CN106995437A - Substituted indole or indazole pyrimidine derivatives and its production and use - Google Patents

Substituted indole or indazole pyrimidine derivatives and its production and use Download PDF

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Publication number
CN106995437A
CN106995437A CN201610369625.4A CN201610369625A CN106995437A CN 106995437 A CN106995437 A CN 106995437A CN 201610369625 A CN201610369625 A CN 201610369625A CN 106995437 A CN106995437 A CN 106995437A
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methyl
compound
amido
ethyl
hydrogen
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张龙
赵树雍
陈栋
郑善松
周豪杰
李玉浩
杨莹莹
郑庆梅
范传文
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Qilu Pharmaceutical Co Ltd
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Qilu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to substituted indole or indazole pyridine derivatives and preparation method thereof, pharmaceutical composition and purposes.Specifically, it is related to compound of formula I or its pharmaceutically acceptable salt or solvate, wherein, R1‑R7, X, Y definition are as described in specification and claims.The invention further relates to the preparation method of compound of formula I, include its pharmaceutical composition and their pharmaceutical applications.The compound of formula I of the present invention is effective tyrosine kinase irreversible inhibitor, particularly has stronger inhibitory action to EGFR T790M drug-resistant tumors.

Description

Substituted indole or indazole pyrimidine derivatives and its production and use
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to the substituted indole or indazole pyrimidine with antitumor activity of a class newly There is analog derivative and preparation method thereof, substituted indole or the indazole pyridine derivatives effective tyrosine-kinase enzyme level to make With, with prepare for treat or auxiliary treatment mammal (including people) the tumour mediated by receptor tyrosine kinase or by Purposes in terms of the propagation of tumour cell and the medicine of migration of the driving of body EGFR-TK.
Background technology
Is pointed out in the global cancer report (2014) of WHO issues, the number of cancer is died from up to 820 in the whole world in 2012 Ten thousand.Due to the change of living environment and life habit, in the presence of poor environment and some unfavorable factors, tumour Morbidity and mortality are in rising trend.According to WHO address prediction, global cancer new cases are by by 2012 14000000 people, cumulative year after year was up to 24,000,000 people to 19,000,000 people of 2025 by 2035.
The treatment of tumour was realized by finding tumour and destroying in the past, now with to cellular signal transduction way What footpath was studied deepens continuously, and it is more and more deeper that people are understood the oncogene of inside tumor cells and the effect of antioncogene Enter, increasingly attracted attention for the new antineoplastic of the specific molecular shot design of tumour, the heat as research Point field, and anti-tumor drugs targeting has also been applied to clinic as a kind of new treatment method, and in a few years Significant progress is inside obtained.It is well known that protein tyrosine kinase (Protein tyrosine kinases, PTK) is believed Propagation, differentiation, migration and the apoptosis of number path and tumour cell have substantial connection (Li Sun, et al., Drug Discov Today, 2000,5,344-353), utilize protein tyrosine kinase inhibitor interference or blocks protein EGFR-TK Path can be used for oncotherapy (Fabbro D., et al., Curr Opin Pharmacol, 2002,2,374-381)； It can also be used for treatment leukaemia, Huppert's disease or lymthoma etc..
In recent years, people are directed to suppressing cellular signal transduction pathways developing new target spot antineoplastic.Signal turns Existence and proliferation signal that inhibitor lowers tumour are led, promotes Apoptosis, rather than by CDCC, therefore The higher, toxic side effect of selectivity is smaller.The clinical treatment that ten several signal transduction inhibitors are applied to tumour is had at present, Predominantly protein tyrosine kinase inhibitor series antineoplastic medicament, wherein 4- (substitution phenylamino) quinazoline structure type Compound exploitation comparative maturity, such as EGFR EGFR-TK target spots micromolecular inhibitor Gefitinib, angstrom Sieve is for Buddhist nun and Lapatinib etc..In addition, patent application WO96/33977, WO97/30035, WO98/13354, WO 00/55141st, WO02/41882, WO03/82290 and EP837063 etc. disclose on 4- positions carry phenylamino substitution and Some quinazoline derivants of substituent are carried on 6- and/or 7- positions, they have receptor tyrosine kinase activity.
However as kinases variation and the appearance of drug resistance of tumor, the second generation can not retroactive inhibition for EGFR families target spot Agent is arisen at the historic moment.Irreversible inhibitor has many advantages, such as with ATP-binding site Covalent bonding together, therefore is firmly combined with, Higher drug concentration need not be maintained, dosage can be reduced, extends administration time, reduction drug resistance etc..Mesh The preceding irreversible inhibitor in the clinic III phases has HKI-272, Dacomitinib and afatinib.It is directed to as the second generation Improved seeds in the irreversible inhibitor of EGFR target spots, afatinib has been listed at present.But the second generation can not retroactive inhibition Although agent preclinical study shows good overriding resistance tumor effect, clinic does not show obvious curative effects to drug-resistant tumor. Trace it to its cause and be to limit its clinical medicine dose to the toxic reaction caused by high inhibition excessively of Wild type EGFR, do not reach In vivo to effective exposed amount of drug-resistant tumor.Third generation selectivity irreversible inhibitor such as CO-1686, AZD-9291 etc. have To mutation activation EGFR and EGFR-T790M have higher inhibitory activity, and to Wild type EGFR it is weaker the characteristics of, with good Good security is had outstanding performance in clinical studies, current in later phase clinical research for drug resistant non-small cell lung.
Small molecule tyrosine kinase inhibitors, as new anti-tumor drugs targeting, are that the treatment and prevention of tumour open a fan New window, and its side effect is slight, there is good tolerance.Although having more than 10 small molecule tyrosine kinase suppression at present Preparation is that clinical cancer therapy has made very big contribution, but still needs to find some than existing tyrosine kinase inhibitor The other compound of pharmacological characteristics with more preferable activity in vivo and/or improvement, or find that some are powerful or are directed to Make a variation still effective inhibitor such as irreversible inhibitor of kinases etc..Therefore new improved or more efficient tyrosine-kinase is developed The mechanism of enzyme inhibitor, the relation gained more insight between such medicine and known target protein and its performance antitumor action Have great importance to clinical therapy of tumor.
The content of the invention
The present inventor is by further investigation it was unexpectedly observed that the substituted indole with Formulas I structure or indazole pyridine derivatives have There is effective tyrosine kinase irreversible inhibitory action and/or with good interior medicine dynamics behavior, and in vitro study is aobvious Show, the compounds of this invention has significant inhibitory action to H1975 tumour cells (EGFR-T-790 mutant drug-resistants tumour), And it is weaker to EGFR-wt inhibitory action, show preferable selectivity.In view of this kind of compound can reduce because Toxic side effect caused by EGFR-wt target spot extra-inhibitories (such as skin acne, diarrhoea), can be more suitable for for swelling Knurl is treated.The present invention is accomplished based on this discovery.
First aspect present invention provides compound and its pharmaceutically acceptable salt, solvate shown in Formulas I：
Wherein, R1Selected from hydrogen, C1-4 alkyl, C1-4 alkoxies, the C1-4 alkyl of halo, the C1-4 alkoxies of halo, C1-4 heterocyclylalkoxy groups, halogen；It is preferred that hydrogen, methoxyl group, ethyoxyl, methyl, ethyl, isopropyl, difluoro-methoxy, Fluorine, chlorine, bromine；More preferably methoxyl group, ethyoxyl, difluoro-methoxy；
R2Selected from hydrogen, C1-3 alkyl, C1-3 alkoxies, C1-3 alkane sulfydryl, the C1-3 alkyl of halo, halogen, alkenyl, Cyano group, alkynyl, amide groups, sulfoamido, sulfamic；It is preferred that hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, Alkenyl, cyano group, alkynyl, fluorine, chlorine, bromine, more preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine；
R3Selected from alkyl, halogen ,-N (CH3)CH2R6、-N(CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2- N(CH3)2、-N(CH3)CH2CH2N(Boc)CH3、-N(CH3)CH2CH2CH2-N(CH3)2、-N(CH3)CH2CH2-N(C H2CH3)2、-N(CH3)CH2CH2-N(CH2CH3)CH3、-N(CH2CH3)CH2CH2-N(CH3)2；It is preferred that-N (CH3)C H2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2、-N(CH3)CH2CH2N(Boc)CH3；More preferably-N (CH3)C H2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CR4Or N；
Y is selected from CR5；
R4、R5、R6It is each independently selected from H, C1-3 alkyl, C1-3 alkoxies or C1-3 haloalkyls, halogen, cyanogen Base, carboxyl or amine acyl group；
R7Selected from hydrogen, C1-3 alkyl, C1-3 alkoxyl oxygen alkyl ethyls；
And if only if, and X is CH or N, and Y is selected from CH, C-Cl, C-F, C-CF3、C-CHF2、C-CH3、C- During CN, R2 is not hydrogen；
In the technical scheme of the present invention, R1Selected from hydrogen, methyl, ethyl, methoxyl group, ethyoxyl, isopropoxy, Difluoro-methoxy, trifluoromethoxy, fluorine, chlorine, bromine；More preferably methyl, ethyl, methoxyl group, ethyoxyl, difluoro first Epoxide, trifluoromethyl, most preferably methoxyl group, ethyoxyl,；
R2Selected from hydrogen, C1-3 alkyl, C1-3 alkoxies, C1-3 alkane sulfydryl, halo C1-3 alkyl, halogen, sulphonyl Amido, amide groups, sulfonyl, alkenyl, cyano group, alkynyl；It is preferred that hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, Alkenyl, cyano group, alkynyl, fluorine, chlorine, bromine；More preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2、 -N(CH3)CH2CH2N(Boc)CH3；More preferably-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, C-CH3, N, preferably CH, C-CH3；
Y is selected from CH, C-Cl, C-F, C-CF3、C-CH3、C-CN、CCOOH、CCONH2；It is preferred that CH, C-CF3、 C-CH3、CCOOH、CCONH2；More preferably CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
When and if only if X is CH or during N, and Y is selected from CH, C-Cl, C-F, C-CF3、C-CH3, C-CN when, R2 is not hydrogen；
In another technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl, difluoro-methoxy, trifluoromethoxy, It is preferred that methoxyl group, ethyoxyl；
R2Selected from hydrogen, methyl, fluorine, chlorine；Most preferably hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3、C-CF3、C-CN、CCOOH、CCONH2；It is preferred that CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3、C-CF3, C-CN when, R2 be hydrogen；
In the preferred technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl；
R2Selected from hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3、CCOOH、CCONH2；It is preferred that CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3When, R2 is not hydrogen；
In another preferred technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl；
R2Selected from hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3When, R2For fluorine；
In first aspect present invention, the halogen or halogen atom are selected from fluorine, chlorine or bromine, in one embodiment preferred fluorine； Described alkyl refers to the alkyl being connected between carbon atom and between carbon atom and hydrogen atom with singly-bound, and it includes straight chain Alkyl, branched alkyl, cycloalkyl；It is preferred that C1-6Or C1-4Alkyl, specifically, described straight or branched alkyl choosing From methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl and the tert-butyl group；The halogenated alkane refer to by one or The alkyl of multiple halogen atom substitutions, the example of haloalkyl includes trifluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl； The cycloalkyl refers to the cycloalkyl of the alkyl with cyclic structure, preferably C3-7, C4-6 or C3-5, the example of cycloalkyl Including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；The Heterocyclylalkyl refers to carbon atom in ring-type carbon skeleton structure by 1-2 The cycloalkyl of individual hetero atom substitution, its hetero atom can be selected from N, O, S, the example of Heterocyclylalkyl include azacyclo- ethyl, Tetrahydro-thienyl, tetrahydrofuran base, nafoxidine base, hexahydropyridine base, piperidyl；Tetrahydrofuran -3- the bases include (S) - Tetrahydrofuran -3- bases, (R)-tetrahydrofuran -3- bases；Tetrahydrofuran -3- bases the epoxide include (S)-tetrahydrofuran -3- bases epoxide, (R)-tetrahydrofuran -3- base epoxides；" Boc " refers to that (English full name is tert-butoxycarbonyl：t-Butyloxy carbonyl).
