CN106083736A - A kind of pyrimidines, EGFR inhibitor and application thereof - Google Patents

A kind of pyrimidines, EGFR inhibitor and application thereof Download PDF

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CN106083736A
CN106083736A CN201610462600.9A CN201610462600A CN106083736A CN 106083736 A CN106083736 A CN 106083736A CN 201610462600 A CN201610462600 A CN 201610462600A CN 106083736 A CN106083736 A CN 106083736A
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egfr
compound
pyrimidines
egfr inhibitor
medicine
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吴豫生
牛成山
耿阳
梁阿鹏
郭中伟
刘建涛
杨俊亮
霍云峰
韩兴旺
孟庆国
李敬亚
郭瑞云
邹大鹏
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Tetranov Pharmacy Stock Inc
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Priority to PCT/CN2016/098057 priority patent/WO2017219500A1/en
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Abstract

The invention discloses a kind of pyrimidines, EGFR inhibitor and application thereof.This pyrimidines includes the compound shown in Formulas I, or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug；EGFR inhibitor comprises above-mentioned pyrimidines.The pyrimidines of the present invention can suppress activation or the resistant mutation of one or more EGFR；It can suppress the propagation of the double mutant enzyme of EGFR T790M/L858R under nanomolar concentration, and the suppression to Wild type EGFR enzyme is the most relatively weak；May not only be applied to the treatment of EGFR sensitive mutant cancer, apply also for current EGFR TKI treatment produces the case of secondary resistance；Its Catastrophic selection greatly reduces the toxic and side effects produced because of suppression Wild type EGFR simultaneously, is the medicine of a kind of disease preferably caused by EGFR sudden change.

Description

A kind of pyrimidines, EGFR inhibitor and application thereof
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of pyrimidines, also relate to a kind of EGFR and press down Preparation and be used for regulating EGFR TYR kinase activity or treatment EGFR relevant disease, especially nonsmall-cell lung cancer in preparation Medicine in terms of application.
Background technology
EGF-R ELISA EGFR (Epidermal Growth Factor Receptor) is erbB receptor family The kinase whose one of transmembrane protein tyrosine.When it combines with somatomedin part (such as epidermal growth factor (EGF)), it is subject to Body can with additional EGFR molecule generation homologous dimerization, or with another family member (such as erbB2 (HER2), erbB3 (HER3) or erbB4 (HER4)) occur heterodimeric.The homologous dimerization of erbB receptor and/or heterodimeric cause intracellular territory The phosphorylation of middle key tyrosine residue, and cause participating in cell proliferation and many Cellular Signaling Transduction Mediated paths of existence Stimulation.The imbalance of erbB family signal conduction promotes breed, invades, shifts, angiogenesis and tumor cell are survived, and In many human cancers, (including pulmonary carcinoma, incidence cancer and breast carcinoma etc.) is described.
Therefore, the reasonable target spot developed for representative as cancer therapy drug using erbB family, such as being permitted of targeting EGFR or erbB2 Drug is widely applied now the most clinically, including gefitinib (IRESSATM), Erlotinib (TARCEVATM) and Lapatinib (TYKERBTM) etc..New England Journal of Medicine (the 2008, the 358th phase, 1160-1174) and Biochemical and Biophysical Research Communications (the 2004, the 319th phase, 1-11) provides To being discussed in detail of the conduction of erbB receptor signal and the participation in tumor occurs thereof.
Pulmonary carcinoma is the cancer that global incidence is the highest, in lung cancer in China sickness rate occupies all cancers first, is also The cancer that China's M & M is the highest, in the lung cancer patient of China, the patient of about 30% has EGFR sudden change, its Middle L858R and exons 19 deletion mutation account for about more than 90%, and this kind of patient is the most sensitive to EGFR inhibitor.Existing go up City first generation EGFR inhibitor such as Erlotinib, gefitinib etc. have preferable curative effect to this kind of patient, it is possible to make wherein 60% Above patient's tumor regression, hence it is evident that extend the Progression free survival phase of patient.But most humans can obtain at 6-12 month Drug resistance, this drug resistance pattern is the further sudden change of EGFR, this reduces its sensitivity to first generation EGFR inhibitor.This A little sudden changes are most commonly that so-called " gatekeeper " mutation T 790M (Science, 2004, Vol.304,1497-1500； New England Journal of Medicine 2004,350,2129-2139), by the original L-threonine in this site (T) being that METHIONINE (M) substitutes, EGF tyrosine kinase R after variation is no longer combined with gefitinib, Erlotinib, thus Make first generation EGFR inhibitor by no longer onset, cause this kind of patient be currently in without medicine can state.Clinical discovery is to The patient of generation EGFR inhibitor generation drug resistance there is 50% detection to have EGFR T790M to suddenly change.At T790M mutational cell line First generation EGFR inhibitor in H1975, such as gefitinib and Erlotinib, is all higher than 3 μMs, does not substantially have activity.
EGFR is suddenlyd change by the second filial generation irreversible pan-EGFR inhibitor (Afatinib BIBW2992) of exploitation listing at present Lung cancer patient is evident in efficacy is better than first generation EGFR inhibitor.But second filial generation inhibitor also has the strongest Wild type EGFR simultaneously The toxic and side effects such as inhibitory activity, is significantly higher than the sudden change of drug resistance T790M to the inhibitory activity of Wild type EGFR, patient's erythra serious and Drug resistance patient's curative effect is poor, and only fraction first generation EGFR inhibitor drug resistance patient produces response to this kind of medicine.
In order to improve the inhibitory activity that drug resistance EGFR T790M etc. is suddenlyd change, and reduce simultaneously Wild type EGFR is pressed down System activity, exploitation activity third generation EGFR mutant selective depressant higher, that selectivity more preferable, toxicity is lower has important Meaning.
Summary of the invention
It is an object of the invention to provide a kind of pyrimidines, EGFR is had good inhibitory activity.
Second object of the present invention is to provide a kind of EGFR inhibitor.
Third object of the present invention is to provide a kind of above-mentioned EGFR inhibitor and prepares for regulating EGFR TYR kinases Application in terms of the medicine of activity or treatment EGFR relevant disease.
