CN104860890B - T790M mutant egfs R inhibitor and its application in antineoplastic is prepared - Google Patents

T790M mutant egfs R inhibitor and its application in antineoplastic is prepared Download PDF

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CN104860890B
CN104860890B CN201510214627.1A CN201510214627A CN104860890B CN 104860890 B CN104860890 B CN 104860890B CN 201510214627 A CN201510214627 A CN 201510214627A CN 104860890 B CN104860890 B CN 104860890B
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compound
inhibitor
salt
ethyl
present
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CN104860890A (en
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周鼎
崔大为
蔡振伟
陈平
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Shanghai Hongbo Zhiyuan Pharmaceutical Ltd By Share Ltd
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Shanghai Hongbo Zhiyuan Pharmaceutical Ltd By Share Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

The invention provides T790M mutant egfs R inhibitor and its application in antineoplastic is prepared, the inhibitor is the pyrimidines with logical formula (I) architectural feature.Such compound can suppress kinds of tumor cells, especially can selectively acting in EGFR L858R/T790M and EGFRE745_A750/T790M lung carcinoma cells.Wild type cancer cell is contrasted, the IC50 of such compound wants high 10 times even 100 times of order of magnitude difference.Such compound be it is a kind of novel can overcome existing EGFR TKI drug resistance and selective protease inhibitors, can be applied to prepare antineoplastic.

Description

T790M mutant egfs R inhibitor and its application in antineoplastic is prepared
Technical field
The present invention relates to the medicine for treating tumour, and in particular to T790M mutant egfs R inhibitor and its is making Application in standby antineoplastic.
Background technology
In Past 30 Years, lung cancer mortality rises 465%, and the incidence of disease increases by 26.9% every year, instead of liver cancer into For China first place Death Cause for Malignant Tumors.A kind of this disease of death rate highest, serious threat the health of the mankind.Wherein Non-small cell lung cancer (non-small cell lung cancer, abbreviation NSCLC) accounts for more than the 80% of all lung cancer, only three There is the chance of operative treatment in/mono- NSCLC patient, about 70% patient has belonged to Locally Advanced or appearance when medical DISTANT METASTASES IN, lose operative treatment chance.In this case, drug therapy, which seems, is even more important.
In traditional cancer treatment procedure, chemotherapy is main treatment means；Chemotherapeutics non-specifically blocks carefully Born of the same parents divide so that cell death, they also destroy the growth of human normal cell significantly while tumour cell is killed, Bring many adverse reactions.Many people make mood pessimistic or even abandon treating because of the serious side effects of worry chemotherapy, then add The drug resistance of upper chemotherapeutics, NSCLC chemotherapy is set to allow of no optimist, and the cycle for extending chemotherapy merely add toxic side effect, and Do not increase curative effect.The cancer cell of non-small cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, and Overall response rate also only has 25% Left and right；Limitation for these reasons, Patients with Non-small-cell Lung five year survival rate are less than 20%.
In 50%-80% patient NSCLC, their EGF-R ELISA (epidermal growth Factor receptor, EGFR) all over-express, so as to cause canceration.Targeting EGFR medicine mainly has two classes：One kind is to make Small molecule tyrosine kinase inhibitors (TKI) for acceptor intracellular region；Another kind of is the monoclonal for acting on receptor extracellular region Antibody (MAb).It is applied to clinical first generation EGFR inhibitor such as Iressa, Erlotinib, Lapatinib etc., they are right Very big success is achieved in the treatment of NSCLC lung cancer, Patients with Non-small-cell Lung five year survival rate improves.Meanwhile with chemotherapy Compare, their advantage is that bone marrow suppression, the side effect such as nausea and neurotoxicity will not be produced；But they are in monotherapy Drug effect is relatively low, and has the side effect such as obviously fash and diarrhoea, and after using 1 year, patient resistance occurs to medicine Property.Research thinks that the mutation in EGFR gene T790M sites is the main inducing of such Drug-resistant, has clinical case data to show Show, about 50% patient's acquired resistance is all originated from caused by the mutation in T790M sites.Further research confirms, due to EGFR gene T790M is mutated, that is, the threonine encoded is changed into methionine, inhibitor is hindered so as to cause steric hindrance Combined with ATP-binding domain and ultimately resulted in inhibitor activity forfeiture.Also there is research to show that the mutation in T790M sites is not straight at present Connecing influences inhibitor and EGFR compatibility, but mutation causes EGFR and ATP compatibility to greatly increase so that inhibitor with EGFR compatibility is relative to be greatly reduced (inhibitor and ATP are competitive bindings).Second generation inhibitor such as Afatinib, Da Ke replaces Buddhist nun (Dacomitinib), and they are characterised by the identity increase to EGFR better than the first generation, can distinguish tumour Cell and normal cell, such side effect will be reduced；But these molecules cause to the poor selectivity of EGFRT790M mutant Clinical drug tolerance dose is relatively low, and under its maximum tolerated dose (MTD), medicine can not reach its valid density in vivo and make Must be invalid to most resistance patients.
In a word, current EGFR tyrosine kinase inhibitors (EGFR-TKI) can not be still solved caused by drug resistance Clinical pressure, and existing medicine is using quinazoline or quinoline amine as the EGFR of basic parent nucleus is reversible or irreversible suppression mostly Preparation, the toxic side effect that its poor selectivity to wild-type cell is brought is also inevitable.Therefore, there is an urgent need for new class Type, the compound of especially novel skeleton solves the problems such as drug resistance, poor selectivity.
The content of the invention
It is an object of the present invention to provide the inhibitor of T790M mutant egfs R a kind of and its in antineoplastic is prepared Application.
To achieve the above object, the present invention provides following technical scheme：
A kind of T790M mutant egfs R inhibitor, the inhibitor have the structure of logical formula (I)：
Wherein, X, Y, Z and U are independently selected from N, CH；
V is selected from CO, CHR8, wherein R8Selected from hydrogen, C1-C4Substitute alkyl；
W is selected from O, NR9, wherein R9Selected from hydrogen, C1-C4Substitute alkyl；
R1Selected from hydrogen, halogen, C1-C4Substitute alkyl；
R2Selected from hydrogen, halogen, C1-C4Alkoxy, C1-C4Substitute alkyl；
R3And R4It is independently selected from hydrogen, C1-C4Substitute alkyl；Or R3、R4With forming substituted monocyclic, loop coil together with N atoms Or bridged ring；
R5、R6And R7It is independently selected from hydrogen, halogen, C1-C4Substitute alkyl.
Preferably, the inhibitor of the T790M mutant egfs R has the structure of logical formula (V)：
Wherein, R1Selected from hydrogen, halogen, C1-C4Substitute alkyl；R2Selected from hydrogen, halogen, C1-C4Alkoxy, C1-C4Substitute alkane Base；R3And R4It is independently selected from hydrogen, C1-C4Substitute alkyl；Or R3、R4With forming substituted monocyclic, loop coil or bridge together with N atoms Ring；R5、R6And R7It is independently selected from hydrogen, halogen, C1-C4Substitute alkyl.
Preferably, the inhibitor of the T790M mutant egfs R has the structure of logical formula (VI)：
Wherein, R1Selected from hydrogen, halogen, C1-C4Substitute alkyl；R2Selected from hydrogen, halogen, C1-C4Alkoxy, C1-C4Substitute alkane Base；R3And R4It is independently selected from hydrogen, C1-C4Substitute alkyl；Or R3、R4With forming substituted monocyclic, loop coil or bridge together with N atoms Ring.
Preferably, the inhibitor of the T790M mutant egfs R is selected from the compound of following structural formula：
The present invention also provides a kind of pharmaceutical composition, and the pharmaceutical composition contains at least one T790M as elucidated before Mutant egf R inhibitor or its enantiomer, diastereomer, resonating body, or the inhibitor pharmaceutically acceptable salt or its Prodrugs, and pharmaceutically acceptable carrier.
Present invention also offers application of the described T790M mutant egfs R inhibitor in antineoplastic is prepared.
In one embodiment, this application provides a kind of using the compound with Formulas I and its pharmaceutically acceptable The excess proliferative disease such as salts for treating people or other mammal tumors or symptom.
In one embodiment, the compound designed by the application and its pharmaceutically acceptable salt can be used for treatment or Control non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, The hyperproliferative diseases such as cell carcinoma, GISTs, leukaemia, histiocytic lymph cancer, nasopharyngeal carcinoma.