Described compound of formula I according to a first aspect of the present invention, it is selected from following structural compounds：
Second aspect of the present invention provides the preparation of compound of formula I or its pharmaceutically acceptable salt described in first aspect present invention Method, it comprises the following steps：
(1) in the presence of a lewis acid, as shown in Formula II compound and compound shown in formula III in higher boiling anhydrous solvent Reaction obtains intermediate compound IV：
(2) intermediate compound IV obtains intermediate VI with compound V under optimum conditions, and intermediate VI is under the effect of suitable alkali Reaction, then reduce to obtain intermediate VII through reducing agent：
(3) intermediate VII obtains compound of formula I with acryloyl chloride or acrylic anhydride reaction：
Or intermediate VII reacts with 3- chlorpromazine chlorides, then through eliminating to obtain compound of formula I：
And optionally,
(4) compound of formula I obtains the pharmaceutically acceptable salt of compound of formula I with corresponding acid reaction, or passes through alkali tune Obtain the base of corresponding Formulas I；
Wherein, R1-R3And R7, X, Y there is first aspect present invention identical implication.
In step (1), the higher boiling anhydrous solvent is selected from glycol dimethyl ether, dimethylbenzene；The lewis acid is selected from Anhydrous AlCl3, FeCl3；The catalyst is palladium catalyst, preferably tetrakis triphenylphosphine palladium；
In step (2), described suitable acid is selected from p-methyl benzenesulfonic acid, hydrochloric acid, hydrobromic acid, preferably p-methyl benzenesulfonic acid；Institute The suitable alkali stated is selected from organic base or inorganic base, preferably triethylamine, diisopropyl ethyl amine, sodium hydride, hydrofining and hydrogenation Calcium；The reducing agent is selected from SnCl2 concentrated hydrochloric acids, Zn powder acetic acid, Fe powder acetic acid, iron powder ammonium chloride, Pd-C catalytic hydrogenations； It is preferred that Pd-C catalytic hydrogenations, Fe powder ammonium chlorides.
For the preparation method described in second aspect of the present invention, when necessary, to prevent some group (such as amino, hydroxyl Deng) occur undesirable reaction, it is necessary to be protected to corresponding group, meanwhile, protection group is removed in due course. These examples are too numerous to enumerate, and the method for using and being deprotected for the protection group not referred to specifically falls within the model of the present invention Within enclosing.
In the preparation method described in second aspect of the present invention, reaction various raw material used are those skilled in the art It can be prepared, or be can be by made from method known to document according to existing knowledge, or can be with By commercially available.Used intermediate, raw material, reagent, reaction condition etc. can be with above reaction scheme It can make what is suitably changed according to the existing knowledge of those skilled in the art.Or, those skilled in the art can also basis Preparation method method synthesis not specifically enumerated other compound of formula I of the invention of the present invention.
In the present invention, the initiation material 2 shown in Formula II, indoles or indazole described in 4- dichloro pyrimidines and formula III can be with Finish to obtain medical limited public affairs from the Shanghai auspicious chemical Science and Technology Ltd. of win, Tianjin Heowns Biochemical Technology Co., Ltd., Shanghai Department, Shanghai Mai Ruier chemical technologies Co., Ltd, AlfaAesar (China) Chemical Co., Ltd., the uncommon love (Shanghai) of ladder Chemical conversion industry Development Co., Ltd etc. buys or prepared by method as be shown in the examples.
In the present invention, the initiation material substituted aromatic amines shown in Formula V can be prepared according to conventional methods, or market purchase The fluoro- 2- nitrophenols purchase preparation methods from Tianjin Heowns Biochemical Technology Co., Ltd., scripture of 5- such as are can buy to obtain Corresponding substituted aromatic amines, the fluoro- 5- nitroanilines of 2- methoxyl groups -4- are purchased from Shanghai Hanhong Chemical Industry Co., Ltd..It is other conventional Reagent or solvent if not otherwise indicated, are directly bought, unprocessed directly to use.Such as N, N, N '-trimethyl Ethylenediamine-hydrochloride or the N of list Boc protections, N '-dimethyl ethylenediamine is purchased from chemical (Shanghai) Science and Technology Ltd. of nine ancient cooking vessels； Acrylic anhydride, acryloyl chloride or 3- chlorpromazine chlorides are radically reformed Chemical Co., Ltd. purchased from Changzhou.
Third aspect present invention is related to a kind of pharmaceutical composition, and it includes the compound of formula I described in first aspect present invention Or its pharmaceutically acceptable salt or solvate, and optional one or more pharmaceutically acceptable carriers or figuration Agent.
Fourth aspect present invention provides the compound and its pharmaceutically acceptable salt, solvent shown in first aspect present invention Formulas I Compound is in the medicine for treating or/and preventing mammal (including people) disease related to receptor tyrosine kinase or illness Purposes.
Fifth aspect present invention provides third aspect present invention described pharmaceutical composition for treating or/and preventing mammal Purposes in the medicine of (including people) disease related to receptor tyrosine kinase or illness.
Sixth aspect present invention provides a kind of be used in the middle treatment of mammal in need (including people) and/or prevention and acceptor The method of the related disease of EGFR-TK or illness, this method includes applying therapeutically effective amount to mammal in need Compound shown in formula I, its pharmaceutically acceptable salt, the third party of the present invention of solvate or effective dose Pharmaceutical composition described in face.
The present inventor shows that the compound shown in Formulas I described in first aspect present invention is prominent to EGFR by biological test Become (EGFR-delE746-A750) cell line (HCC827) and EGFR-T790M medicament-resistant mutation cell lines H1975 all to show Show powerful inhibitory activity, and it is weaker to Wild type EGFR overexpression cell line A431 inhibitory action, therefore can be pre- Phase the compounds of this invention and its pharmaceutical composition can be used for EGFR mutation and EGFR-T790M resistance receptor tyrosine kinase lists The treatment of the disease of only or part mediate, and avoid or reduce because being produced to EGFR wild type kinases extra-inhibitory Larger toxic side effect (such as skin acne, diarrhoea, vomiting).The compounds of this invention is mainly by suppressing one or more EGFR families tyrosine-kinase enzyme mutant, or produce anti-tumour cell proliferative, migration or rush by suppressing the activity of mutant kinase The effect of apoptosis of tumor cells.
In the present invention, particularly in the method described in the purposes described in the aspect of the present invention fourth, fifth and the 6th aspect, institute State " disease or illness related to receptor tyrosine kinase " preferably " tumour mediated by receptor tyrosine kinase ", " by by The propagation of the tumour cell of body EGFR-TK driving and migration " or " EGFR receptor tyrosine kinase susceptible neoplasms.Its In, the tumour of " the EGFR receptor tyrosine kinases cancer susceptible " the preferably expression of EGFR families height and EGF drivings, It is including but not limited to prominent by EGFR L858R mutant and/or the missing activation of EGFR-T790M mutant and/or Exon19 Variant and/or the mutant mediated tumours of EGFR-delE746-A750 or to EGFR inhibitor such as Gefitinib (Gefitinib) or the resistance such as Erlotinib (Erlotinib) tumour, specifically include entity tumor, such as bile duct, bone, wing Guang, central nervous system (such as brain), breast, Colon and rectum, stomach, head and neck, liver, lung (especially non-small cell lung cancer), Neuron, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid gland, uterus (such as carcinoma of endometrium) With the cancer of vulva etc., and non-solid tumors, such as leukaemia, Huppert's disease or lymthoma.
Term used herein " composition " means to include the product of each specified composition comprising specified amount, and directly or Any product produced indirectly from the combination of each specified composition of specified amount.Those skilled in the art can be by changing the present invention The actual dose level of each active component in pharmaceutical composition, can be effectively for specific trouble so as to the reactive compound amount of gained Person, composition and administering mode obtain required therapeutic response.Dosage level need to be according to the active of particular compound, administration on the way The patient's condition and medical history in footpath, the order of severity for treating the patient's condition and patient to be treated is selected.But, this area is done Method is, the dosage of compound is since the level required less than therapeutic effect needed for obtaining, gradually incremental dose, until Obtain required effect.In the present invention, described pharmaceutical composition especially can supply mouth by particular formulation into solid or liquid form Clothes administration, for parental injection or supply rectally.
Compound or its pharmaceutically acceptable salt shown in the Formulas I of the present invention of term " treatment and/or prevention effective dose " Refer to the compound for the sufficient amount that obstacle is treated with the reasonable effect suitable for any therapeutic treatment and/or prevention/Hazard ratio.But should Recognize, total consumption per day of compound shown in formula I or its pharmaceutically acceptable salt and composition must be by attending physician Maked decision in reliable medical judgment scope.For any specific patient, the specific horizontal fibrous root for the treatment of effective dose Depending on many factors, the factor includes treated obstacle and the order of severity of the obstacle；The particular compound used Activity；The concrete composition used；Age, body weight, general health, sex and the diet of patient；Used Particular compound administration time, method of administration and excretion rate；Treat the duration；With the particular compound group used Close and use or medicine used at the same time；And similar factor known to medical field.For example, the way of this area is, compound Dosage since the level required less than therapeutic effect needed for obtaining, gradually incremental dose, until obtaining required effect Really.It is, in general, that compound shown in formula I or its pharmaceutically acceptable salt are used for the agent of mammal particularly people Amount can between 0.001~1000mg/kg body weight/days, such as between 0.01~100mg/kg body weight/days, for example between 0.01~10mg/kg body weight/days.
