CN110467638A - A kind of double amino Chloropyrimide class compounds containing m-chloroaniline class substituent group, preparation method and applications - Google Patents

A kind of double amino Chloropyrimide class compounds containing m-chloroaniline class substituent group, preparation method and applications Download PDF

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CN110467638A
CN110467638A CN201810728288.2A CN201810728288A CN110467638A CN 110467638 A CN110467638 A CN 110467638A CN 201810728288 A CN201810728288 A CN 201810728288A CN 110467638 A CN110467638 A CN 110467638A
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base
propyl
acid
methyl
ethyl
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张强
冯守业
王中祥
徐占强
杨海龙
张宏波
周利凯
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Beijing Saite Mingqiang Medicine Technology Co Ltd
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

It is an object of the invention to solve the problems, such as kinase inhibitor drug drug resistance in the prior art, provide a kind of double amino Chloropyrimide class compounds containing m-chloroaniline class substituent group, preparation method and applications, more particularly to compound shown in formula (I), its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its prodrug, preparation method and its preparing the application in the drug as kinase inhibitor.The compounds of this invention is to mutant egf RT790MAnd EGFRC797SKinases all has good inhibitory activity, while showing and also have appropriate inhibitory activity to Wild type EGFR kinases.

Description

A kind of double amino Chloropyrimide class compounds containing m-chloroaniline class substituent group, system Preparation Method and its application
Technical field
The invention belongs to pharmaceutical technology fields, are related to Chloropyrimide class compound, the preparation method of a kind of double amino substitutions And its application.
Background technique
Protein kinase is the important signal envoy of cell activities, can be catalyzed the γ of the end ATP-phosphate group transfer On hydroxyl receptor into substrate amino acid residue (serine, threonine, tyrosine), to activate target protein (Johnson L.N.,and Lewis R.J.,Structural basis for control by phosphorylation, Cheminform,2001,101,2209.).Protein kinase takes part in numerous physiology courses, including cell Proliferation, survives, withers (Adams J.A., the Kinetic and catalytic mechanisms of protein such as die, be metabolized, transcribe and break up kinases,Chemical reviews,2001,101,2271.).In the existing drug target of human body, protein kinase family at Member's accounting is up to 10% (Santos R., Ursu O., Gaulton A., et al., A comprehensive map of molecular drug targets,Nature Reviews Drug Discovery,2017,16,19.)。
EGF-R ELISA (ErbB) tyrosine kinase can adjust through a variety of ways cell Proliferation, migration, differentiation, Apoptosis and cell are mobile.In the malignant tumour of diversified forms, ErbB family member and its some ligands are usually overexpressed, Amplification or mutation, this becomes important therapeutic targets.The family protein kinases includes: ErbB1/EGFR/HER1, ErbB2/ HER2, ErbB3/HER3 and ErbB4/HER4.Wherein EGFR is the important target spot (Dienstmann for developing non-small cell lung cancer R.,et.al.,Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer,ONCOTARGET,2001,2(3),165.)。
Gefitinib (Gefitinib), Erlotinib (Erlotinib), Conmana (Icotinib) are first generation targets To the reversible kinase inhibitor of EGFR, for treating non-small cell carcinoma.Such inhibitor is simultaneously to wild type and activated mutant Type EGFR is inhibited, and clinically achieves biggish success, but subject patient takes drug resistance after a period of time Property appearance, especially T790M be mutated caused by drug resistance make curative effect reduce or failure.Second generation EGFR inhibitor Afatinib It (Afatinib) is non-reversible type inhibitor, it, can be with the half Guang ammonia positioned at ATP binding pocket inlet containing michael acceptor Covalent bonding together occurs for sour residue (Cys797), which is directed to T790M mutant egf R kinases and Wild type EGFR kinases Extremely strong activity is shown, and Wild type EGFR kinases is higher than for the inhibitory activity of T790M mutant egf R kinases, this makes It is relatively narrow to obtain treatment window in clinical drug application, using effect unsatisfactory (Camidge, D.R., et.al., Acquired resistance to TKIs in solid tumours:learning from lung cancer.Nature Reviews Clinical Oncology,2014,11,473.).EGFR kinase inhibitor Austria of the third generation it is uncommon for Buddhist nun (Osimertinib) and It is difficult to understand that the highly selective suppression that Wild type EGFR kinases is compared to T790M mutant egf R kinases is not realized for Buddhist nun (Olmutinib) System, has widened clinical use window, has realized effective treatment to T790M mutated patient.Unfortunately, three generations EGFR kinases presses down Preparation clinically also produces drug resistance phenomenon after a period of use.One of its reason is since EGFR produces C797S Secondary mutation.The mechanism of action of existing three generations's small molecule EGFR inhibitor and target is that the Cys797 of drug molecule and EGFR are formed Covalent bond.But when the secondary mutation of C797S occurring in patient body, drug molecule loses the covalent bond with Cys797, leads Cause failure (the Harun Patel., et.al., 2017, Recent updates on third generation EGFR of drug inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance,Eur J Med Chem.,2017,142,32).Based on this, exploitation has to T790M mutant egf R kinases Good inhibitory activity, while there is the newtype drug molecule to the good inhibitory activity of C797S mutant egf R kinases with weight Want meaning.
Brigatinib is a kind of ALK inhibitor of targeting, is researched and developed by Ariad pharmaceuticals and in 2017 U.S. Nian Huo FDA approval lists the non-small cell lung cancer for treating the ALK positive.According to the literature, Brigatinib is to C797S saltant type EGFR kinases has certain inhibiting effect.
It is learnt from the crystal structure (5J7H) in Protein Data Bank (RCSB Protein Data Bank), Piperidine ring in Brigatinib compound structure phenyl ring coupled in the interaction with alk protein forms closely In 90 degree of dihedral angle.However, the coupled phenyl ring of piperidines ring nitrogen is formed by conjugated system and makes piperidines Ring tends to the dihedral angle that coupled phenyl ring formation is bordering on 0 degree.
As shown in above-mentioned compound structure (A) and (B), replace group (Cl etc.) will have in the introducing on position of facing of phenyl ring Help the transposition between piperidine ring and phenyl ring, is more advantageous to its compound three-dimensional structure and forms interaction with alk protein.This Kind structural modification will greatly increase compound (A) and (B) and similar compound to the bioactivity of alk protein.For same One reason, compound (A) and (B) and similar compound will also greatly improve the bioactivity of the C797S EGFR being mutated.
Summary of the invention
A purpose of the invention is to solve the problems, such as kinase inhibitor drug drug resistance and adverse reaction in the prior art, mentions For compound shown in a kind of formula (I), its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its prodrug,
In formula (I),
R1For unsubstituted or substituted aryl, heteroaryl, naphthenic base, naphthenic base caged scaffold or simultaneously ring structure,
Substituted aryl, heteroaryl, naphthenic base, substituent group is-CF in naphthenic base caged scaffold or simultaneously ring structure3,-OCF3, Hydroxyl, cyano, halogen, C1-C6Alkyl, C3-C5Naphthenic base, C1-C6Alkoxy, C3-C5Cycloalkyl oxy ,-S (=O)2R6,-C (= O)R6,-P (=O) R6R7,-S (O)2NR6R7,
R6And R7It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base；
Described and ring structure is selected from aromatic ring and 5-6 member heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, and aromatic ring is simultaneously Simultaneously 5-6 member is miscellaneous for 5-6 member naphthenic base, aromatic ring and 5-6 circle heterocyclic ring base, 5-6 member hetero-aromatic ring and 5-6 member naphthenic base or 5-6 member hetero-aromatic ring Ring group；
R2For-H ,-CF3,-OCF3, hydroxyl, cyano, C1-C6Alkyl, C3-C4Naphthenic base, C1-C6Alkoxy, C3-C6Naphthenic base Oxygroup；
R3For-H ,-CF3, C1-C6Alkyl, C3-C6Naphthenic base, C3-C4The C that naphthenic base replaces1-C2Alkyl, or-OR8,
R8For-H ,-CF3,-CH2CF3, C1-C6Alkyl, C3-C6Naphthenic base, C3-C4The C that naphthenic base replaces1-C2Alkyl contains one The 4-6 circle heterocyclic ring base of a oxygen atom, or-(CH2)mR9,
Wherein m is 1,2,3 integers,
R9For-OH ,-CN ,-C (O) NH2,-S (=O)2CH3, C1-C3Alkoxy, C1-C3Alkylthio group；
R4And R5It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base, containing a nitrogen-atoms or containing oxygen atom 4-6 circle heterocyclic ring base or-(CH2)nR10,
Wherein n is 1,2,3 integers,
Described nitrogen-atoms or the 4-6 circle heterocyclic ring containing an oxygen atom of containing is non-substituted or by C1-C3Alkyl taken Generation,
R10For-OH ,-CN ,-C (O) NH2,-S (=O)2CH3,-NR'R ", C1-C3Alkoxy, C1-C3Alkylthio group,
R', R " are independently H or C1-C3Alkyl；
R4、R5Nitrogen-atoms that can also be coupled constitutes 4-6 circle heterocyclic ring or 6-9 member loop coil, and the heterocycle is containing 1-2 choosing From the hetero atom of N, O or S or the-C containing group (=O)-or-S (=O)2As its ring members,
The R4、R5The 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is unsubstituted or is selected from halogen by 1-2 respectively Element, cyano, hydroxyl, amino, C1-C3Alkyl, C1-C3Alkoxy, halogenated C1-C3The C that alkyl, cyano replace1-C3Alkyl, hydroxyl take The C in generation1-C3Alkyl, C1-C3The C that alkoxy replaces1-C3Replaced alkyl；
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is single loop coil comprising a nitrogen-atoms.