In order to realize object above, the technical solution adopted in the present invention is:
A kind of pyrimidines, including the compound shown in Formulas I, or its pharmaceutically acceptable salt, stereoisomer, Solvate or prodrug:
Wherein, Ar is selected from phenyl or substituted phenyl；
R1Selected from hydrogen, halogen, trifluoromethyl or cyano group；
R2Selected from methoxyl group, difluoro-methoxy, the deuterated methoxyl group of difluoro or trifluoromethoxy；
R3Selected from any one structure following:
X1、X2、X3It is independently selected from hydrogen or halogen.
When Ar is substituted phenyl, described substituted phenyl is a replacement, two replacements or trisubstd phenyl, substituent group It is independently selected from halogen, cyano group, nitro, ester group, C1-4Alkyl or cycloalkyl, C1-4Alkoxyl or cycloalkyloxy, C1-4Halo Alkyl, C1-4Acyl group, C1-6Alkylamino or naphthene amino.
Preferably, in described pyrimidines, the compound shown in Formulas I is selected from:
Described pharmaceutically acceptable salt is inorganic acid salt or acylate, and described inorganic acid salt is selected from hydrochlorate, hydrogen bromine Hydrochlorate, hydriodate, sulfate, disulfate, nitrate, phosphate, acid phosphate；Described acylate is selected from formic acid Salt, acetate, trifluoroacetate, propionate, pyruvate, oxyacetate, oxalate, malonate, fumarate, Malaysia Hydrochlorate, lactate, malate, citrate, tartrate, mesylate, esilate, benzene sulfonate, salicylate, hardship Sour in the mouth salt, glutamate, Glu, salicylate, Ascorbate, Camphora hydrochlorate, camsilate.
The pyrimidines of the present invention, for the compound shown in Formulas I, or its pharmaceutically acceptable salt, stereoisomerism Body, solvate or prodrug, this compound can suppress activation or the resistant mutation of one or more EGFR, and such as L858R swashs Mutant alive, Exon19 lack EGFR activated mutant body, T790M resistant mutants；This compound improves drug resistance EGFR The inhibitory activity of the sudden change such as T790M, and reduce the inhibitory activity to Wild type EGFR simultaneously, can be used for developing activity more Third generation EGFR mutant selective depressant high, that selectivity is more preferable, toxicity is lower.
The pyrimidines of the present invention, experiment in vitro shows that it can suppress EGFR T790M/ under nanomolar concentration The propagation of the double mutant enzyme of L858R, the suppression to Wild type EGFR enzyme is the most relatively weak.Therefore, this compounds not only can be used In the treatment of EGFR sensitive mutant cancer, apply also for current EGFR-TKI treatment produces the case of secondary resistance；With Time its Catastrophic selection greatly reduce the toxic and side effects that produces because suppression Wild type EGFR, be a kind of preferably to be dashed forward by EGFR Become the medicine of the disease caused.
Solvate mentioned in the present invention refers to the coordination compound that the compound of the present invention is formed with solvent.They or In a solvent reaction or from solvent Precipitation or crystallize out.Such as, the coordination compound formed with water is referred to as hydrate； Other also include alcohol adduct, ketone compound etc..Solvate of the present invention include the compound shown in formula I and Salt, the solvate of stereoisomer.
Stereoisomer mentioned by the present invention refers to that in the present invention, the compound shown in Formulas I can be containing one or more Chiral centre, and exist with different optical active forms.When compound contains a chiral centre, compound comprises mapping Isomer.The present invention includes the mixture of both isomers and isomer, such as racemic mixture.Enantiomer can be led to Cross methods known in the art to split, such as the method such as crystallization and chiral chromatogram.When the compound shown in Formulas I contains many When a chiral centre, non-corresponding isomer can be there is.It is optically pure that the stereoisomer of the present invention includes splitting Specific isomer and the mixture of non-corresponding isomer.Diastereomer can be split by method known in the art, Such as crystallization and preparative hplc.
Prodrug mentioned by the present invention refers to known amino protecting group and carboxyl-protecting group, in physiological conditions by Hydrolysis or the parent compound obtained via enzyme reaction release.Concrete front medicament preparation can refer to prior art (Saulnier, M.G.；Frennesson, D.B.；Deshpande, M.S.；Hansel, S.B and Vysa, D.M.Bioorg.Med.ChemLett.1994,4,1985-1990；And Greenwald, R.B.；Choe, Y.H.；Conover, C.D.；Shum, K.；Wu, D.；Royzen, M.J.Med.Chem.2000,43,475.).
The preparation method of a kind of above-mentioned pyrimidines, including by molten to intermediate A, intermediate B and p-methyl benzenesulfonic acid Solution in organic solvent, at protective atmosphere, is reacted under the conditions of 50～100 DEG C, and reaction adds dichloromethane and saturated carbon after terminating Acid sodium aqueous solution, layering, after taking organic facies removal solvent, isolated and purified, to obtain final product；
Described intermediate A, the structural formula of intermediate B are distinguished the most as follows:
Wherein, Ar, R1、R2、R3、X1、X2、X3As defined in Formulas I.
The reaction equation that this preparation method relates to is as follows:
Described intermediate A is 1～5:1 with the mol ratio of intermediate B.Described p-methyl benzenesulfonic acid is with a water p-methyl benzenesulfonic acid Form add；P-methyl benzenesulfonic acid is 0.5～2:1 with the mol ratio of intermediate B.Organic solvent used is 2-amylalcohol；Institute The consumption stating organic solvent is: every 50mg intermediate B correspondence uses organic solvent 5ml.Described protective atmosphere is nitrogen.Described point It is to use column chromatography to separate from purification.
Described intermediate A is prepared by following methods:
Method 1: compound a 1 is mixed to obtain mixture with diisopropylethylamine, n-butyl alcohol, mixture is cooled to-20 DEG C, add compound a 2 react, after be warming up to room temperature, after being stirred overnight, remove reaction system solvent, in residue Add ethyl acetate and water, layering, take organic facies and remove solvent, isolated and purified, to obtain final product；
Or, method 2: compound a 1 is mixed to obtain with diisopropylethylamine, n-butyl alcohol, compound a 2 mixture, will be mixed Compound is heated to 100 DEG C of reactions overnight, the rear solvent removing reaction system, adds ethyl acetate and water, be layered in residue, Take organic facies and remove solvent, isolated and purified, to obtain final product；
Described compound a 1, compound a 2 structural formula as follows:
Wherein, Ar, R1Defined in same formula (I).