Compound shown in the Formulas I of the present invention can be used with other medicines active ingredient combinations, as long as it does not produce other not Profit effect, such as allergic reaction.
Compound shown in formula I can be used separately as cancer therapy drug, or can be resisted with one or more other Tumour medicine is used in combination.Therapeutic alliance by by each therapeutic component simultaneously, order or separate administration and realize.
The compound of the present invention can be used in the form of the pharmaceutically acceptable salt derived from inorganic acid or organic acid. Term " pharmaceutically acceptable salt " refers in reliable medical judgment scope, is suitable for and the mankind and lower animal Tissue contact and occur without excessive toxicity, stimulation, allergic reaction etc., and match with rational effect/Hazard ratio Salt.Pharmaceutically acceptable salt is well known in the art.The salt can be by making the free alkali function of the compounds of this invention Degree and suitable organic acid reaction, are prepared or independent in the final separation of the compounds of this invention and purge process situ Prepare.
Formula I also include its isomers, raceme, enantiomer, diastereomer, enantiomer enriched substance, Solvate and ester, formula I and its isomers, raceme, enantiomer, diastereomer, enantiomer Enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct.Above-claimed cpd may be used also In the form of being prodrug or can discharge the active component after metabolic alterations in vivo.Select and prepare appropriate prodrug Derivative is technology as well known to those skilled in the art.It is and pharmaceutically acceptable generally, for the purpose of the present invention Solvent such as water, ethanol etc. solvate form thereof it is suitable with non solvate form.
Embodiment
Embodiment and the biological experiment further description present invention are prepared below by specific, still, should be managed Solution, these embodiments and biological experiment, which are only used for specifically describing, to be used, and should not be construed as being used for Any form limitation present invention.It will be apparent to those skilled in the art that hereinafter, if not specified, material used Material and operating method are well known in the art.Unless otherwise indicated, wherein：(i) temperature is represented with degree Celsius (DEG C), and operation exists Carry out at room temperature, the room temperature refers generally to 15-35 DEG C, more preferably preferably 20-30 DEG C, 20-25 DEG C；(ii) organic solvent nothing Aqueous sodium persulfate is dried, and the removal of solvent is evaporated under reduced pressure using Rotary Evaporators, and bath temperature is not higher than 60 DEG C；(iii) course of reaction is used Thin-layer chromatography (TLC) is tracked；(iv) end-product have satisfied hydrogen nuclear magnetic resonance spectrum (1H-NMR), nuclear magnetic resonance of carbon spectrum (13) and mass spectrum (MS) data C-NMR.
Embodiment 1：2- ((2- acrylamidos -4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- base amine Base) 5- methoxyphenyls) (methyl) amido) and ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 1) synthesis:
A.3- the synthesis of (the chloro- 5- methylpyrimidines -4- bases of 2-) fluoro- 1- Methyl-1H-indoles of -5-
Raw material 5- fluoro indoles (10g, 1eq) are added in round-bottomed flask, 150ml DMF are added, the addition of -10 degrees centigrades is cooled to 60% sodium hydride (6g, 2eq), stir about instills iodomethane (15.7g, 1.5eq) after 20 minutes, reaction, TLC is stirred at room temperature in complete be warming up to After completion of the reaction, system is poured into 1L water for detection, and equivalent dichloromethane is extracted 2 times, and organic layer anhydrous sodium sulfate drying is concentrated under reduced pressure The fluoro- 1- Methyl-1H-indoles 11g of intermediate 5-.
The chloro- 5- methylpyrimidines (12g, 1.1eq) of 2,4- bis- are added in round-bottomed flask, 150ml glycol dimethyl ethers is added, is warming up to 60 Degree Celsius, anhydrous ferric trichloride (13g, 1.1eq) is disposably added, the fluoro- 1- Methyl-1H-indoles (11g, 1.1eq) of 5- is added and continues to stir Reaction, TLC is detected after completion of the reaction, and system is down into room temperature, adds the mixed solvent 500ml of methanol/water=2/1, separates out solid, is filtered, Solid is beaten with methanol and washed, dry 3- (the chloro- 5- methylpyrimidines -4- bases of 2-) fluoro- 1- Methyl-1H-indoles 12g of -5-.
B.2- ((4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) 5- methoxyl group -2- nitrobenzene Base) (methyl) amido) ethyl (methyl) amidocarbonic acid tert-butyl ester synthesis:
By the fluoro- 1- Methyl-1H-indoles (6g, 1.0eq) of 3- (the chloro- 5- methylpyrimidines -4- bases of 2-) -5-, the fluoro- 5- of 2- methoxyl groups -4- Nitroaniline (4.45g, 1.1eq) and p-methyl benzenesulfonic acid (4.1g, 1.1eq) are added in 250ml single port bottle, 60ml Isosorbide-5-Nitraes-dioxane is added, back flow reaction is warming up to after stirring, TLC and liquid matter tracking and monitoring are to having reacted Finish, Temperature fall, separate out a large amount of solids, filtering, filter cake is washed with a small amount of methanol, dry title intermediate N- (4- Fluoro- 2- methoxyl groups -5- nitrobenzophenones) -4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- amine (7g, yield 76%).
By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- amine (4.25g, 1.0eq) ,-N of single Boc protections, N '-dimethyl ethylenediamine (3g), diisopropyl ethyl amine (3ml), three Fluoroethanol 50ml is added in tube sealing, and 100 DEG C are reacted about 12 hours, and TLC display reactions are complete, and evaporated under reduced pressure is molten Agent, rapid column chromatography, methylene chloride/methanol 100/1 elutes to obtain 2- ((4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- Methylpyrimidine -2- bases amido) 5- methoxyl group -2- nitrobenzophenones) (methyl) amido) ethyl (methyl) amidocarbonic acid tert-butyl ester (5.46g, yield 92%).
C.2- ((2- acrylamidos -4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) 5- first Phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 1) synthesis：
Take 2- ((4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) 5- methoxyl group -2- nitrobenzene Base) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (5.46g) is added in 500ml single port bottle, Absolute methanol (300ml) is added, nitrogen displacement adds 10%Pd/C (400mg), and hydrogen is replaced for several times, room temperature After the completion of stirring reaction 8h, TLC monitoring reaction, pumping rate, filtrate decompression concentration removes solvent and obtains intermediate amine. Gained intermediate amine is dissolved in 50ml dichloromethane, triethylamine (3.6g) is added thereto, 0 is cooled to Celsius Below degree, acrylic anhydride (3.7g) is slowly added dropwise thereto, drop Bi Ziran is warmed to room temperature reaction about 1h, TLC prison Survey reaction is complete, adds 100ml water, and equivalent dichloromethane is extracted 3 times, merging organic phase, anhydrous sodium sulfate drying, Be concentrated under reduced pressure rapid column chromatography, and methylene chloride/methanol 50/1 elutes target product 2- ((2- acrylamidos -4- (4- (5- Fluoro- 1- Methyl-1H-indoles -3- bases) -5- methylpyrimidine -2- bases amido) 5- methoxyphenyls) (methyl) amido) ethyl (first Base) the amidocarbonic acid tert-butyl ester (compound 1) (2.39g, yield 42%).MS(m/z):[M+H]+618.4。
Embodiment 2：N- (5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) -4- methoxyl groups - 2- (methyl (2- (methylamino) ethyl) amido) phenyl) acrylamide (compound 2) synthesis:
Gained compound 1 (2.0g) in embodiment 1 is dissolved in 8ml dichloromethane, trifluoroacetic acid 4ml is added, 2h is stirred at room temperature, TLC detection raw material reactions are complete, are cooled to less than 0 degree Celsius, add 80ml unsaturated carbonate hydrogen Sodium and 80ml dichloromethane, are stirred 30 minutes, and point liquid, aqueous phase is extracted 3 times with equivalent dichloromethane, are merged organic Phase, anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain target product (compound 2) (1.53g, yield 91%).
1H-NMR(400MHz,DMSO-d6,δppm)：10.38(s,1H),9.90(s,1H),9.63(s,1H),8.62 (s, 1H), 8.15 (s, 2H), 7.59 (m, 1H), 7.30 (m, 1H), 7.16 (s, 1H), 7.00 (s, 1H), 6.18 (d, 1H, J= 16.8Hz), 5.78 (s, 1H), 5.66 (d, 1H, J=8.8Hz), 3.97 (s, 3H), 3.79 (s, 3H), 3.37 (s, 2H), 3.17(s,3H),3.12(s,2H),2.65(s,3H),2.45(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：167.2,164.0,160.7,158.3,152.1,151.3, 144.6,143.9,140.7,134.2,133.2,127.9,127.8,126.4,122.4,116.5,112.4,112.3,112.2, 111.9,111.8,109.6,109.3,105.7,56.5,50.9,45.9,42.7,34.3,32.8,18.6；MS(m/z): [M+H]+518.2。
Embodiment 3：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (fluoro- 1- Methyl-1H-indoles -3- of 5- Base) -5- methylpyrimidine -2- bases amido) -4- methoxyl groups-phenyl) and acrylamide (compound 3) synthesis:
a.N1- (2- (dimethylamino) ethyl)-N4- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- base amine Base) -5- methoxyl groups-N1The synthesis of the triamine of-methylbenzene -1,2,4：
By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-), (synthetic method is shown in implementation to -5- methylpyrimidine -2- amine Example 1) (7g, 1eq), trimethyl ethylenediamine dihydrochloride (5.7g, 2eq), triethylamine (8.3g, 5eq), trifluoroethanol (100ml) It is added in tube sealing, is warming up to 100 degrees Celsius, gradually dissolved with reaction carry out system, TLC and liquid quality supervision is surveyed reaction and finished after about 8h, It is concentrated under reduced pressure into dry, obtains crude product 7.5g, it is not purified to be directly used in next step reaction.