In a preferred scheme,
R1Selected from following group:
Q is N or CH,
X is-NH ,-O, or-S.
R11Selected from-H ,-OH ,-F, Cl, Br ,-CN ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, ring Butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl oxygroup, cyclobutyl oxygroup or following group:
R12For-H ,-F, Cl, Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethoxy Base, propoxyl group or isopropoxy.
R13For-H, methyl, ethyl, propyl, isopropyl,
R2Selected from-H ,-CF3,-OCF3, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, cyclopropyl oxygroup, cyclobutyl oxygroup；
R3Selected from-H ,-CF3, methyl, ethyl, propyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl, cyclopropyl, ring fourth Base, Cvclopropvlmethvl, cyclobutylmethyl, or-OR8,
R8Selected from-H ,-CF3,-CH2CF3, methyl, ethyl, propyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl, cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, propylene oxide -3- base, tetrahydro furan It mutters -3- base, tetrahydropyran -4-base, tetrahydropyran -3-base, methylmercaptoethyl, methylthio, methoxy ethyl, methoxy propyl Base, ethoxyethyl group, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, aminopropionyl, methylsulphur Acyl ethyl, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl.
R4And R5It is independently selected from-H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, epoxy Propane -3- base, tetrahydrofuran -3- base, tetrahydropyran -4-base, tetrahydropyran -3-base, N- methyl piperidine -3- base, N- methyl piperazine Pyridine -4- base, N- methylpyrrolidin- 3- base, N- methyl nitrogen (miscellaneous) cyclobutane -3- base, methylmercaptoethyl, methylthio, methoxy Base ethyl, methoxy-propyl, ethoxyethyl group, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, Aminopropionyl, mesylethyl, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl, first Amino-ethyl, dimethylaminoethyl, methylaminopropyl, dimethylamino-propyl or R4、R5Coupled nitrogen-atoms constitutes 4-6 member Heterocycle or 6-9 member loop coil, the 4-6 circle heterocyclic ring are substituted or non-substituted heterocycle,
The R4、R5The substituted or non-substituted 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is selected from following ring structure:
R14Selected from-H, methylamino, ethylamino, dimethylamino,
R15Selected from-H, methyl, ethyl, propyl, isopropyl, formoxyl, acetyl group or mesyl.
R16And R17It is independently selected from-H ,-F ,-CF3, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyano methyl, cyano ethyl, methoxy, methoxy ethyl, methoxyl group Propyl, methylol, ethoxy, hydroxypropyl,
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is selected from following spirane structure:
In the preferred scheme of other,
R4It is selected from: cyclopropyl, cyclobutyl, cyclopenta, propylene oxide -3- base, tetrahydrofuran -3- base, oxinane -4- Base, tetrahydropyran -3-base, N- methyl piperidine -3- base, N- methyl piperidine -4- base, N- methylpyrrolidin- 3- base, N- methyl nitrogen (miscellaneous) cyclobutane -3- base,
R5Selected from-H, methyl, ethyl, propyl, isopropyl, methylmercaptoethyl, methylthio, methoxy ethyl, methoxy Base propyl, ethoxyethyl group, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, aminopropionyl, Mesylethyl, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl, methylaminoethyl, two Methylaminoethyl, methylaminopropyl, dimethylamino-propyl,
Or R4、R5Coupled nitrogen-atoms constitutes 4-6 circle heterocyclic ring or 6-9 member loop coil, the 4-6 circle heterocyclic ring be replace or Non-substituted heterocycle,
The R4、R5The substituted or non-substituted 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is selected from following ring structure:
R14Selected from-H, methylamino, ethylamino, dimethylamino,
R15Selected from-H, methyl, ethyl, propyl, isopropyl, formoxyl, acetyl group or mesyl.
R16And R17It is independently selected from-H ,-F ,-CF3, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyano methyl, cyano ethyl, methoxy, methoxy ethyl, methoxyl group Propyl, methylol, ethoxy, hydroxypropyl,
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is selected from following spirane structure:
The present invention also provides preparation respective compound method, can be used a variety of synthetic methods prepare it is as described herein Compound, including following methods, the compound of the present invention or its pharmaceutically acceptable salt, isomers or hydrate can be with Using synthetic method known to following methods and organic chemical synthesis field, or by those skilled in the art understand that these sides The changing method of method synthesizes, and preferred method includes but is not limited to following methods.
It is a kind of prepare the compounds of this invention, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its The method of prodrug, includes the following steps,
Wherein, R1、R2、R3、R4And R5As defined hereinabove.
Preferably, prepare the compounds of this invention, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and The method of its prodrug, includes the following steps,
In embodiment further preferably, above-mentioned reaction carries out under the following conditions:
Compound shown in formula (V) in step 1) withIt comes into full contact with to obtain compound shown in formula (IV)；
Preferably, which can carry out in a solvent, the solvent including but not limited to: methylene chloride, tetrahydrofuran, Acetonitrile, N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), n-methyl-2-pyrrolidone (NMP), dioxy The a combination of one or more of six rings, dichloroethanes, glycol dimethyl ether；
Preferably, which can carry out in the presence of base, and the alkali is including but not limited to potassium carbonate, sodium carbonate, vinegar Sour sodium, triethylamine, diisopropyl ethyl amine, triethylene diamine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicylo 11 The a combination of one or more of carbon -7- alkene or N-methylmorpholine；
Formula (IV) in step 2) carries out nitro-reduction reaction and obtains compound shown in formula (II)；
Preferably, the condition of nitro-reduction reaction is including but not limited to hydrogen and Raney's nickel, hydrogen and palladium carbon, iron powder, zinc Powder or stannous chloride；
Compound shown in formula (II) and formula (III) in step 3) comes into full contact with to obtain compound shown in formula (I)；
Preferably, which can carry out in organic solvent, and the organic solvent is including but not limited to N, N- dimethyl Formamide (DMF), DMAC N,N' dimethyl acetamide (DMA), n-methyl-2-pyrrolidone (NMP), glycol dimethyl ether, isopropanol, The a combination of one or more of n-butanol, 2- butanol, the tert-butyl alcohol；
Preferably, which can carry out in the presence of base, and the alkali is including but not limited to potassium carbonate, sodium carbonate, vinegar Sour sodium, triethylamine, diisopropyl ethyl amine, triethylene diamine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicylo 11 The a combination of one or more of carbon -7- alkene or N-methylmorpholine；
Preferably, which can carry out in the presence of acid, the described acid including but not limited to: trifluoroacetic acid, to toluene Sulfonic acid；
Preferably, which can carry out under the conditions of palladium metal catalyzed coupling reaction, and the palladium metal catalytic coupling is anti- Answering condition is common Buchward-Hartwig reaction palladium ligand, solvent and alkali used；
Detailed description of the invention
Term " substitution " referred to here, including complicated substituent group (for example, phenyl, aryl, miscellaneous alkyl, heteroaryl), Proper is 1 to 5 substituent group, preferably 1 to 3, preferably 1 to 2, can freely be selected from substituent group list It selects.
Unless there are specified otherwise, alkyl as used herein includes the alkyl of saturation unit price, these alkyl have a straight chain, branch or Annulus.For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n- butyl, isobutyl group, sec-butyl, tert- Butyl, cyclobutyl, n- amyl, 3- (2- methyl) butyl, 2- amyl, 2- methyl butyl, neopentyl, cyclopenta, n- hexyl, 2- oneself Base, 2- methyl amyl and cyclohexyl.Alkoxy is by previously described straight chain, the oxide ether of branched chain or cyclic alkyl composition.Class As, alkenyl and alkynyl include straight chain, branched chain or cyclic alkenyl radical and alkynyl.