The reaction equation that the preparation method of intermediate A relates to is as follows:
Wherein, compound a 1 is 1:0.5～2 with the mol ratio of compound a 2.The consumption of described diisopropylethylamine is: every The diisopropylethylamine of the corresponding addition 1～3ml of the compound a 1 of 4～9mmol.The consumption of described n-butyl alcohol is: every 4～9mmol Compound a 1 corresponding add 20～30ml n-butyl alcohol.Prepare intermediate A time, described isolated and purified be use column chromatography enter Row separates.The mixture that developing solvent is ethyl acetate and petroleum ether that described column chromatography uses.
Preferably, described intermediate A is selected from following compound:
Described intermediate B is prepared by following methods:
Compound b1 is made sodium phenolate, with iodomethane or ethyl bromide difluoride or deuterium-oxide and ethyl bromide difluoride Mixture (R2Precursor) occur after substitution reaction, through reduction (hydrogenation), nitrification, protect amino with Bis(tert-butoxycarbonyl)oxide, then With substituent R3Precursor generation substitution reaction, rear reduction (hydrogenation), more anti-with acrylic acid, the acrylic acid of halogen substiuted or acyl chlorides Intermediate B should be obtained.
The reaction equation related to is as follows:
In the preparation method of above-mentioned intermediate B, can open from any one step according to prior art can obtain the situation of raw material Begin until obtaining intermediate B.
Preferably, intermediate B is selected from following compound:
A kind of EGFR inhibitor, comprises above-mentioned pyrimidines.
Described EGFR inhibitor, also comprises pharmaceutically acceptable carrier.
Described EGFR inhibitor can be the compound shown in above-mentioned Formulas I, or its pharmaceutically acceptable salt, three-dimensional different Structure body, solvate or prodrug, it is also possible to be the pharmaceutical composition comprising above-claimed cpd.Described pharmaceutical composition also includes medicine Acceptable carrier on.
The EGFR inhibitor of the present invention, can be by the compound shown in Formulas I, or its pharmaceutically acceptable salt, stereoisomerism Body, solvate or prodrug, form applicable dosage form with one or more pharmaceutical carriers and use.These dosage forms are applicable to be administered orally, It is administered in rectally, topical, mouth and other parenteral routes use (such as, subcutaneous, muscle, vein etc.).
When the EGFR inhibitor of the present invention is pharmaceutical composition, compositions is prepared in the way of meeting medical practice specification, Quantitatively and be administered.Give " effective dose " of compound by concrete disease to be treated, the individuality for the treatment of, the cause of disease, medicine Target spot and the factor such as administering mode determine.
A kind of above-mentioned EGFR inhibitor is used for regulating and controlling EGFR TYR kinase activity or treatment EGFR is correlated with disease in preparation The sick application in terms of medicine.
Described regulation and control EGFR TYR kinase activity or treatment EGFR relevant disease refer to cancer, diabetes, immune system Disease, neurodegenerative diseases or cardiovascular disease.
The application in terms of the medicine of preparation treatment nonsmall-cell lung cancer of a kind of above-mentioned EGFR inhibitor.The present invention's EGFR inhibitor is particularly suited for preparation treatment cancer, such as the medicine of nonsmall-cell lung cancer.
The EGFR inhibitor of the present invention can be used for preparation regulation and control EGFR tyrosine kinase activity or treatment EGFR relevant disease The medicine of aspect, such as cancer, diabetes, disease of immune system, neurodegenerative diseases or cardiovascular disease etc., is particularly suited for Suddenlyd change by EGFR, including sensitive mutant (as L858R sudden change or the outer aobvious factor 19 lack) and resistance mutation (such as EGFR T790M suddenlys change), the medicine of the nonsmall-cell lung cancer caused.
The EGFR inhibitor of the present invention, containing compound shown in formula I or its pharmaceutically acceptable salt, three-dimensional different Structure body, solvate or prodrug, can be as the medicinal application of monotherapy or the most all right in anticancer therapy With conventional operation or X-ray therapy or chemotherapy or immunotherapy use in conjunction.Above-mentioned therapy suppresses with the EGFR of the present invention Agent can be administered side by side, simultaneously, sequentially or respectively.
For regulating and controlling EGFR TYR kinase activity or the medicine for the treatment of EGFR relevant disease, except the EGFR of the present invention suppresses Outside agent, it is also possible to comprise any one or more in following medicine: gefitinib, Erlotinib, Conmana, draw handkerchief to replace Buddhist nun, XL647, NVP-AEE-788, ARRY-334543, ZD6474, PF00299804, Cetuximab, handkerchief Buddhist nun dash forward monoclonal antibody, handkerchief Trastuzumab, prick Shandong wood monoclonal antibody, Buddhist nun's trastuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, KOS-953, Ah Spiramycin, IPI-504, NVP-AUY922.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further illustrated.
In detailed description of the invention, eq is the molar equivalent of reactant.
In detailed description of the invention, intermediate A used and the synthesis of intermediate B are as follows.In intermediate A and intermediate B In synthetic reaction formula, Ar is selected from phenyl or substituted phenyl, and described substituted phenyl is a replacement, two replacements or trisubstituted benzene Base, substituent group is independently selected from halogen, cyano group, nitro, ester group, C1-4Alkyl or cycloalkyl, C1-4Alkoxyl or cycloalkanes oxygen Base, C1-4Haloalkyl, C1-4Acyl group, C1-6Alkylamino or naphthene amino；R1Selected from hydrogen, halogen, trifluoromethyl or cyano group；R2It is selected from The deuterated methoxyl group of methoxyl group, difluoro-methoxy, difluoro or trifluoromethoxy；R3Selected from any one structure following:
X1、X2、X3It is independently selected from hydrogen or halogen.
The preparation method of intermediate A is method A1, method A2 or method A3, specific as follows.
