CN108676009A - Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and its application - Google Patents
Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and its application Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of novel pyridine derivatives, which is compound shown in formula I, its pharmaceutically acceptable salt.The compound can be used in the drug for being prepared into treatment and/or pre- preventing tumor.
Description
Technical field
The invention belongs to biomedicine technical field, be related to as HER2 tyrosine kinase inhibitors pyrimidine derivatives and
It is applied.
Background technology
Human epidermal growth factor acceptor -2 (HER2) also known as ErbB2 belong to epidermal growth factor (EGF) receptor family
A member, other family members include HER1 (EGFR), HER3, HER4.HER2 is distributed in cell membrane surface, is in cell signal
Downstream cellular signal transduction pathway after dimerization occurs with family other receptors, is activated in the upstream of Signal Transduction Pathways, as MAPK signals are logical
Road and PI3K-AKT-mTOR signal paths, and then cause the biological effects such as cell differentiation, existence, migration, invasion, adherency.HER2
Overexpression, lead to the up-regulation of cell-signaling pathways, and then promote cell Proliferation, inhibit Apoptosis, increase cell invasion
Power, final generation, development and the migration for causing tumour.
Breast cancer is the most common cancer of women, accounts for about the 25% of female cancer patients, about 1,600,000 women are true every year in the whole world
Breast cancer is examined, more than 500,000 patients because of the disease death.About 20%-25% patient with breast cancers are diagnosed as HER2 positive breasts
Cancer, HER2, which is overexpressed indication tumour, has stronger invasion, is more easy to early stage relapse and metastasis.There are about the HER2 of 30%-50% sun
Property patient with breast cancer can tumorigenic brain metastes, the brain metastes of tumour are the lethal most important originals of HER2 breast cancer patients with positive
One of because, and HER2 breast cancer patients with positive tumour brain metastes incidence is in ascendant trend year by year.
It is directed to the brain metastes of HER2 positive breast tumors at present, clinical treatment mainly uses：Whole-brain radiotherapy, stereotaxis
Radiosurgery and operation excision, these therapeutic schemes offer limited effectiveness first are secondly inevitably serious
Side effect.With the extensive use of HER2 targeted drugs, the life cycle of HER2 breast cancer patients with positive is obviously prolonged, however at present
The HER2 targeted drugs of listing are difficult to penetrate blood-brain barrier such as monoclonal antibody drug and small molecule kinase inhibitors drug,
Cause exposed amount in brain limited, be unable to reach effective treatment concentration, and then leads to the outer lesion control of cranium, intracranial lesion progress occur
The case where.
Thus, for the deficiency of current HER2 targeted drugs, there is an urgent need to more safely and effectively therapeutic schemes.It opens
Safer, the efficient newtype drug for being directed to HER2 breast cancer patients with positive tumour brain metastes is sent out, there is huge social valence
Value and economic benefit, and the research hotspot of major pharmaceutical manufacturer at present.
Invention content
The technical problem to be solved by the present invention is in order to overcome the defect of existing HER2 targeted drugs, and provide one kind
Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and its application, the compound activity is good, to the selectivity of HER2 more
By force, permeability higher, and blood-brain barrier can be penetrated, reach effective treatment concentration.The compound can be used for being prepared into treatment and/or
The drug of pre- preventing tumor improves the survival rate of brain tumor transfer patient, extending life period.Meanwhile the compound of the present invention pair
EGFR tyrosine kinase also has good inhibiting effect.
According to the first aspect of the invention, the present invention provides a kind of compound shown in formula I, its is pharmaceutically acceptable
Salt：
Wherein, the R1For C1-C6Alkyl；
The R2For
The R3For hydrogen, halogen, hydroxyl, amino or C1-6Alkyl；
The R4For hydrogen, halogen, hydroxyl, amino, C1-6Alkyl or-O (CH2)m-R8；
The R5For hydrogen, halogen, C1-C6Alkyl, R7-(C(R6)2) s- or Het- (C (R6)2)r-；
The R6For hydrogen or C1-C6Alkyl；
The R7For-NR6R6、-OR6、-NHR6、-C(R6)3、-CHR6R6Or-CH2R6；
The R8For
The Y is-C (R9)n, O or-NR9；
The R9For hydrogen, C1-C6Alkyl or C1-C6Alkoxy；
The m is 1,2 or 3；
The n is 1,2；
The s is 1,2 or 3；
The r is 1,2 or 3；
The Het heterocycles be piperidines, dihydropyridine, pyrroles, nafoxidine, imidazoles, piperazine, oxinane, oxinane,
Morpholine, thiomorpholine or thiophene.
According to an embodiment of the invention, the R1In, the C1-6Alkyl is C1-4Alkyl；
And/or the R3In, the R3For hydrogen or halogen；
And/or the R3In, the C1-6Alkyl is C1-4Alkyl；
And/or the R4In, the R4For hydrogen, halogen or-O (CH2)m-R8；
And/or the R4In, the C1-6Alkyl is C1-4Alkyl；
And/or the R5In, the C1-6Alkyl is C1-4Alkyl；
And/or the R6In, the C1-6Alkyl is C1-4Alkyl；
And/or the R9In, the C1-6Alkyl is C1-4Alkyl；
And/or the R9In, the C1-6Alkoxy is C1-4Alkoxy.
According to an embodiment of the invention, the R1In, the C1-4Alkyl be methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, sec-butyl or tertiary butyl；
And/or the R3In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or tertiary butyl；
And/or the R3In, the halogen is fluorine, chlorine or bromine；
And/or the R4In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or tertiary butyl；
And/or the R4In, the halogen is fluorine, chlorine or bromine；
And/or the R5In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or tertiary butyl；
And/or the R5In, the halogen is fluorine, chlorine or bromine；
And/or the R6In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or tertiary butyl；
And/or the R9In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl
Base, sec-butyl or tertiary butyl；
And/or the R9In, the C1-4Alkoxy is methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just
Butoxy, isobutoxy, sec-butoxy or tert-butoxy.