Term " aryl " used herein refers to unsubstituted or substituted virtue unless otherwise specified Perfume base, such as phenyl, naphthalene, anthryl.Term " aroyl " refers to-C (O)-aryl.
Term " heterocycle " used herein represents unsubstituted or substituted steady unless there are specified otherwise 3 to 8 fixed unit monocycle saturated ring systems, they are made of carbon atom and 1 to 3 hetero atom selected from N, O, S, wherein N, S hetero atom can be aoxidized arbitrarily, and N hetero atom can also be by arbitrarily quaternized.Heterocycle can be with any hetero atom or carbon atom In conjunction with thus one stable structure of composition.The example of this kind of heterocycle includes but is not limited to piperidine base, pyrroles Alkyl, piperidyl, piperazinyl aoxidize piperazinyl, and oxyl base aoxidizes azepine base, azepine base, tetrahydrofuran base, dioxy penta Ring group, imidazolidine base, tetrahydro-thiazoles base, tetrahydro oh oxazolyl, THP trtrahydropyranyl, morpholine base, thio-morpholine group, thiophene morphine Quinoline sulfoxide, thiophene morpholine sulfone and oh di azoly.
Term " heteroaryl " used herein represents unsubstituted or substituted stabilization unless otherwise specified 5 or 6 unit monocycle aromatic ring systems, unsubstituted or substituted thick benzene heteroaromatic ring systems of 9 or 10 yuan of benzene can also be represented Or bicyclic heteroaromatic ring system, they are formed by carbon atom and by 1 to 4 hetero atom selected from N, O, S, wherein N, the miscellaneous original of S Son can be aoxidized arbitrarily, and N hetero atom can also be by arbitrarily quaternized.Heteroaryl can stick with any hetero atom or carbon atom Get up, thus one stable structure of composition.The example of heteroaryl includes but is not limited to thianthrene group, furyl, imidazoles Base, isoxazolyl, oh oxazolyl, pyrazolyl, pyrrole radicals, thiazolyl, thiadiazolyl group, triazolyl, pyridyl group, pyridazinyl, indyl, Azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzo isoxazolyl, benzoxazolyl, benzene And pyrazolyl, benzothiazolyl, diazosulfide base, benzotriazole base, adenyl, quinolyl or isoquinolyl.
Term " carbonyl " refers to C (O) base.
No matter when term " alkyl " or " aryl " or they any prefix root appear in the title of a substituent In (for example, aralkyl, dialkyl amino), those of it will be considered containing the above are " alkyl " and " aryl " and provide limit System.The specified quantity of carbon atom is (for example, C1-C6) indicate independent in a moieties or in a bigger substituent group In moieties (wherein alkyl is as its prefix root) in carbon atom quantity.
It is clear that the compound of Formulas I, isomers, crystal form or prodrug and its officinal salt there may be solvation form and Nonsolvated forms.Such as solvation form can be water-soluble form.The present invention include all these solvations and non-solvent The form of change.
The compound of the present invention may have asymmetric carbon atom, according to their physical and chemical difference, by known technology Mature method, for example, this diastereoisomeric mixture can be separated into single by chromatography or Steppecd crystallization Diastereoisomer.The separation of enantiomter can be by first with suitably there is the compound of optically active to be reacted, right The mixture for reflecting isomery is converted to diastereoisomeric mixture, separates diastereoisomer, then single diastereoisomer (hydrolysis) is converted into corresponding pure enantiomter.All such isomers, including non-enantiomer mixture and pure Enantiomer is considered as a part of the invention.
As the compound of the present invention of active constituent, and the method for preparing the compound, it is all the contents of the present invention. Moreover, the crystalline forms of some compounds can be used as polycrystal presence, this form may also be included in that current invention In.In addition, some compounds can be formed together solvate, this solvent with water (i.e. hydrate) or common organic solvent Compound is also included in the scope of the present invention.
The compound of the present invention can be used to treat in a free form, or in the appropriate case with pharmaceutically acceptable Salt or other derivatives form for treating.As used herein, term " pharmaceutically acceptable salt " refers to of the invention The organic salt and inorganic salts of compound, this salt be suitable for the mankind and lower animal, no excessive toxicity, irritation, allergic reaction etc., With reasonable interests/Hazard ratio.The pharmaceutically acceptable salt of amine, carboxylic acid, phosphonate and other types of compound is in institute Category is well-known in field.The salt can be reacted by the compound of the present invention with suitable free alkali or acid.Including But be not limited to, with inorganic acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acid for example acetic acid, oxalic acid, maleic acid, The salt that tartaric acid, citric acid, succinic acid, malonic acid are formed, or by using method well known in the art, such as ion exchange Method, to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphor hydrochlorate, camsilate, citrate, two Portugals Sugar lime, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconic acid Salt, Hemisulphate, caproate, hydriodate, 2- isethionate, Lactobionate, lactate, laruate, lauryl sulphur It is hydrochlorate, malate, maleate, methane sulfonates, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, double Hydroxynaphthoate, persulfate, crosses 3- phenylpropionic acid salt, phosphate, picrate, propionate, stearate, sulphur at pectate Hydrochlorate, rhodanate, tosilate, undecanoate etc..Representative alkaline or alkaline-earth salts include sodium, lithium, potassium, Calcium, magnesium etc..Other pharmaceutically acceptable salts include nontoxic ammonium appropriate, quaternary ammonium, and using such as halogen ion, hydroxyl, The amido cation that carboxylate radical, sulfate radical, phosphate radical, nitrate anion, low-grade alkane sulfonate and arylsulphonate are formed.
In addition, terms used herein " prodrug ", which refers to a compound in vivo, can be converted into shown in formula (I) of the present invention Compound.This conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for parent compound It rings.
Pharmaceutical composition of the invention includes structure formula (I) compound described herein or its pharmaceutically acceptable salt, swashs Enzyme inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressor, anticarcinogen, antivirotic, anti-inflammatory agent, antifungal agent, antibiosis The other activating agent of plain or anti-angiogenic antihyperproliferative compound；And any pharmaceutically acceptable carrier, adjuvant or figuration Agent.
The compound of the present invention can be used as exclusive use, can also with one or more other the compound of the present invention or It is used with one or more other drug combinations.When being administered in combination, therapeutic agent can be configured to be administered simultaneously or sequentially exist Different time administrations or the therapeutic agent can be used as single composition administration.So-called " combination treatment ", refer to using The compound of the present invention is used together with another medicament, and administration mode is that co-administered or every kind of medicament are suitable simultaneously for every kind of medicament Sequence administration, no matter which kind of situation, purpose is all the optimum efficiency of drug to be reached.Co-administered includes while delivering dosage form, with And the independent dosage form of every kind of compound respectively.Therefore, the compound of the present invention administration can with known this field other Therapy uses simultaneously, for example, using radiotherapy or cytostatic agent, cytotoxic agent, Qi Takang in cancer treatment The adjunctive therapies such as cancer agent improve cancerous symptom.The present invention is not limited to the sequences of administration；The compound of the present invention can be applied previously With being administered simultaneously, or applied after other anticancer agents or cytotoxic agent.
In order to prepare the Pharmaceutical Compositions of this invention, one or more chemical combination of the molecule formula (I) as its active constituent Object or salt can be mixed closely with pharmaceutical carriers, this be carried out according to traditional pharmacy ingredients technical, wherein Carrier can be used a variety of more according to by different administration mode (for example, oral or parenteral administration) designed preparation form The form of sample.Pharmaceutically acceptable carrier appropriate is technically well-known.To some of such pharmaceutically acceptable The description of carrier can be found " pharmaceutical excipient handbook " is inner, and the book is by American Pharmaceutical Association and pharmacy society, Britain combined publication.
Pharmaceutical composition of the present invention can have following form, such as, it is suitble to oral administration, such as tablet, capsule, medicine Ball, medicinal powder, the form of sustained release, solution or suspension；For parental injection such as transparent liquid, suspension, emulsion；Or For local application's such as cream, frost；Or rectally is used for as suppository.Pharmaceutical Compositions can also be suitble in the form of unit dose Once daily for exact dose.The Pharmaceutical Compositions will be including a kind of traditional pharmaceutical carriers or excipient and according to mesh Compound made of preceding invention as active constituent, alternatively, it is also possible to include others medicine or pharmaceutical formulations, carrier, Adjuvant, etc..
Therapeutic compound can also award mammal and non-human.It will be taken to drug dose used in a mammal Certainly in the type of the animal and its disease condition or the de-synchronization state locating for it.Therapeutic compound can be with capsule, greatly The form of pill, tablet liquid medicine is fed for animal.Therapeutic compound can also be allowed to enter animal by way of injecting or inculcating In vivo.We prepare these medicament forms according to the traditional mode for meeting veterinary practice standard.As a kind of selectable Mode, pharmacy synthetic drug can mix with animal feed and be fed for animal, therefore, the feed addictive of concentration or mix and stir in advance Material can be in case of to mix common animal feed.
