CN1972917B - Aminopyrimidine compound and its salt, its preparation method and pharmaceutical use - Google Patents

Abstract

The present invention provides aminopyrimidine compounds of formula (I) and their salts, wherein R1, R2, R3, R4, R5, R6, Q, Z, L, m, n are defined as the description, the methods for preparation thereof, the uses thereof and the pharmaceutical compositions comprising the effective amount of compounds of formula (I). The compounds of formula (I) and their salts can be used as protein kinase inhibitors.

Description

Aminopyrimidine compound and its salt, its preparation method and pharmaceutical use

technical field

The present invention relates to an aminopyrimidine compound of general formula (I) and its salt, a preparation method thereof, and the application of the compound alone or in combination with other drugs in the treatment of cell proliferative diseases (such as cancer).

Background technique

In more than 95% of chronic myelogenous leukemia patients, due to chromosomal translocation, BCR-ABL fusion protein is produced, resulting in high expression of ABL tyrosine kinase activity. Drug indications. Human chronic myelogenous leukemia K562 cells express Bcr-Abl protein, so the present invention is a common cell model for researching drugs targeting BCR-ABL.

In the prior art, chronic myelogenous leukemia is treated with, for example, recombinant interferon α-2a, which has broad-spectrum antiviral, antitumor and immunomodulatory functions. Interferon binds to cell surface receptors, induces cells to produce a variety of antiviral proteins, inhibits virus reproduction in cells, improves immune function, including enhancing macrophage phagocytosis, enhancing lymphocyte cytotoxicity and natural killing of target cells cell function.

Recently, Gleevec, also known as imatinib, has become a front-line drug for the treatment of chronic myeloid leukemia, but some patients develop drug resistance after taking it. A second-generation version of Gleevec may help drug-resistant patients, new research says. The drug binds and blocks the activity of BCR-ABL, an enzyme that promotes the growth of leukemia cells. In most cases, drug resistance arises because BCR-ABL has mutated, changing the shape of the enzyme so that drugs cannot bind to it. Neil P. Shah and colleagues isolated a variant of imatinib, termed BMS-354825, that is less selective for binding to the BCR-ABL enzyme. The authors' experiments with leukemia mouse models and cultured bone marrow cells from leukemia patients showed that BMS-354825 is more effective than imatinib and can deal with most imatinib resistance without obvious toxicity . (About 15-20% of imatinib resistance is caused by another mutation, and the new drug is ineffective in these cases.) BMS-354825 is now in phase 1 clinical trials. (Overriding Imatinib Resistance With a Novel ABL Kinase Inhibitor, Neil P. Shah, et al.).

Before the discovery of imatinib, the active drugs for Philadelphia chromosome (Ph) positive myeloid leukemia (CML) include IFN-α, cytarabine and homoharringtonine (HHT), which can be used alone or in combination . However, these drugs that have been used still have unsatisfactory effects.

Contents of the invention

In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of aminopyrimidine compound and salt thereof; Another object of the present invention is to provide a kind of method for preparing aminopyrimidine compound and salt thereof; Another aspect of the present invention The purpose is to provide an application of the compound and its salt alone or in combination with other drugs in the treatment of cell proliferation diseases (such as cancer).

The object of the present invention is achieved by the following technical solutions, and the present invention relates to a kind of general formula is (I) aminopyrimidine compound and salt thereof:

In the formula,

_R is selected from substituted or unsubstituted aryl, heterocyclic aryl or heterocyclic, substituents are selected from halogen atoms, C1-4 straight or branched chain alkyl, amino, alkoxy, cycloalkyl;

R _{and R} are independently selected from hydrogen, halogen atoms, amino, alkylamino, dialkylamino, cyano, nitro, hydroxyl, alkoxy, haloalkoxy; or substituted or unsubstituted alkyl group, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclic aryl, aralkyl and heterocyclic aralkyl, substituents are selected from halogen atoms, C1-4 straight or branched chain alkyl, amino, Alkoxy group, nitro group; or a 4-7 membered or unsubstituted carbocyclic or heterocyclic ring formed by _R2 , _R3 and the carbon atom connected to it, and the substituents are selected from halogen atoms, amino groups, alkylamino groups, Dialkylamino, cyano, nitro, hydroxy, alkoxy, haloalkoxy;

_R is selected from hydrogen, halogen atom, amino, alkylamino, dialkylamino, cyano or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, and the substituent is selected from halogen atom, Amino, hydroxyl;

_R is selected from hydrogen, halogen atom, nitro, cyano, hydroxyl, alkoxy, methylenedioxy, haloalkoxy, amino or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, Alkynyl, aryl, heterocyclic aryl, substituents are selected from halogen atoms, amino, hydroxyl;

_R is selected from hydrogen or substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclic aryl, heterocyclic aralkyl, heterocycle, heterocycloalkyl, and the substituent is selected from Halogen atom, amino group, C1-4 alkyl group;

m = 0, 1, 2 or 3;

n=0, 1, 2 or 3;

Q is selected from aryl, heterocyclic aryl or heterocyclic;

Z is selected from aryl, heterocyclic aryl or heterocyclic;

L from

(1) -NR ₇ CO-

(2)-CONR _8-

(3) NR ₉ SO ₂ -

(4)-SO ₂ NR ₁₀ -

(5) -NR ₁₁ COO-

(6)-NR ₁₂ CONR ₁₃ -

(7)-OCONR _14-

Wherein R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, substituents are selected from halogen atoms, amino , hydroxyl.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned compound of general formula (I) and its salt, is characterized in that _R is selected from substituted or unsubstituted heterocyclic aryl, preferably substituted or unsubstituted A substituted six-membered heterocyclic aryl group, more preferably a substituted or unsubstituted pyridine ring, and the substituents are selected from halogen atoms, C1-4 straight chain or branched chain alkyl groups.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is ( _I ) compound and salt thereof, it is characterized in that R and _R Be selected from hydrogen, halogen atom, amino, alkylamino, cyano, Nitro, substituted or unsubstituted alkyl, cycloalkyl, substituents are selected from halogen atoms; preferably hydrogen or halogen atoms, wherein halogen atoms refer to fluorine, chlorine, bromine, iodine atoms.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that _R Selected from substituted or unsubstituted alkyl, cycloalkyl, alkenyl, The alkynyl group is preferably a substituted or unsubstituted alkyl group, more preferably a substituted or unsubstituted alkyl group with 1-4 carbon atoms, and the substituent is selected from halogen atoms and amino groups.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that _R is selected from hydrogen, halogen atom, nitro or substituted or unsubstituted alkyl , cycloalkyl, alkenyl, alkynyl; preferably hydrogen, halogen atom or substituted or unsubstituted alkyl, cycloalkyl, the substituent is selected from halogen atom or hydroxyl.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that _R Selected from heterocyclic aryl, heterocyclic aralkyl, heterocyclic and heterocycloalkane The above groups may be substituted or unsubstituted, preferably substituted or unsubstituted heterocyclic aryl and heterocycloalkyl, and the substituent is preferably C1-4 alkyl.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that m and n are independently selected from 0,1,2,3.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that Q is selected from aryl, heterocyclic aryl or heterocyclic, preferably aryl or heterocyclic aromatic Base; Z is selected from aryl, heterocyclic aryl or heterocyclic, preferably aryl or heterocyclic aryl.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned compound of general formula (I) and its salt, it is characterized in that L is selected from (1)-NR ₇ CO-, (2)-CONR ₈ -, ( 3)-NR ₉ SO ₂ -, (4)-SO ₂ NR ₁₀ -, (5)-NR ₁₁ COO-, preferably (1)-NR ₇ CO- or (2)-CONR ₈ -; R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are selected from alkyl or hydrogen, preferably hydrogen.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is (I) compound and its salt, it is characterized in that can refer to single pairs such as (R), (S) or (RR), (SS) Compounds and salts thereof in enantiomerically or enantiomerically enriched form.

The object of the present invention is further achieved by the following technical scheme, the above-mentioned general formula is the compound of (I) and salt thereof, it is characterized in that described compound can form a salt with the acid (such as equal substance quantity) of certain substance quantity, used The acid is selected from organic acids (such as acetic acid, trichloroacetic acid, propionic acid, butyric acid, aspartic acid, p-toluenesulfonic acid, maleic acid, lactic acid) or inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid ), preferably hydrochloric acid and methanesulfonic acid.

The object of the present invention is further achieved by the following technical schemes, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that described compound can form a salt with the alkali (such as the same amount of substance) of a certain amount of substance, so The formed salts include those formed with alkali metals (such as lithium, sodium, potassium, etc.), alkaline earth metals (such as magnesium, calcium, etc.) or quaternary ammoniums (such as NY ₄ , wherein Y refers to a carbon atom of 1-4 alkyl) .