Compared with prior art, the present invention has the advantages that：
The present invention relates to the pyrimidines with logical formula (I) architectural feature, kinds of tumor cells can be suppressed, especially Be can selectively acting in EGFR L858R/T790M and EGFR E745_A750/T790M lung carcinoma cells.Contrast wild type Cancer cell, the IC50 of such compound want high 10 times even 100 times of order of magnitude difference.Such compound is a kind of novel energy Enough overcome existing EGFR-TKI drug resistance and selective protease inhibitors.Such compound can suppress a variety of swollen The growth of oncocyte, and to EGFR, other protease of Her families produce inhibitory action, available for preparing antineoplastic, and can To overcome the resistance of the inductions such as existing medicine Gefitinib, Tarceva.As understood by those skilled in the art, the application institute The compound being related to and its pharmaceutically acceptable salt can be used for preparing antineoplastic, to treat the mankind and other mammals The transition proliferative diseases such as tumour.
Following is the definition of term used in this specification.Unless otherwise noted, provided herein is group or term Initially definition is applied in this specification individually or as a part for other groups.
Term " alkyl " refers to straight or branched alkyl, comprising 1-12 carbon atom, especially 1-6 carbon atom.Allusion quotation " alkyl " of type includes methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, isopentyl, heptyl, 4, 4-dimethyl amyl group, octyl group, 2,2,4- tri-methyl-amyls, nonyl, decyl, undecyl, dodecyl etc..Term " (C1- C4) alkyl " straight or branched alkyl is referred to, including from 1-4 carbon atom, such as methyl, ethyl, propyl group, isopropyl, positive fourth Base, the tert-butyl group, isobutyl group." substitution alkyl " refers to that one or more of alkyl position is substituted, especially 1-4 substitution Base, it can substitute on any position.Typical substitution includes but is not limited to one or more following groups：Such as hydrogen, halogen (example Such as, single halogenic substituent or more halogenic substituents, the latter's such as trifluoromethyl or include Cl3Alkyl), itrile group, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, ORa、SRa, S (=O) Re、S (=O)2Re, P (=O)2Re, S (=O)2ORe, P (=O)2ORe、NRbRc、NRbS (=O)2Re、NRbP (=O)2Re, S (=O)2NRbRc, P (=O)2NRbRc, C (=O) ORd, C (=O) Ra, C (=O) NRbRc, OC (=O) Ra, OC (=O) NRbRc、NRbC (= O)ORe,NRdC (=O) NRbRc、NRdS (=O)2NRbRc、NRdP (=O)2NRbRc、NRbC (=O) RaOr NRbP (=O)2Re, its In the R that occurs hereinaHydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R can independently be representedb、RcAnd Rd Hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring can be independently represented, in other words RbAnd RcWith heterocycle can be formed together with N atoms；ReCan Hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring are represented with independent.Above-mentioned typical substituent, as alkyl, Cycloalkyl, alkenyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can optionally substitute.
Term " halogen " or " halogen " refer to chlorine, bromine, fluorine, iodine.
Unless otherwise indicated, it is assumed that the hetero atom of any discontented valence state has enough hydrogen atoms to supplement its valence state.
The salt that compound in the present invention is likely to form is also to belong to the scope of the present invention.Unless otherwise indicated, it is of the invention In compound be understood to include its esters.Term " salt " as used herein, refer to and form acid with inorganic or organic bronsted lowry acids and bases bronsted lowry Or the salt of alkali formula.In addition, when the compound in the present invention contains a basic moiety, it includes but is not limited to pyridine or imidazoles, During containing an acidic moiety, including but not limited to carboxylic acid, it is possible to create amphion (" inner salt ") be included in term " salt " In the range of.Pharmaceutically acceptable (i.e. nontoxic, physiologically acceptable) salt is preferred, although other salts are also useful, such as can With the isolated or purified step in preparation process.The compound of the present invention is likely to form salt, for example, compound I with it is certain The amount such as acid of equivalent or alkali reaction, salt out come in media as well, or freeze-drying is got in aqueous.
The basic moiety that compound in the present invention contains, including but not limited to amine or pyridine or imidazole ring, may be with Organic or inorganic acid forming salt.Acetate can be included (as used acetic acid or three halogenated acetic acids, such as trifluoro second into the typical acid of salt Acid), adipate, alginate, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, boric acid Salt, butyrate, citrate, camphor salt, camsilate, cyclopentane propionate, diethylene glycol (DEG) hydrochlorate, lauryl sulfate, Ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrochloride, hydrogen Bromate, hydriodate, isethionate (e.g., 2- isethionates), lactate, maleate, mesylate, naphthalene sulphur Hydrochlorate (e.g., 2- naphthalene sulfonates), nicotinate, nitrate, oxalates, pectate, persulfate, phenpropionate (such as 3- phenylpropyl alcohols Hydrochlorate), phosphate, picrate, Pivalate, propionate, salicylate, succinate, sulfate (are such as formed with sulfuric acid ), sulfonate, tartrate, rhodanate, mesylate such as tosilate, dodecanoate etc..
The acidic moiety that the compound of the present invention contains, including but not limited to carboxylic acid, may be with various organic or inorganics Alkali forming salt.The salt that typical alkali is formed includes ammonium salt, alkali metal salt such as sodium, lithium, sylvite, alkali salt such as calcium, magnesium salts, and The salt (such as organic amine) that organic base is formed, if benzyl star, dicyclohexyl amine, extra large bar amine are (with N, N- bis- (dehydroabietyl) ethylenediamine shape Into salt), N- methyl-D-glucosamines, N- methyl-D-glucamides, tert-butylamine, and with amino acid such as arginine, rely ammonia The salt that acid etc. is formed.Basic nitrogen-containing groups can with halide quaternary ammonium salt, as lower alkyl halide (such as methyl, ethyl, The chloride of propyl group and butyl, bromide and iodide), dialkyl sulfate (e.g., dimethyl suflfate, diethylester, dibutyl ester and Diamyl ester), long chain halide (such as chloride of decyl, dodecyl, myristyl and myristyl, bromide and iodate Thing), aralkyl halide (such as benzyl and pheriyl bromide).
The prodrug of compound and solvate are also within the scope of covering in the present invention.Term " prodrug " refers to one herein Kind of compound, when treat relevant disease, through metabolism or the chemical conversion of chemical process and produce the compound in the present invention, Salt or solvate.The compound of the present invention includes solvate, such as hydrate.
Compound, salt or solvate in the present invention, it is understood that there may be tautomeric form (such as acid amides and imines Ether).All these dynamic isomers are all the parts of the present invention.
The stereoisomer of all compounds is (for example, those are due to former to various substitution asymmetric carbons that may be present Son), including its enantiomeric form and diastereomeric forms, belong to imagination scope of the invention.Compound in the present invention is independent Stereoisomer may not with other isomers simultaneously exist (for example, optics pure as one or substantially pure Isomers has special activity), or be also likely to be mixture, such as raceme, or with every other stereoisomer or its In a part formed mixture.The chiral centre of the present invention has two kinds of configurations of S or R, is joined by theoretical with the applied chemistry world Credit union (IUPAC) definition of suggestion in 1974.Racemic form can solve by physical method, such as fractional crystallization, or by spreading out It is raw to be crystallized for diastereomeric separation, or separated by chiral column chromatography.Single optical isomer can be by suitable Method is obtained by racemic modification, including but not limited to traditional method, such as with optically active acid into recrystallizing after salt.
Compound in the present invention, pass sequentially through preparation, isolate and purify the compound of acquisition its weight content be equal to or More than 90%, for example, equal to or more than 95%, equal to or more than 99% (compound of " very pure "), listed in text description. The compound of " very pure " present invention this herein also serves as the part of the present invention.
All configurational isomer of compound of the present invention all within the scope of covering, either mixture, it is pure or Very pure form.Cis (Z) is included in the definition of the compounds of this invention and returns two kinds of olefin isomers of formula (E), and carbocyclic ring With the cis and trans isomers of heterocycle.
Throughout the specification, group and substituent can be selected to provide stable fragment and compound.
Particular functional group and technical terms of chemistry definition are all described in detail as follows.For purposes of the invention, chemical element with Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics, 75thEd. it is consistent defined in.The definition of particular functional group also describes wherein.In addition, the basic principle of organic chemistry and Particular functional group and reactivity are in " Organic Chemistry ", Thomas Sorrell, University Science Books,Sausalito:1999, also it is described, entire contents include the row of bibliography.
Some compounds of the present invention are likely to be present in specific geometry or stereoisomer form.The present invention covers all Compound, including its cis and trans isomers, R and S enantiomters, diastereomer, (D) type isomers, (L) type isomery Body, racemic mixture and other mixtures.Other asymmetric carbon atom can represent substituent, such as alkyl.All isomers with And their mixture, all forgive in the present invention.
According to the present invention, the ratio that the mixture of isomer contains isomers can be various.For example, only The mixture of two isomers can have following combination：50:50,60:40,70:30,80:20,90:10,95:5,96:4,97: 3,98:2,99:1, or 100:0, all ratios of isomers are all within the scope of the present invention.Those skilled in the art hold in this specialty Intelligible similar ratio, and for more complicated isomers mixture ratio also within the scope of the present invention.