Method A1: joined by the compound a 1-1 of 7.8mmol in the single port bottle of 100ml, adds the diisopropyl second of 3ml The n-butyl alcohol of amine and 30ml obtains mixture；Use cryostat that mixture is cooled to-20 DEG C, dropping compound a 2 slowly (13.8mmol), add rear low-temp reaction 1h, go cryostat to be warming up to room temperature, be stirred overnight, solvent under reduced pressure is evaporated, by residue Adding the ethyl acetate (EA) of 100ml, the water adding 50ml washs 2 times, organic facies is evaporated, and residue carries out column chromatography and divides From (eluant is ethyl acetate: petroleum ether=1:30 (volume ratio)), obtain intermediate A 1.
The reaction equation that said method A1 relates to is as follows:
Wherein, Ar is selected from phenyl or substituted phenyl, and described substituted phenyl is a replacement, two replacements or trisubstituted benzene Base, substituent group is independently selected from halogen, cyano group, nitro, ester group, C1-4Alkyl or cycloalkyl, C1-4Alkoxyl or cycloalkanes oxygen Base, C1-4Haloalkyl, C1-4Acyl group, C1-6Alkylamino or naphthene amino.
Method A2: joined by the compound a 1-2 of 4.35mmol in the single port bottle of 50ml, adds the diisopropyl second of 1ml Amine and the n-butyl alcohol of 20ml, the compound a 2 adding 2.2mmol obtains mixture, heats the mixture to 100 DEG C of reactions overnight, Being evaporated by solvent under reduced pressure, residue adds the ethyl acetate (EA) of 50ml, and the water adding 50ml washs 2 times, organic facies is evaporated, Residue carries out column chromatography for separation, obtains intermediate A 2.
The reaction equation that said method A2 relates to is as follows:
Method A3: joined by the compound a 1-3 of 9mmol in the single port bottle of 50ml, adds the diisopropylethylamine of 1ml With the n-butyl alcohol of 25ml, the compound a 2 adding 9mmol obtains mixture, heats the mixture to 100 DEG C of reactions overnight, by molten Agent evaporated under reduced pressure, residue adds the ethyl acetate (EA) of 50ml, and the water adding 50ml washs 2 times, organic facies is evaporated, remaining Thing carries out column chromatography for separation (eluant is ethyl acetate: petroleum ether=1:20 (volume ratio)), obtains intermediate A 3.
The reaction equation that said method A3 relates to is as follows:
The preparation method of intermediate B is method B1 or method B2, specific as follows.
Method B1 comprises the following steps:
1) synthesis of compound b1-2: 50g compound b1-1 is dissolved in 250ml oxolane, by 12.6g hydroxide Sodium is dissolved in 250ml water, and by two solution mix and blends overnight, rotation is evaporated off oxolane, is washed by aqueous phase dichloromethane Twice, rotation is evaporated off major part water, is naturally volatilized by remainder, and vacuum drying oven is thoroughly dried, and obtains 55g crocus solid Body, for compound b1-2.The analytical data of this compound is as follows: 1H-NMR (400MHz ， &DMSO): δ: 7.73 (t, J=8.22, 1H)；6.02 (dd, J=2.97,13.79,1H)；5.77 (dt, J=2.87,7.45,1H).
2) synthesis of compound b1-3: adding in reaction bulb by 7g compound b1-2 with 17.5g potassium carbonate, then argon is protected Protect down, in reaction bulb, add the DMF (dimethylformamide) of 700ml, 70g deuterium-oxide and 17.5g bromo difluoro acetate ethyl ester, by Gradually being warming up to 50 DEG C, be stirred overnight, TLC display raw material major part disappears, and after cooling, by reactant liquor dilute with water, uses dichloromethane Alkane extracts three times, merges organic facies, washes with water 5 times, be dried by organic layer and be spin-dried for, and residue obtains 6.2g through column chromatography for separation Pale yellow oil, for compound b1-3.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3): δ: 8.01 (q, J=5.58,3.51,1H)；7.07-7.15(m,2H).
3) synthesis of compound b1-4: be dissolved in 25ml ethanol by 1g compound b1-3, adds palladium carbon, atmosphere of hydrogen Under, room temperature atmospheric agitation is overnight；TLC detection raw material disappears, and filters out palladium carbon, washing with alcohol, is spin-dried for solvent and obtains 0.78g chemical combination Thing b1-4, for yellow oil.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3):: δ: 6.70-6.84 (m,3H)；3.71(br,2H)；MS m/z(ESI):179[M+H]+。
4) synthesis of compound b1-5: 0.78g compound b1-4 is dividedly in some parts in the 5ml concentrated sulphuric acid of ice-water bath cooling, Temperature is less than 10 DEG C so that it is all dissolving, be subsequently adding 0.45g potassium nitrate, stirred overnight at room temperature, reaction terminates, by reactant liquor Pour in frozen water, then alkalize with ammonia, be extracted with ethyl acetate organic layer, merge organic layer, wash one with saturated aqueous common salt Secondary, it is dried and is spin-dried for organic layer, residue carries out column chromatography for separation, obtains 0.8g yellow solid, is compound b1-5.This chemical combination The analytical data of thing is as follows: 1H-NMR (400MHz, CDCl3): δ: 7.46 (d, J=6.48,1H)；6.99 (d, J=10.94, 1H)；4.03(br,1H)；MS m/z(ESI):224[M+H]+。
5) synthesis of compound b1-6: the DMAP (DMAP) of 3.1g compound b1-5 Yu 171mg is dissolved In 40ml acetonitrile, add (Boc) 2O (Bis(tert-butoxycarbonyl)oxide) of 3.6g under ice bath, be then gradually increased to be stirred at room temperature At night, TLC detection raw material disappears, and is the most directly spin-dried for reactant liquor, and residue carries out column chromatography for separation, obtains 3g yellow solid, i.e. For compound b1-6.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3): δ: 8.99 (d, J=8.10, 1H)；7.07 (d, J=12.15,1H)；6.85(br,1H)；MS m/z(ESI):324[M+H]+。
6) synthesis of compound b1-7: by the N of 1.5g compound b1-6,950mg, N, N'-trimethyl ethylenediamine and 1.8g Diisopropyl diamidogen is dissolved in the DMAC (N,N-dimethylacetamide) of 20ml, then heats to 60 DEG C and is stirred overnight, and TLC examines Survey raw material disappears, and is poured into by reactant liquor in water and ethyl acetate (EA), and water layer washed once by ethyl acetate (EA) again, then closes And EA layer washes with water 5 times and removes DMA, then it is dried and is spin-dried for organic layer；Residue carries out column chromatography for separation, obtains 2.2g yellow Solid, is compound b1-7.