The object of the present invention is further achieved by the following technical schemes, the above-mentioned general formula is (I) compound and salt thereof, it is characterized in that described compound comprises:

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 3-] benzamide,

4-((4-ethyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 3-] benzamide,

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 3-]-3-fluoro-benzamide,

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 3-]-3-chloro-benzamide,

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 3-]-3-(trifluoromethyl)-benzamide,

6-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-5-[4-(3-pyridyl)-2 -(pyrimidinyl)amino]nicotine,

6-Methyl-N-[4-((4-methylpiperazin-1-yl)methyl-3-(trifluoromethyl)phenyl)-5-[4-(3-pyridyl)- 2-(pyrimidinyl)amino]nicotine,

4-((4-methyl-1-piperazinyl)methyl)-N-[5-methyl-4-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl- 2-]-3-(trifluoromethyl)-benzamide,

5-Methyl-N-[4-((4-methylpiperazin-1-yl)methyl-3-(trifluoromethyl)phenyl)-4-[4-(3-pyridyl)- 2-(pyrimidinyl)amino]pyridineamide,

5-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-4-[4-(3-pyridyl)-2 -(pyrimidinyl)amino]pyridineamide.

Another object of the present invention is further achieved by the following technical solutions. The present invention provides a method for preparing a compound of general formula (I) and a salt thereof, which is characterized in that it comprises the steps:

(A) react the compound of general formula as (II) and the compound of general formula (III) under alkaline condition, obtain the compound of general formula as (IV):

(B) Condensing the compound of the general formula (IV) and the compound of the general formula (V) in the presence of a condensing agent to obtain the compound of the general formula (I).

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Q, L, m, and n are as defined above; L', M' refer to groups that can undergo condensation reactions with each other, such as amino, carboxyl Acid group, acid anhydride group, ester group, acyl halide group, etc., preferably amino, carboxylic acid group or acyl halide group; it can also refer to organic groups that can be converted into amino, carboxylic acid group or acyl halide group by conventional methods, such as nitric acid Group, ester group; R ₁₅ refers to an easily leaving group, selected from halogen atoms (such as fluorine, chlorine, bromine, iodine) or methanesulfonyl, ethylsulfonyl, p-toluenesulfonyl, etc.

Another object of the present invention is further achieved by the following technical solutions. The present invention provides a method for preparing a compound of general formula (I) and a salt thereof, which is characterized in that

(A) When preparing compound (IV), the base used is selected from organic bases (such as n-butyl lithium, sodium methylate, sodium ethylate, potassium tert-butoxide) or inorganic bases (such as sodium, sodium hydroxide, potassium hydroxide , sodium amide, sodium hydrogen), preferably sodium hydrogen.

(B) When preparing compound (I), when the reaction is condensation of carboxylic acid group and amino group, the condensing agent is N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, N, N-diethylcarbodiimide, a mixture of triphenylphosphine and diethyl azodicarboxylate or a mixture of triphenylphosphine and diisopropyl azodicarboxylate, etc., preferably N , N-dicyclohexylcarbodiimide; when the reaction is condensation of acyl halide and amino group, the condensing agent is an inorganic base (such as sodium carbonate, potassium carbonate, calcium carbonate) or an organic base (such as triethylamine, pyridine, 4 - dimethylaminopyridine, tripropylamine, tributylamine), preferably pyridine or triethylamine.

Another object of the present invention is further achieved by the following technical scheme. The present invention provides an application of the compound and its salt alone or in combination with other drugs in the treatment of cell proliferative diseases (such as cancer).

In the present invention, "alkyl" refers to a branched or straight chain saturated aliphatic hydrocarbon group; preferably a branched or straight chain saturated aliphatic alkyl group with 1-10 carbon atoms, such as methyl, ethyl, propane Base, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, etc.; "cycloalkyl" refers to a saturated aliphatic hydrocarbon group containing a single ring, preferably with carbon atoms of 3-10 cycloalkyl groups, such as cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, ethyl-cyclopentyl, cyclohexyl, etc.; In "alkyl" and "C1-C6 heterocyclic aralkyl", "C1-C6" refers to the number of carbon atoms in the alkyl part.

In the present invention, "alkenyl" refers to a branched, linear or cyclic non-aromatic hydrocarbon group with 2-10 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, butyl alkenyl, cyclohexene, etc. In "C2-C6 alkenyl" it means that the alkenyl has 2-6 carbon atoms.

In the present invention, "alkynyl" refers to a branched, linear or cyclic hydrocarbon group with 2-10 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl , 3-methylbutynyl, etc. In "C2-C6 alkynyl", it means that the alkynyl group has 2-6 carbon atoms.

In the present invention, "alkoxy" refers to a cyclic or acyclic alkyl group with 1-10 carbon atoms connected through oxygen.

In the present invention, "aryl" refers to any stable monocyclic or bicyclic ring, wherein each ring has no more than 7 carbon atoms and at least one ring is an aromatic ring, such as phenyl, naphthyl, tetrahydronaphthalene, diphenyl Base etc. If the aryl group is bicyclic and one of the rings is non-aromatic, the reaction is via aromatic ring linkage.

In the present invention, "halogen atom" refers to fluorine, chlorine, bromine and iodine.

In the present invention, "heterocyclic aryl" refers to a stable monocyclic or bicyclic ring, wherein each ring has no more than 7 carbon atoms and at least one ring is an aromatic ring and contains 1-4 heteroatoms, the heteroatoms are selected from O , N, S. According to this definition, "heterocyclic aryl" includes but is not limited to the following types: furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, triazinyl, pyryl Azinyl, pyridazinyl, pyridyl, pyrimidinyl, benzothienyl, benzofuryl, indolyl, benzotriazolyl, quinolinyl, quinoxalinyl, isoquinolyl, tetrahydroquinolyl Linyl, etc. When the heteroaryl group contains N atoms, "heteroaryl" also includes N-oxygen derivatives thereof. If the heterocyclic aryl is bicyclic and one of the rings is non-aromatic or does not contain heteroatoms, the reaction is connected through an aromatic ring or a heteroatom-containing ring.

In the present invention, "heterocyclic ring" refers to a monocyclic ring of 4-8 atoms, a bicyclic ring of 7-12 atoms or a tricyclic ring of 1-16 atoms; the ring may be saturated or unsaturated, and consists of carbon atoms and one Or a plurality of heteroatoms, wherein the heteroatoms are selected from N, O, S, when N and S are heteroatoms, they can be oxidized; when N is a heteroatom, they can be quaternized. The reaction can be linked via any heteroatom or carbon atom as long as a stable structure is obtained. When the heterocyclic ring has substituents, the substituents may be attached to any atom in the ring. It includes benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, carbazolyl, carbolinyl, furyl, imidazolyl, indolinyl, indolinyl, Indolyl, indazolyl, isobenzofuryl, isoindolyl, isoquinolyl, isothiazolyl, nepyridyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridine Base, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiophene Base, triazolyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzene Thienyl, dihydrofuryl, dihydroimidazolyl, dihydroindolyl, dihydroisothiazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydro Pyrrolyl, dihydroquinolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylene Dioxybenzoyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazinyl, dioxythiadiazinyl, dioxythiadiazolidinyl, isodioxthiadiazolidinyl, etc.; "heterocycle" also includes the following Bicyclic compounds, such as imidazo[4,5-b]pyridyl, dihydroimidazo[4,5-b]pyridyl, pyrazolin[4,3-c]pyridinyl, dihydropyrazolin[4,3 -c]pyridyl, tetrahydropyrazolin[4,3-c]pyridyl, pyrrole[1,2-a]pyrazinyl, dihydropyrrole[1,2-a]pyrazinyl, tetrahydropyrrole [1,2-a]pyrazinyl, cinnolinyl, purinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl, imidazo[1,2-a]pyrimidinyl, 2,3-di Hydrogen imidazo[2,1-b][1,3]thiazolyl, benzazepinyl, dihydrobenzazepinyl, benzodiazepine, dihydrobenzodiazepinyl, tetrahydrobenzodi Azapine, etc.; "heterocycle" also includes the following tricyclic compounds, such as phenothiazinyl, carbazolyl, β-carbazolyl, phenazinyl, etc.

The above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic aryl and heterocyclic groups can also be substituted, and its substituents include but are not limited to the following categories: hydroxyl, alkyl, haloalkyl, halogen, Cyano, nitro, carbonyl, ester, amino, alkoxy, alkylamino, dialkylamino, etc.

The compounds obtained in the present invention and salts thereof can be administered orally, dermally or parenterally (eg by injection, inhalation, spray, sublingually, rectally or vaginally). "Administration by injection" includes intravenous injection, joint injection, intramuscular injection, subcutaneous injection, parenteral injection and infusion. Dermal administration includes topical or cross-administration. Oral administration is prepared according to methods well known to those skilled in the art, and one or more auxiliary agents, such as diluents, sweeteners, flavoring agents, coloring agents and preservatives, may also be included in such preparations.