Gained crude product (7.5g) and 100ml methanol are added in round-bottomed flask, nitrogen displacement, added after 10% palladium carbon (750mg), Hydrogen is replaced 3 times, and reaction is stirred at room temperature, and TLC tracking about 10h reactions are finished, filtered, filtrate decompression is concentrated to dryness to obtain 5g crude product amine, not It is purified to be directly used in next step.
b.N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methyl Pyrimidine -2-base amido) -4- methoxyl groups-phenyl) acrylamide (compound 3) synthesis:
By crude product amine (5g, 1eq), potassium carbonate (2.9g, 2eq) and 150ml acetone are added in round-bottomed flask, System is cooled to -10 degrees centigrades, instills 3- chlorpromazine chlorides (2g, 1.5eq), there is solid generation immediately, and drop finishes, Naturally stirring is warmed to room temperature, TLC is monitored after completion of the reaction, is filtrated to get filter cake 5g.By the filter cake, triethylamine (4 Ml) it is added to 100ml acetonitriles in round-bottomed flask, 85 degrees Celsius of stirring reactions, liquid matter is warming up to after being well mixed React and finish after monitoring about 7h, system is down to room temperature naturally, water 65ml is instilled thereto, gradually there are a large amount of solids to analyse Go out, filter and dry target product N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (fluoro- 1- methyl of 5- - 1H- indol-3-yls) -5- methylpyrimidine -2- bases amido) -4- methoxyl groups-phenyl) acrylamide (1.8g, 97.2% purity).
1H-NMR(400MHz,DMSO-d6,δppm)：10.09(s,1H),8.66(s,1H),8.19(s,1H),8.13(s, 1H),8.10(m,1H),8.07(s,1H),7.48(m,1H),7.05(m,1H),7.01(s,1H),6.34(m,1H),6.15(dd, 1H, J=16.8Hz, J=5.2Hz), 5.70 (m, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 2.87 (m, 2H), 2.72 (s, 3H), 2.36(s,3H),2.32(m,2H),2.21(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,160.6,159.8,159.5,159.3,157.2,148.6, 139.3,135.6,133.8,132.8,128.0,127.7,127.6,126.4,125.7,116.9,116.3,112.7,111.3,111.2, 110.9,110.6,108.8,108.6,106.1,57.4,56.2,45.7,42.7,33.7,18.3；MS(m/z):[M+H]+532.2。
Embodiment 4：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (fluoro- 1- Methyl-1H-indoles -3- of 5- Base) -5- methylpyrimidine -2- bases amido) -4- ethyoxyls-phenyl) and acrylamide (compound 4) synthesis:
a.The synthesis of the fluoro- 5- nitroanilines of 2- ethyoxyls -4-
By the fluoro- 2- nitrophenols (120g, 1eq) of 5-, potassium carbonate (316g, 3eq) is suspended in 2L DMF, is instilled Bromoethane (166g, 2eq), is warming up to 37 DEG C of stirring reactions, TLC is detected after completion of the reaction, and system is poured into frozen water, Product is separated out, and the fluoro- 2- nitrophenetols of 5- (138.6g, yield 98%) are washed to obtain in filtering.
The fluoro- 2- nitrophenetols (68g) of 5- are dissolved in 1L methanol, nitrogen displacement, added after palladium carbon (5g), hydrogen Displacement 2 times, TLC detections after hydrogenation, about 4h are stirred at room temperature, and after completion of the reaction, filtering, filtrate decompression steams solvent and obtains 4- Fluoro- 2- phenetidines (56g).
Less than -10 DEG C, the fluoro- 2- phenetidines (30g) of 4- are dissolved in the 30ml concentrated sulfuric acids, by potassium nitrate (22g) point Criticize in addition system, stirring is then warmed to room temperature naturally, TLC is monitored after completion of the reaction, and system is poured slowly into 600ml In frozen water, instill concentrated ammonia liquor and adjust PH to 7-8, add dichloromethane extracted several times, organic phase anhydrous sodium sulfate drying, decompression Column chromatography obtains the fluoro- 5- nitroanilines of 2- ethyoxyls -4- (16.3g, yield 42%) after concentration.
b.N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methyl Pyrimidine -2-base amido) -4- ethyoxyls-phenyl) acrylamide (compound 4) synthesis:
Method similar to Example 3, N- (2- ((2- (two can be obtained by raw material of the fluoro- 2- ethyoxyls -5- nitroanilines of 4- Methylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) -4- second Epoxide-phenyl) acrylamide (compound 4).
1H-NMR(400MHz,DMSO-d6,δppm)：10.08(s,1H),8.77(s,3H),8.21(s,1H),8.14 (s,2H),7.97(s,1H),7.48(m,1H),7.04(m,1H),7.00(s,1H),6.34(m,1H),6.14(d,1H,J =16.8Hz), 5.69 (d, 1H, J=9.6Hz), 4.06 (m, 2H), 3.89 (s, 3H), 2.86 (m, 2H), 2.70 (s, 3H), 2.37(s,3H),2.30(m,2H),2.20(s,6H),1.27(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.7,160.6,159.6,159.5,159.3,157.2, 147.1,138.8,135.6,133.8,132.8,128.2,127.7,127.6,126.3,126.2,116.5,115.9,112.7, 112.6,111.4,111.3,110.9,110.6,108.8,108.5,107.3,64.6,57.4,56.4,45.7,42.8,33.7, 18.2,15.2；MS(m/z):[M+H]+546.2。
Embodiment 5：N- (5- (4- (1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- Ethoxyl phenenyl) acrylamide (compound 5) synthesis:
a.The synthesis of N- (the fluoro- 5- nitrobenzophenones of 2- ethyoxyls -4-) -4- (1H- indol-3-yls) pyrimidine -2- amine
2,4- dichloro pyrimidines (17.9g, 1.1eq) are added in round-bottomed flask, 100ml glycol dimethyl ethers and nothing is added 60 degrees Celsius are warming up to after aqueous ferric chloride (21.1g, 1.2eq), nitrogen displacement, 1H- indoles (12.7g, 1eq) is added dropwise, Bi Jixu stirring reactions are dripped, TLC is detected after completion of the reaction, and system is down into room temperature, add water 150ml, no solid is separated out, Equivalent ethyl acetate is extracted 3 times, anhydrous sodium sulfate drying, and column chromatography obtains intermediate 3- (2- chlorine pyrimidines -4- after being concentrated under reduced pressure Base) -1H- indoles (8.8g, yield 25%).
By 3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2.78g, 1eq) and the fluoro- 5- nitroanilines (2.7g, 1.2eq) of 2- ethyoxyls -4- It is suspended in 70ml n-butanols, adds p-methyl benzenesulfonic acid (2.71g, 1.3eq), 105 degrees Celsius is warming up under nitrogen protection instead Should about 5h, TLC display reactions are complete, stop heating, room temperature is down to naturally and separates out a large amount of solids, pumping rate, filter cake vacuum is done It is dry to obtain title intermediate N- (the fluoro- 5- nitrobenzophenones of 2- ethyoxyls -4-) -4- (1H- indol-3-yls) pyrimidine -2- amine (3.1g, 65% receipts Rate).
b.N- (5- (4- (1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls Phenyl) acrylamide (compound 5) synthesis:
Method similar to Example 3, with N- (the fluoro- 5- nitrobenzophenones of 2- ethyoxyls -4-) -4- (1H- indol-3-yls) pyrimidine -2- amine It is that raw material can obtain N- (5- (4- (1H- indol-3-yls) pyrimidine -2-base amine with the fluoro- 2- ethyoxyls -5- nitroanilines of 4- Base) -2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethoxyl phenenyls) acrylamide (compound 5).
1H-NMR(400MHz,DMSO-d6,δppm)：11.83(s,1H),10.19(s,1H),9.08(s,1H),8.57(s, 1H), 8.32 (m, 2H), 7.92 (s, 1H), 7.46 (m, 1H), 7.28 (d, 1H, J=3.6Hz), 7.15 (m, 1H), 7.09 (m, 1H), 7.01 (s, 1H), 6.43 (m, 1H), 6.30 (d, 1H, J=16.8Hz), 5.76 (d, 1H, J=9.6Hz), 4.10 (m, 2H), 2.87(m,2H),2.71(s,3H),2.29(m,2H),2.20(s,6H),1.34(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.9,162.8,160.6,157.8,146.0,138.2,137.7, 132.7,130.1,128.2,126.7,126.1,125.5,122.4,122.0,121.0,114.7,114.0,112.5,107.8,106.9, 64.7,57.4,56.3,45.7,43.1,15.2；MS(m/z):[M+H]+500.3。
Embodiment 6：((4- (the fluoro- 1H- indol-3-yls of 5-) is phonetic by 2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- by N- Pyridine -2- bases amido)-phenyl) acrylamide (compound 6) synthesis:
Method similar to Example 5, N- (2- ((2- (dimethylamino) ethyl) (first can be obtained by raw material of the fluoro- 1H- indoles of 5- Base) amido) -4- ethyoxyls -5- (4- (the fluoro- 1H- indol-3-yls of 5-) pyrimidine -2-base amido)-phenyl) acrylamide (compound 6).
1H-NMR(400MHz,DMSO-d6,δppm)：10.15(s,1H),9.93(s,1H),8.55(s,1H),8.29(d, 1H, J=4.8Hz), 8.05 (m, 2H), 7.47 (m, 1H), 7.24 (d, 1H, J=5.2Hz), 6.99 (m, 2H), 6.39 (m, 1H), 6.24 (d, 1H, J=16.8Hz), 5.73 (d, 1H, J=9.6Hz), 4.08 (m, 2H), 2.87 (m, 2H), 2.71 (s, 3H), 2.31(m,2H),2.21(s,6H),1.30(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.5,160.8,159.4,157.6,157.1,146.8, 138.6,134.4,132.8,131.7,128.2,126.5,126.1,126.0,125.9,115.4,114.0,113.5,113.4,110.6, 110.4,107.5,107.3,107.2,64.6,57.4,56.4,45.7,42.9,15.2；MS(m/z):[M+H]+518.3。
Embodiment 7：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (5- methyl -4- (1- Methyl-1H-indoles -3- Base) pyrimidine -2-base amido)-phenyl) and acrylamide (compound 7) synthesis:
Method similar to Example 4, N- (2- ((2- (dimethylamino) can be obtained by raw material of 1- Methyl-1H-indoles Ethyl) (methyl) amido) -4- ethyoxyls -5- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base amido)-phenyl) third Acrylamide (compound 7).