According to an embodiment of the invention, the R3In, the R3For chlorine；
And/or the R4In, the R4For fluorine or-O (CH2)m-R8。
As a result, throughout this manual, those skilled in the art can be to R described in compound shown in Formulas I1~R9And Y
Group or substituent group selected, with provide it is described in the embodiment of the present invention, stablize Formulas I shown in compound, its medicine
Acceptable salt on.
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application,
For describing chemical bond, the point that the chemical bond is part or substituent group, core structure or skeleton structure is connected.
In a certain technical solution, the Formulas I compound represented can be following any structure：
In the second aspect of the present invention, the present invention proposes a kind of method preparing foregoing compound.According to this
The embodiment of invention, this method include：Compound shown in formula a is contacted with compound shown in formula g, to obtain Formulas I institute
Show compound.
Wherein, R described in compound shown in Formulas I1~R9And the group or substituent group of Y are as defined above.
Inventor has found, being capable of fast and effeciently compound or its pharmacy shown in formula I using this method of the present invention
Upper acceptable salt, and short, environmental-friendly, target product the yield of synthetic route and purity are higher, raw material is easy to get, operate and after
Processing is simple, is suitble to industrialized production.
According to an embodiment of the invention, compound shown in the formula a carries out contacting further packet with compound shown in formula b
It includes：Under the conditions of -5 DEG C~5 DEG C, by compound shown in the mixed solution of compound and N-Methyl pyrrolidone shown in formula g and formula a
Mixing, and at ambient temperature, obtained mixture is reacted, after TLC detections have been reacted, is post-processed and be purified into
Come, obtains the compound described in formula I.
A specific example according to the present invention, the method for preparing foregoing compound include：In 0 DEG C~5 DEG C items
Under part, compound shown in formula a is added into reaction bulb, compound and N-Methyl pyrrolidone shown in formula g are added dropwise into reaction solution
The solution of composition adds in 30 minutes, reacts 12 hours at room temperature.Suitable quantity of water is added, by institute after the reaction was complete in TLC detections
The sodium hydrate aqueous solution tune pH to 10.0~11.0 of 2 mol/Ls of obtained mixed solution, is precipitated a large amount of solids, by gained
Solid is filtered successively, is washed, dry, the solid crude product of target compound is obtained, by solid crude product methanol/acetone weight
Crystallize (methanol/acetone=3:1 (v/v)), purify to obtain white solid product, the compound described in as formula I.
Compound of formula I of the present invention can be prepared according to the chemical synthesis process of this field routine, step and item
Part can refer to this field similar the step of reacting and condition.
Reaction dissolvent is not particularly limited used in each reaction step of the present invention, any to a certain extent
It dissolves starting material and the solvent of reaction is not inhibited to be included in the present invention.In addition, many similar changes of this field, etc.
With replacement, or it is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the present invention
Scope.
The present invention also provides a kind of pharmaceutical compositions comprising the compound of formula I, its pharmaceutically acceptable salt,
And pharmaceutic adjuvant.The Pharmaceutical composition can also further include the conventional additives such as odorant agent, flavouring agent.
In the pharmaceutical composition, the compound of formula I, the dosage of its pharmaceutically acceptable salt can be treatment
Effective quantity.
The pharmaceutic adjuvant can be those of widely used auxiliary material in drug production field.Auxiliary material is mainly used for offer one
A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is with institute after so that subject is received administration
Expected rate dissolves out, or promotes subject to receive active constituent after composition is administered and effectively absorbed.The pharmaceutic adjuvant
It can be inert filler, or certain function is provided, such as stablize the whole pH value of the composition or prevent composition active
The degradation of ingredient.The pharmaceutic adjuvant may include one or more in following auxiliary material：Adhesive, suspending agent, emulsifier,
Diluent, filler, granulating agent, adhesive, disintegrant, lubricant, antitack agent, glidant, wetting agent, gelling agent, absorption
Delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.
According to an embodiment of the invention, the gross mass based on pharmaceutical composition, pharmaceutical composition provided by the present invention are excellent
Choosing contains the foregoing compound that weight ratio is 1%~80% as active ingredient, it is further preferred that foregoingization
It closes object and accounts for the 5%~20% of pharmaceutical composition total weight as active constituent, rest part is pharmaceutically acceptable carrier, assigns
At least one of shape agent and conventional additives.
According to an embodiment of the invention, pharmaceutical composition provided by the present invention can take various forms, including but unlimited
In tablet, capsule, injection, injection powder needle, pulvis, syrup, solution shape, suspension and aerosol etc., and can reside in
The carrier or dilution of suitable solid or liquid neutralize in the suitable disinfector for injecting or instiling.
The present invention pharmaceutical composition can according to disclosure using any method well known by persons skilled in the art come
It prepares.For example, conventional mixing, dissolving, granulation, emulsification, levigate, encapsulating, embedding or lyophilized technique.The compound of the present invention and medicine
Compositions can pass through mouth, nose, skin, lung or gastrointestinal tract etc. to mammal Clinical practice, including humans and animals
Approach is administered.No matter which kind of instructions of taking used, depending on personal optimal dose should be according to specific therapeutic scheme.Normal conditions
Under be to gradually increase dosage until find most suitable dosage since low dose.Most preferred administration route is oral.
According to the fourth aspect of the invention, the present invention also provides the compound of formula I, its pharmaceutically acceptable salt,
Application in preparing HER2 tyrosine kinase inhibitors.