In tablets, the active ingredient is admixed with nontoxic, pharmaceutically acceptable excipients. These excipients include: inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate), granulating or disintegrating agents (such as corn starch, alginic acid) and binders (such as magnesium stearate , stearic acid, talc). The tablet can be uncoated, or can be coated with a known method to delay the decomposition and absorption in the gastrointestinal tract so as to prolong the drug effect time, for example, glyceryl stearate or glyceryl distearate can be used. These compounds can also be prepared in solid state, immediate release form.

In hard capsules, the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or clay; in soft capsules, the active ingredient is mixed with water or an oil vehicle such as peanut oil, paraffin or olive oil.

In aqueous suspensions, the active ingredient is admixed with pharmaceutically acceptable excipients. These excipients are suspending agents (such as sodium hydroxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, acacia), dispersing agents or wetting agents. Agents [including naturally occurring phospholipids (such as lecithin) or condensates of alkylene oxides and fatty acids (such as polyoxyethylene stearate) or condensates of alkylene oxides and long-chain fatty alcohols (such as heptadecene cetyl alcohol) or ethylene oxide with partial esters derived from fatty acids and hexitols (e.g. polyoxyethylene sorbitan monooleate) or ethylene oxide with partial esters derived from fatty acids and hexose anhydrides substances (such as polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate); one or more colorants; one or more fragrances and a or more sweeteners (such as sucrose or saccharin).

Dispersible powders and granules suitable for preparation of an aqueous suspension are prepared by mixing water, the active ingredient and a dispersing or wetting agent, suspending agent and one or more preservatives. Other excipients such as sweeteners, coloring agents, and flavoring agents may also be added thereto.

The compounds of general formula (I) and their salts obtained in the present invention can also be prepared into non-aqueous liquid preparations. Oily suspensions suspend the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil) or mineral oil (such as liquid paraffin); oily suspensions may contain a thickening agent (such as beeswax, hard paraffin, or cetyl alcohol) ; Sweeteners and flavoring agents can also be added to increase the mouthfeel of the preparation; in order to increase the stability of the preparation, antioxidants (such as ascorbic acid) can be added.

The compounds of the general formula (I) and their salts obtained in the present invention can also be prepared into oil-water emulsions. The oily phase is selected from vegetable oils (such as olive oil, peanut oil) or mineral oils (such as liquid paraffin) or mixtures of the above. The emulsifier is selected from natural gums (such as tragacanth, gum arabic) or natural phospholipids (such as soybeans, lecithin) or partial esters derived from fatty acids and hexose anhydrides (such as sorbitol monooleate) or the above-mentioned esters and Ethylene oxygen condensation products (such as polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening and flavoring agents.

The sweetening agent in the syrup and cemet is selected from glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents.

The compounds of the general formula (I) and their salts obtained in the present invention can also be prepared as suppositories for rectal or vaginal administration. This suppository is prepared by mixing the active ingredient with a suitable nontoxic excipient selected to be solid at ordinary temperatures but to release the drug by melting in the rectum or vagina, such as cocoa butter and polyethylene glycol.

The compounds of the general formula (I) and their salts obtained in the present invention can also be administered to the dermis by methods well known to those skilled in the art. For example, in a volatile solvent, the obtained solution or suspension of compound (I), a penetration enhancer and additives well-known to those skilled in the art are mixed, and after aseptic treatment, the resulting mixture is prepared according to well-known procedures and certain procedures. Doses are prepared into desired formulations; alternatively, solutions or suspensions of Compound (I) can be prepared into lotions or ointments after treatment with emulsifiers or water.

The solvents used in the transdermal delivery system are well known to those skilled in the art, including lower alcohols (such as ethanol or isopropanol), lower ketones (such as acetone), lower carboxylates (such as ethyl acetate), polar ethers ( Such as tetrahydrofuran), lower hydrocarbons (such as n-hexane, cyclohexane or benzene) or halogenated hydrocarbons (such as dichloromethane, chloroform, trichlorotrifluoroethane); the solvent used also includes selected from lower alcohols, One or more mixed solvents of lower ketones, lower carboxylates, polar ethers, lower hydrocarbons, and halogenated lower hydrocarbons.

Penetration enhancers used in transdermal delivery systems are well known to those skilled in the art, including monohydric or polyhydric alcohols (such as ethanol, propylene glycol or benzyl alcohol), saturated or unsaturated C8-C18 fatty alcohols (such as lauryl alcohol or cetyl alcohol), saturated or unsaturated C8-C18 fatty acids (such as stearic acid), saturated or unsaturated esters with no more than 24 carbon atoms (such as acetic acid, caproic acid, lauric acid, myristic acid, stearic acid or Esters of palmitic acid and methanol, ethanol, propanol, butanol, isobutanol, tert-butanol or monoglycerol) or diesters of saturated or unsaturated dicarboxylic acids (such as diisoadipate Propyl esters, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate; penetration enhancers also include phospholipid derivatives (such as lecithin or cephalin), terpenes, ammonia, ketones , urea and its derivatives and ethers (such as isosorbide dimethyl ether, diethylene glycol monoethyl ether); suitable penetration enhancers also include monohydric or polyhydric alcohols, saturated or unsaturated C8-C18 fatty alcohols , saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated esters with no more than 24 carbon atoms, diesters of saturated or unsaturated dicarboxylic acids, phospholipid derivatives, terpenes, ammonia, ketones, urea and A mixture of one or more substances in its derivatives, ethers.

Adhesives for transdermal delivery systems are well known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block copolymers, styrene-butadiene copolymers, natural or synthetic rubbers, fibers Polyvinyl, polyethylene derivatives and silicates can also be used as backbone constituents. In addition, additives such as tackifying resins or oils may also be added to increase the viscosity of the backbone.

The compound of general formula (I) and salt thereof obtained in the present invention, its oral administration daily dosage is preferably 0.01-200mg/kg; Its injection administration daily dosage (such as intravenous injection, intramuscular injection, subcutaneous injection, parenteral injection or transfusion ) is preferably 0.01-200mg/kg; its daily dosage for rectal or vaginal administration is preferably 0.01-200mg/kg; its daily dosage for local administration is preferably 0.1-200mg, and it is administered 1-4 times a day; its anti-dermal administration concentration is preferably 0.01 -200 mg/kg; the daily dosage for inhalation administration is preferably 0.01-10 mg/kg, wherein "mg" represents the weight unit of the active ingredient in the pharmaceutical composition, and "kg" represents the weight unit of the human body.

Of course, as is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's gender, patient’s diet, time of administration, administration method, excretion rate, drug combination, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compound (I) or pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

In another aspect, the present invention provides a use of the compound and its salt alone or in combination with other drugs in the treatment of cell proliferation diseases (such as cancer). Antitumor agents that can be used in combination with the compounds provided by the present invention and their salts include polynucleotides, polypeptides, biomimetic drugs, alkaloids, alkylating agents, antitumor antibiotics, antimetabolites, hormones, platinum compounds , monoclonal antibodies combined with antineoplastic drugs, toxins and or radioactive nuclei, biological response modifiers (such as interferon), immunotherapeutic agents, hematopoietic growth factors, gene therapy agents, antisense therapeutic agents, nucleosides, antitumor agents Vaccines etc. Preferred antineoplastic agents have inducing or stimulating apoptosis (apoptosis) agents, and inducing apoptosis (apoptosis) agents include but are not limited to the following categories: radiation, kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, angiogenesis factors Receptor kinase inhibitors, derived platelet growth factor receptor kinase inhibitors and Bcr-abl kinase inhibitors such as STI-157, Gleevec), also preferably antisense molecules, antibodies (such as Hercepin and Rituxan), antiestrogens (such as raloxifene and tamoxifen), antiandrogens (such as flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids), COX-2 inhibitors (such as Celecoxib, meloxicam, NS-398, non-steroidal anti-inflammatory drugs, and cancer chemotherapy drugs ( Such as irinotecan), CPT-11, fludarabine, dacarbazine, dexabethasone, mitoxantrone, Mylotarg, VP-16, cisplatin, 5-FU, Doxrubicin, TAXOTERE, cell marker molecules, ceramide, cytokine, staurosprine, etc.