Present invention additionally comprises the compound of isotope marks, is equal to original chemical and is disclosed.It is but actually right One or more atoms is substituted by the atom different from its atomic weight or quality ordinal number and generally occurred.The present invention can be classified as The example of compound isotope include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as2H、3H、13C、11C、14C 、15N、18O、17O、31P、32P、35S、18F and36Cl.Compound in the present invention, or enantiomer, diastereomer, isomers, or medicine Acceptable salt or solvate on, wherein containing the isotope of above-claimed cpd or other other isotope atoms all at this Within the scope of invention.Some compound isotopically labelleds in the present invention, such as3H and14C radio isotope also wherein, It is useful in the experiment of the Tissue distribution of medicine and substrate.Tritium, i.e.,3H and carbon-14, i.e.,14C, their preparation and detection are compared Easily.It is the first choice in isotope.In addition, higher isotope substitution such as deuterium, i.e.,2H, because its good metabolic stability is at certain It is advantageous in a little therapies, such as increase half-life period in vivo or reduce dosage, therefore, it can pay the utmost attention in some cases. The compound of isotope marks can use in general method, be replaced with by using the isotope labeling reagent being easy to get non isotopic Reagent, with disclose in the diagram and (or) scheme in example can be prepared.
If designing the synthesis of a specific enantiomer of compound of the invention, it can be prepared with asymmetric syntheses, Or with chiral auxiliaries derivatization, caused mixture of diastereomers is separated, then remove chiral auxiliaries and obtain pure enantiomer. In addition, if containing a basic functionality, such as amino acid, or acidic functionality in molecule, such as carboxyl, suitable light can be used The acid of activity or the formation diastereomeric salt therewith of alkali are learned, then is separated by conventional meanses such as fractional crystallization or chromatograms, so Pure enantiomer has just been obtained afterwards.
As described herein, the compound in the present invention can take with any quantity substituent or functional group and expand it and forgive model Enclose.Generally, term " substitution " includes the logical of substituent no matter occurring in term " optional " above or below in inventive formulation Formula, refer to use specified structure substituent, instead of hydroperoxyl radical.As multiple in specific structure in position by multiple specific substitutions When base substitutes, each position of substituent can be identical or different.Term " substitution " used herein includes all fair Perhaps organic compound substitutes.In broad terms, it is allowed to substituent include non-annularity, ring-type, side chain non-branched, carbon It is ring and heterocycle, aromatic ring and non-aromatic ring organic compound.In the present invention, as hetero atom nitrogen can have hydrogen substituent or The organic compound described above of any permission supplements its valence state.In addition, the present invention be not intended to be in any way limiting it is fair Perhaps substituted organic compound.It is considered herein that the combination of substituent and variable groups is in the controlling in disease in the form of stable compound It is good, such as infectious disease or proliferative disease in treatment.Term " stabilization " refers to stable compound, enough herein Detection is enough the integrality for maintaining compound structure in the long time, is preferably all imitating within the sufficiently long time, is existing herein This is for the above purpose.
The metabolite of compound and its pharmaceutically acceptable salt involved by the application, and can be changed into vivo The prodrug of the structure of compound and its pharmaceutically acceptable salt involved by the application, is also contained in claims hereof In.
Compound of formula I can be combined to the known other drugs for treating or improving similar symptom.During administering drug combinations, originally The administering mode ＆ dosage of medicine keeps constant, and subsequently or simultaneously takes the compound of Formulas I.When compound of formula I and other one kind Or several drugses are simultaneously when taking, preferably using the pharmaceutical compositions containing one or more of known drugs and compound of formula I simultaneously Thing.Drug combination is also included within the overlapping period and takes compound of formula I and other one or more of known drugs.When Formulas I When compound carries out drug combination with other one or more of medicines, the dosage of compound of formula I or known drug may be more single than them The dosage that private medicine is is low.
The medicine of drug combination or active component can be carried out with I to be included but is not limited to：ERs is adjusted Save agent, androgen receptor adjustment, retina receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase It is inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitors, RTI, angiogenesis inhibitors, thin Born of the same parents breed and survival signaling inhibitor, the medicine and cell death inducer of interference cell cycle check, cytotoxic drug, junket Propylhomoserin protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, C-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, histidine are gone Acetylase inhibitor, protesome inhibitors, CDK inhibitor, Bcl-2 family protein inhibitors, MDM2 family proteins suppress Agent, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitor, ATK inhibitor, integrin retarding agent, Interferon, interleukin-I2, cox 2 inhibitor, P53, P53 activator, VEGF antibody, EGF antibody etc..
The present invention also provides a kind of drug regimen, is subjected to comprising at least one compound described herein or pharmaceutically Salt, solvate or pharmaceutically acceptable carrier.
Refer to pharmaceutically acceptable material, composition or medium, such as liquid used herein of phrase " pharmaceutically acceptable carrier " Body or solid packing, diluent, auxiliary material, solvent or encapsulating material, including from certain part of an organ or body to another Certain of organ or body part carry or transport main pharmaceutical reagent.Each carrier must be " can receive ", can it is compatible other The medicine of form is not damaged into and to patient.Some can include as the example of pharmaceutically acceptable carrier：Sugar, such as Lactose, dextrose and saccharose sugar；Starch, such as wheaten starch and farina starch；Cellulose and its derivates, such as sodium carboxylic first Base cellulose, ethyl cellulose, cellulose acetate, powdered gum tragacanth, malt, gelatin, talcum powder；Auxiliary material, such as cocoa butter And suppository wax；Oil, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycol, such as butanediol； Polyalcohol, such as glycerine, sorbierite, mannitol and polyethylene glycol；Ester, such as ethyl oleate and ethyl laurate；Agar；Buffer, Such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Apirogen water；Physiological saline；Ringer's solution；Ethanol；Phosphate buffer, and Other nontoxic compatible materials applied in pharmaceutical preparation.
As described above, some examples of this medicament can be presented as the form of pharmaceutically acceptable salt.In this side Face, the present invention in term " pharmaceutically acceptable salt ", refer to relative nontoxic, organic and inorganic acid compound add what is formed Salt.These salts in the present invention can be when being finally separating with purifying compound caused by scene, or in list in the present invention Formed in individual reaction during purifying compound with suitable organic or inorganic acid and free alkali, so as to separate and forming salt.Allusion quotation The salt of type includes hydrobromate, hydrochloric acid, sulfate, disulfate, phosphate, nitrate, acetate, valerate, oleate, palm fibre Palmitic acid hydrochlorate, stearate, laruate, benzoate, lactate, tosilate, citrate, maleate, rich horse Hydrochlorate, succinate, tartrate, naphtholate, mesylate, gluceptate, Lactobionate and dodecane sulfonate etc. Deng.(example is referring to Berge et al., (1977) " Pharmaceutical Salts ", J.Pharm.Sci.66:1-19.)
The main compound of pharmaceutically acceptable salt includes the salt or quaternary ammonium salt of traditional non-toxic compound, as nontoxic Organic or inorganic acid.This nontoxic salt includes the derivative of inorganic acid, such as hydrochloride, hydrobromate, sulfate, amino sulphur Hydrochlorate, phosphate, nitrate etc.；The salt prepared than organic acid, such as acetate, butyrate, succinate, glycol hydrochlorate, hard Resin acid salt, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxyl horse Come hydrochlorate, phenylacetate, glutamate, benzoate, salicylate, sulfanilate, Aspirin salt, Fumarate, toluene fulfonate, methane sulfonates, ethane disulfonic acid hydrogen salt, oxalates, isethionate etc..
In other cases, compound of the invention may include one or more acidic functionalities, therefore energy and medicine Acceptable alkali formation and pharmaceutically acceptable salt on.Term " pharmaceutically acceptable salt " refers to this hair in this case The salt that the inorganic and organic base of bright compound and relative nontoxic is formed.These salt in the present invention can be finally separating Caused by scene during purifying compound, or use suitable organic or nothing in the present invention during purifying compound in single reaction Machine alkali is formed with free acid, such as hydroxide, carbonate or the bicarbonate of pharmaceutically acceptable metal cation, or ammoniacal liquor, Pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine.Typical alkali metal salt or alkaline earth salt include lithium salts, sodium salt, sylvite, calcium Salt, magnesium salts, aluminium salt etc..Being typically used for the organic amine of forming salt includes ethamine, diethylamine, ethylenediamine, monoethanolamine, diethanol Amine, piperazine etc..(example is referring to Berge et al., supra.)
Wetting agent, emulsifying agent and lubricant, such as lauryl sodium sulfate, magnesium stearate, polyethylene oxide and polybutene The copolymer of oxide, and colouring agent, releasing agent, coating agent, sweetener, spices and fumigating agent, preservative and antioxidant Among the composition existed in.