Meanwhile the present invention also provides the compound of formula I, its pharmaceutically acceptable salts, are preparing EGFR tyrosine
Application in kinase inhibitor.
EGFR the and HER2 tyrosine kinase inhibitors can be used in organism；In vitro is can also be used for, mainly
As experimental use, such as：Comparison is provided as standard sample or control sample, or kit is made according to this field conventional method,
Quick detection is provided for the inhibition of EGFR and HER2.
According to the fifth aspect of the invention, the present invention also provides the compound of formula I, its pharmaceutically acceptable salt,
Application in preparing the drug for the treatment of and/or pre- preventing tumor.According to an embodiment of the invention, drug of the present invention is used as swashing
Enzyme inhibitor.It was found by the inventors of the present invention that compound of formula I of the present invention can be used as kinase inhibitor, tyrosine is adjusted
Signal transduction of kinases.Compound of the present invention is the potent inhibitor of ErbB2 (HER2), and the compound of the present invention pair
The inhibiting effect of ErbB2 declares the stage better than existing drug linatinib (Neratinib) and in registration
Dacomitinib.Simultaneously.Compound of the present invention is also a kind of potent EGFR inhibitor.Using the chemical combination of the present invention
Object can be effectively treated or prevented by least one of EGFR and the ErbB2 cancer mediated or tumor disease.Therefore, institute of the present invention
The compound stated can treat or prevent the cancer mediated by least one of EGFR and ErbB2 effectively as kinase inhibitor
Disease or tumor disease, the tumour can be related tumour with EGFR and HER2 activity.Described is active with EGFR and HER2
Related tumour can be related cancer with EGFR and HER2 activity.The related cancer with EGFR and HER2 activity is choosing
From breast cancer, gastric cancer, non-small cell lung cancer, solid tumor, colorectal cancer, cancer of pancreas, the cancer of the esophagus, glioma, head and neck neoplasm, ovary
It is cancer, uterine cancer, carcinoma of urinary bladder, cholangiocarcinoma, endometrioid carcinoma, colorectal cancer, prostate cancer, acute myelocytic leukemia, black
At least one of melanoma, late period Hodgkin lymphoma, brain tumor or liver cancer.
Unless otherwise prescribed, all technical terms and scientific terms used herein have claimed theme fields
Standard meaning.If to Mr. Yu's term, there are multiple definition, then to be defined herein as standard.When Referral URL or other identifier or
Address, it should be appreciated that such identifier can change, and the specific information on internet can change, but mutual by searching for
Networking can find same information.Reference this type of information can get and open propagate.
It should be understood that above-mentioned general explanation and following detailed description are merely illustrative of, to the present invention not by
This limitation.The singulative being used in the present invention, as "an" or "one", including plural, unless otherwise prescribed.This
Outside, term " comprising " is open limits and non-enclosed.
Unless otherwise indicated, the present invention using mass spectrum, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology or
The conventional method of pharmacology detection, each step and condition can refer to the operating procedure and condition of this field routine.Unless otherwise specified,
The present invention is using the standard name of analytical chemistry, Synthetic Organic Chemistry and medical chemistry and standard laboratory step and technology.
In some cases, standard technique is used for chemical synthesis, chemical analysis, medicine preparation, formula and drug delivery and patient
Treatment.
Term " pharmaceutically acceptable " as used in the present invention is for those compounds, material, composition
And/or for dosage form, within the scope of reliable medical judgment, being contacted suitable for the tissue with human and animal makes for they
With without excessive toxicity, irritation, allergic reaction or other problems or complication, with rational interests/Hazard ratio phase
Claim.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group
To pass through the side for using the alkali of sufficient amount to be contacted with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group
Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as
Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts”,Journal of Pharmaceutical Science 66:1-19(1977)).Certain specificization of the present invention
It closes object and contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.Preferably, in a usual manner
So that salt is contacted with alkali or acid, then detach parent compound, thus the neutral form of raw compounds again.The parent fo of compound with
The form of its various salt is the difference is that certain physical properties, such as the different solubility in polar solvent.
" pharmaceutically acceptable salt " used in the present invention belongs to the derivative of the compounds of this invention, wherein by with acid
The parent compound is modified at salt or with alkali at the mode of salt.The example of pharmaceutically acceptable salt includes but not limited to：Alkali
The inorganic acid of base such as amine or the alkali metal of acylate, acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt
Include the quaternary ammonium salt of conventional avirulent salt or parent compound, such as nontoxic inorganic acid or organic acid are formed by salt.
Conventional avirulent salt includes but not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid
Selected from Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid,
Citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid,
Hydrochloric acid, hydriodate, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, methane
Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, ammonia
Base sulfonic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
" pharmaceutically acceptable salt " of the present invention can pass through conventional chemical by the parent compound containing acid group or base
Method synthesizes.Under normal circumstances, the preparation method of such salt is：In the mixture of water or organic solvent or both, via
These compounds of free acid or alkali form react to prepare with the alkali appropriate of stoichiometry or acid.It is generally preferable that ether, second
The non-aqueous medias such as acetoacetic ester, ethyl alcohol, isopropanol or acetonitrile.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach
To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition
" effective quantity " refer to when another active material is combined in the composition for the required dosage that achieves the desired results.Have
The determination of effect amount varies with each individual, and depends on age and the ordinary circumstance of receptor, also depends on specific active material, closed in case
Suitable effective quantity can be determined by those skilled in the art according to routine test.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can have
The therapeutic purpose disorder of effect ground, disease or illness.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise
Content.
Inventor has found that the compound of the present invention can be used as kinase inhibitor, adjusts tyrosine kinase signal transduction.This hair
The bright compound is the potent inhibitor of ErbB2 (HER2), and the compound of the present invention is better than the inhibiting effect of ErbB2
Neratinib and Dacomitinib, simultaneously.Compound of the present invention is also a kind of potent EGFR inhibitor, application
The compound of the present invention can be effectively treated or prevented by least one of EGFR and the ErbB2 cancer mediated or tumor disease.