A further object of the present invention is to be to provide a kind of method for treating cancer in subject in need, packet Include a kind of method that the therapeutically effective amount of the composition containing the compound of the present invention is applied to subject.
The invention also includes the use of the compound of the present invention or its pharmaceutically acceptable derivates, preparation treatment and junket Application in the drug of the relevant cancer of histidine kinase HER1, HER2, HER3, HER4 and autoimmune disease.The cancer (including non-physical knurl, solid tumor, primary or metastatic cancer, as pointed by the other places this paper and including cancer it is resistant or Refractory one or more other treatments) and Other diseases (including but not limited to fundus oculi disease, psoriasis, atheroma, Pulmonary fibrosis, liver fibrosis, myelofibrosis etc.) medicament.The cancer includes but is not limited to: non-small cell lung cancer, small thin Born of the same parents' lung cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, cervix cancer, colorectal cancer, black Plain tumor, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic grain are thin Born of the same parents' leukaemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and T cell leaching Any one of bar tumor, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.
Examples provided below can better illustrate the present invention, and unless stated otherwise, all temperature are degree Celsius.
Specific embodiment
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- (dimethylamino) the piperidin-1-yl) -2- methoxyphenyl) ammonia of embodiment 1. Base) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide preparation
By 1- (4- amino -2- chloro-5-methoxyl phenyl)-N, 28 milligrams of amine of N- lupetidine -4- (0.1mmol), (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) 32 milligrams of dimethyl phosphine (0.1mmol), 17 milligrams of p-methyl benzenesulfonic acid (0.1mmol) is placed in a reaction flask, heating stirring to end of reaction, and concentrated by rotary evaporation rear pillar chromatographs to obtain product 27mg, yield 50%.1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.46(s,1H),8.19(s,1H),8.16(s,1H),7.77 (s, 1H), 7.60-7.53 (m, 1H), 7.43 (t, J=8.0,8.0Hz, 1H), 7.16-7.11 (m, 1H), 6.81 (s, 1H), 3.82(s,3H),3.35(s,1H),3.32–3.28(m,2H),2.70–2.64(m,2H),2.22(s,6H),1.88–1.83(m, 2H),1.79(s,3H),1.76(s,3H),1.60–1.52(m,2H)；MS:563[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) of embodiment 2. Phenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine oxide preparation
The preparation method of reference implementation example 1, with the chloro- 2- methoxyl group -4- of the 5- of equimolar equivalent (4- (4- methyl piperazine -1- Base) piperidin-1-yl) aniline substitution 1- (4- amino -2- chloro-5-methoxyl phenyl)-N, N- lupetidine -4- amine.1HNMR (400MHz,DMSO-d6)δ11.22(s,1H),8.48–8.43(m,1H),8.15(s,1H),8.12(s,1H),7.79(s, 1H), 7.56 (dd, J=14.0,7.6Hz, 1H), 7.44 (t, J=7.8,7.8Hz, 1H), 7.14 (t, J=7.4,7.4Hz, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.33-3.31 (m, 2H), 2.67 (t, J=11.4,11.4Hz, 2H), 2.57-2.51 (m, 4H), 2.37-2.26 (m, 5H), 2.15 (s, 3H), 1.85 (d, J=12.2Hz, 2H), 1.79 (s, 3H), 1.76 (s, 3H), 1.63–1.54(m,2H).MS:618[M+H]+.
(2- ((2- ((4- ([1,4'- joins piperidines] -1'- base) the chloro- 2- methoxyphenyl of -5-) the amino) -5- chlorine of embodiment 3. Pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine oxide preparation
The preparation method of reference implementation example 1, with 4- ([Isosorbide-5-Nitrae '-connection piperidines] -1'- base) chloro- 2- first of -5- of equimolar equivalent Oxygroup aniline substitutes 1- (4- amino -2- chloro-5-methoxyl phenyl)-N, N- lupetidine -4- amine.1H NMR(400MHz, DMSO-d6) δ 11.21 (s, 1H), 8.45 (s, 1H), 8.16-8.11 (m, 2H), 7.78 (s, 1H), 7.56 (dd, J=13.8, 7.6Hz, 1H), 7.44 (t, J=8.0,8.0Hz, 1H), 7.14 (t, J=7.4,7.4Hz, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.34-3.31 (m, 6H), 2.67 (t, J=11.4,11.4Hz, 2H), 2.38-2.31 (m, 1H), 1.85-1.80 (m, 2H),1.79(s,3H),1.76(s,3H),1.67–1.58(m,2H),1.53–1.48(m,4H),1.43–1.37(m,2H).MS: 603[M+H]+.
(((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (4- morpholine piperidin-1-yl) phenyl) amino) is phonetic by 2- for embodiment 4. Pyridine -4- base) amino) phenyl) and dimethyl phosphine oxide preparation
The preparation of step 1) 4- (1- (2- chloro-5-methoxyl -4- nitrobenzophenone) piperidin-4-yl) morpholine
By 170 milligrams of morpholine of 4- (piperidin-4-yl) (1mmol), 205 milligrams of the fluoro- 4- methoxyl group -5- nitrobenzene of the chloro- 2- of 1- (1mmol) is placed in a reaction flask, and 2 milliliters of DMF and 138 milligrams of potassium carbonate (1mmol) are added, and stirring to end of reaction adds water, takes out 300 milligrams of product are filtered to obtain, yield 85%.MS:356[M+H]+.
The preparation of the chloro- 2- methoxyl group -4- of step 2) 5- (4- morpholine piperidin-1-yl) aniline
4- (1- (2- chloro-5-methoxyl -4- nitrobenzophenone) piperidin-4-yl) is placed in for 300 milligrams of morpholine (0.85mmol) In reaction flask, be added 5 ml methanols, 476 milligrams of iron powder (8.5mmol) and 450 milligrams of ammonium chloride (8.5mmol) be heated to reacting It finishes, filters, wet chemical is added is adjusted to alkalinity, ethyl acetate extraction is concentrated to give 193 milligrams of product, yield 70%. MS:326[M+H]+.
Step 3) (2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (4- morpholine piperidin-1-yl) phenyl) amino) pyrimidine - 4- yl) amino) phenyl) and dimethyl phosphine oxide preparation
The preparation method of reference implementation example 1, with the chloro- 2- methoxyl group -4- of the 5- of equimolar equivalent (4- morpholine piperidin-1-yl) Aniline substitutes 1- (4- amino -2- chloro-5-methoxyl phenyl)-N, N- lupetidine -4- amine.1H NMR(400MHz,DMSO- D6) δ 11.22 (s, 1H), 8.48-8.42 (m, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.56 (dd, J= 14.0,7.6Hz, 1H), 7.44 (t, J=7.8,7.8Hz, 1H), 7.14 (t, J=7.6,7.6Hz, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.59 (t, J=4.4,4.4Hz, 4H), 3.31-3.28 (m, 2H), 2.68 (t, J=11.4,11.4Hz, 2H), 2.56-2.51 (m, 4H), 2.29 (t, J=11.8,11.8Hz, 1H), 1.89 (d, J=12.2Hz, 2H), 1.79 (s, 3H), 1.76(s,3H),1.63–1.53(m,2H).MS:605[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of 5- (4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) of embodiment 5. Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide preparation
The preparation step 1 of reference implementation example 4) to step 3), starting material substitutes 4- with 4- (pyrrolidin-1-yl) piperidines (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.48–8.43(m,1H),8.15(s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.56 (dd, J=13.8,7.4Hz, 1H), 7.44 (t, J=8.0,8.0Hz, 1H), 7.14 (t, J=7.6,7.6Hz, 1H), 6.81 (s, 1H), 3.82 (s, 3H), 3.27-3.22 (m, 2H), 2.72 (t, J=11.2, 11.2Hz,2H),2.57–2.52(m,4H),2.17–2.08(m,1H),1.97–1.92(m,2H),1.79(s,3H),1.76(s, 3H),1.72–1.68(m,4H),1.64–1.56(m,2H)；MS:589[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (dimethylamino) piperidin-1-yl) -5- methoxyphenyl) of embodiment 6. Amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine oxide preparation
The preparation step 1 of reference implementation example 4) to step 3), starting material substitutes 4- with N, N- lupetidine -4- amine (piperidin-4-yl) morpholine substitutes the fluoro- 4- methoxyl group -5- nitrobenzene of the chloro- 2- of 1- with the fluoro- 3- methoxyl group -5- nitrobenzene of the chloro- 2- of 1- 。1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.41(s,1H),8.61–8.55(m,1H),8.23(s,1H), 7.60 (dd, J=13.8,7.6Hz, 1H), 7.55-7.51 (m, 2H), 7.19 (t, J=7.6,7.6Hz, 1H), 7.14 (d, J= 2.4Hz, 1H), 3.67 (s, 3H), 3.13 (t, J=11.6,11.6Hz, 2H), 2.92-2.84 (m, 2H), 2.20 (s, 6H), 2.16–2.11(m,1H),1.81(s,3H),1.77(s,3H),1.75–1.71(m,2H),1.52–1.43(m,2H).MS:563 [M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 3- (4- (dimethylamino) the piperidin-1-yl) -5- isopropoxy benzene of embodiment 7. Base) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine oxide preparation
The preparation step 1 of reference implementation example 4) to step 3), starting material substitutes 4- with N, N- lupetidine -4- amine (piperidin-4-yl) morpholine substitutes the fluoro- 4- methoxyl group -5- nitro of the chloro- 2- of 1- with the fluoro- 3- isopropoxy -5- nitrobenzene of the chloro- 2- of 1- Benzene.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.37(s,1H),8.58–8.52(m,1H),8.22(s,1H), 7.60 (dd, J=13.8,7.6Hz, 1H), 7.54 (t, J=8.0,8.0Hz, 1H), 7.49 (s, 1H), 7.22-7.18 (m, 1H), 7.17–7.15(m,1H),4.38–4.32(m,1H),3.20–3.12(m,2H),2.91–2.80(m,2H),2.20(s,6H), 2.16–2.09(m,1H),1.81(s,3H),1.77(s,3H),1.75–1.71(m,2H),1.51–1.42(m,2H),1.27– 1.24(m,6H)；MS:591[M+H]+.
