, using 1-chloro-2 (ethylsulfonyl) ethane as the starting material. The total yield of the reaction was 77%.1H NMR(400MHz，DMSO-d6)：δ＝1.86(t,3H),3.25(dd,2H),3.31-3.42(m,2H),3.62-73(m,6H),4.03(s,2H),4.34(s,2H),7.18(t,1H),7.42(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.76(dd,2H),9.74(s,1H),11.66(s,1H).13C NMR(100MHz，DMSO-d6):δ＝14.36,26.32,30.06,42.34,49.35,50.67,52.80,105.86,118.40,121.02,121.59,122.14,127.63,128.01,128.19,131.43,139.13,142.01,154.55,155.08,157.35,168.87,169.34,195.60.
Example 37: preparation of 1-oxoethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate
The synthesis method was the same as in example 9, using acetyl chloride as the starting material. The total reaction yield was 81%.1H NMR(400MHz，DMSO-d6)：δ＝2.32(s,3H)，2.84(d,3H),3.80(s,4H)，4.04(dd,2H),4.43(s,2H),7.17(t,1H),7.41(d,2H),7.55(t,1H),7.79(t,3H),8.28(s,1H),8.76(dd,2H),9.74(s，1H)，11.64(s，1H).13C NMR(100MHz，DMSO-d6):δ＝26.28,26.76,49.33,50.45,105.83,118.38,121.03,121.60,122.15,127.68,127.89,128.03,131.44,139.12,141.96,154.50,155.06,157.57,168.89,169.36,189.90,196.05.
Example 38: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid 2-oxopropyl ester
The synthesis method is the same as that of example 9, using bromoacetone as a raw material. The total yield of the reaction is 75%.1H NMR(400MHz，DMSO-d6)：δ＝2.35(s,3H),2.86(s,3H),3.56(s,2H),3.88(s,4H),4.05(s,2H),4.32(s,2H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.81(t,3H),8.28(s,1H),8.78(dd,2H),9.75(s,1H),11.66(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.40,26.82,46.12,49.34,50.56,105.86,118.40,121.02,121.61,122.15,127.86,128.03,128.13,131.46,139.14,142.01,154.53,155.07,157.40,168.05,168.90.169.36,196.10.
Example 39: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-methylamino)
The synthesis method was the same as in example 9, using N-methylaminobromoethane as the starting material. The total reaction yield was 78%.1H NMR(400MHz，DMSO-d6)：δ＝2.36(d,3H),2.65(dd,2H),2.85(d,3H),3.52(t,2H),3.74(s,4H),4.04(dd,2H),4.332(s,2H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.81(t,3H),8.28(s,1H),8.78(dd,2H),9.76(s,1H),11.69(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.42,34.50,45.20,49.31,50.45,57,40,105.61,118.42,120.99,121.58,122.10,127.66,128.02,128.21,131.44,139.15,142.01,154.48,155.07,157.38,168.80,169.36,196.09.
Example 40: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3- (N, N-dimethylamino)) propyl ester
The synthesis method is the same as that of example 9, using N, N-dimethylamino-3-chloropropane as a raw material. The total reaction yield was 83%.1H NMR(400MHz，DMSO-d6)：δ＝2.20(s,6H),2.31(dd,2H),2.45(dd,2H),2.86(d,3H),3.42(t,2H),3.70(s,4H),4.03(dd,2H),4.33(s,2H),7.18(t,1H),7.43(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.77(dd,2H),9.76(s,1H),11.68(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.43,28.22,34.22,45.76,49.30,50.23,57.21,105.82,118.40,121.03,121.64,122.10,127.65,128.06,128.20,131.45,139.18,142.03,154.49.155.08,157.38,168.89,169.40,195.78.
Example 41: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-2-thiazole ester
The synthesis method is the same as example 9 with 2-bromothiazole as the raw material. The total reaction yield is 84%.1H NMR(400MHz，DMSO-d6)：δ＝2.85(d，3H)，3.82(s,4H),4.02(dd,2H),4.32(s,2H),7.17(t,1H),7.30(d,2H),7.46(d,1H),7.47(d,1H),7.55(t,1H),7.79(dd,3H),8.28(s,1H),8.77(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.35,49.36,50.40,105.88,118.39,118.60,121.02,121.58,122.16,127.68,128.04,128.20,131.46,139.15,142.00,142.61,154.51,155.09,157.37,166.42,168.88,169.37,195.60.