In addition, the compound of the present invention also shows better choice, good dissolubility, has excellent blood plasma steady in vitro
Qualitative and hepatomicrosome stability, bioavilability are high.
Compound shown in the preparation-obtained Formulas I of the present invention has good human breast cancer cell (MDA-MB-231)
Inhibiting effect, the results showed that, the present invention can be used for being prepared into the drug for treating antitumor/anticancer, is particularly suitable for being prepared into and control
Treat the drug of breast cancer.Moreover, for the anticancer drug linatinib of existing treatment breast cancer, chemical combination of the present invention
Object inhibits the effect of human breast cancer cell to be better than linatinib.
Pyrimidine derivatives of the present invention as HER2 tyrosine kinase inhibitors, may be used as single dose, or and its
He is combined therapeutic agent, to enhance the effect of these therapeutic agents.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that：Miazines of the present invention as HER2 tyrosine kinase inhibitors
Derivative, structure novel, Orally-administrable treatment.Compound of the present invention shows in the early-stage study of inventor
Compared to linatinib and Dacomitinib, active more preferable, the EGFR and HER2 selectivity of series compound of the present invention is more
By force, permeability higher.Compound of the present invention can be used for being prepared into the medicine of the brain metastes of HER2 positive breast tumors
Object.
Specific implementation mode
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it is carried out according to technology or condition described in document in the art or according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
The embodiment provides compound shown in Formulas I, its pharmaceutically acceptable salt, chemical combination shown in formula Ι
Object, the method for its pharmaceutically acceptable salt and intermediate, pharmaceutical composition and the compound of the present invention are in medicine preparation
Purposes.
Formulas I
Embodiment 1：The preparation of compound shown in Formulas I -1
Under the conditions of -5 DEG C~0 DEG C, compound 19.1g (0.102 mole) shown in formula a-1 is added into reaction bulb, to anti-
Answer the solution for being added dropwise that compound 35.8g (0.1 mole) and 160 milliliters of N-Methyl pyrrolidones are formed shown in formula g-1 in liquid, 20 points
It adds, reacts at room temperature 12 hours in clock.TLC detections are added suitable quantity of water, obtained mixed solution are rubbed with 2 after the reaction was complete
You/liter sodium hydrate aqueous solution tune pH10.0~11.0, a large amount of solids are precipitated, filter, wash, it is dry, obtain off-white powder
Crude product recrystallizes (methanol/acetone=3 with methanol/acetone:1 (v/v)), white solid product is purified to obtain, as shown in Formulas I -1
Compound 22.2g, yield 45.6%, purity 99.2%.
LCMS:511(M+1)+。
Embodiment 2：The preparation of compound shown in Formulas I -2
Under the conditions of -5 DEG C~0 DEG C, compound 9.45g (0.105 mole) shown in formula a-2 is added into reaction bulb, to anti-
Answer the solution for being added dropwise that compound 35.8g (0.1 mole) and 160 milliliters of N-Methyl pyrrolidones are formed shown in formula g-1 in liquid, 30 points
It adds, reacts at room temperature 10 hours in clock.TLC detections are added suitable quantity of water, obtained mixed solution are rubbed with 2 after the reaction was complete
You/liter sodium hydrate aqueous solution tune pH10.0~11.0, a large amount of solids are precipitated, filter, wash, it is dry, obtain off-white powder
Crude product, with isopropanol/acetone recrystallization (isopropanol/acetone=2:1 (v/v)), purify to obtain white solid powder, as Formulas I -2
Shown compound 25.6g, yield 62.1%, purity 99.4%.
LCMS:414(M+1)+。
Embodiment 3：The preparation of compound shown in Formulas I -3
The preparation method of compound shown in Formulas I -3 differs only in reaction raw materials difference with embodiment 2.Yield 55.7%,
Purity 98.6%.
LCMS：413(M+1)+。
Embodiment 4：The preparation of compound shown in Formulas I -4
The preparation method is the same as that of Example 1 for compound shown in Formulas I -4, differs only in reaction raw materials difference.Yield 71.0%,
Purity 98.5%.
LCMS：607(M+1)+。
Embodiment 5：The preparation of compound shown in Formulas I -5
Under the conditions of 0 DEG C~5 DEG C, compound 9.45g (0.105 mole) shown in formula a-2 is added into reaction bulb, to reaction
The solution of compound 44.5g (0.1 mole) and 200 milliliters of N-Methyl pyrrolidones composition shown in dropwise addition formula g-5 in liquid, 30 minutes
It inside adds, reacts 12 hours at room temperature.The reaction was complete for TLC detections, and suitable quantity of water is added, obtained mixed solution is rubbed with 2
You/liter sodium hydrate aqueous solution tune pH10.0~11.0, a large amount of solids are precipitated, obtained solid is filtered successively, wash,
It is dry, the solid crude product of target compound is obtained, solid crude product methanol/acetone is recrystallized into (methanol/acetone=3:1(v/
V)), white solid product is purified to obtain, the compound 33.3g described in formula I-5, yield 66.8%, purity 99.5% are obtained.