The chloro- N of embodiment 8.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) - N4The preparation of phenyl pyrimidine -2,4- diamines
The preparation method of reference implementation example 2 substitutes (2- with the chloro- N- phenyl pyrimidine -4- amine of 2,5- bis- of equimolar equivalent ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,Chloroform-d)δ8.33 (s, 1H), 8.08 (s, 1H), 7.65-7.59 (m, 2H), 7.45 (t, J=7.7Hz, 2H), 7.38 (s, 1H), 7.19 (t, J= 7.4Hz, 1H), 7.09 (s, 1H), 6.61 (s, 1H), 3.88 (s, 3H), 3.42 (d, J=11.2Hz, 2H), 2.75-2.55 (m, 8H), 2.44 (s, 1H), 2.35 (s, 3H), 1.95 (d, J=11.1Hz, 2H), 1.84-1.79 (m, 2H), 1.27 (s, 2H)；MS: 542[M+H]+.
The chloro- N of embodiment 9.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) phenyl) - N4The preparation of hexamethylene yl pyrimidines -2,4- diamines
The preparation method of reference implementation example 2 substitutes (2- with the chloro- N- hexamethylene yl pyrimidines -4- amine of 2,5- bis- of equimolar equivalent ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,DMSO-d6)δ8.27(s,1H), 7.98-7.90 (m, 1H), 7.53 (s, 1H), 6.80 (d, J=9.5Hz, 2H), 3.90-3.82 (m, 4H), 3.29-3.23 (m, 3H), 2.65 (t, J=11.0Hz, 2H), 2.36-2.28 (m, 5H), 2.17-2.13 (m, 4H), 1.88-1.82 (m, 5H), 1.76–1.72(m,2H),1.68–1.51(m,4H),1.42–1.36(m,4H),1.15–1.11(m,1H)；MS:548[M+H]+.
The chloro- N of embodiment 10.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of cyclobutyl pyrimidines -2,4- diamines
The preparation method of reference implementation example 2 substitutes (2- with the chloro- N- cyclobutyl pyrimidines -4- amine of 2,5- bis- of equimolar equivalent ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,DMSO-d6)δ8.35(s,1H), 7.96 (d, J=16.7Hz, 1H), 7.53 (s, 1H), 7.34 (d, J=7.1Hz, 1H), 6.80 (d, J=21.0Hz, 1H), 4.55-4.43 (m, 1H), 3.87 (s, 3H), 3.25 (s, 3H), 2.66 (d, J=11.0Hz, 2H), 2.38-2.24 (m, 8H), 2.15(s,6H),1.99–1.80(m,3H),1.73–1.64(m,2H),1.60–1.53(m,2H)；MS:520[M+H]+.
The chloro- N of embodiment 11.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of (4- fluorophenyl) pyrimidine -2,4- diamines
The preparation method of reference implementation example 2 is replaced with 2,5- bis- chloro- N- (4- fluorophenyl) pyrimidine -4- amine of equimolar equivalent Generation (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,Chloroform-d)δ 8.22 (s, 1H), 8.07 (s, 1H), 7.57-7.49 (m, 2H), 7.39 (s, 1H), 7.15 (t, J=8.6Hz, 2H), 7.01 (s, 1H), 6.60 (s, 1H), 3.87 (s, 3H), 3.41 (d, J=11.3Hz, 2H), 2.75-2.52 (m, 9H), 2.46-2.39 (m, 1H), 2.34 (s, 3H), 1.95 (d, J=10.9Hz, 2H), 1.87-1.84 (m, 1H), 1.81-1.73 (m, 2H)；MS:560[M+ H]+.
The chloro- N of embodiment 12.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of (2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) pyrimidine -2,4- diamines
The preparation method of reference implementation example 2, with the chloro- N- of 2,5- bis- (2, the 3- dihydrobenzos [b] [Isosorbide-5-Nitrae] of equimolar equivalent Dioxanes -5- base) pyrimidine -4- amine substitution (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1HNMR (400MHz, DMSO-d6) δ 8.12 (d, J=4.2Hz, 2H), 7.94 (s, 1H), 7.80 (s, 1H), 7.43 (d, J=8.0Hz, 1H), 6.77 (d, J=7.0Hz, 2H), 6.73-6.66 (m, 1H), 4.30-4.22 (m, 4H), 3.81 (s, 3H), 3.26 (s, 3H), 2.65 (t, J=11.3Hz, 2H), 2.55-2.52 (m, 2H), 2.48-2.46 (m, 1H), 2.34 (s, 5H), 2.17 (s, 3H), 1.85 (d, J=11.7Hz, 2H), 1.57 (d, J=12.3Hz, 2H)；MS:600[M+H]+.
The chloro- N of embodiment 13.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of (1- methyl-cyclobutyl) pyrimidine -2,4- diamines
The preparation method of reference implementation example 2, with 2,5- bis- chloro- N- (1- methyl-cyclobutyl) pyrimidine -4- of equimolar equivalent Amine substitutes (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,DMSO-d6)δ 8.19 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 6.92 (s, 1H), 6.77 (s, 1H), 3.85 (s, 3H), 3.26 (d, J= 11.0Hz, 3H), 2.64 (t, J=11.3Hz, 2H), 2.57-2.52 (m, 2H), 2.49-2.45 (m, 2H), 2.32-2.26 (m, 6H),2.17–2.13(m,5H),1.88–1.75(m,4H),1.60–1.52(m,5H)；MS:534[M+H]+.
Embodiment 14.N4(bicyclic [1.1.1] pentane -1- base) chloro- N of -5-2(5- chloro- 2- methoxyl group -4- (4- (4- methyl Piperazine -1- base) piperidin-1-yl) phenyl) and pyrimidine -2,4- diamines preparation
The preparation method of reference implementation example 2, with N- (bicyclic [1.1.1] pentane -1- base) -2,5- dichloro of equimolar equivalent Pyrimidine -4- amine substitutes (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz, DMSO-d6)δ7.98(s,1H),7.93(s,1H),7.67(s,1H),7.62(s,1H),6.78(s,1H),3.84(s,3H), 3.27 (s, 3H), 2.65 (t, J=11.3Hz, 2H), 2.56-2.52 (m, 2H), 2.49-2.45 (m, 2H), 2.42 (s, 1H), 2.31 (d, J=11.0Hz, 4H), 2.17-2.14 (m, 3H), 2.10-2.06 (m, 6H), 1.84 (d, J=10.8Hz, 2H), 1.64–1.51(m,2H)；MS:532[M+H]+.