The formula of the present invention include those suitable oral cavities, nasal cavity, external application (including oral cavity and sublingual), rectum, vagina and Vein treatment.The formula can easily turn into unit dosage form, and can be prepared by pharmaceutically any of method.Active ingredient Dosage can be combined with a carrier material and produce single formulation, can factor receptor therapeutic modality, specific mode of administration It is different and different.The dosage of effective ingredient can be combined with carrier material and produce single formulation, will typically be used as the chemical combination Thing produces the dosage for the treatment of.In general, outside 100%, the active ingredient of this dose is best between about 1%-99% It is that optimal is about 10%-30% or so from about 5%-70% or so.
The method that these formulas or chemical analysis are prepared in the present invention enters including compound and combines one or more loads The step of body and assistant agent composition.In general, formula be prepared into it is uniform can, can nearly with the carrier knot in the present invention Close, as liquid-carrier, solid smalls carrier, or both have both at the same time.Then, product is fashioned into if necessary.
The suitable oral preparation of the present invention can have following form, such as capsule, cachet, pill, tablet, lozenge (being typically sucrose and Acacia or tragacanth, there is certain taste), pulvis, granule, or as a solution or outstanding The non-aqueous liquid in water is floated over, or is used as Water-In-Oil or oil-in-water emulsion liquid, or is used as elixir or syrup, or it is granular (inert base for using such as gelatin and glycerine, sucrose and Acacia) and/or mouthwash etc, each includes the present inventionization A predetermined close of the compound as active ingredient.The compounds of this invention can also be used as bolus, paste or plaster.
The present invention oral solid formulation (capsule, tablet, pill, dragee, powder, particle etc.), its effective ingredient with One or more pharmaceutically acceptable carrier mixing, such as sodium citrate or calcium monohydrogen phosphate, and/or any herein below：Filler Or filler, such as starch, lactose, sucrose, glucose, mannitol；And/or silicic acid, such as adhesive, sodium carboxymethylcellulose, Alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic, such as NMF, glycerine；Disintegrant, such as agar, carbon Sour calcium, potato or tapioca, alginic acid, some silicate, sodium carbonate, ethanol and sodium starch；Solution retarder, such as paraffin, Sorbefacient, such as quarternary ammonium salt compound；Wetting agent, such as hexadecanol, glyceryl monostearate and PEO, polyoxygenated are common Polymers；Absorbent, such as kaolin clay, bentonite, such as lubricant, talcum powder, calcium stearate, magnesium stearate, the poly- second two of solid Alcohol, lauryl sodium sulfate and its mixture；And colouring agent.In the case of capsule, tablet, pill, drug regimen may be also Including sustained release agent.Auxiliary material can be used to turn into soft filling and hard filling capsule for similar solids versions composition, such as lactose or milk sugar, And the filler of ultra-high molecular weight polyethylene ethylene glycol etc.
Tablet can select one or more auxiliary ingredients to compress or be molded.Compressed tablets can be prepared (such as bright with binding agent Glue or HBMC), lubricating oil, inert diluent, antistaling agent, disintegrant (such as ethanol or sodium starch crosslinking carboxylic Sodium carboxymethylcellulose pyce), surface-active or dispersant.Model tablet may pass through powdered compounds and inert fluid dilution Mixture, being molded on a suitable injection machine.
Active component can use above-mentioned auxiliary material microencapsulation.The medicine group of tablet and other solid pharmaceutical preparations of the present invention Close, such as dragee, capsule, pill, granule, selectively can be prepared with coating and shell or moulding, such as enteric coating layer, with And the coating of other known pharmaceutical forms.The preparation of slow or control release active ingredient may also be provided, for example, hydroxyl Butyl methyl cellulose provides required release profiles, other polymers matrix, liposome and/or fento in different situations Dimension element.They be able to may sterilize, for example, keep off filter by filter bacteria, or merge anti-microbial agents and sterile consolidate Body composition, they are dissolved in sterilized water, or in some sterile injectable mediums.These compositions may also containing opacifiers into Part, or the composition of the active material slowly discharged, or preferentially form a kind of mode of delay in some parts of intestines and stomach.It is embedding The material that entering composition can use includes polymer and wax.Active component can also be prepared into micro- glue using one or more auxiliary materials Scrotiform formula.
Pharmaceutically acceptable emulsion included to the compound oral liquid formulation of the present invention, microemulsion, solution, suspension, Syrup and elixir.Except active component, the liquid of formulation may contain pharmaceutically conventional inert diluent, for example, water or other Solvent, solubilising reagent and emulsifying agent, such as ethanol, isobutanol, ethyl carbonate, ethyl acetate, phenmethylol, Ergol, butylene Ethylene glycol, 1,3-BDO, oil (particularly cottonseed oil, peanut oil, maize germ oil, olive oil, castor oil, sesame oil) are sweet Oil, tetrahydrofuran alcohol, polyethylene glycol and fatty acid ester sorbierite and its mixture.In addition, cyclodextrin, such as hydroxyl butyl-beta- Cyclodextrin, it can also be used to the compound of dissolving.
Except inert diluent, oral composition can also be included such as wetting agent, emulsification and suspending agent, sweetener, essence, color Element, antistaling agent and preservative.
Except reactive compound, suspension may contain suspending agent, such as isostearic acid ethyl ester, polyoxyethylene sorbitol and Sorbitol ester, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar and tragacanth and its mixture.
Present invention treatment rectum or intravaginal drug composite formula can be suppository, and it can be by one or more invention Compound mixes sponsors with one or more suitable nonirritant excipients or carrier including preparation, for example, cocoa butter, poly- second Glycol, a suppository wax or salicylic acid, and be solid at room temperature, but the liquid of body temperature, therefore, rectum or vaginal canal will be melted in With the invention of release active agents.
The formula of the present invention is adapted for treating vagina class disease, including containing such as pessary of known carrier in pharmacy, cotton balls, Paste, gel, paste, foam or spray agent.
Part or transdermal administration for the compounds of this invention include pulvis, spray, ointment, ointment, face cream, breast Liquid, gel, solution, plaster and inhalant.Under reactive compound aseptic condition with pharmaceutically acceptable carrier, and any anti-corrosion Agent, buffer, or may need to mix.
Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment, such as animal and plant may be included in ointment and gel The auxiliary material of fat, oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, organosilicon, organobentonite are lived Property compound, silicic acid, talcum powder, zinc oxide, or their mixture.
Except the active ingredient beyond the region of objective existence in the present invention, auxiliary material such as lactose that powder and spray can include, talcum, silicic acid, Aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray may add it is conventional, such as fluorochlorohydrocarbon and The unsubstituted hydrocarbon of volatility, such as butane and butylene.
The patch of compound is controllable in the body to medicine in the present invention is distributed with extra benefit.This formulation can Formed by the medicament being dissolved or dispersed in buffer medium.Sorbefacient can also be used for increase in the skin present invention The flux of medicament.The rate controlling membranes or be dispersed in polymeric matrix or gel that this rate of change can be provided by either party Compound is controlled.
Ophthalmic preparation, spongaion, powder, solution etc., fall within the scope of the present invention.
The drug regimen of suitable one or more compounds of the invention includes and one or more medicines in parenteral treatment The acceptable sterile physiological aqueous solution or non-aqueous solution, dispersant, suspending agent or emulsion on, or aseptic powdery.They may The dispersant for being reassembled as aseptic injection or preferentially using, may contain antioxidant, buffer, bacteriostatic agent, can make preparation with it is pre- The blood or suspending agent or thickener of phase acceptor is isotonic fused.
When the compound of the present invention is treated as medicament to human and animal, they can be in itself or as medicine Composition and be administered.For example, the active component comprising 0.1%-99.5% (preferably 0.5%-90%) and pharmaceutically acceptable Carrier.
Compound and pharmaceutical composition in the present invention can apply to combination treatment, i.e. compound and pharmaceutical composition can Before or after simultaneously, treatment or medical procedure that one or more required medicines use.It is this to apply in the specific of rule of combination Combination treatment (treatment or program) will allow for the compatibility of the treatment needed for realizing and/or program and preferable therapeutic effect. The application of this therapy can realize required effect (for example, the compound of the present invention may be anti-with another to identical disease HCV reagents work simultaneously), or it is possible to reach different effects (such as controlling any harmful effect).
The compound of the present invention intramuscular injection, can be injected intraperitoneally, be subcutaneously injected, external application by intravenous injection, orally, or Other acceptable methods treat disease.These compounds can be used for the condition mammal for the treatment of of arthritis (for example, people Class, domestic animal and domestic animal), birds, lizard, and it is any can these compatible compound other biologicals.
Present invention also offers Key works Drug packing or external member, including one or more packagings, wherein containing in the present invention The drug regimen of one or more compositions.Optional such packaging is produced in the form of announcing by government organs' specification, with production The open method permitted in regulation uses or sale medicine or biological products, the treatment preparation of use or sale to people.