LCMS：501(M+1)+。
Embodiment 6：The preparation of compound shown in Formulas I -6
Under the conditions of -5 DEG C~0 DEG C, compound 9.45g (0.105 mole) shown in formula a-2 is added into reaction bulb, to anti-
Answer the solution for being added dropwise that compound 49.2g (0.1 mole) and 200 milliliters of N-Methyl pyrrolidones are formed shown in formula g-6 in liquid, 30 points
It adds in clock, reacts 15 hours at room temperature.The reaction was complete for TLC detections, and suitable quantity of water is added, by obtained mixed solution with 2
Sodium hydrate aqueous solution tune pH10.0~11.0 of mol/L, are precipitated a large amount of solids, and obtained solid is filtered successively, is washed
Wash, it is dry, obtain the solid crude product of target compound, by the solid crude product with isopropanol/recrystallize with dichloromethane (isopropanol/
Dichloromethane=4:1 (v/v)), white solid product is purified to obtain, the compound 29.5g described in formula I-6, yield are obtained
54.0%, purity 98.0%.
LCMS：548(M+1)+。
Embodiment 7：The preparation of compound shown in Formulas I -7
Under the conditions of -5 DEG C~0 DEG C, compound 15.0g (0.102 mole) shown in formula a-7 is added into reaction bulb, to anti-
Answer the solution for being added dropwise that compound 35.8g (0.1 mole) and 180 milliliters of N-Methyl pyrrolidones are formed shown in formula g-1 in liquid, 30 points
It adds, reacts at room temperature 15 hours in clock.TLC detections are added suitable quantity of water, obtained mixed solution are rubbed with 2 after the reaction was complete
You/liter sodium hydrate aqueous solution tune pH10.0~11.0, a large amount of solids are precipitated, filter, wash, it is dry, obtain off-white powder
Crude product recrystallizes (acetonitrile/THF=2 with acetonitrile/THF:1 (v/v)), purify to obtain white solid product, as -7 shownization of Formulas I
Close object 32.5g, yield 69.3%, purity 99.4%.
LCMS:471(M+1)+。
Embodiment 8：The preparation of compound shown in Formulas I -8
The preparation method is the same as that of Example 1 for compound shown in Formulas I -8, differs only in reaction raw materials difference.Yield 58.9%,
Purity 98.6%.
LCMS：505(M+1)+。
Embodiment 9：The preparation of compound shown in Formulas I -9
The preparation method of compound shown in Formulas I -9 differs only in reaction raw materials difference with embodiment 7.Yield 70.2%,
Purity 97.9%.
LCMS：566(M+1)+。
Embodiment 10：The preparation of compound shown in Formulas I -10
The preparation method is the same as that of Example 1 for compound shown in Formulas I -10, differs only in reaction raw materials difference.Yield
68.7%, purity 98.8%.
LCMS：619(M+1)+。
Embodiment 11：The preparation of compound shown in Formulas I -11
Under the conditions of 0 DEG C~5 DEG C, compound 15.0g (0.102 mole) shown in formula a-7 is added into reaction bulb, to reaction
The solution of compound 46.1g (0.1 mole) and 220 milliliters of N-Methyl pyrrolidones composition shown in dropwise addition formula g-5 in liquid, 30 minutes
It inside adds, reacts 12 hours at room temperature.The reaction was complete for TLC detections, and suitable quantity of water is added, obtained mixed solution is rubbed with 2
You/liter sodium hydrate aqueous solution tune pH10.0~11.0, a large amount of solids are precipitated, obtained solid is filtered successively, wash,
It is dry, the solid crude product of target compound is obtained, solid crude product methanol/acetone is recrystallized into (methanol/acetone=3:1(v/
V)), white solid product is purified to obtain, the compound 31.6g described in formula I-11, yield 55.2%, purity 99.5% are obtained.
LCMS：573(M+1)+。
Embodiment 12：Kinase assays
Reagent and operation：
Basic reaction buffer solution：20mM 4- hydroxyethyl piperazineethanesulfonic acids (Hepes, pH 7.5), 10mM MgCl2, 1mM second
Bis- (the 2- amino-ethyls ether) tetraacethyls (EGTA) of glycol, 0.02% Brij-35 (Brij35), 0.02mg/ml oxen
Seralbumin (BSA), 0.1mM Na3VO4, 2mM dithiothreitol (DTT)s (DTT), 1% dimethyl sulfoxide (DMSO) (DMSO).
Prepare the specified substrate in freshly prepared basic reaction buffer solution；
Any desired co-factor is added into above-mentioned substrate solution；
Specified kinases is added into the substrate solution and is gently blended；
The compound being dissolved in DMSO is added into the kinase reaction mixture；
It is added into the reaction mixture33P-ATP (specific activity is 0.01 μ Ci/ μ l final volumes) is with initiation reaction.End reaction
Volume is 5 μ l；
Kinase reaction object is incubated into 120min at room temperature；
It will be on reactant point sample to P81 ion exchange papers (Whatman#3698-915)；
Filter paper is fully washed with 0.1% phosphoric acid；
(become oblique using the S types dose response in Prism programs (GraphPad Software, Inc., La Jolla, CA)
Rate) Algorithm Analysis IC50 generation data.
Kinases information：
EGFR-Genbank accession number #NP_005219.2.Recombinate catalytic domain, amino acid 668-1210, GST label, purifying
From insect cell.Activated in Vitro is carried out by autophosphorylation.Final concentration=4nM in measurement.Substrate：pEY.Peptide sequence：It is poly-
Glu-Tyr, ratio 4：1.Final concentration=0.2mg.mL in measurement.It is added into the reaction mixture as co-factor
2mM MnCl2。
ErbB2/HER2-Genbank accession number #X03363.Catalytic domain is recombinated, amino acid 679-1255, GST label is pure
Change from insect cell.Final concentration=50nM in measurement.Substrate：pEY.Peptide sequence：Poly- Glu-Tyr, ratio 4：1.In measurement
Final concentration=0.2mg.mL.The 2mM MnCl2 as co-factor are added into the reaction mixture.
Biological assessment
Compound shown in compound~Formulas I -11 shown in the preparation-obtained Formulas I -1 of the test present invention.