1H-NMR(400MHz,DMSO-d6,δppm)：10.10 (s, 1H), 8.83 (s, 1H), 8.35 (d, 1H, J=7.2Hz), 8.23 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.47 (d, 1H, J=8.0Hz), 7.20 (m, 2H), 7.04 (m, 1H), 6.99 (s, 1H), 6.39 (m, 1H), 6.18 (d, 1H, J=16.8Hz), 5.71 (d, 1H, J=10.0Hz), 4.07 (m, 2H), 3.89 (s, 3H),2.86(m,2H),2.70(s,3H),2.36(s,3H),2.29(m,2H),2.20(s,6H),1.30(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,161.0,159.4,159.2,146.7,138.6,137.1, 134.0,132.8,128.0,127.2,126.4,126.3,123.5,122.5,120.8,116.9,115.8,112.7,110.3,107.0, 64.6,57.4,56.3,45.7,43.0,33.4,18.2,15.2；
MS(m/z):[M+H]+528.2。
Embodiment 8：2- ((2- acrylamidos -5- (difluoro-methoxy) -4- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- Base amido) phenyl) (methyl) amido) and ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 8) synthesis:
a.The synthesis of the fluoro- 5- nitroanilines of 2- difluoro-methoxies -4-：
By the fluoro- 2- nitrophenols (50g, 1eq) of 5-, potassium carbonate (66g, 1.5eq) and chloro difluoro acetic acid sodium (72 G) it is suspended in 800ml DMF, 90 DEG C of stirring reactions, TLC detects that 100 DEG C of decompressions steam solvent after completion of the reaction, 800ml water is added, equivalent dichloromethane is extracted 3 times, merges organic layer, anhydrous sodium sulfate drying, after being concentrated under reduced pressure Column chromatography obtains the fluoro- 2- difluoro-methoxies nitrobenzene of 4- (34.3g, yield 52%).
The fluoro- 2- difluoro-methoxies nitrobenzene (31g) of 4- are dissolved in 600ml methanol, after nitrogen displacement, palladium carbon are added After (2.4g), hydrogen is replaced 2 times, and hydrogenation is stirred at room temperature, and TLC monitorings about 7h reactions are finished, filtered, filtrate It is concentrated under reduced pressure into dry the fluoro- 2- difluoro-methoxy-anilines (26.3g) of 4-.
At -10 DEG C, the fluoro- 2- difluoro-methoxy-anilines (26g) of 4- are dissolved in the 50ml concentrated sulfuric acids, nitric acid is added portionwise Potassium (20g), is finished completely, returns back to naturally and reaction is stirred at room temperature, and TLC monitorings about 2h reactions are finished, by body System is poured slowly into 1L saturation NaHCO3 frozen water, there is solid precipitation, suction filtration, and filtrate adds equivalent dichloromethane extraction Take 3 times, filter cake is filtered again after being dissolved in dichloromethane extract, anhydrous sodium sulfate drying, column chromatography after being concentrated under reduced pressure Obtain the fluoro- 5- nitroanilines of 2- difluoro-methoxies -4- (22.8g, yield 70%).
b.2- ((2- acrylamidos -5- (difluoro-methoxy) -4- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-bases Amido) phenyl) (methyl) amido) and ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 8) synthesis:
Method similar to Example 1,2- ((2- can be obtained using the fluoro- 5- nitroanilines of 2- difluoro-methoxies -4- as raw material Acrylamido -5- (difluoro-methoxy) -4- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base amido) benzene Base) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 8).MS(m/z):[M+H]+636.3。
Embodiment 9：N- (4- difluoro-methoxies) -2- (methyl (2- (methylamino) ethyl) amido) -5- (5- methyl -4- (1- Methyl-1H-indoles - 3- bases) pyrimidine -2-base amido)-phenyl) and acrylamide (compound 9) synthesis:
Method similar to Example 2, gained compound 8 in embodiment 8 is sloughed into Boc can obtain N- (4- bis- Fluorine methoxyl group) -2- (methyl (2- (methylamino) ethyl) amido) -5- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-bases Amido)-phenyl) acrylamide (compound 9).
1H-NMR(400MHz,DMSO-d6,δppm)：10.34(s,1H),10.11(s,1H),9.52(s,1H),8.55 (s, 2H), 8.36 (s, 1H), 8.20 (m, 1H), 7.56 (d, 1H, J=6.8Hz), 7.30 (m, 2H), 7.20 (s, 1H), 7.13 (m, 1H), 6.20 (d, 1H, J=16.8Hz), 5.70 (d, 1H, J=9.2Hz), 3.95 (s, 3H), 3.15 (m, 2H), 2.67(s,3H),2.55(m,5H),2.46(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：167.3,164.3,152.2,144.5,144.4,142.9, 139.6,137.5,132.8,130.9,127.1,124.1,123.9,123.0,119.7,117.1,114.5,112.7,111.9, 111.1,50.9,45.8,42.5,34.0,32.8,18.6；
ESI-MS(m/z):[M+H]+536.2
Embodiment 10：N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) -5- methylpyrimidine -2- bases amido) -2- ((2- (dimethylamino) Ethyl) (methyl) amido) -4- methoxyl groups-phenyl) and acrylamide (compound 10) synthesis:
Method similar to Example 3, is that raw material can obtain N- (5- (4- (1,2- with 1,2 dimethyl -1H- indoles Dimethyl -1H- indol-3-yls) -5- methylpyrimidine -2- bases amido) -2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- first Epoxide-phenyl) acrylamide (compound 10).
1H-NMR(400MHz,DMSO-d6,δppm)：10.05(s,1H),8.86(s,1H),8.36(s,1H),7.83(s, 1H), 7.47 (d, 1H, J=7.6Hz), 7.29 (m, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.95 (s, 1H), 6.37 (m, 1H), 6.22 (d, 1H, J=16.8Hz), 5.73 (d, 1H, J=8.8Hz), 3.83 (s, 3H), 3.73 (s, 3H), 2.84 (m, 2H), 2.67(s,3H),2.41(s,3H),2.27(m,2H),2.18(s,6H),2.05(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.2,159.5,159.1,146.8,138.4,137.6, 136.6,132.8,127.8,126.4,126.3,125.8,121.1,120.1,119.9,119.4,114.9,111.1,110.0,105.5, 57.3,56.4,45.6,42.9,30.0,15.9,11.7；
MS(m/z):[M+H]+528.3。
Embodiment 11：N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) -5- methylpyrimidine -2- bases amido) -2- ((2- (dimethylamino) Ethyl) (methyl) amido) -4- ethyoxyls-phenyl) and acrylamide (compound 11) synthesis:
Method similar to Example 4, is that raw material can obtain N- (5- (4- (1,2- diformazans with 1,2 dimethyl -1H- indoles Base -1H- indol-3-yls) -5- methylpyrimidine -2- bases amido) -2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls - Phenyl) acrylamide (compound 11).
1H-NMR(400MHz,DMSO-d6,δppm)：10.04(s,1H),8.92(s,1H),8.37(s,1H),7.76(s, 1H), 7.48 (d, 1H, J=7.6Hz), 7.28 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.94 (s, 1H), 6.34 (m, 1H), 6.21 (d, 1H, J=16.4Hz), 5.73 (d, 1H, J=8.8Hz), 4.08 (m, 2H), 3.74 (s, 3H), 2.83 (m, 2H), 2.66(s,3H),2.42(s,3H),2.25(m,2H),2.17(s,6H),2.05(s,3H),1.34(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.3,159.5,159.0,145.5,138.1,137.6, 136.6,132.8,128.0,126.4,126.2,121.1,120.1,119.3,114.3,111.1,110.0,106.6,64.7,57.3, 56.1,45.6,43.0,30.0,15.9,15.2,11.7；
MS(m/z):[M+H]+542.2。
Embodiment 12：N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) second Base) (methyl) amido) -4- methoxyl groups-phenyl) and acrylamide (compound 12) synthesis:
Method similar to Example 3, is that raw material can be obtained with 1,2 dimethyl -1H- indoles and 2,4- dichloro pyrimidine N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amine Base) -4- methoxyl groups-phenyl) acrylamide (compound 12).
1H-NMR(400MHz,DMSO-d6,δppm)：10.11 (s, 1H), 8.77 (s, 1H), 8.37 (d, 1H, J=7.2Hz), 8.04 (s, 1H), 7.98 (d, 1H, J=8.0Hz), 7.47 (d, 1H, J=8.0Hz), 7.15 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.99 (s, 1H), 6.36 (m, 1H), 6.20 (dd, 1H, J=16.4Hz, J=2.0Hz), 5.73 (m, 1H), 3.83 (s, 3H),3.71(s,3H),2.89(m,2H),2.71(s,3H),2.65(s,3H),2.30(m,2H),2.21(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.0,162.9,161.0,157.9,148.1,140.1,139.3, 137.0,132.8,127.8,126.5,126.2,125.4,121.7,120.9,120.1,116.8,110.6,110.5,110.1,105.7, 57.4,56.4,45.6,42.9,30.0,12.4；
MS(m/z):[M+H]+514.3
Embodiment 13：N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) second Base) (methyl) amido) -4- ethyoxyls-phenyl) and acrylamide (compound 13) synthesis:
Method similar to Example 4, is that raw material can be obtained with 1,2 dimethyl -1H- indoles and 2,4- dichloro pyrimidine N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amine Base) -4- ethyoxyls-phenyl) acrylamide (compound 13).
1H-NMR(400MHz,DMSO-d6,δppm)：10.10 (s, 1H), 8.81 (s, 1H), 8.38 (d, 1H, J=5.2Hz), 7.97 (m, 2H), 7.49 (d, 1H, J=8.0Hz), 7.15 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.99 (s, 1H), 6.37 (m, 1H), 6.20 (dd, 1H, J=16.4Hz, J=1.6Hz), 5.73 (m, 1H), 4.09 (m, 2H), 3.73 (s, 3H), 2.87(m,2H),2.70(s,3H),2.67(s,3H),2.30(m,2H),2.21(s,6H),1.31(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.9,160.9,157.9,146.8,140.2,139.0,137.0, 132.8,127.9,126.5,126.1,125.8,121.7,120.9,120.0,116.2,110.7,110.5,110.2,106.9,64.7, 57.3,56.1,45.6,30.0,15.2,12.4；
MS(m/z):[M+H]+528.3
Embodiment 14：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (fluoro- 1,2- dimethyl -1H- indoles -3- of 5- Base) -5- methylpyrimidine -2- bases amido) -4- methoxyl groups-phenyl) and acrylamide (compound 14) synthesis:
Method similar to Example 3, is that raw material can obtain N- (2- ((2- (two with fluoro- 1, the 2- dimethyl -1H- indoles of 5- Methylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1,2- dimethyl -1H- indol-3-yls of 5-) -5- methylpyrimidine -2- bases amido) - 4- methoxyl groups-phenyl) acrylamide (compound 14).