7) synthesis of compound b1-8: 2.2g compound b1-7 is dissolved in the ethyl acetate (EA) of 40ml, then adds Entering 0.2g palladium carbon, under atmosphere of hydrogen, stirred overnight at room temperature, TLC detection raw material disappears, and filters out palladium carbon, is spin-dried for mother solution and obtains 2g Yellow oil, is compound b1-8.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3): δ: 7.47 (s,1H)；6.78(s,1H)；6.69(br,1H)；4.25(br,2H)；2.85 (t, J=6.89,1H)；2.62(s,3H)；2.36 (t, J=6.48,1H)；2.25(s,6H)；MS m/z(ESI):376[M+H]+。
8) synthesis of intermediate B-1: 2g compound b1-8 is dissolved in 40ml dichloromethane, is subsequently adding 0.83g bis- Wopropyl ethyl amine, then under nitrogen protection, cryosel bath is cooled to about 0 DEG C, and then dropping 0.55g acryloyl chloride, drips complete After be gradually heating to room temperature, stir two hours, TLC detection raw material disappears, and is then spin-dried for reactant liquor, then adds in residue 5ml concentrated hydrochloric acid, stirs two hours, and TLC display raw material disappears, and then adjusts PH to about 8 with saturated aqueous sodium carbonate, makes body System's alkalization, uses (ethyl acetate) EA extractive reaction liquid three times, merges organic layer, is dried, is spin-dried for, and residue carries out column chromatography and divides Analysis, obtains 750mg yellow oil, is intermediate B 1.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3): δ: 8.07 (s, 1H)；6.92(s,1H)；6.39 (dd, J=1.63,17.09,1H)；6.22 (dd, J=10.48, 17.47,1H)；5.68 (dd, J=1.42,9.91,1H)；3.81(br,2H)；2.77 (t, J=5.44,1H)；2.63(s,3H)； 2.23(s,8H)；MS m/z(ESI):330[M+H]+。
The reaction equation that method B1 relates to is as follows:
Method B2 comprises the following steps:
1) synthesis of compound b2-2: take 50g compound b2-1, adds 500ml methanol CL, adds the Pd/C of 10g (palladium carbon), hydrogenation two days at 35 DEG C；Point board monitoring, raw material reaction is complete, directly filters Pd/C, is spin-dried for methanol and is changed mutually Compound b2-2 crude product 39g.
2) synthesis of compound b2-3: take compound b2-2 crude product 39g, joins (cryosel bath) in the concentrated sulphuric acid of 500ml, Stir the most molten under the conditions of T < 10 DEG C, hold at the potassium nitrate adding 1ep, be stirred overnight under room temperature；Next day will be anti- Answer liquid to pour in frozen water, regulate PH with ammonia 7, ethyl acetate extracts, and is dried, carries out column chromatography for separation, obtain 44g product, i.e. For compound b2-3.The analytical data of this compound is as follows: 1H NMR (CDCl3) δ 7.39 (d, J=7.2Hz, 1H), 6.63 (d, J=12.4Hz, 1H), 3.94 (s, 3H), 3.90 (broad, 2H).
3) synthesis of compound b2-4: take the compound b2-3 of 20g, joins in the dichloromethane of 500ml, and cryosel bath is cold But-5 DEG C are arrived, the dichloromethane solution of the Bis(tert-butoxycarbonyl)oxide of dropping 1.1eq, drips and finishes, add DMAP (the 4-diformazan of 0.2eq Aminopyridine), naturally it is warmed up to room temperature, is stirred overnight；Next day, put plate, react complete, carry out column chromatography for separation, obtain 24g yellow Color solid, is compound b2-4.The analytical data of this compound is as follows: 1H NMR (CDCl3)δ8.89(s,1H),6.97(s, 1H), 6.71 (d, J=12.4Hz, 1H), 3.97 (s, 3H), 1.53 (s, 9H)；MS:Calcd for C12H15FN2O5(M-H)-: 286.1,Found:285.0。
4) synthesis of compound b2-5: take the compound b2-4 of 13.5g, joins DMAC (N, the N-dimethyl second of 200ml Amide) in, the most molten under stirring；Add the N of 2eq, N, N '-trimethyl ethylenediamine and DIEA (N, the N-diisopropyl second of 3eq Amine), it is warmed up to 110 DEG C and is stirred overnight；Next day, react complete, obtain 22g grease crude Compound b2-5.This compound Analytical data is as follows:1H NMR(CDCl3)δ8.54(s,1H),6.85(s,1H),6.60(s,1H),3.90(s,3H),3.22(t, J=6.8Hz, 2H), 2.81 (s, 3H), 2.55 (t, J=7.2Hz, 2H), 2.26 (s, 6H), 1.49 (s, 9H)；MS:Calcd for C17H28N4O5(M+H)+:368.21,Found:369.3。
5) synthesis of compound b2-6: take 22g crude Compound b2-5, joins in the ethyl acetate of 400ml, under stirring Quan Rong, adds the Pd/C (palladium carbon) of 4.07g, and at 20 DEG C, hydrogenation is overnight；Next day, raw material reaction is complete, directly filters Pd/ C, concentrates, obtains compound b2-6 crude product 17g, for dark oil thing.The analytical data of this compound is as follows:1H NMR(CDCl3) δ7.517(s,1H),6.941(s,1H),6.61(s,1H),4.10(m,2H),3.76(s,3H),2.92(m,2H),2.62(s, 3H),2.40(m,2H),2.27(s,6H),1.49(s,9H)；MS:Calcd for C17H30N4O3(M+H)+:338.23, Found:339.4。
6) synthesis of compound b2-7: take 17.3g compound b2-6 crude product, adds the dichloromethane of 500ml and 1.2eq DIEA (DIPEA), cryosel bath is cooled to-5 DEG C, drips the acryloyl chloride of 1.1eq under argon shield, drips and finish, from So being warmed up to room temperature, after 3 hours, react complete, under direct low temperature, concentrated by rotary evaporation removes solvent, obtains 23g crude Compound b2- 7。