First this hair is tested with the 10 dosage IC50 patterns (10-dose IC50mode) that 3 times since 10 μM are serially diluted
Compound described in Ming Dynasty style I-1.The result shows that -1 compound of Formulas I is the potent inhibitor of EGFR and ErbB2 (HER2), and Formulas I -1
Compound is better than existing drug Neratinib and Dacomitinib to the inhibiting effect of EGFR and ErbB2.Likewise, we
It was found that compound shown in compound~Formulas I -11 shown in the preparation-obtained Formulas I -2 of the present invention has EGFR and ErbB2 measurement
There is the activity (IC of ＜ 25nM50), and compound shown in compound~Formulas I -11 shown in Formulas I -2 makees the inhibition of EGFR and ErbB2
With being better than Neratinib and Dacomitinib, compound ratio Neratinib shown in Formulas I of the present invention and
Dacomitinib has higher EGFR and erbB2 kinase inhibitory activity.Specifically it is shown in Table 1.
Table 1：
| Compound | EGFR(IC50)(nM) | ErbB2(IC50)(nM) |
| Neratinib | 97.4 | 62.5 |
| Dacomitinib | 8.04 | 58.6 |
| The compound of Formulas I -1 | 11.7 | 7.95 |
| The compound of Formulas I -2 | 23.9 | 6.57 |
| The compound of Formulas I -3 | 12.3 | 12.1 |
| The compound of Formulas I -4 | 18.1 | 10.8 |
| The compound of Formulas I -5 | 9.08 | 4.88 |
| The compound of Formulas I -6 | 10.7 | 7.90 |
| The compound of Formulas I -7 | 7.80 | 5.34 |
| The compound of Formulas I -8 | 8.97 | 11.4 |
| The compound of Formulas I -9 | 22.5 | 9.43 |
| The compound of Formulas I -10 | 15.6 | 9.82 |
| The compound of Formulas I -11 | 8.65 | 4.33 |
Note：Selleck companies report official website：Neratinib (HKI-272) be a kind of HER2 of high selectivity and
EGFR inhibitor, IC50 is respectively 59nM and 92nM in Cell free assay.Dacomitinib (PF299804, PF299) is one
Kind of effective, irreversible general ErbB inhibitor, most effective to act on EGFR, the IC50 of EGFR is 6nM in Cell free assay,
The IC50 of ERBB2 is 45.7nM.Above-mentioned two comparison medicine is consistent with our measurement.
The anti tumor activity in vitro experiment of embodiment 13, compound of the present invention
(1) material
Cell strain：Human breast cancer cell (MDA-MB-231).
Reagent：MTT, Amresco company；DMEM, DMEM/F12 culture medium, Gibco companies；Calf serum, Lanzhou Min Hai
Biology；Trypsase, Amresco companies.
Instrument：Superclean bench, Suzhou Decontamination Equipment Plant；CO2 incubators, Thermo companies, model：HERA
Cell150；Inverted microscope, Carl Zeiss companies, model：Axiovert200；Enzyme-linked immunosorbent assay instrument, TECAN companies,
Model：Sunrise；Centrifuge, Kerdro companies, model：Heraeus.
(2) method
Cell culture：Cell inoculation is containing 10% calf serum, 100IU/ml penicillin G sodium salts and 100ug/ml sulfate chains
In DMEM the or DMEM/F12 complete culture solutions of mycin, set 37 DEG C, 100% relative humidity, in the incubator containing 5%CO2, passage
It is spare after 3 times.
MTT colorimetric determinations：The cell of logarithmic growth phase, (suspension cell need not after 0.25% trypsin digestion
Digestion), it is suspended in the culture solution containing 10% calf serum, single cell suspension is gently blown and beaten into glass dropper, under microscope
With blood cell counts plate numeration living cells.Per 90 μ l of hole inoculating cell suspension, (cell concentration is 3~6 × 10 to 96 well culture plates4
A/mL), after setting incubator for 24 hours, add 10 μ l liquids per hole.In addition, each concentration sets negative control (isoconcentration DMSO) and blank
Background (is not added with cell), and each group is all provided with 6 multiple holes.48h is continuously cultivated again, and the MTT solution of 10 μ l5mg/mL is then added per hole,
Continue after cultivating 4h, carefully sucks supernatant.100 μ l DMSO are added per hole, sets micro oscillator and shakes 5min so as to crystallize
Fully dissolved measures OD values in microplate reader 492nm Single wavelength colorimetrics, and test result is shown in Table 1.
Inhibiting rate (%)=[1- (experimental group OD mean values-blank group OD mean values)/(control group OD mean values-blank group OD is equal
Value)] × 100%.Bliss methods calculate test-compound IC50It is worth (μ g/ml).
(3) as a result, see the table below.
As a result it shows：Compound is to human milk gland shown in compound~Formulas I -11 shown in the preparation-obtained Formulas I -1 of the present invention
Cancer cell (MDA-MB-231), have good inhibiting effect, the results showed that, the present invention can be used for being prepared into treatment it is antitumor/
The drug of anticancer is particularly suitable for being prepared into the drug for the treatment of breast cancer.Moreover, the anticarcinogen relative to existing treatment breast cancer
For object linatinib, compound of the present invention inhibits the effect of human breast cancer cell to be better than linatinib.Specifically it is shown in Table 2:.
Table 2
| Compound number | Human breast cancer cell (MDA-MB-231) |
| Linatinib | 1.29 |
| I-1 | 0.16 |
| I-2 | 0.50 |
| I-3 | 2.09 |
| I-4 | 0.45 |
| I-5 | 0.39 |
| I-6 | 1.58 |
| I-7 | 0.091 |
| I-8 | 3.57 |
| I-9 | 0.92 |
| I-10 | 1.60 |
| I-11 | 0.065 |
Embodiment 14：Compound of the present invention enters the research of blood-brain barrier
1 data and method
1.1 experiment material：1. (this experiment measures formula I-11 to compound shown in formula I-11 using HPLC methods
The concentration of shown compound)；2. atoleine (Chengdu AR chemical reagent factory)；3. methanol (Tedia, the U.S.).