1H-NMR(400MHz,DMSO-d6,δppm)：10.05(s,1H),8.84(s,1H),8.36(s,1H),7.88(s, 2H), 7.50 (m, 1H), 6.95-7.04 (m, 3H), 6.34 (m, 1H), 6.20 (dd, 1H, J=16.8Hz, J=2.0Hz), 5.72(m,1H),3.84(s,3H),3.74(s,3H),2.85(m,2H),2.68(s,3H),2.41(s,3H),2.28(m, 2H),2.19(s,6H),2.05(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,161.7,159.7,159.2,159.1,156.8, 147.1,139.5,138.5,133.4,132.8,127.9,126.6,126.5,126.3,125.8,119.8,115.1,111.3, 111.1,111.0,109.1,108.9,105.6,104.3,104.1,57.4,56.4,45.6,42.9,30.2,15.8,12.0；
MS(m/z):[M+H]+546.3。
Embodiment 15：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (4- (fluoro- 1,2- dimethyl of 5- - 1H- indol-3-yls) pyrimidine -2-base amido)-phenyl) and acrylamide (compound 15) synthesis:
Method similar to Example 4, is that raw material can be with fluoro- 1, the 2- dimethyl -1H- indoles of 5- and 2,4- dichloro pyrimidine Obtain N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (4- (fluoro- 1,2- dimethyl -1H- indoles of 5- - 3- bases) pyrimidine -2-base amido)-phenyl) acrylamide (compound 15).
1H-NMR(400MHz,DMSO-d6,δppm)：10.07 (s, 1H), 8.77 (s, 1H), 8.37 (d, 1H, J=5.2 Hz),8.04(s,1H),7.75(m,1H),7.50(m,1H),6.95-7.02(m,3H),6.34(m,1H),6.16(m, 1H), 5.72 (d, 1H, J=9.6Hz), 4.08 (m, 2H), 3.74 (s, 3H), 2.86 (m, 2H), 2.70 (s, 3H), 2.67 (s, 3H),2.30(m,2H),2.20(s,6H),1.30(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.5,161.0,159.6,158.0,157.3, 177.2,141.8,139.1,133.7,132.8,128.0,126.6,126.5,126.4,125.8,116.4,111.2,111.1, 110.7,110.1,109.7,109.4,107.1,105.7,105.5,64.6,57.4,56.3,45.7,42.9,30.3,15.2, 12.7；
MS(m/z):[M+H]+546.2。
Embodiment 16：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- of 5- (2- methoxy ethyls) -1H- Yin Diindyl -3- bases) pyrimidine -2-base amido) -4- methoxyphenyls) and acrylamide (compound 16) synthesis:
a.The synthesis of the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indoles：
Raw material 5- fluoro indoles (5.0g, 1eq) are added in round-bottomed flask, 50ml DMF are added, system is placed in 0 and taken the photograph Family name's degree low temperature adds sodium hydride, and stirring instills chloroethyl methyl ether (5.2g, 1.5eq) after 20 minutes, drop finishes, and rises naturally Stirring reaction is warmed to room temperature, TLC is monitored to reaction and finished, system is poured into 400ml water, equivalent dichloromethane extraction Take 3 times, organic layer anhydrous sodium sulfate drying, product 6g, yield 82% are obtained after being concentrated under reduced pressure.
b.N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indol-3-yls) Pyrimidine -2-base amido) -4- methoxyphenyls) acrylamide (compound 16) synthesis：
Method similar to Example 3, with the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indoles and 2,4- dichloro pyrimidine for raw material N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indoles can be obtained - 3- bases) pyrimidine -2-base amido) -4- methoxyphenyls) acrylamide (compound 16).
1H-NMR(400MHz,DMSO-d6,δppm)：10.18(s,1H),8.95(s,1H),8.61(s,1H),8.30(d, 1H, J=5.2Hz), 8.10 (s, 1H), 8.03 (m, 1H), 7.60 (m, 1H), 7.19 (d, 1H, J=5.2Hz), 7.00-7.08(m,2H),6.37(m,1H),6.22(m,1H),5.74(m,1H),4.54(m,2H),3.84(s,3H), 3.72(m,2H),3.22(s,3H),2.89(m,2H),2.73(s,3H),2.33(m,2H),2.23(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.9,161.9,160.7,159.7,158.0,157.4,147.5, 138.6,134.9,134.3,132.8,128.2,126.4,126.2,125.6,115.2,113.2,112.3,112.0,110.6, 110.4,107.4,107.3,106.0,71.1,58.6,57.4,56.4,46.6,45.7,42.9；
MS(m/z):[M+H]+562.3。
Embodiment 17：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (4- (fluoro- 1,2- dimethyl of 5- - 1H- indol-3-yls) -5- methylpyrimidine -2- bases amido)-phenyl) and acrylamide (compound 17) synthesis:
Method similar to Example 4, is that raw material can obtain N- (2- ((2- (two with fluoro- 1, the 2- dimethyl -1H- indoles of 5- Methylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (4- (the fluoro- 1,2- dimethyl -1H- indol-3-yls of 5-) -5- methylpyrimidines - 2- bases amido)-phenyl) acrylamide (compound 17).
1H-NMR(400MHz,DMSO-d6,δppm)：10.04(s,1H),8.91(s,1H),8.38(s,1H),7.80 (s,1H),7.50(m,1H),6.95-7.03(m,3H),6.34(m,1H),6.19(m,1H),5.72(m,1H),4.09(m, 2H),3.75(s,3H),2.83(m,2H),2.66(s,3H),2.42(s,3H),2.27(m,2H),2.19(s,6H),2.05 (s,3H),1.34(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,161.7,159.7,159.1,159.0,156.8, 145.7,139.6,138.1,133.4,132.8,127.9,126.6,126.5,126.4,126.2,119.9,114.4,111.2, 111.1,109.1,108.9,106.7,104.3,104.0,64.7,57.3,45.6,42.9,30.3,15.8,15.2,12.0；
MS(m/z):[M+H]+560.4。
Embodiment 18：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (2- Methyl-1H-indole -3- bases) pyrimidines - 2- bases amido) phenyl) acrylamide (compound 18) synthesis:
Method similar to Example 3, is that raw material can be obtained with 2 dimethyl -1H- indoles and 2,4- dichloro pyrimidine N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (2- Methyl-1H-indole -3- bases) pyrimidine -2-bases Amido) phenyl) acrylamide (compound 18).
1H-NMR(400MHz,DMSO-d6,δppm)：11.56(s,1H),10.14(s,1H),8.75(s,1H),8.35(d, 1H, J=5.2Hz), 8.01-8.06 (s, 2H), 7.33 (d, 1H, J=8.0Hz), 7.01-7.09 (m, 4H), 6.38 (m, 1H), 6.20 (dd, 1H, J=16.8Hz, J=2.8Hz), 5.73 (m, 1H), 3.83 (s, 3H), 2.88 (m, 2H), 2.72 (s, 3H), 2.64(s,3H),2.29(m,2H),2.21(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.2,162.9,161.0,157.7,148.2,139.5,139.3, 135.6,132.8,127.9,127.1,126.5,125.5,121.6,120.7,120.6,117.0,111.3,110.1,119.7,105.8, 57.4,56.4,56.2,45.7,43.0,14.8；
MS(m/z):[M+H]+500.1
Embodiment 19：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (fluoro- 1,2- dimethyl -1H- indoles -3- of 5- Base) pyrimidine -2-base amido) -4- methoxyl groups-phenyl) and acrylamide (compound 19) synthesis:
Method similar to Example 3, with fluoro- 1, the 2- dimethyl -1H- indoles of 5- and 2,4 dichloro pyrimidines are that raw material can be with Obtain N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1,2- dimethyl -1H- indol-3-yls of 5-) pyrimidines - 2- bases amido) -4- methoxyl groups-phenyl) acrylamide (compound 19).
1H-NMR(400MHz,DMSO-d6,δppm)：10.12 (s, 1H), 8.68 (s, 1H), 8.35 (d, 1H, J=5.2 Hz),8.17(s,1H),7.75(m,1H),7.49(m,1H),6.97-7.01(m,3H),6.36(m,1H),6.16(m, 1H),5.72(m,1H),3.82(s,3H),3.73(s,3H),2.87(m,2H),2.72(s,3H),2.66(s,3H),2.30 (m,2H),2.20(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.5,161.2,159.6,158.0,157.2, 148.6,141.8,139.6,133.7,132.7,127.9,126.6,126.5,126.4,125.3,117.2,111.2,111.1, 110.7,110.0,109.7,109.4,105.9,105.8,105.5,57.4,56.3,45.7,42.8,30.3,12.8；
MS(m/z):[M+H]+532.2。
Embodiment 20：((4- (the fluoro- 1H- indol-3-yls of 1- ethyls -5-) is phonetic by 2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- by N- Pyridine -2- bases amido) -4- methoxyphenyls) acrylamide (compound 20) synthesis:
a.The synthesis of the fluoro- 1- ethyls -1H- indoles of 5-：
Raw material 5- fluoro indoles (5.0g, 1eq) are added in round-bottomed flask, 50ml DMF are added, system is placed in 0 and taken the photograph Family name's degree low temperature adds 60% sodium hydride (3.0g, 2eq), and stirring instills bromoethane (6.0g, 1.5eq) after 20 minutes, drop finishes, Warm naturally to that reaction is stirred at room temperature, TLC is monitored to reaction and finished, system is poured into 400ml water, equivalent dichloro Methane is extracted 3 times, organic layer anhydrous sodium sulfate drying, and product 5.5g, yield 91% are obtained after being concentrated under reduced pressure.
b.N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1H- indol-3-yls of 1- ethyls -5-) pyrimidine -2-bases Amido) -4- methoxyphenyls) acrylamide (compound 20) synthesis：
Method similar to Example 3, is that raw material can be obtained with the fluoro- 1- ethyls -1H- indoles of 5- and 2,4- dichloro pyrimidine N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indol-3-yls) pyrimidines - 2- bases amido) -4- methoxyphenyls) acrylamide (compound 20).
1H-NMR(400MHz,DMSO-d6,δppm)：10.14(s,1H),8.97(s,1H),8.67(s,1H),8.30(d, 1H, J=5.2Hz), 8.09 (s, 1H), 8.03 (m, 1H), 7.58 (m, 1H), 7.20 (d, 1H, J=5.2Hz), 7.07 (m, 1H), 7.04 (s, 1H), 6.47 (m, 1H), 6.23 (m, 1H), 5.75 (m, 1H), 4.32 (m, 2H), 3.84 (s, 3H), 2.93 (m, 2H),2.71(s,3H),2.40(m,2H),2.27(s,6H),1.42(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.0,161.9,160.7,159.7,158.0,157.4,147.3, 138.6,134.0,133.8,132.9,128.0,126.4,126.3,126.2,125.7,115.2,113.2,112.1,112.0,110.7, 110.4,107.5,107.3,105.9,57.0,56.4,45.4,43.0,15.8；
MS(m/z):[M+H]+532.3。
Embodiment 21：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (the fluoro- 1H- indol-3-yls of 5-) Pyrimidine -2-base amido)-phenyl) acrylamide (compound 21) synthesis:
Method similar to Example 5, can be obtained using the fluoro- 1H- indoles of 5- and the fluoro- 5- nitroanilines of 2- methoxyl groups -4- as raw material To N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (the fluoro- 1H- indol-3-yls of 5-) pyrimidine -2-base amido) - Phenyl) acrylamide (compound 21).