The abbreviation used in the present invention：
ACN：Acetonitrile；EA：Ethyl acetate；DMF：N,N-dimethylformamide；PE：Petroleum ether；DCM：Dichloromethane； MeOH：Methanol；THF：Tetrahydrofuran；K2CO3：Potassium carbonate；TEA：Triethylamine；DIPEA：Diisopropyl ethyl amine；DMAP：N,N- Dimethyl -4- amido pyridines；TFA：Trifluoroacetic acid；NMP：1-METHYLPYRROLIDONE；Boc：Tertbutyloxycarbonyl；Tris：Three hydroxyl first Base aminomethane；BSA：Bovine serum albumin(BSA)；DTT：Dithiothreitol (DTT)；ATP：Adenosine triphyosphate.
Embodiment
Representational example is intended to help and illustrates the present invention below, and is not necessarily to be construed as limiting the scope of the present invention. In fact, in addition to those occur and be described herein, the full content of file in the present invention, including according to cited herein The example of scientific and technical literature and patent, and resulting various modifications and many are further change in general technology in this specialty Personnel are clearly clear.Following example contains important side information, example and guidance, is adaptable in the present invention Various change and analogue.
The compound covered in the present invention can be synthesized by known conventional art.It is the chemical combination that the present invention synthesizes below The general synthetic schemes of thing.These schemes disclosed herein are descriptive, are not offered as limiting those skilled in the art's use Other possible method synthesis compounds.In addition, different synthesis steps can be applied synthesizes targeted in different schemes Compound.Among all documents cited herein are all incorporated herein by way of reference.
It can be synthesized with compounds of formula I by following scheme.Scheme 1, which describes, synthesizes these intermediates not Same method, these methods can be applied in patent of the present invention in the preparation of the compound with formula I-IV structures.This area Technical staff the synthesis of author's analogue compounds disclosed below can be completed by the various modifications of these methods.
Prepared (scheme 1) as follows with compounds of formula I：
Step 1：Using THF/DMF as solvent, either benzylamine II in the presence of alkali (such as NaH) or passes through coupling method to benzylalcohol React to obtain benzyl oxide or benzylamine III with substituted pyrimidine.
Step 2：Intermediate III takes off Boc under TFA effects and obtains arylamine IV.
Step 3：Intermediate compound IV is under alkali (such as pyridine) effect and acryloyl chloride reacts to obtain final compound I.
Embodiment 1, (R)-N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- three L -4- bases) oxygen) ethyl) propyl group) acrylamide
Synthesis step：
Step 1：The preparation of 3- acetylbenzenes carbamate (compound 2)
Add in dioxane (100mL) solution of 1- (3- aminophenyls) ethyl ketone (compound 1) (8.0g, 59.3mmol) Enter (Boc)2O(16.8g,77.1mmol).Obtained reaction solution is concentrated under reduced pressure after being reacted 4 hours at 150 DEG C.Residue silicagel column Chromatograph (PE:EA=8:1to 4:1) white solid target product (12.4g, 88.6% yield) is obtained.1H NMR(400MHz, CDCl3) δ 7.95 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.60 (d, J=7.8Hz, 1H), 7.37 (t, J=7.9Hz, 1H),6.88(s,1H),2.59(s,3H),1.52(s,9H)。
Step 2：(R)-(3- (1- ethoxys) phenyl) preparation of t-butyl carbamate (compound 3)
(+)-DIP-Cl (5.5g, 17.0mmol), which is dissolved in anhydrous THF (5mL), is cooled to -25 DEG C, then adds 3- acetyl Base phenylcarbamate (2.0g, 8.5mmol).Reaction solution stirring reaction 16 hours at this temperature, are then added Acetaldehyde (748mg, 17.0mmol).Obtained reaction solution was raised to room temperature in 30 minutes, was then concentrated under reduced pressure.Residue is dissolved in Et2O (30mL), then add diethanol amine (1.9g, 25.5mmol).Obtained mixture stirring is until a large amount of white precipitates are given birth to Into then filtering.Filter vacuum is concentrated under reduced pressure, residue silica gel column chromatography1H NMR(400MHz,DMSO-d6)δ9.28(s, 1H), 7.51 (s, 1H), 7.30-7.21 (m, 1H), 7.16 (t, J=7.8Hz, 1H), 6.92 (d, J=7.5Hz, 1H), 5.12 (d, J=4.0Hz, 1H), 4.64 (dd, J=6.3,4.2Hz, 1H), 1.47 (s, 9H), 1.29 (d, J=6.4Hz, 3H).
Step 3：(R)-(3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- (trifluoros Methyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) and t-butyl carbamate (compound 5) preparation
(R)-(3- (1- ethoxys) phenyl) t-butyl carbamate (237mg, 1mol) is dissolved in dry dioxane In (20mL) solution, 10 DEG C are cooled to, NaH (240mg, 60%wt, 6mmol) was then added portionwise in 10 minutes.Obtain Mixture dissolves away the insoluble matter of bottle wall in room temperature reaction half an hour, then addition DMF (5mL).Disposably add into above-mentioned solution Enter 1- (4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3- Methoxyphenyl) pip erazin-1-yl) ethan-1-one (compound 4) (214mg, 0.5mmol), obtained mixing Thing reacts 2 hours at 75 DEG C and then is cooled to room temperature.With vigorous stirring toward addition frozen water (150mL) in reaction solution, Ran Houyong DCM (2x50mL) is extracted.Extract merges, and is concentrated under reduced pressure after drying, residue silica gel column chromatography obtains yellow solid target Compound (150mg (AP:70%), 33% thick yield).LC-MS:m/z 631(M+H)+。
Step 4：(R) -1- (4- (4- ((4- (1- (3- aminophenyls) ethyoxyl) -5- (trifluoromethyl) pyrimidine -2-base) ammonia Base) -3- methoxyphenyls) piperazine -1- bases) and ethyl ketone (compound 6) preparation
Compound 5 (150mg, 0.17mmol) is dissolved in DCM (10mL), is cooled to 0 DEG C, is then added dropwise to TFA (0.5mL). Reaction solution is slowly raised to room temperature and reacted at room temperature 2 hours, is then slowly dropped in 5 minutes in stirring S.aq.NaHCO3In (30mL) solution.Obtained mixture is extracted with DCM (2x10mL).Extract merges, and uses saturated aqueous common salt Dried after (2x15mL) washing, be then concentrated under reduced pressure to give yellow solid crude product (130mg, 100% thick yield) and directly use Reacted in next step.LC-MS:m/z 531(M+H)+.
Step 5：(R)-N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- trifluoros Methylpyrimidine -4- bases) oxygen) ethyl) propyl group) acrylamide (compound 7) preparation
The crude product of compound 6 (130mg, 0.24mol) that upper step obtains is dissolved in dry DCM (10mL) solution, be cooled to- 30 DEG C, pyridine (0.2mL) is then added, with the DCM (0.5mL) for the drying that acryloyl chloride (32mg, 0.36mmol) is added dropwise Solution.Obtained mixture is subsequently poured into frozen water (20mL) for 15 minutes in -30 DEG C of reactions, then is extracted with DCM (2x10mL).Extraction Vacuum-concentrcted after taking liquid merging dry.Residue with liquid chromatogram be prepared white solid target product (11mg, 13% yield).1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.85 (m, 2H), 7.49 (m, 3H), 7.31 (t, J= 7.8Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 6.57 (d, J=8.7Hz, 1H), 6.53-6.38 (m, 2H), 6.27 (m, 2H), 5.79 (d, J=10.2Hz, 1H), 3.86 (s, 3H), 3.80-3.69 (m, 2H), 3.70-3.53 (m, 2H), 3.28-2.96 (m, 4H), 2.15 (s, 3H), 1.61 (d, J=6.6Hz, 3H) .LC-MS:m/z 585(M+H)+.
Embodiment 2, (S)-N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- three L -4- bases) oxygen) ethyl) propyl group) acrylamide
Synthetic method such as embodiment 1,
1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.86 (m, 2H), 7.57 (m, 3H), 7.30 (t, J=7.8Hz, 1H), 7.16 (d, J=7.4Hz, 1H), 6.64-6.37 (m, 3H), 6.28 (m, 2H), 5.78 (d, J=10.3Hz, 1H), 3.87 (s, 3H), 3.80-3.70 (m, 2H), 3.69-3.54 (m, 2H), 3.22-2.98 (m, 4H), 2.19 (s, 3H), 1.66 (d, J= 6.6Hz,3H).LC-MS:m/z 585(M+H)+.
Embodiment 3, N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- fluoroforms Yl pyrimidines -4- bases) oxygen) ethyl) propyl group) acrylamide
Synthetic method such as embodiment 1,
1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.85 (m, 2H), 7.48 (m, 3H), 7.31 (t, J=7.8Hz, 1H), 7.16 (d, J=7.6Hz, 1H), 6.64-6.37 (m, 3H), 6.27 (m, 2H), 5.79 (d, J=10.2Hz, 1H), 3.86 (s, 3H), 3.82-3.70 (m, 2H), 3.68-3.58 (m, 2H), 3.25-2.91 (m, 4H), 2.06 (s, 3H), 1.66 (d, J= 6.5Hz,3H).LC-MS:m/z 585(M+H)+.