1.2 instrument：Waters 2690 is pumped, 996PDA detectors, 32 chromatographic work stations of Millenium.Chromatographic column：
Waters Syrmaetry ODS 150 × 3.9mm, 5 μm.Irrigation stomach device (pipe).
1.3 chromatography test conditions：Mobile phase：Methanol:Water (65:35,v/v)；Temperature, 40 DEG C；Flow velocity, lml/min；Wavelength
254nm。
1.4 experimental animal：Wistar rat 200g ± 20g are purchased from Wuhan University's Experimental Animal Center.
2 methods and result
2.1 drug in blood serum standard curves are established：Compound shown in formula I-11 is added in rat serum, it is a concentration of
1mg/ml.1 times of amount physiological saline is added.After 20min, 10min (10000rpm) is centrifuged.500 μ l of supernatant are taken, it is standby to survey.By 20,
10,8,5,2.5,2.0,1.0,0.5 μ l sample introductions calculate peak area.Make linear regression with sample size-peak area, obtains recurrence side
Journey：A=28603+541.86 × C, R=0.9998.
The foundation of drug standard curve in 2.2 brain tissues：The brain tissue for taking out normal rat, is gently rushed with physiological saline
It washes, filter paper blots, and removes meningovascular, and compound shown in formula I-11 is added in the physiological saline that doubles homogenate, a concentration of
After 1mg/ml, 20min, 10min (10000rpm) is centrifuged, takes supernatant 1ml is standby to survey (500 μ g/m1).By 20,10,8,5,2.5,
2.0,1.0,0.5 μ l sample introductions measure peak area：A=14521+577.35 × C, R=are returned to obtain by one peak area of sample size
0.9994。
2.3 the compounds of this invention are to blood-brain barrier through effect
2.3.1 experiment packet：
Experimental group：Compound injection liquid (1mg/kg) shown in formula I-11 is injected intraperitoneally.Taken after 20min whole blood 2~
3ml breaks end take out brain tissue immediately after.
Control group (paraffin group)：Gavage the paraffin fluid of same volume.Remaining is same as above.
2.3.2 sample treatment：1. blood serum sample：1 times of amount physiological saline is added in 2ml blood samples, centrifuges 10min
(10000rpm), Aspirate supernatant.0.22 μm of membrane filtration mistake.10 μ l injection HPLC are taken, peak area is calculated.It is calculated by calibration curve method
Content.2. brain tissue sample：The brain tissue of taking-up is washed away into bloodstain with physiological saline, filter paper blots, and meningovascular is removed, by brain
Tissue：Physiological saline=1：The ratio of 1.5 (w/v) is homogenized, and is centrifuged 10min, is taken supernatant.0.22 μm of membrane filtration mistake.Take 10 μ l notes
Enter HPLC, calculates peak area.Content is calculated by calibration curve method.
2.3.3 experimental result：Brain tissue and drug in blood serum concentration, brain tissue drug concentration knot are measured using HPLC methods
Fruit is shown in Table 3.
Drug concentration (the μ g/ in brain tissue after twenty minutes of compound shown in table 3, rats by intraperitoneal injection formula I-11
g)
#Note：Compared with the control group, P<0.001
After this to big white mouse it is experimentally confirmed that be injected intraperitoneally compound shown in formula I-11, brain tissue homogenate's Chinese style
The concentration of compound shown in I-11 is apparently higher than control group, prompts compound shown in formula I-11 that can enter brain group well
It knits, compound of the present invention, blood-brain barrier can be penetrated, reach effective treatment concentration, the compound of the present invention can be used for making
For at the drug for the treatment of and/or pre- preventing tumor, the survival rate of brain tumor transfer patient, extending life period are improved.
Likewise, compound shown in formula I-1, Formulas I -2, Formulas I -4, Formulas I -5, Formulas I -6, Formulas I -7, Formulas I -9 also rises
Identical effect has been arrived, blood-brain barrier can have also been penetrated, reach effective treatment concentration.
Embodiment 15：Capsule for oral medication
| Ingredient | % w/ws |
| Active constituent | 5.0% |
| Lactose | 75.0% |
| Microcrystalline cellulose | 19.5% |
| Magnesium stearate | 0.5% |
Ingredient in upper table is mixed, and active constituent (the compound of the present invention) distribution is prepared into altogether in capsule
1000 grams of powder, filling at capsule, the active constituent of every capsule is 50mg.
Embodiment 16：Tablet for oral administration
Ingredient in upper table is mixed, and uses solvent such as alcohol granulation.Then preparation is dried, is prepared into 1000 altogether
Gram powder, and be formed as tablet with suitable tablet press machine, every active constituent (the compound of the present invention) is 200mg.
Embodiment 17：Capsule for oral medication
| Ingredient | % w/ws |
| Active constituent | 10.0% |
| Lactose | 55.0% |
| Microcrystalline cellulose | 34.5% |
| Magnesium stearate | 0.5% |
Ingredient in upper table is mixed, and active constituent (the compound of the present invention) distribution is prepared into altogether in capsule
1000 grams of powder, filling at capsule, the active constituent of every capsule is 100mg.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example
It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms differ
Surely identical embodiment or example are referred to.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in one or more embodiments or example.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective
In the case of can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.