1H-NMR(400MHz,DMSO-d6,δppm)：11.88(s,1H),10.15(s,1H),8.86(s,1H),8.51(s, 1H),8.27(m,1H),8.16(s,1H),8.05(m,1H),7.43(m,1H),7.22(m,1H),7.10(m,1H),7.02(m, 2H), 6.37 (m, 1H), 6.24 (d, 1H, J=16.8Hz), 5.74 (d, 1H, J=9.2Hz), 3.82 (s, 3H), 2.89 (m, 2H), 2.73(s,3H),2.32(m,2H),2.22(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：162.8,162.6,161.0,159.5,157.6,157.2,148.0, 139.0,134.2,132.8,131.3,128.1,126.5,126.1,126.0,125.5,116.1,114.2,114.1,113.3,113.2, 110.7,110.5,107.6,107.4,107.2,106.0,57.4,56.4,56.3,45.7,42.8；
MS(m/z):[M+H]+504.2。
Embodiment 22：N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- ethyls -1H- indol-3-yls of 5-) -5- Methylpyrimidine -2- bases amido) -4- methoxyl groups-phenyl) acrylamide (compound 22) synthesis:
Method similar to Example 3, N- (2- ((2- (dimethylamine can be obtained by raw material of the fluoro- 1- ethyls -1H- indoles of 5- Base) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- ethyls -1H- indol-3-yls of 5-) -5- methylpyrimidine -2- bases amido) -4- methoxyl groups - phenyl) acrylamide (compound 22).
1H-NMR(400MHz,DMSO-d6,δppm)：10.10(s,1H),8.91(s,1H),8.67(s,1H),8.30(d, 1H, J=5.2Hz), 8.09 (s, 1H), 8.03 (m, 1H), 7.58 (m, 1H), 7.20 (d, 1H, J=5.2Hz), 7.07 (m, 1H), 7.04 (s, 1H), 6.47 (m, 1H), 6.23 (m, 1H), 5.75 (m, 1H), 4.32 (m, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.93(m,2H),2.71(s,3H),2.40(m,2H),2.27(s,6H),1.42(m,3H)；
MS(m/z):[M+H]+546.3。
Following compound can also be obtained by the similar synthetic method in above-described embodiment：
Biological experiment
1) cancer cell multiplication suppresses experiment：
Tests below can be used, and to determine part of compounds of the present invention, to people's squamous epidermal carcinoma A431, (EGFR-wt is high Expression), Non-small cell lung carcinoma NCI-H1975 (EGFR T790M mutation) and HCC827 Non-small cell lung carcinomas it is thin The inhibited proliferation of born of the same parents (EGFR E746-A750del).
A) the compounds of this invention is to EGFR-wt height expression A431 cell inhibitory effect function analysis
The compounds of this invention is determined to EGFR height expression people's squamous epidermal carcinoma A431 (being purchased from ATCC) Proliferation Ability and used SRB methods, SRB (Sulforhodamine B) is a kind of pink anionic dye, in acid condition can specifically with The basic amino acid of intracellular constitutive protein matter is combined, and produces absworption peak under 540nm wavelength, light absorption value and cell concentration into Linear positive correlation.
A431 cells are in the DMEM in high glucose culture medium containing 10% hyclone, 2mM glutamine and nonessential amino acid In, 37 DEG C, cultivate under conditions of 5%CO2, using trypsase/ethylenediamine tetra-acetic acid (EDTA) from Tissue Culture Flask Harvesting.Cell adds 96 porocyte culture plates with 3000/ hole (100 μ l culture mediums), in 37 DEG C, 5%CO2 cells Adhere-wall culture is stayed overnight in incubator, adds the fresh culture (100 μ l) of various concentrations testing compound, DMSO's is final Concentration is 0.2%, by Tissue Culture Plate in 37 DEG C, 5% CO2Under the conditions of incubate 72h, remove nutrient solution, then add TCA (i.e. trichloroacetic acid) solution (10%, w/v) of 4 DEG C of precoolings, stands in 5min 4 DEG C of refrigerators of immigration and fixes 1h, take Go out to use deionized water rinsing 5 times, room temperature is dried.After 96 orifice plates dry at room temperature, 0.4% (w/v) SRB is added per hole Dye liquor is outwelled after the μ L of dye liquor (1% peracetic acid formulation) 50, dyeing 30min, is rinsed 5 times with 1% (v/v) acetic acid, removal is not tied The dyestuff of conjunction, room temperature is dried.
The dyestuff combined with cell protein is dissolved with 100 μ L non-buffered Tris-base alkali lye (10mM, pH=10.5), level is shaken 20min is vibrated on bed, using absorbance value is determined at ELIASA 540nm, using GraphPad Prism4 analyze datas, Seek IC50, as a result as shown in table 1.
Table 1：The inhibitory action that the compounds of this invention is bred to A431 cells
Note：Positive control medicine：AZD-9291.
B) the compounds of this invention is analyzed drug-resistant cell strain NCI-H1975 inhibited proliferation
To drug-resistant cell strain NCI-H1975, (cell is the non-small cell lung cancer of EGFR T90M mutation to the compounds of this invention Cell, to the EGFR tyrosine kinase inhibitors such as Gefitinib, Tarceva, Lapatinib resistance) it is (thin purchased from Shanghai Born of the same parents institute) proliferation inhibition activity be measured using SRB methods.
NCI-H1975 is in the culture mediums of RPMI 1640 containing 10% hyclone, 2mM glutamine and nonessential amino acid In, 37 DEG C, 5%CO2Under conditions of cultivate, received using trypsase/ethylenediamine tetra-acetic acid (EDTA) from Tissue Culture Flask Obtain cell.Cell adds 96 porocyte culture plates with 5000/ hole (100 μ l culture mediums), in 37 DEG C, 5%CO2Cell culture Adhere-wall culture is stayed overnight in case, adds the fresh culture (100 μ l) of various concentrations testing compound, DMSO ultimate density For 0.25%, by Tissue Culture Plate in 37 DEG C, 5% CO2Under the conditions of incubate 72h, remove nutrient solution, then add 4 TCA (i.e. trichloroacetic acid) solution (10%, w/v) of DEG C precooling, stands 5min and moves into and 1h is fixed in 4 DEG C of refrigerators, take out and use Deionized water rinsing 5 times, room temperature is dried.After 96 orifice plates dry at room temperature, 0.4% (w/v) SRB dye liquors are added per hole Dye liquor is outwelled after (1% peracetic acid formulation) 50 μ L, dyeing 30min, is rinsed 4 times with 1% (v/v) acetic acid, removes what is be not associated with Dyestuff, room temperature is dried.
The dyestuff combined with cell protein is dissolved with 100 μ L non-buffered Tris-base alkali lye (10mM, pH=10.5), level is shaken 20min is vibrated on bed, using absorbance value is determined at ELIASA 540nm, using GraphPad Prism4 analyze datas, Seek IC50, as a result as shown in table 2.
Table 2：Inhibited proliferation of the compounds of this invention to NCI-H1975 cells
Tester IC50(nM) Selectivitya
Compound 2 5.852 65.91
Compound 3 2.368 89.15
Compound 4 3.151 208.0
Compound 5 3.359 21.24
Compound 6 3.027 3.218
Compound 7 2.911 89.25
Compound 9 4.472 47.27
Compound 10 65.544 ---
Compound 11 104.723 ---
Compound 12 2.134 194.9
Compound 13 5.046 80.9
Compound 14 37.921 ---
Compound 15 5.017 〉200
Compound 16 1.021 170.4
Compound 17 82.531 ---
Compound 18 1.743 64.8
Compound 19 2.217 〉454
Compound 20 2.031 171.4
Compound 21 1.538 0.1168
Compound 23 〉200 ---
Compound 26 〉200 ---
Compound 28 〉200 ---
Compound 41 102.5 ---
Compound 42 4.322 80
Compound 46 〉200 ---
Positive controlb 2.5 63.3
Note：A, Selectivity are compound to EGFR-wt height expression A431 cell inhibitory activities (IC50) with to EGFR-T790M be mutated it is resistance to Medicine NCI-H1975 cell inhibitory activities (IC50) ratio, the ratio represents the selectivity to EGFR-T790M medicament-resistant mutations, ratio Bigger, selectivity is better, for weaker to EGFR-wt kinase inhibitory activities under the equally effective dosage of medicament-resistant mutation, thus can reduce because EGFR-wt kinases crosses toxic side effect caused by high inhibition；B, positive control medicine：AZD-9291.
It can see from above-mentioned experimental result, the compounds of this invention is thin to EGFRT790M mutant drug-resistant cell lines H1975 The propagation of born of the same parents has stronger inhibitory activity, and it just can effectively suppress EGFR-T790M under nanomole (nmol/L) concentration The propagation of height expression H1975 cells, wherein compound 3,12,16,18,19,20,21 etc. is prominent to EGFRT790M The proliferation inhibition activity for becoming drug-resistant cell strain H1975 cells is better than control drug AZD-9291.The compounds of this invention pair EGFR-wt height expression A431 tumour cells also have certain inhibitory action, but activity is resistance to less than being mutated to EGFRT790M The inhibitory activity of medicine cell.In addition, most of the compounds of this invention for example compound 2,3,4,7,12,13,15,16, 18th, 19,20 etc. the selectivity higher than AZD-9291 is shown for EGFR-T790M resistances.
2) stability test of the part of compounds in different genera blood plasma
Selection drug effect and the preferable test-compound of selectivity enter in pedestrian, SD rats, Beagle dogs and nude mouse blood plasma Stability test：
Prepare the plasma containing drug solution that cumulative volume is 300 μ L, including the blank plasma that medium is 285 μ L, 15 μ L mark Quasi- product solution, final concentration is calculated as 100ng/mL with each compound.It is vortexed after mixing, divides the EP for taking 90 μ L to enter 0.5mL Pipe, 37 DEG C of incubation 1.0h.After reaction terminates, 400 μ L ice-cold acetonitrile terminating reactions are added.Take reaction terminating liquid, vortex 1 10min is centrifuged under min, 12000rpm；The μ L of supernatant 100 are taken, 200 μ L acetonitrile-waters (50/50, v/v), whirlpool are added Revolve and centrifuge 10min under 1min, 12000rpm, take the μ L sample introductions of supernatant 2.0 to analyze.Examined using LC/MS/MS methods The remaining content of medicine to be measured is surveyed, as a result such as table 3.