The present invention relates to the preparation method of the compound of general formula (I) and salt thereof, and its preparation method specifically comprises:

Stage A: This stage includes the reaction of compound (II) and compound (III) to prepare compound (IV). This reaction is carried out in an alkaline environment, and the base used is selected from organic bases (such as pyridine, triethylamine, hexahydropyridine, N-methylpiperazine, 4-dimethylaminopyridine, etc.) or inorganic bases (such as sodium carbonate , potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methylate, sodium ethylate, sodium amide, sodium hydrogen, n-butyllithium, etc.), the amount of alkali used is controlled at 1-10 times of the compound (II) substance quality, preferably 1 -3 times; the reaction temperature is from -80°C to 100°C, preferably 0°C to 60°C; the time used for this reaction depends on the type of compound (II) and (III), the solvent used and the temperature of the reaction, etc., generally controlled at 1min-72hrs, preferably 15min-24hrs.

Stage B: This stage includes the condensation reaction of compound (IV) and compound (V) to prepare compound (I). When the condensation reaction is carried out between acid and amino group, the condensing agent used is selected from N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, N,N-diethylcarbodiimide A mixture of diimine, triphenylphosphine and diethyl azodicarboxylate, or a mixture of triphenylphosphine and diisopropyl azodicarboxylate, etc., preferably N,N-dicyclohexylcarbondi Imine; the solvent used is selected from toluene, benzene, dichloromethane, chloroform, tetrafuran or a mixture of the above solvents, etc., preferably dichloromethane; the reaction temperature is controlled at -80°C to 100°C, preferably 0°C to 60°C The time used for the reaction depends on the compound (IV) and (V) type, the solvent used and the temperature of the reaction, etc., generally controlled at 1min-72hrs, preferably 15min-24hrs. When the condensation reaction is carried out between acid halides and amino groups, the condensing agent used is selected from organic bases (such as pyridine, triethylamine, hexahydropyridine, N-methylpiperazine, 4-dimethylaminopyridine, etc.) or inorganic bases (such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methylate, sodium ethylate, sodium amide, sodium hydrogen, n-butyllithium, etc.), the amount of alkali used is controlled at 1-10% of the compound (IV) substance quality times, preferably 1-3 times; the reaction temperature is from -80°C to 100°C, preferably 0°C to 60°C; the time used for this reaction depends on the type of compounds (II) and (III), the solvent used and the temperature of the reaction, etc. , generally controlled at 1min-72hrs, preferably 15min-24hrs.

Detailed description of the drawings

Figure 1: The relationship between the drug concentration of aminopyrimidines and the inhibition rate of promyelocytic leukemia HL-60 cells.

Figure 2: The relationship between the drug concentration of aminopyrimidine compounds and the inhibition rate of human myeloid leukemia K562 cell proliferation.

Fig. 3: The inhibitory effect of aminopyrimidine compounds on the proliferation of human myeloid leukemia K562 and promyelocytic leukemia HL-60 cells.

Fig. 3-a: Control map of human myeloid leukemia K562 cells.

Fig. 3-b: Control map of promyelocytic leukemia HL-60 cells.

Figure 3-c: HH-GV-E (0.3uM) inhibits the proliferation of human myeloid leukemia K562 cells.

Figure 3-d: HH-GV-E (10uM) inhibits the proliferation of promyelocytic leukemia HL-60 cells.

Figure 3-e: HH-GV-F (0.03uM) inhibits the proliferation of human myeloid leukemia K562 cells.

Figure 3-f: HH-GV-F (10uM) inhibits the proliferation of promyelocytic leukemia HL-60 cells.

Fig. 3-g: The compound Imatinib (0.3 uM) inhibits the proliferation of human myeloid leukemia K562 cells.

Fig. 3-h: The compound Imatinib (10 uM) inhibits the proliferation of promyelocytic leukemia HL-60 cells.

Figure 4: Effects of HH-GV-E, HH-GV-F, and Gleevec on transplanted tumors of human myeloid leukemia K562 nude mice

Figure 5: Effects of HH-GV-E, HH-GV-F, and Gleevec on the body weight of tumor-bearing nude mice.

Figure 6: Tumor photos of the curative effect of HH-GV-E, HH-GV-F, and Gleevec on transplanted tumors of human myeloid leukemia K562 nude mice.

Figure 7. The curative effect of HH-GV-678 and Gleevec on human myeloid leukemia K562 nude mice transplanted tumor

Figure 8. Effects of HH-GV-678 and Gleevec on body weight of tumor-bearing nude mice

Detailed ways

In order to illustrate the present invention in more detail, the following preparation examples are given. However, the scope of the present invention is not limited thereto.

Example 1

Preparation of N-(5-nitro-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine

Put 2-methylsulfonyl-4-(3-pyridyl)pyrimidine (3.0 g), 2-methyl-3-amino-5-nitropyridine (5.0 g) and DMF (50 ml) into the reaction flask , cooled to 0-5°C, added sodium hydrogen (60%, 2.3 g), and naturally rose to room temperature for 6 hours. Add 50 ml of chloroform and 50 ml of water to the reaction solution, separate the layers, back-extract the aqueous layer with chloroform (2×100 ml), combine the organic layers, dry, filter, concentrate to dryness, and purify by column chromatography to obtain N-(5-nitrate Base-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine: 5.2 g.

Example 2

Preparation of N-(5-amino-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine

Method A : N-(5-nitro-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine (3.0 grams), active nickel (0.3 grams) and methanol ( 100 milliliters) into the reaction flask, hydrogenation at normal pressure until there is no raw material. Filter and concentrate to dryness to obtain N-(5-amino-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine: 2.8 g.

Method B : N-(5-nitro-2-picoline-3-)-4-(3-pyridyl)-2-pyrimidinamine (18 grams), ethanol (180 milliliters), hydrazine hydrate ( 9 milliliters) and active nickel (0.5 grams) into the reaction flask, reflux reaction for 3 hours, filtered, the filtrate was concentrated under reduced pressure to precipitate a solid, left overnight at 0°C, filtered, and dried to obtain N-(5-amino-2-formazan Pyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine: 15 g.

Method C : put N-(5-nitro-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine (18 grams) and tetrahydrofuran (200 milliliters) into the reaction flask , cooled to 0-5°C, added lithium aluminum hydride (about 2.2 grams in total) in batches, kept the temperature for 2 hours, added 1N hydrochloric acid to the reaction solution to adjust the pH to 5-6, and dichloromethane (2×100 ml ) extraction, combined organic layers, dried, filtered, and concentrated to dryness to give N-(5-amino-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine: 12 grams.

Example 3

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-benzamide

Method D : 4-(4-methylpiperazinemethyl)benzoic acid (3.2 grams) and thionyl chloride (100 milliliters) were dropped into a reaction flask, heated to reflux for 4 hours, concentrated to dryness under reduced pressure, The obtained solid is directly used for feeding in the next step.

N-(5-amino-2-methylpyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine (3.0 g) was dissolved in pyridine (80 ml), and the solution was dissolved The solution was added dropwise to the above acid chloride and stirred overnight at room temperature. Concentrate to dryness under reduced pressure, add 100 ml each of water and chloroform to the reaction solution, extract, dry, filter, concentrate to dryness, and purify by column chromatography to obtain 4-((4-methyl-1-piperazinyl)methyl)- N-[6-Methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide: 4.2 g.

Method E : 4-(4-methylpiperazinemethyl)benzoic acid (3.2 g), N,N-dicyclohexylcarbodiimide (3.0 g), N-(5-amino-2-methyl Pyridyl-3-)-4-(3-pyridyl)-2-pyrimidinamine (3.0 g) and dichloromethane (100 ml) were put into a reaction flask, and stirred at room temperature overnight. Filtered, the filtrate was washed with water (2×100 ml), dried, filtered, concentrated and purified by column chromatography to obtain 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl- 5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide: 4.0 g.

Example 4

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-benzamide methanesulfonate

Method F : 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino ]pyridyl-3-]-benzamide (2.0 grams), methanesulfonic acid (0.40 grams) and purified water (100 milliliters) are dropped in the reaction flask, filter after dissolving, and the filtrate is lyophilized to obtain 4-((4 -Methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzene Formamide mesylate: 2.2 g.

Method G : 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino ]pyridyl-3-]-benzamide (2.0 g), methanesulfonic acid (0.40 g) and methanol (100 ml) were put into a reaction flask, dissolved and concentrated under reduced pressure to about 20 ml, and crystallized by adding acetone , filtered and dried to give 4-((4-methyl-1-piperazinyl)methyl)-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl] Amino]-pyridyl]-benzamide mesylate: 2.0 g.

Example 5

4-((4-ethyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino] Preparation of pyridyl-3-]-benzamide

It can be prepared in the same way as D and E in Example 3, except that 4-(4-ethylpiperazine methyl) benzoic acid (3.3 grams) is used instead of 4-(4-methylpiperazine methyl) base) benzoic acid (3.2 g).

Example 6

4-((4-Ethyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-benzamide methanesulfonate

It can be prepared in the same way as F and G in Example 4, except that 4-((4-ethyl-1-piperazinyl)methyl)-N-[6-methyl-5- [[4-(3-Pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide (2.10 g) in place of 4-((4-methyl-1-piperazinyl)methyl )-N-[6-Methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide (2.0 g).