Embodiment 4, N- (3- (1- ((2- ((2- methoxyl group -4- morpholinyl phenyls) amino) -5-5- trifluoromethyl pyrimidines -4- Base) oxygen) ethyl) propyl group) acrylamide
Synthetic method such as embodiment 1,
1H NMR(400MHz,CDCl3)δ8.35(s,1H),8.00-7.15(m,7H),6.68-6.61(m,2H),6.48- 6.35 (m, 1H), 6.34-6.24 (m, 2H), 5.78 (d, J=4.8Hz, 1H), 3.92-3.86 (m 7H), 3.19 (m, 4H), 1.82 (d, J=8.4Hz, 3H) .LC-MS:m/z 544(M+H)+.
Embodiment 5, (R)-N- (3- (1- ((2- ((2- methoxyl group -4- morpholinyl phenyls) amino) -5-5- trifluoromethyl pyrimidines - 4- yls) oxygen) ethyl) propyl group) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3) δ 8.34 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.53 (d, J= 10.0Hz, 1H), 7.43 (s, 1H), 7.31 (t, J=7.9Hz, 1H), 7.26-7.22 (m, 1H), 7.17 (d, J=7.6Hz, 1H), 6.57 (d, J=8.8Hz, 1H), 6.53-6.39 (m, 2H), 6.26 (m, 2H), 5.79 (d, J=10.2Hz, 1H), 3.92- 3.83 (m, 7H), 3.20-3.09 (m, 4H), 1.67 (d, J=6.6Hz, 3H) .LC-MS:m/z 544(M+H)+.
Embodiment 6, (R)-N- (3- (1- ((2- ((4- (isopropylamino) -2- methoxyphenyls) amino) -5- (fluoroforms Base) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.68(s,1H),8.34(s,1H),7.87–7.62(m, 1H), 7.57 (d, J=6.4Hz, 1H), 7.42-6.61 (m, 3H), 6.43 (m, 1H), 6.25 (m, 2H), 6.11 (m, 1H), 5.95 (m, 1H), 5.76 (m, 1H), 5.36 (m, 1H), 3.63 (m, 3H), 3.56 (m, 1H), 1.54 (m, 3H), 1.14 (t, J= 6.7Hz,6H).LC-MS:m/z 516(M+H)+.
Embodiment 7, (R)-N- (3- (1- ((2- ((4- (6- acetyl group -2,6- diaza spiroheptane -2- bases) -2- Methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.72(s,1H),8.36(s,1H),7.75(s,1H), 7.55(m,1H),7.27-7.15(m,3H),6.48-5.75(m,5H),4.30(s,2H),4.00(s,2H),3.94(s,4H), 3.71(s,3H),1.76(s,3H),1.53(s,3H).LC-MS:m/z 597(M+H)+.
Embodiment 8, (R)-N- (3- (1- ((2- ((4- (4- acetyl group -4,7- diaza spiro [2.5] octane -7- bases) -2- Methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3) δ 8.33 (s, 1H), 7.82 (m, 2H), 7.50 (m, 3H), 7.31 (t, J=7.6Hz, 1H), 7.16 (d, J=7.0Hz, 1H), 6.56-6.37 (m, 3H), 6.27 (m, 2H), 5.80 (m, 1H), 4.06-3.69 (m, 5H),3.20(m,2H),2.98(s,2H),2.27–1.99(m,4H),1.09(m,4H).LC-MS:m/z 611(M+H)+.
Embodiment 9, (R)-N- (3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- Methoxyphenylaminos) -5- (trifluoros Methyl) pyrimidine-4-yl oxygen) ethyl) -4- chlorphenyls) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3) δ 8.36 (s, 1H), 7.93 (d, J=7.7Hz, 1H), 7.39-7.32 (m, 2H), 6.60-6.50 (m, 3H), 6.43 (dd, J=16.8,0.9Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H), 5.78 (d, J =11.0Hz, 1H), 3.86 (s, 3H), 3.82-3.77 (m, 2H), 3.68-3.62 (m, 2H), 3.17-3.09 (m, 4H), 2.16 (s, 3H), 1.66 (d, J=6.5Hz, 3H)；LC-MS:m/z 619(M+H)+.
Embodiment 10, (R)-N- (3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- Methoxyphenylaminos) -5- (three Methyl fluoride) pyrimidine-4-yl oxygen) ethyl) -5- fluorophenyls) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.67-7.60(m,2H),7.47–7.36(m,2H),6.84 (d, J=8.6Hz, 1H), 6.59-6.43 (m, 3H), 6.30-6.13 (m, 2H), 5.84-5.77 (m, 1H), 3.86 (s, 3H), 3.81-3.75 (m, 2H), 3.66-3.61 (m, 2H), 3.19-3.09 (m, 4H), 2.16 (s, 3H), 1.65 (d, J=6.6Hz, 3H).LC-MS:m/z 603(M+H)+.
Embodiment 11, N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- (trifluoros Methyl) pyrimidine-4-yl) amino) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3) δ 8.14 (s, 1H), 7.79 (m, 3H), 7.49 (s, 1H), 7.38 (d, J=7.5Hz, 1H), 7.30 (t, J=7.8Hz, 1H), 7.09 (d, J=7.5Hz, 1H), 6.56-6.12 (m, 4H), 5.78 (d, J=10.2Hz, 1H), 5.35 (m, 2H), 3.77 (m, 5H), 3.60 (t, J=4.9Hz, 2H), 3.10 (s, 4H), 2.14 (s, 3H), 1.58 (d, J =6.6Hz, 3H) .LC-MS:m/z 584(M+H)+.
Embodiment 12, (R)-N- (3- (1- ((2- ((4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) amino) -5- Chlorine pyrimidine-4-yl) oxygen) ethyl) propyl group) acrylamide
Synthetic method such as embodiment 1
1H NMR(400MHz,CDCl3) δ 8.11 (s, 1H), 7.92 (d, J=8.7Hz, 1H), 7.78 (s, 1H), 7.45 (d, J=7.7Hz, 1H), 7.34 (m, 3H), 7.19 (d, J=7.7Hz, 1H), 6.59-6.42 (m, 3H), 6.24 (m, 2H), 5.80 (m,1H),3.86(s,3H),3.81–3.74(m,2H),3.67–3.61(m,2H),3.19–3.05(m,4H),2.15(s,3H), 1.69 (d, J=6.6Hz, 3H) .LC-MS:m/z 551(M+H)+.
Embodiment 13, (R)-N- (3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- chlorphenylaminos) -5- (fluoroforms Base) pyrimidine-4-yl oxygen) ethyl) phenyl) acrylamide
Synthesis step：
Step 1：(R) preparation of -3- (1- (the chloro- 5- iodine pyrimidines -4- bases oxygen of 2-) ethyl) phenylcarbamate
(R) -3- (1- ethoxys) phenylcarbamate (4.0g, 16.8mmol) and sodium tert-butoxide are dissolved in THF In (100mL), -10 DEG C are cooled to, then adds the chloro- 5- iodine pyrimidines (5.1g, 18.5mmol) of 2,4- bis-.Reaction solution is protected in nitrogen Reacted 10 minutes at -10 DEG C under shield, then add water (100mL).EA is extracted with ethyl acetate in obtained mixture (3x100mL).Organic phase is washed after merging, and uses anhydrous Na2SO4Vacuum-concentrcted after drying, residue column chromatography purify to obtain Yellow oily (R) -3- (1- (the chloro- 5- iodine pyrimidines -4- bases oxygen of 2-) ethyl) phenylcarbamate (7.5g, 93% production Rate).LC-MS:m/z:476(M+H)+.
Step 2：(R) -3- (1- (2- chloro- 5- (trifluoromethyl) pyrimidine-4-yls oxygen) ethyl) phenylcarbamate Preparation
(R) -3- (1- (the chloro- 5- iodine pyrimidines -4- bases oxygen of 2-) ethyl) phenylcarbamate (7.5g, 15.7mmol) DMFF (40mL) is dissolved in cuprous iodide (6.0g, 31.5mmol), then adds methyl 2, the fluoro- 2- (fluorosulfonyl) of 2- bis- Methyl acetate (6.1g, 31.5mmol).Reaction solution reacts 3 hours at 100 DEG C under nitrogen protection, then adds H2O (200mL).EA (3x200mL) is extracted with ethyl acetate in obtained mixture.Organic phase is washed after merging, and uses anhydrous Na2SO4It is dry Vacuum-concentrcted after dry, residue column chromatography purify to obtain colorless oil (R) -3- (1- (2- chloro- 5- (trifluoromethyl) pyrimidine - 4- bases oxygen) ethyl) phenylcarbamate (3.1g, 47% yield).LC-MS:m/z:418(M+H)+.