Example 42: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid-phenyl ester
The synthesis method is the same as that of example 9, using bromobenzene as raw material. The total reaction yield is 82%.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H),3.68(s,4H),4.01(s,2H),4.35(s,2H),7.14-7.20(m,2H),7.30(m,4H),7.40(d,2H),7.55(t,1H),7.80(t,3H),8.28(s,1H),8.78(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.33,49.23,50.58,105.96,118.40,121.04,121.80,122.26,127.64,128.10,128.21,128.39,129.25,131.49,138.24,139.16,142.00,154.51,155.20,157.38,168.64,169.40,195.30.
Example 43: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2- (2-thienyl)) ester
The synthesis method is the same as that of example 9, using 2- (2-bromoethyl) thiophene as a raw material. The total reaction yield is 82%.1H NMR(400MHz，DMSO-d6)：δ＝2.82(d,3H),3.11-3.26(m,2H),3.25(t,2H),3.68(s,4H),4.02(dd,2H),4.45(s,2H),6.90(s,1H),6.92(d,1H),7.22(s,1H),7.17(t,1H),7.40(d,1H),7.55(t,1H),7.78(dd,3H)，8.28(s，1H)，8.75(dd,2H),9.75(s,1H),11.63(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.30，32.60，34.58，49.16，50.45.105.78，118.36，121.02，121.60，122.15，124.00，126.12，127.68，127.98，128.10，128.21，131.43，139.12，141.20，141.99.154.50，155.06，157.35，168.85，169.35，195.58.
Example 44: preparation of methylene 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithioformate- (3-furan)
The synthesis method is the same as example 9 with 3-bromomethylfuran as the raw material. The total reaction yield was 81%.1H NMR(400MHz，DMSO-d6)：δ＝2.82(d,3H),3.69(s,4H),4.02(s,2H),4.32(s,2H),4.56(s,2H),7.17(t,1H),7.41(d,2H),7.55(t,1H),7.78(t,3H),8.28(s,1H),8.77(dd,2H),9.75(s,1H),11.64(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.30,33.67,105.83,109.72,118.60,121.03,121.62,122.15,127.68,128.02,128.21,131.50,139.16,139.31,142.02,142.83,154.53,155.08,157.36,168.90,169.38,195.90.
Example 45: preparation of 4- (4- ((4- (2-methylcarbamoyl) anilino-5-chloropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarboxylic acid- (3-phenyl) propyl ester
The synthesis method was the same as in example 9, using 1-bromo-3-phenylpropane as the starting material. The total reaction yield is 82%.1H NMR(400MHz，DMSO-d6)：δ＝2.84(d,3H),2.64-2.73(m,2H),2.92(t,2H),3.45(t,2H),3.68(s,4H),4.02(s,2H),4.34(s,2H),7.14-7.26(m,2H),7.32(q,4H),7.41(d,2H),7.55(t,1H),7.81(t,3H),8.28(s,1H),8.78(dd,2H),9.76(s,1H),11.65(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.32,33.62,34.30,34.46,49.91,50.65,105.86,118.40,120.91,121.60,122.11,126.34,127.68,128.01,128.20,128.41,128.45,131,46,139.17,140.01,142.02,154.51,155.07,157.36,168,88,169.36,195.80.
Example 46: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-pyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The synthesis method was the same as in example 9, using 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilinopyrimidine as a starting material. The total reaction yield was 79%.1H NMR(400MHz，DMSO-d6)：δ＝2.17(s,6H),2.52(s,2H),2.81(s,3H),3.40(s,2H),3.68(s,4H),4.03(s,2H),4.32(s,1H),6.37(s,1H),7.11(s,1H),7.41(d,2H),7.51(s,1H),7.71(d,1H),7.86(d,2H),8.13(d,1H),8.47(d,1H),8.68(s,1H),9.56(s,1H),10.80(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.15，34.39，44.80，49.17，50.57，57.33，99.88，118.05，121.61，121.84，127.12，128.11，128.22，131.34，139.59，142.55，156.73，159.28，159.87，168.96，169.49，196.10.