The chloro- N of embodiment 15.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of (2- isopropyl phenyl) pyrimidine -2,4- diamines
The preparation method of reference implementation example 2, with 2,5- bis- chloro- N- (2- isopropyl phenyl) pyrimidine-of equimolar equivalent 4- amine substitutes (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz,DMSO-d6)δ 8.73 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.28 (d, J=7.9Hz, 1H), 7.21-7.12 (m, 2H), 6.77 (s, 1H), 6.66-6.60 (m, 1H), 4.57-4.47 (m, 1H), 3.82 (s, 3H), 3.27 (d, J=11.2Hz, 3H),2.70–2.60(m,2H),2.56–2.52(m,2H),2.49–2.46(m,2H),2.36–2.32(m,4H),2.15(s, 3H), 1.84 (d, J=11.9Hz, 2H), 1.58 (t, J=11.8Hz, 2H), 1.27 (d, J=6.0Hz, 6H)；MS:600[M+H ]+.
The chloro- N of embodiment 16.5-2(the chloro- 2- methoxyl group -4- of 5- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) benzene Base)-N4The preparation of (2- (isopropelsulfonyl) phenyl) pyrimidine -2,4- diamines
The preparation method of reference implementation example 2, with the chloro- N- of 2,5- bis- (2- (isopropelsulfonyl) phenyl) of equimolar equivalent Pyrimidine -4- amine substitutes (2- ((2,5- dichloro pyrimidine -4- base) amino) phenyl) dimethyl phosphine.1H NMR(400MHz, DMSO-d6) δ 9.51 (s, 1H), 8.51 (d, J=8.0Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.87-7.79 (m, 1H), 7.73 (s, 1H), 7.66 (t, J=7.9Hz, 1H), 7.35 (t, J=7.7Hz, 1H), 6.80 (s, 1H), 3.81 (s, 3H), 3.50-3.39 (m, 1H), 3.26 (s, 3H), 2.67 (t, J=11.5Hz, 2H), 2.56 (s, 2H), 2.49-2.44 (m, 2H), 2.32 (s, 4H), 2.15 (s, 3H), 1.86 (d, J=12.0Hz, 2H), 1.65-1.52 (m, 2H), 1.16 (d, J=6.8Hz, 6H)；MS:648[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- (ethyl (methyl) amino) the piperidin-1-yl) -2- methoxyl group of embodiment 17. Phenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with the N- ethyl-N-methyl of equimolar equivalent in starting material Piperazine -4- amine replaces 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.46(s,1H), 8.14 (d, J=7.7Hz, 2H), 7.78 (s, 1H), 7.60-7.53 (m, 1H), 7.47-7.39 (m, 1H), 7.17-7.11 (m, 1H),6.81(s,1H),3.82(s,3H),3.24–2.79(m,4H),2.75–2.62(m,2H),2.39–2.33(m,1H), 2.21 (s, 3H), 1.84-1.80 (m, 2H), 1.79 (s, 3H), 1.76 (s, 3H), 1.66-1.58 (m, 2H), 1.00 (t, J= 7.1Hz,3H)；MS:577[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- (cyclobutyl (methyl) amino) the piperidin-1-yl) -2- methoxy of embodiment 18. Base phenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with the N- cyclobutyl-N- first of equimolar equivalent in starting material Phenylpiperidines -4- amine replaces 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.49–8.40 (m,1H),8.19–8.10(m,2H),7.77(s,1H),7.59–7.52(m,1H),7.46–7.40(m,1H),7.18–7.10 (m,1H),6.81(s,1H),3.81(s,3H),3.15–3.13(m,2H),2.72–2.59(m,3H),2.07(s,3H),2.00– 1.91(m,2H),1.84–1.72(m,9H),1.68–1.57(m,6H)；MS:603[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- (isopropyl (methyl) amino) the piperidin-1-yl) -2- methoxy of embodiment 19. Base phenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with the N- isopropyl-N- first of equimolar equivalent in starting material Phenylpiperidines -4- amine replaces 4- (piperidin-4-yl) morpholine.1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),8.45(s, 1H), 8.14 (d, J=12.4Hz, 2H), 7.77 (s, 1H), 7.59-7.54 (m, 1H), 7.45-7.41 (m, 1H), 7.14 (t, J =7.3Hz, 1H), 6.81 (s, 1H), 3.82 (s, 3H), 3.02 (d, J=10.4Hz, 1H), 2.72-2.66 (m, 2H), 2.57- 2.51(m,3H),2.16(s,3H),1.84–1.80(m,2H),1.78(s,3H),1.76(s,3H),1.66–1.59(m,2H), 0.99 (d, J=6.5Hz, 6H)；MS:591[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- ((2- hydroxyethyl) (methyl) amino) piperidin-1-yl)-of embodiment 20. 2- methoxyphenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with the 2- (methyl (piperidines-of equimolar equivalent in starting material 4- yl) amino) ethane -1- alcohol substitution 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H), 8.39 (d, J=7.4Hz, 1H), 8.09 (d, J=1.0Hz, 2H), 7.71 (s, 1H), 7.53-7.46 (m, 1H), 7.39-7.34 (m,1H),7.10–7.05(m,1H),6.74(s,1H),4.25(s,1H),3.75(s,3H),3.43–3.37(m,2H),3.26– 3.21(m,4H),2.63–2.57(m,2H),2.48–2.46(m,1H),2.18(s,3H),1.77–1.73(m,2H),1.72(s, 3H),1.69(s,3H),1.59–1.50(m,2H)；MS:593[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 2- methoxyl group -4- of the 5- (4- ((2- methoxy ethyl) (methyl) amino) of embodiment 21. Piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with N- (the 2- methoxyl group second of equimolar equivalent in starting material Base)-N- methyl piperidine -4- amine substitution 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H), 8.39 (d, J=6.7Hz, 1H), 8.09 (s, 2H), 7.70 (s, 1H), 7.53-7.47 (m, 1H), 7.39-7.34 (m, 1H), 7.10–7.05(m,1H),6.74(s,1H),3.75(s,3H),3.36–3.32(m,2H),3.26–3.21(m,4H),3.18(s, 3H),2.63–2.60(m,1H),2.58–2.53(m,2H),2.18(s,3H),1.76–1.73(m,2H),1.72(s,3H), 1.69(s,3H),1.58–1.51(m,2H)；MS:607[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- hydroxyl-[1,4'- joins piperidines] -1'- the base) -2- methoxybenzene of embodiment 22. Base) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with [the Isosorbide-5-Nitrae '-connection piperazine of equimolar equivalent in starting material Pyridine] -4- alcohol substitution 4- (piperidin-4-yl) morpholine.1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),8.45(s,1H), 8.14 (d, J=15.9Hz, 2H), 7.78 (s, 1H), 7.59-7.53 (m, 1H), 7.46-7.41 (m, 1H), 7.16-7.12 (m, 1H), 6.80 (s, 1H), 4.50 (d, J=4.2Hz, 1H), 3.82 (s, 3H), 3.45-3.39 (m, 1H), 3.30-3.28 (m, 2H),2.81–2.76(m,2H),2.70–2.63(m,2H),2.41–2.34(m,1H),2.26–2.21(m,2H),1.84–1.80 (m,2H),1.78(s,3H),1.76(s,3H),1.75–1.70(m,2H),1.65–1.58(m,2H),1.40–1.33(m,2H)； MS:619[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (4- hydroxy-4-methyl-[1,4'- joins piperidines] -1'- the base) -2- of embodiment 23. Methoxyphenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), in starting material with the 4- methyl-of equimolar equivalent [Isosorbide-5-Nitrae '- Join piperidines] -4- alcohol substitution 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.39(s, 1H), 8.08 (d, J=1.4Hz, 2H), 7.70 (s, 1H), 7.53-7.46 (m, 1H), 7.39-7.34 (m, 1H), 7.09-7.05 (m,1H),6.73(s,1H),4.00(s,1H),3.75(s,3H),3.25–3.21(m,4H),2.64–2.57(m,2H),2.52– 2.47(m,2H),2.31–2.25(m,1H),1.79–1.73(m,2H),1.72(s,3H),1.69(s,3H),1.61–1.52(m, 2H),1.43–1.36(m,4H),1.03(s,3H)；MS:633[M+H]+.
(2- ((the chloro- 2- of 5- ((the chloro- 4- of 5- (fluoro- [1,4'- joins the piperidines] -1'- base of the 4,4- bis-) -2- methoxyl group of embodiment 24. Phenyl) amino) pyrimidine-4-yl) amino) phenyl) and dimethyl phosphine preparation
The preparation step 1 of reference implementation example 4) to step 3), with 4, the 4- bis- fluoro- 1 of equimolar equivalent in starting material, 4'- joins piperidines and replaces 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.38(s,1H), 8.09(s,2H),7.71(s,1H),7.53–7.46(m,1H),7.39–7.34(m,1H),7.10–7.05(m,1H),6.74(s, 1H),3.75(s,3H),3.26–3.21(m,4H),2.65–2.61(m,1H),2.60–2.57(m,4H),1.93–1.83(m, 4H),1.79–1.74(m,2H),1.72(s,3H),1.69(s,3H),1.62–1.53(m,2H)；MS:639[M+H]+.