Step 3：(R) -3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- chlorphenylaminos -5- (trifluoromethyl) pyrimidine - 4- bases oxygen) ethyl) phenylcarbamate preparation
(R) -3- (1- (2- chloro- 5- (trifluoromethyl) pyrimidine-4-yls oxygen) ethyl) phenylcarbamate (200mg, 0.5mol), 1- (4- (4- amino -3- chlorphenyls) piperazine -1- bases) ethyl ketone (430mg, 1mmol), Pd2(dba)3(96.0mg, 0.1mmol) and Xant-phos (58.0mg, 01mmol) is dissolved in toluene (10mL), then adds Cs2CO3(0.5g,1.5mmol)。 Reaction solution reacts 16 hours at 100 DEG C under nitrogen protection, subsequent vacuum-concentrcted.Residue diluted with ethyl acetate after again It is washed with water, vacuum-concentrcted after drying, residue column chromatography purifies to obtain yellow solid (R) -3- (1- (2- (4- (4- acetyl Piperazine -1- bases) -2- chlorphenylaminos -5- (trifluoromethyl) pyrimidine-4-yls oxygen) ethyl) phenylcarbamate (140mg,AP：80%).LC-MS:m/z:635(M+H)+.
Step 4：(R) -1- (4- (4- ((4- (1- (3- aminophenyls) ethyoxyl) -5- (trifluoromethyl) pyrimidine -2-base) ammonia Base) -3- chlorphenyls) piperazine -1- bases) and ethyl ketone preparation
(R) -3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- chlorphenylaminos -5- (trifluoromethyl) pyrimidine-4-yls Oxygen) ethyl) phenylcarbamate (140mg, AP：80%) it is dissolved in 2,6- lutidines (250mg, 2.5mmol) Dry DCM (10mL), is cooled to 0 DEG C, is then added dropwise to TMSOTf (0.55g, 2.5mmol).Reaction solution is at the same temperature Stirring terminates until reacting, and is then quenched with water.Anhydrous Na is used after organic phase separation2SO4Vacuum-concentrcted obtains Huang after drying Color oily crude product (R) -1- (4- (4- ((4- (1- (3- aminophenyls) ethyoxyl) -5- (trifluoromethyl) pyrimidine -2-base) ammonia Base) -3- chlorphenyls) piperazine -1- bases) ethyl ketone (110mg, AP：70%), it is directly used in without purifying and reacts in next step.LC-MS: m/z:535(M+H)+.
Step 5：(R)-N- (3- (1- (2- (4- (4- acetylpiperazine -1- bases) -2- chlorphenylaminos) -5- (trifluoromethyl) Pyrimidine-4-yl oxygen) ethyl) phenyl) and acrylamide preparation
(R) -1- (4- (4- ((4- (1- (3- aminophenyls) ethyoxyl) -5- (trifluoromethyl) pyrimidine -2-base) amino) -3- Chlorphenyl) piperazine -1- bases) ethyl ketone (110mg, AP：70%) and pyridine (0.4mL) is dissolved in dry DCM (10mL), is cooled to 0 DEG C, then it is added dropwise to DCM (0.5mL) solution of the drying of acryloyl chloride (0.1mL).Reactant mixture reacts at the same temperature 15 minutes, then it is quenched with water.Obtained mixture is extracted (3x10mL) with DCM.Organic phase is washed after merging, and use is anhydrous Na2SO4Vacuum-concentrcted after drying, residue obtain white solid (R)-N- (3- (1- (2- (4- with chromatogram purification is prepared (4- acetylpiperazine -1- bases) -2- chlorphenylaminos) -5- (trifluoromethyl) pyrimidine-4-yls oxygen) ethyl) phenyl) acrylamide (35mg, 29% yield).1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.84(s,2H),7.66(s,1H),7.39(s, 2H), 7.30 (t, J=6.8Hz, 1H), 7.13 (d, J=7.1Hz, 1H), 6.90 (m, 2H), 6.45 (m, 1H), 6.28 (m, 1H), 6.20 (d, J=6.1Hz, 1H), 5.79 (m, 1H), 3.76 (m, 2H), 3.62 (m, 2H), 3.23-3.02 (m, 4H), 2.15 (s, 3H), 1.65 (d, J=6.5Hz, 3H) .LC-MS:m/z:589(M+H)+.
Embodiment 14, ((((2- (4- (4- acetylpiperazine -1- bases)-phenyl amino) -5- trifluoromethyls are phonetic by 1- by 3- by (R)-N- Pyridine -4- bases) oxygen) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 13
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.86(s,2H),7.66(s,1H),7.45-7.25(m,4H), 7.13 (d, J=6.9Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.46 (m, 1H), 6.31 (m, 1H), 6.15 (q, J= 6.5Hz,1H),5.78(m,1H),3.83–3.71(m,2H),3.68–3.58(m,2H),3.19–3.01(m,4H),2.15(s, 3H), 1.64 (d, J=6.6Hz, 3H) .LC-MS:m/z:555(M+H)+.
Embodiment 15, (2- ((2- methoxyl group -4- morpholines phenyl) amino) -5- (trifluoromethyl) is phonetic for 4- acryloyls amine-n - Pyridine -4- bases)-N-methyl-benzamide
Synthesis step：
Step 1：The preparation of the chloro- N- of 4- (2- methoxyl group -4- morpholines phenyl) -5- (trifluoromethyl) pyrimidine -2- amine
Chloro- 5- (trifluoromethyl) pyrimidines (1.6g, 7.37mmol) of 2,4- bis- are dissolved in DCE/tBuOH (1:1,80mL), cool down To 0 DEG C, ZnCl is then added dropwise under nitrogen protection2Diethyl ether solution (1M, 8.1mL, 8.1mmol).It is added dropwise, reaction solution Continuing reaction one hour at 0 DEG C, then added in order in 15 minutes 2- methoxyl group -4- morpholines aniline (1.6g, DCE/tBuOH solution (1 7.37mmol):1,15mL) and TEA (8.2g, 8.1mmol) DCE/tBuOH solution (1:1, 5mL).Obtained mixture is raised to room temperature reaction overnight.Water and ethyl acetate are added after reaction solution concentration, is continued after aqueous phase separation It is extracted with ethyl acetate.Organic phase merges with dry concentration after saturated common salt water washing.Residue is purified to obtain mesh with column chromatography Mark product (1.1g, 38.4% yield).LC-MS:m/z 389(M+H)+.
Step 2：N2- (2- methoxyl group -4- morpholines phenyl)-N4The system of-methyl 5- (trifluoromethyl) pyrimidine -2,4- diamines It is standby
The chloro- N- of 4- (2- methoxyl group -4- morpholines phenyl) -5- (trifluoromethyl) pyrimidine -2- amine (1g) is dissolved in MeOH In (10mL), NH is then added2CH3/ EtOH solution (10mL).After adding, then reactant concentrates for 1 hour in room temperature reaction.It is residual Excess is purified to obtain target product (950mg, 96.3% yield) with column chromatography.LC-MS:m/z 384(M+H)+.
Step 3：N- (2- ((2- methoxyl group -4- morpholines phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl)-N- methyl - The preparation of 4- nitrobenzamides
N2- (2- methoxyl group -4- morpholines phenyl)-N4- methyl -5- (trifluoromethyl) pyrimidine -2,4- diamines (504mg, Anhydrous pyridine (5mL) 1mmol) is dissolved in, is raised to 60 DEG C, then adds 4- nitrobenzoyl chlorides (371mg, 2mmol).Mixture exists Reacted 4 hours at a temperature of this, be then concentrated to give target product, without purifying, be directly used in and react in next step.LC-MS:m/ z 533(M+H)+.
Step 4：4- amino-N- (2- ((2- methoxyl group -4- morpholines phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl) - The preparation of N-methyl-benzamide
N- (2- ((2- methoxyl group -4- morpholines phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl)-N- methyl -4- nitros Benzamide (262mg, 0.5mmol) is dissolved in EtOH (5mL), then adds SnCl2.2H2O(451mg,2mmol).Reactant exists It is quenched after room temperature reaction 4hr with frozen water.Obtained mixture is transferred to pH 14, is then extracted with ethyl acetate.Organic phase merges dry Concentrated after dry, obtained residue column chromatography purifies to obtain target product (95mg, 37.8% yield).LC-MS:m/z 503(M+ H)+.