Example 47: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-fluoropyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The synthesis method was the same as in example 9, using 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-fluoropyrimidine and N, N-dimethylamino bromoethane as starting materials. The total reaction yield is 76%.1H NMR(400MHz，DMSO-d6)：δ＝2.18(s,6H),2.52(d,2H),2.83(d,3H),3.40(s,2H),3.68(s,4H),4.03(d,2H),4.32(s,2H),7.16(t,1H),7.42(d,2H),7.56(t,1H),7.81(d,3H),8.23(d,1H),8.83(d,2H),9.64(s,1H),11.80(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.31,34.50,44.82,49.31,50.53,57.33,117.79,120.09,120.79,121.85,127.26,128.07,128.27,131.83,139.45,140.07,140.42(d,J＝19.8Hz),142.5(d,J＝7.0Hz),149.02,149.12,155.06(d,J＝3.3Hz),169.06,169.43,196.08.
Example 48: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-methylpyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The synthesis method was the same as in example 9, using 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-methylpyrimidine and N, N-dimethylamino bromoethane as the starting materials. The total yield of the reaction was 77%.1H NMR(400MHz，DMSO-d6)：δ＝2.16(d,9H)，2.52(t,2H),2.84(d,3H),3.39(d,2H),3.69(s,4H),4.03(d,2H),4.33(s,2H),7.11(t,1H),7.40(d,2H),7.53(t,1H),7.78(d,1H),7.85(d,2H),8.03(s,1H),8.77(d,1H),8.89(d,1H),9.44(s,1H),11.27(s,1H).13C NMR(100MHz，DMSO-d6):δ＝13.15，26.34，34.51，44.82，49.16，50.50，57.34，107.40，117.70，119.96，121.10，121.20，126.71，127.98，128.26，131.58，140.50，142.87，155.51，157.83，158.47，169.32，169.54,196.11.
Example 49: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-methoxypyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The compound 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-methoxypyrimidine and N, N-dimethylamino bromoethane were used as raw materials, and the synthesis method was the same as in example 9, and the total reaction yield was 77%.1H NMR(400MHz，DMSO-d6)：δ＝2.18(s,6H)，2.53(dd,2H),2.83(d,3H),3.40(t,2H),3.69(s,4H),3.92(s,3H),4.01-4.13(m,2H),4.33(s,2H),7.11(t,1H)，7.41(d,2H),7.53(t,1H),7.75(d,1H),7.85(d,2H),7.95(s,1H),8.70(d,1H),8.93(d,1H),9.36(s,1H),11.42(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.29，34.48，44.78，49.22，50.57，56.88，57.32，117.03，120.49，120.71，121.20，126.26,128.02,128.32,131.50,135.51,136.10,139.72,143.19,150.93,152.99,168.91,169.56,196.07.
Example 50: preparation of ethyl 4- (4- ((4- (2-methylcarbamoyl) anilino-5-trifluoromethylpyrimidin-2-yl) amino) benzoyl) piperazine-1-dithiocarbamate- (2-dimethylamino) ethyl ester
The synthesis method of the compound 2- (4- (N-Boc-piperazinyl) formyl) anilino-4- (2- (N-methyl) amido) anilino-5-trifluoromethylpyrimidine and N, N-dimethylamino bromoethane was the same as in example 9. The total reaction yield was 78%.1H NMR(400MHz，DMSO-d6)：δ＝2.18(s,6H)，2.53(t,2H),2.82(d,3H),3.41(t,2H),3.68(s,4H),4.04(dd,2H),4.34(s,2H),7.22(t,1H),7.40(d,2H),7.55(t,1H),7.78(dd,3H),8.51(s,2H),8.79(d,1H),10.11(s,1H),δ＝11.38(s,1H).13C NMR(100MHz，DMSO-d6):δ＝26.23,34.52,44.80,49.18,50.48,57.34,59.76,119.33,122.45,122.83,123.26,(d,J＝19.1Hz),125.84,128.08,128.69,131.15,138.49,141.14,155.87,156.25,160.59,168.76,169.23,170.31,196.13.
Evaluation of FAK kinase inhibitory Activity
1. The experimental method comprises the following steps:
a system of 5ul per well in 384-well plates, comprising 2ul FAK protein (2.6ng in buffer), 2ul ATP and substrate mixture (ATP final concentration 25uM in buffer, substrate final concentration 0.4ug/ul in buffer), 1ul DMSO or different concentrations of drug-containing DMSO, incubated at room temperature for 1h, and 5ul ADP-Glo addedTMReagent, after incubation for 40min at room temperature, 10ul of Kinase Detection Reagent was added, after incubation for 30min at room temperature, the value of chemiluminescence was read with a microplate reader (integration time 500ms),
setting blank group and control group, blank group: buffer instead of FAK kinase; control group: only DMSO. The other reagents were unchanged.