Example 7

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino] Preparation of pyridyl-3-]-3-fluorobenzamide

It can be prepared in the same way as D and E in Example 3, except that 4-(4-methylpiperazinemethyl)-3-fluoro-benzoic acid (3.3 grams) is used instead of 4-(4- Methylpiperazinemethyl)benzoic acid (3.2 g).

Example 8

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-3-fluorobenzamide methanesulfonate

It can be prepared in the same way as F and G in Example 4, except that 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5- [[4-(3-Pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-3-fluoro-benzamide (2.10 g) in place of 4-((4-methyl-1-piperazine yl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide (2.0 g).

Example 9

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino] Preparation of pyridyl-3-]-3-chloro-benzamide

It can be prepared in the same way as D and E in Example 3, except that 4-(4-methylpiperazinemethyl)-3-chloro-benzoic acid (3.4 grams) is used instead of 4-(4- Methylpiperazinemethyl)benzoic acid (3.2 g).

Example 10

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-3-chloro-benzamide methanesulfonate

It can be prepared in the same way as F and G in Example 4, except that 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5- [[4-(3-Pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-3-chloro-benzamide (2.20 g) instead of 4-((4-methyl-1-piperazine yl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide (2.0 g).

Example 11

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino] Preparation of pyridyl-3-]-3-(trifluoromethyl)benzamide

It can be prepared in the same way as D and E in Example 3, except that 4-(4-methylpiperazinemethyl)-3-(trifluoromethyl)benzoic acid (3.6 grams) is used instead of 4 -(4-Methylpiperazinemethyl)benzoic acid (3.2 g).

Example 12

4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amine Preparation of base]pyridyl-3-]-3-(trifluoromethyl)benzamide methanesulfonate

It can be prepared in the same way as F and G in Example 4, except that 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5- [[4-(3-Pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-3-(trifluoromethyl)benzamide (2.35 g) instead of 4-((4-methyl- 1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-benzamide (2.0 gram).

Example 13

6-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-5-[4-(3- Preparation of pyridyl)-2-(pyrimidinyl)amino]nicotine

Method I : 6-methyl-5-[4-(3-pyridyl)-2-pyrimidinylamino]nicotinic acid (30.7 grams, 0.1mol), 3-(4-methyl-1H-imidazole-1 -yl)-5-(trifluoromethyl)aniline (24.1 grams, 0.1mol), triethylamine (83ml) and DMF (800ml) were put into the reaction flask, cooled to 10°C, and 50% propyl The mixed solution of phosphoric anhydride/DMF (87.5ml) was reacted at room temperature for 24 hours after dropping. Add saturated ammonium chloride solution to the reaction solution, extract three times with ethyl acetate, dry, filter, concentrate to dryness, and obtain the title compound by column chromatography.

Method II : put 6-methyl-5-[4-(3-pyridyl)-2-pyrimidinylamino]nicotinic acid (30.7 grams) and thionyl chloride (500ml) into a reaction flask, and heat to reflux Reacted for 4 hours, concentrated to dryness under reduced pressure, and the obtained solid was directly used for feeding in the next step.

Dissolve 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (24.1 g) in pyridine (200 ml), and add the solution dropwise to the above acid chloride, stirred overnight at room temperature. Concentrate to dryness under reduced pressure, add 500 ml each of water and chloroform to the reaction solution, extract, dry, filter, concentrate to dryness, and purify by column chromatography to obtain the title compound.

Preparation of intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

3-fluoro-5-(trifluoromethyl)-benzenecyanide (17 g, 89 mmol), 4-methylimidazole (22.2 g, 270 mmol) and N,N-dimethylacetamide (80 ml) were put In the reaction flask, react at 145°C for 19 hours. Concentrate under reduced pressure to remove the solvent, add ethyl acetate (200 mL), wash with brine (2×200 mL) successively, and dry. After filtering, concentrating to dryness and recrystallizing with diethyl ether-petroleum ether, the intermediate was obtained: 3-(4-methyl-1H-imidazole-1-)-5-(trifluoromethyl)-benzocyanide.

Put the above intermediate (16.7 g, 66 mmol), dioxane (300 ml) and 1M sodium hydroxide aqueous solution (275 ml) into the reaction flask, and react at 95°C for 18 hours. Concentrate to remove the solvent, adjust the pH to neutral with 1M hydrochloric acid, extract with n-butanol (2×250 ml), dry, and concentrate to dryness to obtain an intermediate: 3-(4-methyl-1H-imidazole-1-)-5 -(trifluoromethyl)-benzoic acid.

Put the intermediate (6.8 g, 25 mmol) and tert-butanol (200 ml) into the reaction flask, add triethylamine (5.23 ml, 37.5 mmol), then add diphenylphosphoric acid azide (DPPA) (7.6 g, 27.5 mmol), reacted at 80°C for 16 hours. Concentrate under reduced pressure to remove the solvent, add water (100 mL), and extract with ethyl acetate (2×100 mL). The organic layer was washed with brine and dried. Concentrated by filtration, purified by column chromatography, and recrystallized from ether-petroleum ether to obtain an intermediate: 3-(4-methyl-1H-imidazole-1-)-5-(trifluoromethyl)-N-(tert-butoxy Carbonyl) aniline.

Put the intermediate (5 mmol) and hydrochloric acid/isopropanol (30 ml, 4M) into the reaction bottle, and react at 60° C. for 5 hours. Concentrate under reduced pressure to remove the solvent, add saturated sodium bicarbonate solution (80 mL), extract with ethyl acetate (3×80 mL), wash with brine, and dry. Filter, concentrate to dryness and recrystallize with diethyl ether-petroleum ether to obtain the intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline.

Example 14

6-Methyl-N-[4-((4-methylpiperazin-1-yl)methyl-3-(trifluoromethyl)phenyl)-5-[4- Preparation of (3-pyridyl)-2-(pyrimidinyl)amino]nicotine

The preparation method refers to methods I and II in Example 13, the difference is that 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (20.7 g, 0.1 mol) Change to 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline (25.9 g, 0.1 mol).

Preparation of intermediate 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline

The raw material 2-bromo-4-nitrotoluene (23.2mmol) was dissolved in NMP (200ml), and sodium trifluoroacetate (8.5g, 62.5mmol) and ketone iodide (8.75g, 46mmol) were added, at 160 °C for 4 hours. After cooling, water (300 mL) was added, filtered, the filter cake was washed well with ether (3×250 mL), and the layers were separated. The organic layer was washed with water and brine in turn, and dried. Filtration, concentration and purification by column chromatography gave 2-(trifluoromethyl)-4-nitrotoluene: 3.12 g.

Put the intermediate (0.5 g, 2.44 mmol) and acetic acid (1.9 ml) into the reaction flask, add NBS (0.651 g, 3.66 mmol) and benzoyl peroxide (6 mg, 0.024 mmol), and react overnight at reflux . Cool and concentrate under reduced pressure to remove the solvent. Ethyl acetate and saturated sodium bicarbonate solution were added, and the layers were separated. The organic layer was dried. Filter and concentrate to dryness to obtain an intermediate: 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene.

Put the intermediate (400 grams) and dichloromethane (2800 milliliters) into the reaction flask, add triethylamine (197 milliliters) and N-methylpiperazine (157 milliliters, 1.41mol), and stir the reaction at room temperature 2 Hour. Saturated sodium bicarbonate solution was added, the layers were separated, the organic layer was dried, filtered and concentrated by column chromatography to obtain an intermediate: 1-[4-nitro-2-(trifluoromethyl)benzyl]-4-methylpiperazine.

Put the intermediate (3.0 g) of the previous step, active nickel (0.3 g) and methanol (100 ml) into the reaction flask, and hydrogenate under normal pressure until no raw materials are left. Filtration, concentration to dryness, and column chromatography gave 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline.

Example 15

4-((4-methyl-1-piperazinyl)methyl)-N-[5-methyl-4-[[4-(3-pyridyl)-2-pyrimidine Base]amino]pyridyl-2-]-3-(trifluoromethyl)-benzamide

Compound N-(4-amino-5-methylpyridine-2-)-4-[(4-methylpiperazinyl-1-)methyl]-3-(trifluoromethyl)benzamide ( 7.1 g), 2-(methylsulfonyl)-4-(3-pyridyl)pyrimidine (5.0 g) and DMF (50ml) were put into the reaction flask, cooled to about 0°C, and added 60% sodium hydrogen ( 1.5 g), after the addition, the reaction was incubated for 2 hours, and then naturally rose to room temperature for 1 hour. Add 100 ml of chloroform/methanol = 30:1 mixture, adjust pH to 7 with 10% citric acid, extract, extract the aqueous layer back, combine the organic layers, wash with brine, and dry. After filtration, concentration and purification by column chromatography, the title compound was obtained.