7) synthesis of intermediate B-2: take 23g crude Compound b2-7, joins in the THF of 50ml, cryosel bath be cooled to- 5 DEG C, adding concentrated hydrochloric acid 100ml, < 10 DEG C, after stirring 2 hours, some plate reaction is complete, carries out column chromatography for separation, obtains for temperature T 5.2g product, is intermediate B 2.The analytical data of this compound is as follows:1H NMR(CDCl3)δ10.10(s,1H),7.97(s, 1H),6.68(s,1H),6.41-6.21(m,2H),5.65(m,1H),3.81(s,3H),3.76(s,2H),2.82(m,2H), 2.65(s,3H),2.20(s,6H)；MS:Calcd for C15H24N4O2(M+H)+:292.19,Found:293.3。
The reaction equation that method B2 relates to is as follows:
Method B3 comprises the following steps:
1) synthesis of compound b3-2: take 50g starting compound b3-1, join in the DMF of 500ml, add 1.5eq Ethyl bromide difluoride and the potassium carbonate of 2eq, 10min be first stirred at room temperature, add the water of 3eq, under argon shield, oil bath heats up To 50 DEG C, after 4 hours, raw material reaction is complete, cools to 0 DEG C, and add water cancellation, mixes by dichloromethane and petroleum ether equal proportion Organic extractant phase, organic facies is dried, and concentrates, carries out column chromatography for separation, obtain compound b3-2 product 77g.Dividing of this compound Analysis data are as follows:1H NMR(CDCl3) δ 8.03 (dd, J=9.2,5.6Hz, 1H), 7.149-7.081 (m, 2H), 6.645 (t, J =72.4Hz, 1H).
2) synthesis of compound b3-3: take 77g compound b3-2, adds 700ml dehydrated alcohol CL, adds Pd/C (palladium carbon) 13g, at 20 DEG C, hydrogenation is overnight；Point board monitoring, raw material reaction is complete, directly filters Pd/C, is spin-dried for obtaining chemical combination Thing b3-3 crude product 55g.The analytical data of this compound is as follows: 1H NMR (CDCl3) δ 6.84-6.70 (m, 3H), 6.468 (t, J =73.6Hz, 1H), 3.16 (broad, 2H)；MS:Calcd for C7H6F3NO(M+H)+:178.04,Found:178.00。
3) synthesis of compound b3-4: take compound b3-3 crude product 55g, join (cryosel in the concentrated sulphuric acid of 600ml Bath), T < 10 DEG C of stirring is the most molten, holds at addition 1ep potassium nitrate, is stirred overnight under room temperature；Next day, pour frozen water into In, regulate PH with ammonia > 7, ethyl acetate extracts, and is dried, carries out column chromatography for separation, obtain 63g yellowish-brown product, be chemical combination Thing b3-4.The analytical data of this compound is as follows:1H NMR(CDCl3) δ 7.46 (d, J=7.2Hz, 1H), 7.01 (d, J= 11.2Hz, 1H), 6.597 (t, J=72.4Hz, 1H), 4.047 (broad, 2H).
4) synthesis of compound b3-5: take 11.1g compound b3-4, joins in the dichloromethane of 200ml, and cryosel bath is cold But-5 DEG C are arrived, the dichloromethane solution of the Bis(tert-butoxycarbonyl)oxide of dropping 1.1eq, drips and finishes, add DMAP (the 4-diformazan of 0.2eq Aminopyridine), naturally it is warmed up to room temperature, is stirred overnight, next day, put plate, react complete, carry out column chromatography for separation, obtain 9.7g Yellow product, is compound b3-5.The analytical data of this compound is as follows: 1H NMR (CDCl3) δ 9.00 (d, J=8Hz, 1H), 7.07 (d, J=10.8Hz, 1H), 6.864 (s, 1H), 6.661 (t, J=71.2Hz, 1H), 1.541 (s, 9H)；MS: Calcd for C12H13F3N2O5(M-H)-:323.08,Found:321.1。
5) synthesis of compound b3-6: take the compound b3-5 of 0.82g, with the DMAC (N,N-dimethylacetamide) of 10ml Dissolve, add the R of 2eq3The DIEA (DIPEA) of H and 3eq, under argon shield, 80 DEG C of reactions are overnight；Secondary daily test Surveying, raw material disappears；At 80 DEG C, rotation is evaporated off DMA, adds 50ml saturated aqueous sodium carbonate and 50ml dichloromethane, dichloromethane Alkane extracts 2 times again, merges organic facies, is dried, and concentrates, obtains compound b3-6 crude product 1.3g.The analytical data of this compound is such as Under: MS:Calcd for C16H21F2N3O6(M+H)+:389.14,Found:390.2。
6) synthesis of compound b3-7: take 1.2g compound b3-6, uses 100mL acetic acid ethyl dissolution, adds 0.4eq's Pd/C (palladium carbon), 20 DEG C of hydrogenations are overnight；Next day is detected, and raw material disappears, and filters Pd/C, concentrates, carries out column chromatography for separation, To compound b3-7 product 0.7g.The analytical data of this compound is as follows: 1H NMR (CDCl3)δ9.32(br,1H),9.23(s, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 6.47 (t, J=74.8Hz, 1H), 5.85 (m, 1H), 5.24 (m, 1H), 3.86 (m, 4H),2.83(m,4H),1.53(s,9H)；MS:Calcd for C16H23F2N3O4(M+H)+:359.17,Found:360.2。
7) synthesis of compound b3-8: take raw material propylene acid (or substituted acrylic acid) 0.1g, with the DCM (two of 20ml Chloromethanes) to dissolve, the oxalyl chloride of addition 0.7eq and a DMF, under argon shield ,-5 DEG C of reactions generate acyl chlorides in 4 hours, obtain acyl Solutions of chlorine is stand-by；Meanwhile, in another reaction bulb, take out the compound b3-7 of 0.2g (0.5eq), the dichloro being dried with 20ml Methane dissolves, and adds the DIEA of 0.15g, at-5 DEG C, the solution of acid chloride made is squeezed in reactant liquor, and reaction is overnight；Next day is straight Connect and be spin-dried for, obtain compound b3-8.The analytical data of this compound is as follows: MS:Calcd for C19H24F3N3O5(M+H)+: 431.17,Found:432.2。