Inhibition rate (Rc-R)/(Rc-Rb) × 100%
Wherein R is the luminous value of the administration group, Rc is the luminous value of the control group, and Rb is the luminous value of the blank group.
Calculating IC by graphpad according to inhibition ratio50The value is obtained.
2. Results
The inhibition of FAK kinase by part of the target compounds and the positive drug TAE226 is shown in the following table
As can be seen from the above table, the compound of the general formula i has a significant FAK kinase inhibitory effect, wherein the activity of the compound shown in example 50 is the best and is significantly better than that of the positive drug TAE 226.
Evaluation of cell Activity
1. The experimental method comprises the following steps:
cell lines: HCT116 colon cancer cells, MCF7 breast cancer cells, PC3 prostate cancer cells,
u87MG brain glioma cells.
The screening method comprises the following steps: MTS method
Acting time: 72h
2. Results
The results of the cell viability assay are shown in the following table, IC50The unit is uM.L-1。
The results in the table show that the compounds all have obvious proliferation inhibition effects on HCT116 colon cancer cells, MCF7 breast cancer cells, PC3 prostate cancer cells and U87MG brain glioma cells, and most of the proliferation inhibition effects are superior to that of positive drug TAE 226. The activity of the compounds shown in examples 19, 24, 15, 27, 28, 29, 47, 48, 50 is particularly significant and significantly better than that of the positive control drug TAE 226. Among these, the compound shown in example 50 had the best effect and IC for inhibition of proliferation of four cells50Values were all less than 100 nM.
Claims (8)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
r is selected from C1-4Substituted or unsubstituted alkyl, allyl, 2-butenyl, thienyl, picolyl, furylmethyl, thienylethyl; the substituents are independently selected from methyl, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, oxo, hydroxy, cyano, 1, 3-dioxolane, tetrahydropyran, dimethylaminoethyl, bisMethylaminopropyl, methylaminoethyl, pyrrolylethyl, piperidinylethyl, methylpiperazinylethyl;
x is independently selected from hydrogen, methyl, methoxy, fluoro, trifluoromethyl.
2. The following compounds or pharmaceutically acceptable salts thereof:
3. a pharmaceutical composition comprising the compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
4. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the manufacture of a medicament for modulating the catalytic activity of a protein kinase, wherein the protein kinase is selected from the group consisting of topical adhesion kinases.
5. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, in the manufacture of a medicament for the treatment or prevention of cancer.
6. Use according to claim 5, wherein the cancer is preferably colon cancer, breast cancer, prostate cancer or brain glioma.
7. A process for the preparation of a compound according to claim 1, said process comprising the steps of:
(1) taking 2-nitrobenzoyl chloride as a raw material, obtaining a compound 2 through methylamine nucleophilic substitution and nitro reduction reaction, and carrying out nucleophilic substitution reaction on the compound 2 and various 5-substituted or unsubstituted 2, 4-dichloropyrimidines under an alkaline condition to obtain a compound 3;
wherein X is selected from hydrogen, fluorine, chlorine, methyl and methoxy;
(2) 4-nitrobenzoyl chloride is used as a raw material, and a compound 5 is obtained through nucleophilic substitution and nitro reduction reaction;
(3) carrying out C-N coupling reaction on the compounds 3 and 5 in the steps (1) and (2) to obtain compounds 6a-6e, and removing Boc protection of the compounds 6a-6e by trifluoroacetic acid and then reacting with CS2And different halogenated hydrocarbons or olefins are subjected to nucleophilic substitution or Michael addition reaction to obtain corresponding target compounds;
wherein X is selected from hydrogen, fluorine, chlorine, methyl and methoxy;
(4) when X is selected from trifluoromethyl, the synthesis method comprises the following steps: firstly, 2, 4-dichloro-5-trifluoromethylpyrimidine reacts with the compound 5 in the step (2) to obtain a compound 7, the compound 7 reacts with the compound 2 in the step (1) under an alkaline condition to obtain a compound 8, the compound 8 is subjected to Boc removal protection by trifluoroacetic acid and then reacts with CS2And different halogenated hydrocarbons or olefins are reacted by nucleophilic substitution or Michael addition to obtain the corresponding compoundsThe target compound of (1);
r in the step (3) and the step (4) is as defined in claim 1.
8. The method according to claim 7, wherein the base is at least one selected from the group consisting of sodium bicarbonate, triethylamine, sodium hydride, and N, N-diisopropylethylamine.
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