1. N-(4-amino-5-methylpyridine-2-)-4-[(4-methylpiperazinyl-1-)methyl]-3-( trifluoromethyl )benzamide preparation

To a solution of 2-chloro-5-picoline (10 g) in acetic anhydride (50 ml), 30% hydrogen peroxide (50 ml) was added in portions, reacted at room temperature for 24 hours, and then reacted at 60° C. for 30 hours. Concentrate under reduced pressure to remove excess acetic acid, add concentrated sulfuric acid (30ml) to the residue, add this solution to a mixture of nitric acid (50ml) and concentrated sulfuric acid (30ml), and react at 100°C for half an hour. The reaction solution was poured into ice water, the pH was adjusted to alkaline with solid ammonium carbonate and ammonia water, and the intermediate was obtained by filtration: 2-chloro-4-nitro-5-methyl-pyridine.

The above intermediate (1.0 g) and 10% ammonia/ethanol solution (20 ml) were put into a reaction flask, and heated to reflux in an autoclave for 4 hours. Cool, concentrate under reduced pressure to remove ethanol, add water, and filter. The solid was recrystallized from water to obtain an intermediate: 2-amino-4-nitro-5-methyl-pyridine.

The intermediate of the previous step (13.4 g, 71 mmol) and chloroform (150 ml) were put into the reaction flask and cooled to 0-5°C. Phosphorus trichloride (19ml) was added to the solution, heated to 70-80°C for 1 hour. Cool, add water, adjust pH to alkaline with sodium hydroxide solution, extract with chloroform, combine organic layers, wash with brine, and dry. Filter, concentrate to dryness and crystallize with petroleum ether to obtain an intermediate: 2-amino-4-nitro-5-picoline.

4-[(4-methylpiperazinyl-1-)methyl]-3-(trifluoromethyl)benzoic acid (3 grams, 10mmol) and thionyl chloride (50ml) were dropped into the reaction flask, Heat to reflux for 5 hours. Concentrate under reduced pressure to remove the solvent, and use dry toluene to remove residual thionyl chloride twice.

Pyridine (50 ml) was added to the obtained acid chloride compound, 2-amino-4-nitro-5-picoline (1.53 g, 10 mmol) was added with stirring, and the reaction was stirred at room temperature overnight. Concentrate under reduced pressure to remove the solvent, add water to the residue, adjust the pH to 8 with saturated sodium bicarbonate, extract with chloroform, combine the organic layers, and dry. Filtration, concentration to dryness, column chromatography to obtain an intermediate: N-(4-nitro-5-methylpyridine-2-)-4-[(4-methylpiperazinyl-1-)methyl]-3 -(trifluoromethyl)benzamide.

Put the above intermediate (5.0 g, 10 mmol), hydrazine hydrate (5.4 ml), methanol (180 ml) and a small amount of Raney nickel into the reaction flask, and heat to reflux for 4 hours. Filtration, the filtrate was concentrated under reduced pressure, dried with toluene, treated with dichloromethane, filtered, and dried to give N-(4-amino-5-methylpyridine-2-)-4-[(4-methylpiperazinyl -1-)methyl]-3-(trifluoromethyl)benzamide.

Example 16

5-Methyl-N-[4-((4-methylpiperazin-1-yl)methyl-3-(trifluoromethyl)phenyl)-4-[4-(3-pyridine base)-2-(pyrimidinyl)amino]pyridineamide

The preparation method refers to methods I and II in Example 13, the difference is that 6-methyl-5-[4-(3-pyridyl)-2-pyrimidinylamino]nicotinic acid (30.7 g, 0.1 mol) is changed to 5-methyl-4-[4-(3-pyridyl)-2-pyrimidinylamino] Picolinic acid (30.7 grams, 0.1mol); 3-(4-methyl-1H-imidazol-1-yl )-5-(trifluoromethyl)aniline (24.1 grams, 0.1mol) was changed to 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline (25.9 grams, 0.1mol ).

Example 17

5-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-4-[4-(3-pyridyl) - Preparation of 2-(pyrimidinyl)amino]pyridineamide

The preparation method refers to methods I and II in Example 13, the difference is that 6-methyl-5-[4-(3-pyridyl)-2-pyrimidinylamino]nicotinic acid (30.7 g, 0.1 mol) is changed to 5-Methyl-4-[4-(3-pyridyl)-2-pyrimidinylamino]picolinic acid (30.7 g, 0.1 mol).

Example 18

Compound F 400g

Starch 100g

Sucrose 20g

Microcrystalline Cellulose 10g

0.5% CMC solution Appropriate amount

Magnesium Stearate 5g

                                     

Conventional wet granulation, tabletting, packaging.

Experimental example one

Anti-tumor activity of HH-GV-E, HH-GV-F and Gleevec in vitro

Note: HH-GV-E refers to 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2 -pyrimidinyl]amino]pyridyl-3-]-3-chloro-benzamide methanesulfonate;

HH-GV-F refers to 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl ]amino]pyridyl-3-]-3-(trifluoromethyl)-benzamide methanesulfonate.

1. Cell line:

HL-60: Human acute promyelocytic leukemia cells, negative for Bcr-Abl tyrosine kinase expression.

K562: human chronic myelogenous leukemia cells expressing ^P210 Bcr-Abl tyrosine kinase

2. Test reagents, drugs and instruments:

RPMI-1640, DMEM was purchased from Gibico BRL; fetal bovine serum was purchased from Hyclone; microplate reader: POLAR star model, product of BMG, Germany; MTT was purchased from Sigma.

3. Test method:

The main steps of the MTT method:

●The cells are cultured with 10% fetal bovine serum, so that the cells are always in the logarithmic growth phase.

●The test cells were seeded in 96-well culture plates, and the initial seeding density was 4×10 ⁴ /ml according to different cells. 37°C, 5% CO ₂ incubator pre-cultivation for 24 hours and dosing, 6-8 drug concentration, continuous action for 48 hours.

●After the drug effect is over, take pictures with a phase-contrast microscope. Then, MTT working solution was added to each well. After 4 hours, DMSO was dissolved, and the OD value of each well was measured with a Plarstar microplate reader.

Test control:

Add 20 μl of culture solution to the blank control well, and choose imatinib as the positive control drug.

Density setting:

Set 5-8 concentrations, and set three replicate wells for each concentration. The range is mainly 0.001-10μM.

4. Efficacy evaluation:

Calculation of cell growth inhibition rate:

5. Test results

Imatinib exerts its effect of inhibiting cell proliferation by inhibiting the activity of Abl tyrosine kinase. In more than 95% of chronic myelogenous leukemia patients, due to chromosomal translocation, Bcr-Abl fusion protein is produced, resulting in high expression of Abl tyrosine kinase activity. Human chronic myelogenous leukemia K562 cells express Bcr-Abl protein, therefore, they are a common cell model for studying drugs targeting Bcr-Abl. This experiment found that the compounds obtained in the present invention have different degrees of inhibitory effect on the proliferation of K562, the effect of compound F is about 40 times stronger than that of imatinib; the effect of compound E is 4 times stronger than that of imatinib. Human promyelocytic leukemia HL-60 does not express Bcr-Abl, therefore, it serves as a model control in this experiment. As a result, it was found that the compounds of the present invention had no significant effect on the proliferation of HL-60 cells even at high concentrations (10 μM), indicating that this type of compounds had good selectivity to the target. Wherein, the selectivity of the contrast drug imatinib About more than 30 times; Compound F is about 1250 times; Compound E is about 125 times. Therefore, compound E and compound F obtained in the present invention show a strong inhibitory effect on the proliferation of targeted leukemia cells, and their effects are better than or equivalent to the control drug Imatinib. (See Table 1, Figure 1, Figure 2, Figure 3 for specific results)

Table 1 The inhibitory effect of aminopyrimidine compounds on the proliferation of leukemia cells cultured in vitro

6 Conclusion

HH-GV-F, HH-GV-E showed a strong inhibitory effect on the proliferation of targeted leukemia cells, and their effects were better than the control drug Imatinib.

Experimental example two

Efficacy of HH-GV-E, HH-GV-F, and Gleevec on Xenograft Tumor of Human Myeloid Leukemia K562 in Nude Mice

Note: HH-GV-E refers to 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2 -pyrimidinyl]amino]pyridyl-3-]-3-chloro-benzamide methanesulfonate;

HH-GV-F refers to 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidinyl ]amino]pyridyl-3-]-3-(trifluoromethyl)-benzamide methanesulfonate.

1. Experimental animals:

BALB/cA-nude nude mice were purchased from Shanghai Slack Experimental Animal Co., Ltd.; 18-21g, ♀, certificate number: SCXK (Shanghai) 2004-0005; they were raised in an SPF environment with constant temperature and humidity.