Embodiment 25.1'- (the chloro- 4- of 2- ((the chloro- 4- of 5- ((2- (solutions of dimethyl phosphoryl base) phenyl) amino) pyrimidine -2-base) ammonia Base) -5- methoxyphenyl)-[1,4'- join piperidines] -4- nitrile preparation
The preparation step 1 of reference implementation example 4) to step 3), with [the Isosorbide-5-Nitrae '-connection piperazine of equimolar equivalent in starting material Pyridine] -4- nitrile substitution 4- (piperidin-4-yl) morpholine.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.46(s,1H), 8.14 (d, J=9.4Hz, 2H), 7.78 (s, 1H), 7.61-7.52 (m, 1H), 7.43 (t, J=8.0Hz, 1H), 7.14 (t, J= 7.5Hz,1H),6.80(s,1H),3.82(s,3H),2.86(s,1H),2.74–2.64(m,4H),2.49–2.33(m,5H), 1.91–1.80(m,4H),1.79(s,3H),1.76(s,3H),1.72–1.59(m,4H)；MS:628[M+H]+.
Experimental example 1.
Small molecule compound inhibits EGFRT790MThe test of kinase activity, test method are as follows:
1) dilution of compound
In 96 orifice plate a, compound DMSO solution is pressed into 3 times of dilution proportions, forms 11 gradients, the 12nd gradient is Pure DMSO solution (as positive control)；One piece of 96 new orifice plate b is taken, above-mentioned solution ultrapure water is diluted 25 times, and (DMSO is dense 4%) degree is.
2) by compound turntable to 384 orifice plates
By the compound solution diluted in above-mentioned 96 orifice plate b with ultrapure water according to the standard turntable of 2 multiple holes to 384 orifice plates In corresponding hole.
3) add 4 × kinase solution: taking the 2.5 above-mentioned 4 × kinase solutions of μ l to be added to the corresponding reacting hole of 384 orifice plates with the volley of rifle fire In, it mixes room temperature pre-reaction 5 minutes.
4) add 2 × substrate/ATP mixed liquor: taking the 5 above-mentioned 2 × substrates of μ l/ATP mixed liquor corresponding to 384 orifice plates with the volley of rifle fire In reacting hole.
5) negative control: being arranged negative control hole in 384 orifice plates, every hole be added 2.5 4 × substrates of μ l, 2.5 μ l 4 × Enzyme solutions, 2.5 μ l 1 × Kinase Assay Buffer and 2.5 ultrapure waters of the μ l containing 4%DMSO.
6) centrifugation mixes, and is protected from light room temperature reaction 2 hours.
7) enzymatic reaction is terminated:
The 5 above-mentioned 4 × terminate liquids of μ l to 384 orifice plate corresponding apertures are drawn, centrifugation mixes, and reacts at room temperature 5 minutes.
8) chromogenic reaction:
It draws 5 μ l above-mentioned 4 × detection liquid and is added to 384 orifice plate corresponding apertures, centrifugation mixes, and reacts at room temperature 1 hour.
9) 384 orifice plates are put into plate reader, transfer corresponding Programmable detection signal.
10)IC50Analysis:
Hole readings=10000*EU665 value/EU615 value
Inhibiting rate=(Positive control wells readings-experimental port readings)/(Positive control wells readings-negative control hole readings) * 100%
Drug concentration and the input processing of GraphPad Prism 5 of corresponding inhibiting rate can be calculated into corresponding IC50。
EGFRT790MKinase activity inhibits molecule to screen experiment condition:
Final concentration of 5 μM of EGFR (T790M) kinases final concentration 0.05nM, ATP, substrate ULight in reaction systemTM- The final concentration 100nM of labeled PolyGT, time of enzymatic reacting are 2 hours.
Final concentration of 2.5 μM of compound highest in reaction system, totally 11 concentration, minimum end are dense after 3 times of gradient dilutions Degree is 0.042nM.DMSO final concentration of 1%.
Table (one) lists in this patent part of compounds to the measurement result of tyrosine-kinase enzyme inhibition activity, wherein A table Show IC50IC is indicated less than or equal to 5nM, B50Greater than 5nM but it is less than or equal to 50nM, C indicates IC50Greater than 50nM.
Table (one): the compounds of this invention is to EGFRT790MKinase inhibiting activity measurement result
Experimental example 2.
Small molecule compound inhibits BaF3-EGFR-L858R-T790M and BaF3-EGFR-L858R-T790M- The test of C797S cell Proliferation, the specific method is as follows:
1) cell is transferred in 15mL centrifuge tube, with 1000rpm centrifugation 4 minutes.
2) liquid is discarded supernatant, complete culture solution is added, piping and druming uniformly, takes 10 μ L cell suspending liquids and 10 μ L0.4% tires to expect Indigo plant mixes, and is counted with cell counter, and cell number and survival rate are recorded.
3) every hole is inoculated with the cell suspension of 80 μ L into 96 orifice plates (different cell inoculation cell densities are shown in Table two).
Table two: cell density
Cell Name Culture medium Inoculum density
BaF3-EGFR-L858R-T790M RPMI 1640+10%FBS 5000/well
BaF3-EGFR-L858R-T790M-C797S RPMI 1640+10%FBS 5000/well
4) the above-mentioned 5 × chemical combination diluted with culture solution of 20 μ L is added in (B row to G row, the 2nd column to the 11st column) in every hole Object, mixing shake up.(each compound setting two is parallel, and 96 orifice plates can test three compounds)；
5) containing 5%CO237 DEG C of incubators in cultivate 72 hours after every hole 10 μ L CCK-8 reagents are added, culture 2 is small When (can be according to shade come adjusting reaction time)；
6) its OD value is read at 450nm in multi-functional plate reading machine.
7) data processing: cell survival rate (%)=[(As-Ab)/(Ac-Ab)] * 100%
As: the OD value of experimental port (containing cell culture medium, CCK-8, compound)；
Ac: the OD value of control wells (containing cell culture medium, CCK-8)；
Ab: the OD value of blank well (culture medium, CCK-8 without cell and compound).
Then numerical value importing Graphpad Prism5 software is carried out curve fitting, calculates IC50。
Table (three) lists in the present invention representative compound to BaF3-EGFR-L858R-T790M and BaF3-EGFR- The determination of activity result of L858R-T790M-C797S cell.
Table (three): measurement result of the representative compound of the present invention to cell activity
Experimental data shows that the compound of the present invention is introduced in facing on position for phenyl ring (relative to coupled piperidine ring) " Cl " atom effectively enhances the cell activity of mutant egf R as substituent group, prominent to EGFR T790M and C797S The inhibitory activity of born of the same parents of attenuating is significantly larger than Brigatinib, promises to be forth generation EGFR T790M and C797S mutation and mediates Non-small cell lung cancer candidate drug compounds.
The above is a preferred embodiment of the present invention, it is noted that for those skilled in the art For, under the premise of not departing from principle of the present invention, embodiments of the present invention can also make several improvements and modify, These improvement and modification also should be regarded as protection scope of the present invention.