8) synthesis of intermediate B-3: take the compound b3-8 of 0.1g, adds the concentrated hydrochloric acid of 3ml, and adding fashionable has bubble to put Go out, stir 3 minutes；Reactant liquor is added drop-wise in the saturated sodium carbonate solution of 10ml, drips and finishes, solution PH > 10；Use dichloromethane 30ml extracts 2 times, is dried, is concentrated to give 0.08g product, is intermediate B 3.The analytical data of this compound is as follows: MS: Calcd for C14H16F3N6O6(M+H)+:331.11,Found:332.1。
The reaction equation that method B3 relates to is as follows:
Embodiment 1
The pyrimidines of the present embodiment, its structural formula is as shown in Formulas I-1:
The preparation method of the pyrimidines of the present embodiment is as follows: by intermediate B, the 150mg of 50mg (0.15mmol) (0.5mmol) intermediate A is dissolved in the 2-amylalcohol of 5ml with a water p-methyl benzenesulfonic acid of 35mg (0.18mmol), then rises Temperature is to 50 DEG C, and overnight, TLC display raw material disappears stirred under nitrogen atmosphere substantially, is spin-dried for volume, is subsequently adding 20ml dichloromethane With 20ml saturated aqueous sodium carbonate, it is layered, then washs aqueous phase twice with 20ml dichloromethane, merge organic facies, be dried and be spin-dried for, TLC isolated 20mg product, is compound I-1.The analytical data of this compound is as follows: 1H-NMR (400MHz, CDCl3): δ: 10.18 (br, 1H)；9.19(br,1H)；8.38(s,1H)；7.52 (dt, J=2.39,11.32,1H), 7.16- 7.24(m,2H)；7.03-7.06(m,2H)；6.86(br,1H)；6.71 (t, J=7.11,1H)；6.30-6.38(m,2H)； 5.67 (dd, J=2.62,9.58,1H)；2.84 (t, J=5.27,2H)；2.70(s,3H)；2.37 (t, J=4.91,2H)； 2.30(s,6H)；MS m/z(ESI):585[M+H]+。
The reaction equation that above-mentioned preparation method relates to is as follows:
Wherein, intermediate A 1-1 is adopted A1 with the aforedescribed process and is made；Intermediate B 1-1 is to adopt B1 with the aforedescribed process Make.
Intermediate A, intermediate B used by pyrimidines of embodiment 2-29 and preparation method thereof are as shown in table 1, its Remaining with embodiment 1.
Intermediate A used by pyrimidines of table 1 embodiment 2-29 and preparation method thereof, intermediate B
Embodiment 30
The pyrimidines of the present embodiment, for the mesylate of the pyrimidines (I-6) shown in embodiment 6, its Structural formula is as shown in Formulas I-30:
The preparation method of the pyrimidines (mesylate) of the present embodiment is: added by the compound I-6 of 0.37g In the single port bottle of 50ml, add acetone and the water of 1ml of 10ml, be slowly added into the methanesulfonic acid of 64mg after adding under stirring, add After under the conditions of 50 DEG C, react 3h, add the acetonitrile of 6ml after being evaporated by reactant liquor and be warming up to 70 DEG C of stirring 30min, slowly cool down Make solid separate out, solid is leached, wash with acetonitrile, obtain the solid 140mg of white after drying, be compound I-30.Adopt Detecting its purity with HPLC is 98.5%.The analytical data of gained compound I-30 is: HNMR (400M, d6-DMSO):9.35(s 1H), 9.14 (s, 1H), 8.76 (s, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 7.95 (s, 2H), 7.85 (d, J=8.10Hz, 1H), 7.41 (m, 2H), 6.97 (s, 1H), 6.60 (m, 1H), 6.24 (d, J=16.7Hz, 1H), 5.78 (d, J=11.4Hz, 1H),3.82(s,3H),3.26(s,4H),2.79(s,6H),2.59(s,3H),2.31(s,3H)。
The reaction equation that this preparation method relates to is as follows:
Experimental example
One, this experimental example to the pyrimidines of embodiment 1-29 to Wild type EGFR and the kinase whose work of mutant egf R Property inhibitory action detects.
This method is utilized to measure determinand to double-mutant EGFR kinases (EGFR T790M/L858R kinases), wild type The inhibitory action of EGFR kinases (EGFR WT) activity.Wild type EGFR used in this detection method and mutant egf R (T790M/L858R) kinases is purchased from Carna Bioscience (card receive bioscience).
Experimental design:
The preparation of testing compound:
1, compound to be tested is configured to the DMSO solution of 10mM (mmol/L), and control sample compound AZD9291 joins Make the DMSO solution of 1mM (mmol/L).
2, being diluted by 3-times, by testing compound solution serial dilution to 12 concentration, (or other required test is dense Degree) on 384 orifice plates of TECAN EVO200.
3, use Echo550 transferase 12 0nL test solution to (Coring 3570) on 384 orifice plates.Use DMSO as sky White comparison.
Carry out enzyme test:
1, prepare containing enzyme, substrate, the 1.3X enzymatic solution of cofactor, as shown in table 2 below.
2, at room temperature, the 1.3X enzymatic solution adding 15 μ L in the hole of each orifice plate is cultivated 30 minutes.
3, the 4X ATP solution adding 5 μ L starts test reaction.Liquor capacity in final each hole should be 20 μ L, contains Composition as shown in table 2 below.
4, orifice plate is at room temperature cultivated 90 minutes, and the stop buffer (containing 0.5M EDTA) being subsequently adding 40 μ L terminates Test reaction.