Claims (10)
1. a kind of compound shown in formula I, its pharmaceutically acceptable salt；
Wherein, the R1For C1-C6Alkyl；
The R2For
The R3For hydrogen, halogen, hydroxyl, amino or C1-6Alkyl；
The R4For hydrogen, halogen, hydroxyl, amino, C1-6Alkyl or-O (CH2)m-R8；
The R5For hydrogen, halogen, C1-C6Alkyl, R7-(C(R6)2) s- or Het- (C (R6)2)r-；
The R6For hydrogen or C1-C6Alkyl；
The R7For-NR6R6、-OR6、-NHR6、-C(R6)3、-CHR6R6Or-CH2R6；
The R8For
The Y is-C (R9)n, O or-NR9；
The R9For hydrogen, C1-C6Alkyl or C1-C6Alkoxy；
The m is 1,2 or 3；
The n is 1,2；
The s is 1,2 or 3；
The r is 1,2 or 3；
The Het heterocycles be piperidines, dihydropyridine, pyrroles, nafoxidine, imidazoles, piperazine, oxinane, oxinane,
Quinoline, thiomorpholine or thiophene.
2. Formulas I compound represented as described in claim 1, its pharmaceutically acceptable salt, which is characterized in that the formula
Compound shown in I, its pharmaceutically acceptable salt are for inhibiting HER2 tyrosine kinase；
And/or compound, its pharmaceutically acceptable salt shown in the Formulas I are for inhibiting EGFR tyrosine kinase；
And/or the Formulas I compound represented, its pharmaceutically acceptable salt are used as HER2 tyrosine kinase inhibitors；
And/or the Formulas I compound represented, its pharmaceutically acceptable salt are used as EGFR tyrosine kinase inhibitors；
And/or the R1In, the C1-6Alkyl is C1-4Alkyl；
And/or the R3In, the R3For hydrogen or halogen；
And/or the R3In, the C1-6Alkyl is C1-4Alkyl；
And/or the R4In, the R4For hydrogen, halogen or-O (CH2)m-R8；
And/or the R4In, the C1-6Alkyl is C1-4Alkyl；
And/or the R5In, the C1-6Alkyl is C1-4Alkyl；
And/or the R6In, the C1-6Alkyl is C1-4Alkyl；
And/or the R9In, the C1-6Alkyl is C1-4Alkyl；
And/or the R9In, the C1-6Alkoxy is C1-4Alkoxy.
3. Formulas I compound represented as described in claim 1, its pharmaceutically acceptable salt, which is characterized in that the R1
In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tertiary butyl；
And/or the R3In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base or tertiary butyl；
And/or the R3In, the halogen is fluorine, chlorine or bromine；
And/or the R4In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base or tertiary butyl；
And/or the R4In, the halogen is fluorine, chlorine or bromine；
And/or the R5In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base or tertiary butyl；
And/or the R5In, the halogen is fluorine, chlorine or bromine；
And/or the R6In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base or tertiary butyl；
And/or the R9In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding
Base or tertiary butyl；
And/or the R9In, the C1-4Alkoxy is methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen
Base, isobutoxy, sec-butoxy or tert-butoxy.
4. Formulas I compound represented as described in claim 1, its pharmaceutically acceptable salt, which is characterized in that the R3
In, the R3For chlorine；
And/or the R4In, the R4For fluorine or-O (CH2)m-R8。
5. Formulas I compound represented as described in claim 1, its pharmaceutically acceptable salt, which is characterized in that the change
It can be following any structure to close object：
6. a kind of pharmaceutical composition comprising such as Formulas I compound represented according to any one of claims 1 to 5, its pharmacy
Upper acceptable salt and pharmaceutic adjuvant；The Formulas I compound represented, the dosage of its pharmaceutically acceptable salt can be to control
Treat effective quantity.
7. pharmaceutical composition according to claim 6, which is characterized in that the gross mass based on described pharmaceutical composition, power
It is 1%~80%, preferably 5%~20% that profit, which requires the mass percent of the compound described in any one of 1-5,.
8. according to the pharmaceutical composition described in claim 6-7, which is characterized in that described pharmaceutical composition is in selected from tablet, glue
At least one of capsule, injection, injection powder needle, pulvis, syrup, solution shape, suspension and aerosol form.
9. the purposes of compound in medicine preparation described in any one of claim 1-5, which is characterized in that the compound
As kinase inhibitor,
And/or the compound is used as the inhibitor of at least one of EGFR and ErbB2；
And/or the compound can be prepared into the drug for the treatment of and/or pre- anti-cancer or tumour.
10. purposes according to claim 9, which is characterized in that the drug for treat or prevent by be selected from EGFR and
The cancer or tumour that at least one of ErbB2 is mediated,
The cancer or tumour be selected from breast cancer, gastric cancer, non-small cell lung cancer, solid tumor, colorectal cancer, cancer of pancreas, the cancer of the esophagus,
Glioma, head and neck neoplasm, oophoroma, uterine cancer, carcinoma of urinary bladder, cholangiocarcinoma, endometrioid carcinoma, colorectal cancer, prostate cancer,
At least one of acute myelocytic leukemia, melanoma, late period Hodgkin lymphoma, brain tumor or liver cancer.
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| WO2020106059A1 (en) * | 2018-11-21 | 2020-05-28 | 한국화학연구원 | Novel tricyclic compound as irak4 inhibitor |
| CN113227095A (en) * | 2018-11-21 | 2021-08-06 | 韩国化学研究院 | Novel tricyclic compounds as IRAK4 inhibitors |
| CN110156792A (en) * | 2019-06-28 | 2019-08-23 | 广州暨南生物医药研究开发基地有限公司 | A kind of pyrimido benzazolyl compounds and its preparation method and application |
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Denomination of invention: Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and their applications Effective date of registration: 20210122 Granted publication date: 20200421 Pledgee: Wuhan area branch of Hubei pilot free trade zone of Bank of China Ltd. Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2021420000004 |