Claims (11)

1. compound shown in a kind of formula (I), its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its preceding Medicine,
In formula (I),
R1For unsubstituted or substituted aryl, heteroaryl, naphthenic base, naphthenic base caged scaffold or simultaneously ring structure,
Substituted aryl, heteroaryl, naphthenic base, substituent group is-CF in naphthenic base caged scaffold or simultaneously ring structure3,-OCF3, hydroxyl Base, cyano, halogen, C1-C6Alkyl, C3-C5Naphthenic base, C1-C6Alkoxy, C3-C5Cycloalkyl oxy ,-S (=O)2R6,-C (=O) R6,-P (=O) R6R7,-S (O)2NR6R7,
R6And R7It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base；
Described and ring structure is selected from aromatic ring and 5-6 member heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, aromatic ring and 5-6 First naphthenic base, aromatic ring and 5-6 circle heterocyclic ring base, 5-6 member hetero-aromatic ring and 5-6 member naphthenic base or 5-6 member hetero-aromatic ring and 5-6 circle heterocyclic ring Base；
R2For-H ,-CF3,-OCF3, hydroxyl, cyano, C1-C6Alkyl, C3-C4Naphthenic base, C1-C6Alkoxy, C3-C6Cycloalkyl oxy；
R3For-H ,-CF3, C1-C6Alkyl, C3-C6Naphthenic base, C3-C4The C that naphthenic base replaces1-C2Alkyl, or-OR8,
R8For-H ,-CF3,-CH2CF3, C1-C6Alkyl, C3-C6Naphthenic base, C3-C4The C that naphthenic base replaces1-C2Alkyl contains an oxygen original The 4-6 circle heterocyclic ring base of son, or-(CH2)mR9,
Wherein m is 1,2,3 integers,
R9For-OH ,-CN ,-C (O) NH2,-S (=O)2CH3, C1-C3Alkoxy, C1-C3Alkylthio group；
R4And R5It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base, the 4-6 member containing a nitrogen-atoms or containing an oxygen atom Heterocycle or-(CH2)nR10,
Wherein n is 1,2,3 integers,
Described nitrogen-atoms or the 4-6 circle heterocyclic ring containing an oxygen atom of containing is non-substituted or by C1-C3Alkyl replaced,
R10For-OH ,-CN ,-C (O) NH2,-S (=O)2CH3,-NR'R ", C1-C3Alkoxy, C1-C3Alkylthio group,
R', R " are independently H or C1-C3Alkyl；
R4、R5Nitrogen-atoms that can also be coupled constitutes 4-6 circle heterocyclic ring or 6-9 member loop coil, and the heterocycle is selected from N, O containing 1-2 Or the hetero atom or the-C containing group (=O)-or-S (=O) of S2As its ring members,
The R4、R5The 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is unsubstituted or is selected from halogen, cyanogen by 1-2 respectively Base, hydroxyl, amino, C1-C3Alkyl, C1-C3Alkoxy, halogenated C1-C3The C that alkyl, cyano replace1-C3Alkyl, hydroxyl replace C1-C3Alkyl, C1-C3The C that alkoxy replaces1-C3Replaced alkyl；
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is single loop coil comprising a nitrogen-atoms.
2. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug, R1Selected from following group:
Q is N or CH,
X is-NH ,-O, or-S.
R11Selected from-H ,-OH ,-F, Cl, Br ,-CN ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl oxygroup, cyclobutyl oxygroup or following group:
R12For-H ,-F, Cl, Br, hydroxyl, cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, third Oxygroup or isopropoxy.
R13For-H, methyl, ethyl, propyl, isopropyl.
3. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug,
R2Selected from-H ,-CF3,-OCF3, hydroxyl, cyano, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxyl group, ethyoxyl, Propoxyl group, isopropoxy, cyclopropyl oxygroup, cyclobutyl oxygroup.
4. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug,
R3Selected from-H ,-CF3, methyl, ethyl, propyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl, cyclopropyl, cyclobutyl, ring Hydroxypropyl methyl, cyclobutylmethyl, or-OR8,
R8Selected from-H ,-CF3,-CH2CF3, methyl, ethyl, propyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, propylene oxide -3- base, tetrahydrofuran -3- Base, tetrahydropyran -4-base, tetrahydropyran -3-base, methylmercaptoethyl, methylthio, methoxy ethyl, methoxy-propyl, second Oxygroup ethyl, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, aminopropionyl, methylsulfonyl second Base, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl.
5. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug,
R4And R5It is independently selected from-H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, epoxy third Alkane -3- base, tetrahydrofuran -3- base, tetrahydropyran -4-base, tetrahydropyran -3-base, N- methyl piperidine -3- base, N- methyl piperidine - 4- base, N- methylpyrrolidin- 3- base, N- methyl nitrogen (miscellaneous) cyclobutane -3- base, methylmercaptoethyl, methylthio, methoxyl group second Base, methoxy-propyl, ethoxyethyl group, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, amino Propiono, mesylethyl, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl, methylamino Ethyl, dimethylaminoethyl, methylaminopropyl, dimethylamino-propyl or R4、R5Coupled nitrogen-atoms constitutes 4-6 circle heterocyclic ring Or 6-9 member loop coil, the 4-6 circle heterocyclic ring are substituted or non-substituted heterocycle,
The R4、R5The substituted or non-substituted 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is selected from following ring structure:
R14Selected from-H, methylamino, ethylamino, dimethylamino,
R15Selected from-H, methyl, ethyl, propyl, isopropyl, formoxyl, acetyl group or mesyl.
R16And R17It is independently selected from-H ,-F ,-CF3, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, cyano methyl, cyano ethyl, methoxy, methoxy ethyl, methoxy-propyl, Methylol, ethoxy, hydroxypropyl,
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is selected from following spirane structure:
6. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug,
R4It is selected from: cyclopropyl, cyclobutyl, cyclopenta, propylene oxide -3- base, tetrahydrofuran -3- base, tetrahydropyran -4-base, tetrahydro Pyrans -3- base, N- methyl piperidine -3- base, N- methyl piperidine -4- base, N- methylpyrrolidin- 3- base, N- methyl nitrogen (miscellaneous) ring fourth Alkane -3- base,
R5Selected from-H, methyl, ethyl, propyl, isopropyl, methylmercaptoethyl, methylthio, methoxy ethyl, methoxy propyl Base, ethoxyethyl group, ethoxycarbonyl propyl, isopropoxyethyl, isopropoxide propyl, glycyl, aminopropionyl, methylsulphur Acyl ethyl, methylsulfonyl propyl, ethoxy, hydroxypropyl, cyano methyl, cyano ethyl, cyanopropyl, methylaminoethyl, diformazan ammonia Base ethyl, methylaminopropyl, dimethylamino-propyl,
Or R4、R5Coupled nitrogen-atoms constitutes 4-6 circle heterocyclic ring or 6-9 member loop coil, and the 4-6 circle heterocyclic ring is to replace or non-take The heterocycle in generation,
The R4、R5The substituted or non-substituted 4-6 circle heterocyclic ring that coupled nitrogen-atoms is constituted is selected from following ring structure:
R14Selected from-H, methylamino, ethylamino, dimethylamino,
R15Selected from-H, methyl, ethyl, propyl, isopropyl, formoxyl, acetyl group or mesyl.
R16And R17It is independently selected from-H ,-F ,-CF3, hydroxyl, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, cyano methyl, cyano ethyl, methoxy, methoxy ethyl, methoxy-propyl, Methylol, ethoxy, hydroxypropyl,
The R4、R5The 6-9 member loop coil that coupled nitrogen-atoms is constituted is selected from following spirane structure:
Prepare that compound described in claim 1-6, its isomers, hydrate, solvate, its is pharmaceutically acceptable 7. a kind of The method of salt and its prodrug, includes the following steps,
8. the compound or its pharmaceutical salt of formula (I) according to claim 1-6, wherein the salt is Acidity/anion salt or basic/cationic salts；The form that pharmaceutically acceptable acidity/anion salt is usually taken is to allow it In basic nitrogen protonated by inorganic or organic acid, representative organic or inorganic acid includes hydrochloric acid, hydrobromic acid, and hydroiodic acid is high Chloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, hydroxyacetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, Citric acid, fumaric acid, gluconic acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzene sulfonic acid, oxalic acid, palmitinic acid, 2- naphthalene sulfonic acids, p-methyl benzenesulfonic acid, cyclohexylamino sulfonic acid, salicylic acid, saccharinic acid, trifluoroacetic acid；Pharmaceutically acceptable alkalinity/sun Ion salt includes being of course not solely limited to this aluminium, calcium, chloroprocanine, choline, diethanol amine, ethylenediamine, lithium, magnesium, potassium, sodium and Zinc.
9. the Pharmaceutical composition of a kind for the treatment of and tyrosine kinase EGFR, HER2 or ALK mutation or overexpression related disease, By the compound of formula described in any one of claims 1-6 (I) or its pharmaceutically acceptable salt or its hydrate or its solvent Compound or its prodrug and pharmaceutically acceptable carrier or excipient form.
10. a kind of Pharmaceutical composition: wherein including the compound or its pharmacy of formula as claimed in any one of claims 1 to 6 (I) Upper acceptable salt, hydrate, solvate or prodrug are as active constituent, one or more of the other therapeutic agent, Yi Jiyi Kind or a variety of pharmaceutically acceptable carriers or excipient.
11. the compound or its pharmaceutically acceptable salt of formula (I) according to claim 1 to 6 or its prodrug It is used to prepare treatment and tyrosine kinase EGFR, HER2 or ALK mutation or is overexpressed relevant cancer and autoimmune disease Application in drug, it is fundus oculi disease, xerophthalmia, psoriasis, white wherein the cancer and autoimmune disease include but is not limited to Purplish or white patches on the skin wind, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic loupus erythematosus, Crohn disease, artery congee Sample, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, nerve Glioma, glioblastoma, oophoroma, cervix cancer, colorectal cancer, melanoma, carcinoma of endometrium, prostate cancer, The white blood of bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelocytic leukemia, acute myelocytic Disease, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and t cell lymphoma, lymthoma, Huppert's disease, It is any etc. in biliary tract carcinosarcoma, cholangiocarcinoma.
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