Step 5：4- acryloyls amine-n-(2- ((2- methoxyl group -4- morpholines phenyl) amino) -5- (trifluoromethyl) pyrimidine - 4- yls)-N-methyl-benzamide preparation
4- amino-N- (2- ((2- methoxyl group -4- morpholines phenyl) amine) -5- (trifluoromethyl) pyrimidine-4-yl)-N- methyl Benzamide (63mg, 0.125mmol) is dissolved in DCM (5mL), is cooled to 0 DEG C, then adds pyridine (79mg, 1mmol) and propylene Acyl chlorides.Reaction solution vacuum-concentrcted, obtained residue after reacting at room temperature 2 hours obtain target with column chromatography purifies and separates Product (10mg, 14.3% yield).LC-MS:m/z 557(M+H)+.1H NMR(CDCl3)δ8.17(s,1H),7.66-7.69 (d, J=8.4Hz, 2H), 7.55-7.57 (d, J=8.4Hz, 2H), 7.35 (s, 1H), 7.08-7.09 (d, J=9.2Hz, 2H), 7.44-7.54(m,3H),6.20-6.28(m,1H),5.80-5.82(m,1H),5.03(s,1H),3.84-3.87(m,4H), 3.74(s,1H),3.19-3.21(m,1H),2.45-2.46(m,3H).
Embodiment 16, (2- ((2- methoxyl group -4- morpholines phenyl) amino) -5- (trifluoromethyl) is phonetic for 3- acryloyls amine-n - Pyridine -4- bases)-N-methyl-benzamide
Synthetic method such as embodiment 15
LC-MS:m/z 557(M+H)+.1H NMR(CDCl3) δ 8.19 (s, 1H), 7.97-8.00 (d, J=8.4Hz, 2H), 7.66-7.69 (d, J=8.4Hz, 2H), 7.25-7.40 (m, 4H), 7.07-7.10 (d, J=9.2Hz, 2H), 7.52-7.54 (m, 1H), 6.40-6.45 (m, 1H), 5.03-5.04 (d, J=8Hz, 1H), 4.84-4.85 (d, J=8Hz, 1H), 3.85- 3.87 (m, 4H), 3.74-3.76 (d, J=6.4Hz, 3H), 3.20-3.22 (m, 4H), 2.40 (s, 3H)
Embodiment 17, (R)-N- (3- (1- ((2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -5- (trifluoromethoxy) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthesis step：
Step 1：(R)-(3- (1- ((2- ((2- methoxyl groups -4- (4- methyl piperidine -1- bases) phenyl) amino) -5- (trifluoros Methyl) pyrimidine-4-yl) oxygen) ethyl) phenylcarbamate preparation
(R)-(3- (1- ((the chloro- 5- trifluoromethyls of 2-) pyrimidine-4-yl) oxygen) ethyl) phenylcarbamate (450mg, 1.08mmol) and triethylamine (1mL) are dissolved in acetonitrile (10mL), add 2- methoxyl groups -4- (4- methyl piperazines -1- Base) aniline (477mg, 2.16mmol).Reaction opening is heated to 130 DEG C, and solvent is stirred for 30 minutes after evaporating, and is as cold as Room temperature.Column chromatography (petroleum ether:Ethyl acetate=1:1 arrives dichloromethane:Methanol=15:1 with 0.5% triethylamine) obtain one Oily compound crude product (740mg).
Step 2：(R) -4- (1- (3- amine phenyl) ethyoxyl)-N- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) benzene Base) -5- (trifluoromethoxy) pyrimidine -2- amine preparation
(R)-((((2- ((2- methoxyl groups -4- (4- methyl piperidine -1- bases) phenyl) amino) -5- (trifluoromethyl) is phonetic by 1- by 3- Pyridine -4- bases) oxygen) ethyl) phenylcarbamate (740mg, crude product) and 2,6- lutidines (0.9mL, 8.1mmol) It is dissolved in anhydrous methylene chloride (10mL), drops to 0 DEG C, TMSOTf (1.5mL, 8.1mmol) is added dropwise.Reaction is small in 0 DEG C of stirring one When, it is poured into water (30mL), dichloromethane is extracted twice (20mL x 2).Organic layer is washed with saturated aqueous common salt (30mL), anhydrous Sodium sulphate is dried, concentration, column chromatography for separation (petroleum ether:Ethyl acetate=1:1 arrives dichloromethane:Methanol=15:1) yellow is obtained Grease crude product (500mg).LC-MS:m/z 503(M+H)+.
Step 3：(R)-N- (3- (1- ((2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) -5- (three Fluorine methoxyl group) pyrimidine-4-yl) oxygen) ethyl) phenyl) and acrylamide preparation
(R) -4- (1- (3- amine phenyl) ethyoxyl)-N- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) -5- (three Fluorine methoxyl group) pyrimidine -2- amine (500mg, crude product) is dissolved in anhydrous methylene chloride (100mL), is as cold as -40 DEG C, add pyridine (0.6mL) and acryloyl chloride (0.3mL).Reaction is stirred 15 minutes at -40 DEG C, is poured into water (50mL), organic layer is eaten with saturation Salt is washed, anhydrous sodium sulfate drying, concentration, is prepared HPLC (neutrality) and is separated to obtain final product (10mg).1H NMR(400MHz, CDCl3)8.33(s,1H),7.80-7.90(m,1H),7.68(s,1H),7.48-7.52(m,2H),7.26-7.31(m,2H), 7.15 (d, J=7.6Hz, 1H), 6.42-6.58 (m, 3H), 6.23-6.30 (m, 2H), 5.78 (d, J=10.0Hz, 1H), 3.85 (s, 3H), 3.20 (t, J=5.2Hz, 4H), 2.60 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.66 (d, J=6.8Hz, 3H).LC-MS:m/z 557(M+H)+.
Embodiment 18, (R)-N- (3- (1- ((the chloro- 2- of 5- ((2-methoxy-4- (4- methylpiperazine-1-yls) phenyl) ammonia Base) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method such as embodiment 17
1H NMR(400MHz,CDCl3) 8.10 (s, 1H), 7.86 (d, J=8.8Hz, 1H), 7.73 (s, 1H), 7.47- 7.52 (m, 2H), 7.28-7.34 (m, 2H), 7.17 (d, J=7.6Hz, 1H), 6.42-6.55 (m, 3H), 6.27-6.35 (m, 1H), 6.18-6.21 (m, 2H), 5.77-5.80 (m, 1H), 3.84 (s, 3H), 3.25 (t, J=4.4Hz, 4H), 2.75 (t, J= 4.4Hz, 4H), 2.47 (s, 3H), 1.69 (d, J=6.4Hz, 3H) .LC-MS:m/z 523(M+H)+.
Embodiment 1-18 Bioexperiment test
The kinases IC50 that such compound is mutated to EGFR wild types and EGFR-T790M is tested：EGFR (WT) is wild type EGF-R ELISA, EGFR (T790M) are that the epidermis for sporting methionine by threonine with the 790th amino acids is given birth to Growth factor receptor body, EGFR (L858R) are to sport arginic epidermal growth factor receptor by leucine with the 858th amino acids Body, EGFR (L858R/T790M) are to sport arginine and the 790th bit amino by leucine simultaneous with the 858th amino acids Acid is sported the EGF-R ELISA of methionine by threonine.
Kinase activity detects：This test uses Kinase-Glo Plus luminescence kinase Assay kit (are purchased from Promega companies).It remains ATP contents to detect kinases work after swashing enzymatic reaction by quantitative analysis Property.Fluorescence signal in test is related to existing ATP contents.50uL reaction solution, including 40mM Tris, pH 7.4 are configured, 10mM MgCl2,0.1mg/ml BSA,1mM DTT,0.2mg/ml Poly(Glu,Tyr)substrate,10M ATP and EGFR.Testing compound is made into 10%DMSO solution, takes 5uL to be diluted in the above-mentioned reaction solutions of 50uL and obtains final DMSO concentration For 1% reaction solution.All enzymic catalytic reactions are carried out 35 minutes all at 30 DEG C.It is first for the reaction of preincubation in 30 minutes, enzyme Hatch 30 minutes with inhibitor, then add ATP and substrate starts to react.After enzymic catalytic reaction terminates, added in reaction solution 50uL Kinase-Glo Plus Luminescence kinase assay solution, continue in incubation at room temperature 5 minutes. Measured during fluorescence signal by BioTek Synergy 2microplate reader.
IC50 is calculated with GraphPadPrism5.00 (four parameter logistic equations).Data are real in following table The biological test data that a 1-18 corresponds to compound are applied, are measured with the method outlined supra.
*NA:Do not test
In competition experiments containing benzyl oxide, benzylamine or aryl amide compound and ATP, due to presence and protein cysteine Site forms irreversible Michael addition reaction, so all embodying higher inhibitory activity to kinases.

Claims (3)

1. a kind of T790M mutant egfs R inhibitor, the inhibitor is selected from the compound of following structural formula,
2. a kind of pharmaceutical composition, the pharmaceutical composition contains at least one inhibitor as claimed in claim 1 or the suppression Preparation pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
3. application of the inhibitor described in claim 1 in antineoplastic is prepared, it is characterised in that：The tumour is non-small Cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer.
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