2. Experimental steps:

After the animals were acclimatized for 1 week, human leukemia K562 cells were inoculated subcutaneously. After the tumors grew to 100-300 mm3, the animals were randomly divided into groups (d0). Orally administered to nude mice. HH-GV-E, Gleevec, the dosages are 75mg/kg, 150mg/kg; HH-GV-F is 37.5mg/kg, 75mg/kg. Dosing once a day for 21 days. The tumor volume was measured 2-3 times a week, the mice were weighed, and the data were recorded. The formula for calculating tumor volume (V) is: V=1/2×a×b2 where a and b represent length and width, respectively.

3. Results:

Mice were administered intragastrically, once a day, for 21 consecutive days.

On the 18th day of the experiment, 1/8 of the mice in the control group died, and 2/8 of the mice died by the end of the experiment. According to the tumor growth and the state of the mice, the death should be caused by tumor growth.

Gleevec had no significant effect on K562 tumor growth according to the current administration regimen; 1/6 mice in the 150mg/kg group died on the 18th day after administration, which should be attributed to tumor-related death.

Administration of HH-GV-E 150mg/kg has obvious inhibitory effect on K562 tumor growth.

On the 9th day after administration of HH-GV-F 75mg/kg, 1/6 mice showed tumor regression; on the 12th day, 4/6 mice showed tumor regression; on the 15th day, 5/6 mice appeared The tumor regressed. However, at the end of the experiment (ie, on the 21st day after administration), the tumor recurred in 1 mouse, therefore, a total of 4/6 mice had tumor regression at the end of the experiment. Administration of 37.5 mg/kg significantly inhibited the growth of K562 tumor, but did not cause tumor regression in mice. The curative effect of HH-GV-F showed obvious dose dependence. Due to tumor regression, the state of the mice in the HH-GV-F administration group was significantly better than that in the control group, Gleevec, and HH-GV-E groups, showing that HH-GV-F has a very good therapeutic effect on chronic myelogenous leukemia. (see Table 2, Figure 4, Figure 5 and Figure 6 for specific results)

Table 2. The curative effect of oral administration of HH-GV-E, HH-GV-F, and Gleevec on human myeloid leukemia K562 nude mice transplanted tumor

d0: cage administration time; dn: 21 days after the first administration; *P<0.01vs control; CR: complete regression.

4 Conclusion:

HH-GV-F and HH-GV-E have a very good curative effect on human myeloid leukemia K562, and their curative effect is obviously better than that of Gleevec.

Experimental example three

Efficacy of HH-GV-678 and Gleevec on human myelogenous leukemia K562 xenografted tumor in nude mice

Note: HH-GV-678 (ie HH-GV-F) refers to 4-((4-methyl-1-piperazinyl)methyl)-N-[6-methyl-5-[[4- (3-pyridyl)-2-pyrimidinyl]amino]pyridyl-3-]-3-(trifluoromethyl)-benzamide methanesulfonate.

1. Experimental animals:

BALB/cA-nude nude mice were purchased from Shanghai Slack Experimental Animal Co., Ltd.; 5-6 weeks old, ♀, certificate number: SCXK (Shanghai) 2004-0005; kept in a constant temperature and humidity SPF environment .

2. Experimental steps

After the animals were acclimatized for 1 week, human leukemia K562 cells were inoculated subcutaneously. After the tumors grew to 100-300 mm ³ , the animals were randomly divided into groups (d0). HH-GV-678 and Gleevec were intragastrically administered to nude mice, and the dosages were 75mg/kg and 150mg/kg for HH-GV-678, and 150mg/kg for Gleevec. HH-GV-678 was administered once a day for 21 days. Gleevec 2 times a day, 150mg/kg each time, for a total of 21 days. The tumor volume was measured 2-3 times a week, the mice were weighed, and the data were recorded. The formula for calculating tumor volume (V) is: V=1/2×a×b ² where a and b represent length and width, respectively.

3. Results:

In the HH-GV-678 group administered at 75 mg/kg, on the 6th day, 3/8 mice had complete tumor regression (CR); by the 9th day, 7/8 mice had tumors completely regressed. On day 12, all tumors (8/8) had regressed.

In the HH-GV-678 group administered at 150 mg/kg, on the 6th day, 6/8 mice had complete tumor regression (CR); on the 9th day, all tumors (8/8) had completely regressed.

In the Gleevec group, on the 12th day after administration, the tumors of 1/8 mice completely regressed; by the end of the experiment, the tumors of 2/8 mice completely regressed.

Experiments have proved that HH-GV-678 has a faster onset of action, while Gleevec has a relatively slower onset of action; and the curative effect of HH-GV-678 is significantly better than that of Gleevec.

Tumor-bearing mice could well tolerate the above two compounds. Relatively speaking, HH-GV-678 was less toxic under the experimental conditions. (See Table 3, Figure 7 and Figure 8 for specific results)

Table 3. The curative effect of oral administration of HH-GV-678 and Gleevec on human myeloid leukemia K562 nude mice transplanted tumor

d0: cage administration time; dn: 21 days after the first administration; *P<0.01vs control; CR: complete regression.

4 Conclusion:

Both HH-GV-678 and Gleevec have significant curative effect on human myeloid leukemia K562; the curative effect of HH-GV-678 is significantly better than that of Gleevec; in comparison, under the experimental conditions, the toxicity of HH-GV-678 is slightly less than that of Gleevec .

Claims (29)

1. an amino-metadiazine compound and pharmacy acceptable salt thereof that general formula is (I):

In the formula,

R ₁Be selected from optional substituted phenyl or 4-8 unit monocyclic heterocycles, substituting group is selected from halogen atom, C _1-4Straight or branched alkyl, amino, C _1-10Alkoxyl group;

R ₂And R ₃Be independently selected from hydrogen, halogen atom, amino, C _1-10Alkylamino, two C _1-10Alkylamino, cyano group, nitro, hydroxyl, C _1-10Alkoxyl group, halo C _1-10Alkoxyl group;

R ₄Be selected from hydrogen, halogen atom, amino, C _1-10Alkylamino, two C _1-10Alkylamino, cyano group or optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, substituting group are selected from halogen atom, amino, hydroxyl;

R ₅Be selected from hydrogen, halogen atom, nitro, cyano group, hydroxyl, C _1-10Alkoxyl group, methylene-dioxy, halo C _1-10Alkoxyl group, amino or optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, substituting group are selected from halogen atom, amino, hydroxyl;

R ₆Be selected from hydrogen or optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, phenyl, phenyl-C _1-10Alkyl, heterocyclic aryl, heterocyclic aryl-C _1-10Alkyl, 4-8 unit monocyclic heterocycles, the monocyclic heterocycles-C of 4-8 unit _1-10Alkyl, substituting group are selected from halogen atom, amino, C _1-4Alkyl;

M=0,1,2 or 3;

N=0,1,2 or 3;

Q is selected from pyridyl;

Z is selected from phenyl, heterocyclic aryl or 4-8 unit monocyclic heterocycles;

L is selected from-NR ₇CO-,-CONR ₈-, NR ₉SO ₂-,-SO ₂NR ₁₀-,-NR ₁₁COO-,-NR ₁₂CONR ₁₃-,-OCONR ₁₄-;

R wherein ₇, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃And R ₁₄Be selected from hydrogen, optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, substituting group are selected from halogen atom, amino, hydroxyl;

Wherein, heterocyclic aryl is represented stable monocycle or dicyclo, and wherein each ring carbon atom is not more than 7 and at least one ring for aromatic nucleus and contain 1-4 heteroatoms that is selected from O, N, S.

2. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₁Be selected from optional substituted pyridyl, substituting group is selected from halogen atom, C _1-4The straight or branched alkyl.

3. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₂And R ₃Be independently from each other hydrogen, halogen atom, amino, C _1-10Alkylamino, cyano group or nitro.

4. compound according to claim 3 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₂And R ₃Be independently from each other hydrogen or halogen atom, wherein halogen atom is selected from fluorine, chlorine, bromine or iodine atom.

5. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₄Be selected from optional substituted C _1-10Alkyl, C _2-10Thiazolinyl or C _2-10Alkynyl, substituting group are selected from halogen atom or amino.

6. compound according to claim 5 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₄Be selected from optional substituted C _1-10Alkyl, substituting group are selected from halogen atom or amino.

7. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₅Be selected from hydrogen, halogen atom, nitro, optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, substituting group are selected from halogen atom or hydroxyl.

8. compound according to claim 7 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₅Be selected from hydrogen, halogen atom or optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, substituting group are selected from halogen atom or hydroxyl.

9. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₆Be selected from optional substituted heterocyclic aryl, heterocyclic aryl-C _1-10Alkyl, 4-8 unit's monocyclic heterocycles and the monocyclic heterocycles-C of 4-8 unit _1-10Alkyl, substituting group are selected from halogen atom or C _1-4Alkyl; Wherein, heterocyclic aryl is represented stable monocycle or dicyclo, and wherein each ring carbon atom is not more than 7 and at least one ring for aromatic nucleus and contain 1-4 heteroatoms that is selected from O, N, S.

10. compound according to claim 9 and pharmacy acceptable salt thereof is characterized in that R in the described compound ₆Be selected from optional substituted heterocyclic aryl, the monocyclic heterocycles-C of 4-8 unit _1-10Alkyl, substituting group are C _1-4Alkyl; Wherein, heterocyclic aryl is represented stable monocycle or dicyclo, and wherein each ring carbon atom is not more than 7 and at least one ring for aromatic nucleus and contain 1-4 heteroatoms that is selected from O, N, S.

11. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that m and n are independently selected from 0,1,2 in the described compound.

12. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that L is selected from-NR in the described compound ₇CO-,-CONR ₈-,-NR ₉SO ₂-,-SO ₂NR ₁₀-,-NR ₁₁COO-, wherein R ₇, R ₈, R ₉, R ₁₀, R ₁₁Be hydrogen.

13. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that L is-NR in the described compound ₇CO-or-CONR ₈-, R wherein ₇, R ₈Be hydrogen.

14. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that in the described compound:

R ₁Be selected from optional substituted phenyl, pyridyl, substituting group is selected from halogen atom, C _1-4Straight or branched alkyl, amino, C _1-10Alkoxyl group;

R ₂And R ₃Be independently selected from hydrogen, halogen atom, amino, C _1-10Alkylamino, two C _1-10Alkylamino, cyano group, nitro, hydroxyl, C _1-10Alkoxyl group, halo C _1-10Alkoxyl group;

R ₄Be selected from hydrogen, halogen atom, amino, C _1-10Alkylamino, two C _1-10Alkylamino, cyano group or optional substituted C _1-10Alkyl, substituting group are selected from halogen atom, amino, hydroxyl;

R ₅Be selected from hydrogen, halogen atom, nitro, cyano group, hydroxyl, C _1-10Alkoxyl group, amino or optional substituted C _1-10Alkyl, C _3-10Cycloalkyl, substituting group are selected from halogen atom, amino, hydroxyl;

R ₆Be selected from optional substituted heterocyclic aryl, heterocyclic aryl-C _1-10Alkyl, 4-8 unit monocyclic heterocycles, the monocyclic heterocycles-C of 4-8 unit _1-10Alkyl, substituting group are selected from halogen atom, amino, C _1-4Alkyl;

M=0 or 1;

N=0 or 1;

Q is selected from pyridyl;

Z is selected from phenyl;

L is selected from-NR ₇CO-,-CONR ₈-;

R wherein ₇, R ₈Be selected from hydrogen, optional substituted C _1-4Alkyl, C _3-10Cycloalkyl, substituting group are selected from halogen atom, amino, hydroxyl;

Wherein, heterocyclic aryl is represented stable monocycle or dicyclo, and wherein each ring carbon atom is not more than 7 and at least one ring for aromatic nucleus and contain 1-4 heteroatoms that is selected from O, N, S.

15. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that described compound and sour salify, used acid is selected from organic acid or mineral acid.

16. compound according to claim 15 and pharmacy acceptable salt thereof, it is characterized in that organic acid is selected from acetate, trichoroacetic acid(TCA), propionic acid, butyric acid, aspartic acid, tosic acid, methylsulfonic acid, toxilic acid, lactic acid, mineral acid comprises hydrochloric acid, sulfuric acid, phosphoric acid.

17. compound according to claim 16 and pharmacy acceptable salt thereof is characterized in that acid is hydrochloric acid or methylsulfonic acid.

18. compound according to claim 15 and pharmacy acceptable salt thereof, it is characterized in that described compound and etc. the sour salify of amount.

19. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that described compound and alkali salify, the salt that is become is selected from the salt that become with basic metal, alkaline-earth metal or quaternary ammonium.

20. compound according to claim 19 and pharmacy acceptable salt thereof is characterized in that described quaternary ammonium is NY ₄, wherein Y refers to that carbon atom is the alkyl of 1-4.

21. compound according to claim 1 and pharmacy acceptable salt thereof is characterized in that described compound is selected from following compound:

4-((4-methyl isophthalic acid-piperazinyl) methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-3-] benzamide,

4-((4-ethyl-1-piperazinyl) methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-3-] benzamide,

4-((4-methyl isophthalic acid-piperazinyl) methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-3-]-3-fluoro-benzamide,

4-((4-methyl isophthalic acid-piperazinyl) methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-3-]-3-chloro-benzamide,

4-((4-methyl isophthalic acid-piperazinyl) methyl)-N-[6-methyl-5-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-3-]-3-(trifluoromethyl)-benzamide,

6-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl]-5-[4-(3-pyridyl)-2-(pyrimidyl) amino] nicotine,

6-methyl-N-[4-((4-methylpiperazine-1-yl) methyl-3-(trifluoromethyl) phenyl)-5-[4-(3-pyridyl)-2-(pyrimidyl) amino] nicotine,

4-((4-methyl isophthalic acid-piperazinyl) methyl)-N-[5-methyl-4-[[4-(3-pyridyl)-2-pyrimidyl] amino] pyridyl-2-]-3-(trifluoromethyl)-benzamide,

5-methyl-N-[4-((4-methylpiperazine-1-yl) methyl-3-(trifluoromethyl) phenyl)-4-[4-(3-pyridyl)-2-(pyrimidyl) amino] picolinamide,

5-methyl-N-[3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl]-4-[4-(3-pyridyl)-2-(pyrimidyl) amino] picolinamide.

22. a method for preparing described compound of claim 1 and pharmacy acceptable salt thereof, its feature comprises the steps:

(A) under alkaline condition, react to such an extent that general formula is the compound of (IV) for the compound of (II) and general formula for the compound of (III) general formula;

(B) general formula is got the compound that general formula is (I) for the compound of (IV) and general formula for compound condensation reaction in the presence of condensing agent of (V);

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, Q, L, Z, m, n as defined in claim 1; L ', M ' refer to the group of phase mutual energy generation condensation reaction, and this group is selected from amino, carboxylic acid group, acid halide group, or refer to can change into through conventional method the organic group of amino, carboxylic acid group or acid halide group; R ₁₅Refer to easy leavings group, it is selected from halogen atom or methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl.

23. according to the described preparation general formula of claim 22 is the method for the compound and the pharmacy acceptable salt thereof of (I), it is characterized in that: described organic group is selected from nitro or ester group.

24. according to the described preparation general formula of claim 23 is the method for the compound and the pharmacy acceptable salt thereof of (I), it is characterized in that:

(A) when preparation compound (IV), use alkali, described alkali is selected from organic bases or mineral alkali, and this organic bases is selected from n-Butyl Lithium, sodium methylate, sodium ethylate, potassium tert.-butoxide, and this mineral alkali is selected from sodium hydroxide, potassium hydroxide, sodium amide, sodium hydrogen;

(B) when preparation compound (I), when reaction is carboxylic acid group and amino condensation, condensing agent is N, N-dicyclohexylcarbodiimide, N, N-DIC, N, the mixture that mixture that N-diethyl carbodiimide, triphenyl phosphorus and diethylazodicarboxylate form or triphenyl phosphorus and diisopropyl azo-2-carboxylic acid form; When reaction was acid halide group and amino condensation, condensing agent was mineral alkali or organic bases.

25. according to the described preparation general formula of claim 24 is the method for the compound and the pharmacy acceptable salt thereof of (I), it is characterized in that:

(A) when preparation compound (IV), described mineral alkali is a sodium hydrogen;

(B) when preparation compound (I), when reaction was carboxylic acid group and amino condensation, described condensing agent was N, the N-dicyclohexylcarbodiimide; When reaction was acid halide group and amino condensation, described condensing agent was pyridine or triethylamine.

26. according to the described preparation general formula of claim 24 is the method for the compound and the pharmacy acceptable salt thereof of (I), it is characterized in that: when preparation compound (I), described mineral alkali is selected from yellow soda ash, salt of wormwood, lime carbonate, and organic bases is selected from triethylamine, pyridine, 4-dimethylamino pyridine, tripropyl amine, Tributylamine.

27. described compound of claim 1 and pharmacy acceptable salt thereof the application in the preparation kinases inhibitor.

28. compound as claimed in claim 1 and pharmacy acceptable salt thereof the application in preparation treatment cell hyperplastic disease medicine.

29. one kind contains the compound as claimed in claim 1 of medicine effective dose and the pharmaceutical composition of salt and pharmaceutically acceptable carrier thereof.