5, EZ detection is used to analyze the experimental data in each hole.
Enzymatic solution parameter list in the test of table 2 enzyme
Data analysis:
1, read conversion ratio (CR) is used, according to equation below calculating inhibition ratio:
2, according to equation below, XLFit (equation 201) is used to calculate IC50 and Ki value,
K i = IC 50 1 + S K m .
Testing result is as shown in table 3 below.
Table 3 Wild type EGFR and mutant egf R kinase whose activity suppression testing result
In conjunction with above-mentioned experimental result, the pyrimidines of the present invention compared with prior art has the advantage that
(1) compound shown in the Formulas I of the present invention has extraordinary inhibitory activity to EGFR, especially (special to EGFR sudden change EGFR T790M/L858R sudden change) inhibitory activity obviously higher than the activity of prior art compound AZD9291, Such as embodiment 1,3,9,11,12,14,15,16,17,18,19,20,21,22 etc..Reaching the premise of identical therapeutic effect Under, dosage can be greatly reduced, thus greatly reduce other side effect caused by medicine.
(2) the compounds against wild type EGFR shown in the formula I of the present invention has low inhibitory activity, hence it is evident that be better than with generation existing Have technical compound AZD9291, such as embodiment 1,2,3,4,6,8 etc., the selective inhibitory activity of enzyme can be reached 10～ 60 times, it will be apparent that be better than 3 times of prior art compound AZD9291, and higher than the selectivity of second filial generation EGFR inhibitor.? Medicinal application aspect, can well reduce owing to Wild type EGFR high inhibition causing the serious secondary works of poison such as patient's erythra With etc. problem.
(3) with other known to compared with EGFR inhibition from mutation agent, the compounds of this invention also demonstrates favourable physical property (such as water solublity etc.), favourable metabolic characteristics (such as preferable Pharmacokinetic Characteristics, such as bioavailability).
Two, compounds on cell growth inhibitory activity test:
Method of testing and step use method well known to those skilled in the art to carry out, and in method, agents useful for same is the most commercially available Obtain.Method of testing:
1. experimental procedure:
(1) Echo (contactless nanoliter of level sound wave liquor-transferring system) is used to take 40nL testing compound solution to test board.
(2) cell is configured to the solution of 25000cell/mL, then takes 40 μ L to the 384 hole test boards specified.
(3) culture plate is at 37 DEG C, the carbon dioxide of 5%, cultivates 72 hours under the humidity of 95%.
(4) every hole adds 40 μ L'sReagent.
(5) by test board at room temperature, hatch 30 minutes, with stabilized illumination signal.
(6) sealing test plate, makes a return journey bubble removing with the centrifugal speed of 1000 revs/min.
(7) test board is shaken 1 minute on shaking table.
(8) read test plate data.
2. data process
(1) use equation below calculating residual rate:
Re m a i n i n g a c t i v i t y ( % ) = 100 % &times; S - M V - M ;
S: test sample reading；
V: blank sample reading；
M:AZD9291 test specimens (1 μM is used for testing PC-9 and H1975, tests for A431 for 30 μMs) reading；
Use XLFIT (V5.3.1.3) computed in software IC50.
Testing result is as shown in table 4.
Table 4 compound on intracellular inhibitory activity testing result
From table 4, it can be seen that EGFR mutant cell (H1975, PC-9) is shown relatively by the example compound of the present invention Strong inhibitory activity；Compared with control sample compound AZD9291, EGFR mutant cell growth is pressed down by the compound of the present invention Specific activity control compound AZD9291 processed improves 4～7 times.
Wherein, control compound AZD9291 (trade name: step auspicious for Buddhist nun) structure is as follows:

Claims (9)

1. a pyrimidines, it is characterised in that: include the compound shown in Formulas I, or its pharmaceutically acceptable salt, vertical Body isomer, solvate or prodrug:
Wherein, Ar is selected from phenyl or substituted phenyl；
R1Selected from hydrogen, halogen, trifluoromethyl or cyano group；
R2Selected from methoxyl group, difluoro-methoxy, the deuterated methoxyl group of difluoro or trifluoromethoxy；
R3Selected from any one structure following:
X1、X2、X3It is independently selected from hydrogen or halogen.
Pyrimidines the most according to claim 1, it is characterised in that: when Ar is substituted phenyl, described replacement Phenyl be a replacement, two replacements or trisubstd phenyl, substituent group be independently selected from halogen, cyano group, nitro, ester group, C1-4Alkyl or cycloalkyl, C1-4Alkoxyl or cycloalkyloxy, C1-4Haloalkyl, C1-4Acyl group, C1-6Alkylamino or naphthene amino.
Pyrimidines the most according to claim 2, it is characterised in that: the compound shown in Formulas I is selected from:
Pyrimidines the most according to claim 1, it is characterised in that: described pharmaceutically acceptable salt is mineral acid Salt or acylate, described inorganic acid salt selected from hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, nitrate, Phosphate, acid phosphate；Described acylate is selected from formates, acetate, trifluoroacetate, propionate, pyruvate, hydroxyl Acetate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, Mesylate, esilate, benzene sulfonate, salicylate, picrate, glutamate, Glu, salicylate, Ascorbate, Camphor tree Olic acid salt, camsilate.
5. an EGFR inhibitor, it is characterised in that: comprise the pyrimidines according to any one of claim 1-4.
EGFR inhibitor the most according to claim 5, it is characterised in that: also comprise pharmaceutically acceptable carrier.
7. an EGFR inhibitor as claimed in claim 5 is used for regulating and controlling EGFR TYR kinase activity or treatment in preparation Application in terms of the medicine of EGFR relevant disease.
Application the most according to claim 7, it is characterised in that: described regulation and control EGFR TYR kinase activity or treatment EGFR Relevant disease refers to cancer, diabetes, disease of immune system, neurodegenerative diseases or cardiovascular disease.
9. an EGFR inhibitor as claimed in claim 5 application in terms of the medicine of preparation treatment nonsmall-cell lung cancer.
CN201610462600.9A 2016-06-21 2016-06-21 A kind of pyrimidines, EGFR inhibitor and application thereof Pending CN106083736A (en)

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