Table 3：Stability of the compounds of this invention in different genera blood plasma
Note：Positive control medicine：AZD-9291.
From above-mentioned experimental result it can be seen that, most compounds of the present invention for example compound 2,3,4,7,13,15,16, 18th, 20 etc. in human plasma stability be significantly better than AZD-9291, point out that more excellent drug effect may be had on human body.

Claims (9)

1. compound and its pharmaceutically acceptable salt shown in Formulas I：
Wherein, R1Selected from hydrogen, C1-4 alkyl, C1-4 alkoxies, the C1-4 alkyl of halo, the C1-4 alkoxies of halo, C1-4 heterocyclylalkoxy groups, halogen；It is preferred that hydrogen, methoxyl group, ethyoxyl, methyl, ethyl, isopropyl, difluoro-methoxy, Fluorine, chlorine, bromine；More preferably methoxyl group, ethyoxyl, difluoro-methoxy；
R2Selected from hydrogen, C1-3 alkyl, C1-3 alkoxies, C1-3 alkane sulfydryl, the C1-3 alkyl of halo, halogen, alkenyl, Cyano group, alkynyl, amide groups, sulfoamido, sulfamic；It is preferred that hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, Alkenyl, cyano group, alkynyl, fluorine, chlorine, bromine, more preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine；
R3Selected from alkyl, halogen ,-N (CH3)CH2R6、-N(CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2- N(CH3)2、-N(CH3)CH2CH2N(Boc)CH3、-N(CH3)CH2CH2CH2-N(CH3)2、-N(CH3)CH2CH2-N(C H2CH3)2、-N(CH3)CH2CH2-N(CH2CH3)CH3、-N(CH2CH3)CH2CH2-N(CH3)2；It is preferred that-N (CH3)C H2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2、-N(CH3)CH2CH2N(Boc)CH3；More preferably-N (CH3)C H2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CR4Or N；
Y is selected from CR5；
R4、R5、R6It is each independently selected from H, C1-3 alkyl, C1-3 alkoxies or C1-3 haloalkyls, halogen, cyanogen Base, carboxyl or amine acyl group；
R7Selected from hydrogen, C1-3 alkyl, C1-3 alkoxyl oxygen alkyl ethyls；
And if only if, and X is CH or N, and Y is selected from CH, C-Cl, C-F, C-CF3、C-CHF2、C-CH3、C- During CN, R2 is not hydrogen；
In the technical scheme of the present invention, R1Selected from hydrogen, methyl, ethyl, methoxyl group, ethyoxyl, isopropoxy, Difluoro-methoxy, trifluoromethoxy, fluorine, chlorine, bromine；More preferably methyl, ethyl, methoxyl group, ethyoxyl, difluoro first Epoxide, trifluoromethyl, most preferably methoxyl group, ethyoxyl；
R2Selected from hydrogen, C1-3 alkyl, C1-3 alkoxies, C1-3 alkane sulfydryl, halo C1-3 alkyl, halogen, sulphonyl Amido, amide groups, sulfonyl, alkenyl, cyano group, alkynyl；It is preferred that hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, Alkenyl, cyano group, alkynyl, fluorine, chlorine, bromine；More preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2、 -N(CH3)CH2CH2N(Boc)CH3；More preferably-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, C-CH3, N, preferably CH, C-CH3；
Y is selected from CH, C-Cl, C-F, C-CF3、C-CH3、C-CN、CCOOH、CCONH2；It is preferred that CH, C-CF3、 C-CH3、CCOOH、CCONH2；More preferably CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
When and if only if X is CH or during N, and Y is selected from CH, C-Cl, C-F, C-CF3、C-CH3, C-CN when, R2 is not hydrogen；
In another technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl, difluoro-methoxy, trifluoromethoxy, It is preferred that methoxyl group, ethyoxyl；
R2Selected from hydrogen, methyl, fluorine, chlorine；Most preferably hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3、C-CF3、C-CN、CCOOH、CCONH2；It is preferred that CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3、C-CF3, C-CN when, R2 be hydrogen；
In the preferred technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl；
R2Selected from hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3、CCOOH、CCONH2；It is preferred that CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3When, R2 is not hydrogen；
In another preferred technical scheme of the present invention, R1Selected from methoxyl group, ethyoxyl；
R2Selected from hydrogen, fluorine；
R3Selected from-N (CH3)CH2CH2-NH-CH3、-N(CH3)CH2CH2-N(CH3)2；
X is selected from CH, CCH3；
Y is selected from CH, C-CH3；
R7Selected from hydrogen, methyl, ethyl, methoxyethyl；
And if only if, and X is CH, and Y is selected from CH, C-CH3When, R2For fluorine.
2. compound according to claim 1 and its pharmaceutically acceptable salt, it is selected from following compounds：
Or its pharmaceutically acceptable salt, solvate.
Preferably, the compound shown in Formulas I described in claim 1 is selected from following compounds：
N- (5- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methylpyrimidine -2- bases amido) -4- methoxyl group -2- (methyl (2- (methylamino) ethyl) amido) phenyl) acrylamide (compound 2)
((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methyl is phonetic by 2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- by N- Pyridine -2- bases amido) -4- methoxyl groups-phenyl) acrylamide (compound 3)
((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) -5- methyl is phonetic by 2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- by N- Pyridine -2- bases amido) -4- ethyoxyls-phenyl) acrylamide (compound 4)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (5- methyl -4- (1- Methyl-1H-indole -3- bases) pyrimidines - 2- bases amido)-phenyl) acrylamide (compound 7)
N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amine Base) -4- methoxyl groups-phenyl) acrylamide (compound 12)
N- (5- (4- (1,2- dimethyl -1H- indol-3-yls) pyrimidine -2-base amido) -2- ((2- (dimethylamino) ethyl) (methyl) amine Base) -4- ethyoxyls-phenyl) acrylamide (compound 13)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- ethyoxyls -5- (4- (the fluoro- 1,2- dimethyl -1H- indol-3-yls of 5-) Pyrimidine -2-base amido)-phenyl) acrylamide (compound 15)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1- of 5- (2- methoxy ethyls) -1H- indol-3-yls) pyrimidines - 2- bases amido) -4- methoxyphenyls) acrylamide (compound 16)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (2- Methyl-1H-indole -3- bases) pyrimidine -2-base amine Base) phenyl) acrylamide (compound 18)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1,2- dimethyl -1H- indol-3-yls of 5-) pyrimidine -2-base amine Base) -4- methoxyl groups-phenyl) acrylamide (compound 19)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -5- (4- (the fluoro- 1H- indol-3-yls of 1- ethyls -5-) pyrimidine -2-base amido) - 4- methoxyphenyls) acrylamide (compound 20)
N- (2- ((2- (dimethylamino) ethyl) (methyl) amido) -4- methoxyl groups -5- (4- (the fluoro- 2- Methyl-1H-indoles -3- bases of 5-) pyrimidines - 2- bases amido)-phenyl) acrylamide (compound 42).
3. the preparation method of the compound of formula I and its pharmaceutically-acceptable salts described in a kind of any one of claim 1-2, the party Method comprises the following steps：
(1) in the presence of a lewis acid, as shown in Formula II compound and compound shown in formula III in higher boiling anhydrous solvent Reaction obtains intermediate compound IV：
(2) intermediate compound IV obtains intermediate VI with compound V under optimum conditions, and intermediate VI is under the effect of suitable alkali Reaction, then reduce to obtain intermediate VII through reducing agent：
(3) intermediate VII obtains compound of formula I with acryloyl chloride or acrylic anhydride reaction：
Or intermediate VII reacts with 3- chlorpromazine chlorides, then through eliminating to obtain compound of formula I：
And optionally,
(4) compound of formula I obtains compound of formula I pharmaceutically acceptable salt with corresponding acid reaction, or passes through alkali tune Obtain the base of corresponding Formulas I；
Wherein, R1-R3And R7, X, Y there is implication same as before.
4. preparation method according to claim 3, it is characterised in that in step (1), the higher boiling is without water-soluble Agent is selected from glycol dimethyl ether, dimethylbenzene；The lewis acid is selected from anhydrous AlCl3、FeCl3；The catalyst is Palladium catalyst, preferably tetrakis triphenylphosphine palladium；
In step (2), described suitable acid is selected from p-methyl benzenesulfonic acid, hydrochloric acid, hydrobromic acid, preferably p-methyl benzenesulfonic acid；Institute The suitable alkali stated is selected from organic base or inorganic base, preferably triethylamine, diisopropyl ethyl amine, sodium hydride, hydrofining and hydrogenation Calcium；The reducing agent is selected from SnCl2Concentrated hydrochloric acid, Zn powder acetic acid, Fe powder acetic acid, iron powder ammonium chloride, Pd-C catalytic hydrogenations； It is preferred that Pd-C catalytic hydrogenations, Fe powder ammonium chlorides.
5. a kind of pharmaceutical composition, its comprising the compound of formula I described in claim any one of 1-2 or its can pharmaceutically connect The salt received, and optional one or more pharmaceutically acceptable excipient.
6. the compound and its pharmaceutically acceptable salt described in claim any one of 1-2 are used to treat or/and pre- in preparation Purposes in the medicine of anti-mammal (including people) disease related to receptor tyrosine kinase or illness.
7. the pharmaceutical composition described in claim 5 is for treating or/and preventing mammal (including people) and receptor tyrosine Purposes in the medicine of the related disease of kinases or illness.
8. the purposes according to claim any one of the 6-7, " disease or disease related to receptor tyrosine kinase Disease " preferably " tumour mediated by receptor tyrosine kinase ", " propagation of the tumour cell driven by receptor tyrosine kinase and Migration " or " EGFR receptor tyrosine kinase susceptible neoplasms.
9. purposes according to claim 8, it is characterised in that " the EGFR receptor tyrosine kinases cancer susceptible " It is preferred that the tumour of the height expression of EGFR families and EGF drivings, include but is not limited to by EGFR L858R mutant and/or EGFR-T790M mutant and/or Exon19 missing activated mutant bodies and/or EGFR-delE746-A750 are mutant mediated Tumour or the resistance such as EGFR inhibitor such as Gefitinib (Gefitinib) or Erlotinib (Erlotinib) is swollen Knurl, specifically includes entity tumor, such as bile duct, bone, bladder, central nervous system (such as brain), breast, Colon and rectum, stomach, Head and neck, liver, lung (especially non-small cell lung cancer), neuron, esophagus, ovary, pancreas, prostate, kidney, skin Skin, testis, thyroid gland, the cancer of uterus (such as carcinoma of endometrium) and vulva, and non-solid tumors, such as leukaemia, Huppert's disease or lymthoma etc..
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