CN108250187A - Indoles -1- carbonats compounds, preparation method and application - Google Patents
Indoles -1- carbonats compounds, preparation method and application Download PDFInfo
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- CN108250187A CN108250187A CN201810172289.3A CN201810172289A CN108250187A CN 108250187 A CN108250187 A CN 108250187A CN 201810172289 A CN201810172289 A CN 201810172289A CN 108250187 A CN108250187 A CN 108250187A
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- 0 CC(Cc1nc(-c(c2ccccc22)c[n]2N)ccn1)C(C)c(c(OC)c1)cc(NC(C=C)=O)c1N(C)CCN(*)* Chemical compound CC(Cc1nc(-c(c2ccccc22)c[n]2N)ccn1)C(C)c(c(OC)c1)cc(NC(C=C)=O)c1N(C)CCN(*)* 0.000 description 1
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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
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Abstract
The invention belongs to pharmaceutical synthesis fields, more particularly to 1 carbonats compound of a kind of indoles, its pharmaceutically acceptable salt, deuterated compound or the solvate as shown in general formula (I), and preparation method thereof and the purposes in the drug being mutated for selective inhibitory activity EGFR resistant mutations T790M and activity is prepared.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of indoles -1- carbonats compounds and preparation method thereof,
And it is being prepared as the purposes in antitumor drug.
Background technology
EGF-R ELISA (Epidermal GrowthFactorReceptor, EGFR) is also known as ErbB1 or HER1,
The important member of ErbB receptor family, with endogenic ligand such as epidermal growth factor (Epidermal GrowthFactor,
EGF after) combining, homologous dimerization occurs or heterodimeric occurs with the other members of ErbB families (such as HER2, HER3, HER4), leads to
The phosphorylation of intracellular end key casein amino acid residue is crossed, activates downstream passages, the proliferation of regulating cell and existence.
Epidemiology finds that the overexpression of EGFR or excessive activation and the occurrence and development of many tumours have close pass
System, as EGFR overexpressions (Fujino, S. occur for the non-small cell lung cancer (NSCLC) of 40-80%；Enokibori,T.；
Tezuka,N.；Asada,Y.；Inoue,S.；Kato,H.；Mori,A.A comparison of epidermal growth
factor receptor levels and otherprognostic parameters in non-small cell
lungcancer.Eur.J.Cancer1996,32,2070–2074.)；There is 50% 3-5 times of generation EGFR gene in the carcinoma of the rectum
Expand (Cappuzzo, F.；Finocchiaro,G.；Rossi,E.；P.A.；Carnaghi,C.；Calandri,C.；
Bencardino,K.；Ligorio,C.；Ciardiello,F.；Pressiani,T.；et al.EGFR FISH assay
predicts for response to cetuximab in chemotherapy refractory colorectal
cancerpatients.Ann.Oncol.2008,19,717–723.)；Also have in spongiocyte cancer and head and neck cancer significant
Overexpression or activation phenomenon.So EGFR is important one of oncotherapy target.Lung cancer death is in malignant tumour
One killer, in China, lung cancer morbidity rate rises year by year, and annual neopathy number is up to 700,000, the ratio being mutated with EGFR activities
Example is up to 40-60%, i.e. China has the EGFR third generations inhibitor demand of bigger.Therefore, high activity, highly selective is developed
Have great importance with the third generation EGFR inhibitor of safety.
The drug of the listing of selectively targeting EGFR approvals at present has Gefitinib (Gefitinib), Tarceva
(Erlotinib), Afatinib (Afatinib), up to gram for Buddhist nun (Dacomitinib) and it is difficult to understand uncommon replace Buddhist nun (Osimertinib),
Wherein Gefitinib and Tarceva are first generation EGFR inhibitor, are Non-covalent binding inhibitor；Afatinib and
Dacomitinib is second generation EGFR covalent bond inhibitor；And difficult to understand wish dashes forward to EGFR resistant mutations T790M and activity for Buddhist nun
Becoming (L858R, delE746-A750 or Exon19 are lacked), activity is higher, and is significantly better than the work of EGFR wild types (EGFRWT)
Property, reduce the skin brought after a generation and two generation inhibitor strong inhibition EGFRWT and gastrointestinal toxicity, be that the third generation inhibits
Agent.Ao Xi achieves huge success for Buddhist nun in clinic, and objective remission rate 61%, and tumor control rate is up to after administration
91%.Its important metabolite AZ5104 activity more preferably (nearly 10 times of differences), to EGFRWT and mutation also have 10 times with
Upper notable selective difference, but itself has poor oral exposure.
Preferably to improve the druggability of third generation EGFR inhibitor and better therapeutic effect may be played in human body,
This patent design synthesis innovatively introduces carbonic ester knot on the basis of AZD9291 and related compound on the nitrogen of indoles
Structure, it is extremely rare in the research of drug (only THOMSON REUTERS CORTELLISTM retrieval only obtain 2 containing indoles-
The compound of 1- carbonic esters, for treating advanced melanoma, search time is in November, 2017).
Invention content
The purpose of the present invention is to provide a kind of indoles -1- carbonats compounds, its pharmaceutically acceptable salt, deuterated
Compound or solvate.
Prepare that the indoles -1- carbonats compounds, it can pharmaceutically connect it is a further object of the present invention to provide a kind of
The method of salt, deuterated compound or solvate received,
It is a further object of the present invention to provide it is a kind of comprising the indoles -1- carbonats compounds, it pharmaceutically may be used
The pharmaceutical composition of the salt of receiving, deuterated compound or solvate.
It is a further object of the present invention to provide the indoles -1- carbonats compounds, its pharmaceutically acceptable salt, deuteriums
For compound or solvate；Or contain indoles -1- carbonats compounds, its pharmaceutically acceptable salt, deuterated
Purposes of the composition of compound or solvate in antitumor drug is prepared.
First aspect present invention, provide a kind of indoles -1- carbonats compounds shown in logical formula (I), its pharmaceutically
Acceptable salt, deuterated compound or solvate,
Wherein,
R is selected from substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6It is cycloalkyl, substituted or unsubstituted
C6-C12Aryl, substituted or unsubstituted benzyl；The substituted substituent group is selected from halogen, nitro, cyano, C1-C6Alkyl, C1-
C6Acyloxy, C1-C6Alkoxy or C2-C6Alkenyl；
R ' is selected from C1-C6Alkyl or C1-C6Deuteroalkyl；Preferably methyl or deuterated methyl.
In a preferred embodiment of the present invention, the compound of the logical formula (I) is selected from general formula (I-A) institute
Indoles -1- carbonats compounds, its pharmaceutically acceptable salt, deuterated compound or the solvate shown,
Wherein, R is as defined above.
Preferably,
R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, methylbenzyl, acyloxybenzyl or alkene
Propyl；Further preferably methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, adjacent methylbenzyl, adjacent acetoxyl group
Benzyl or 2- pi-allyls；
R ' is methyl or deuterated methyl.
It is highly preferred that indoles -1- carbonats compounds shown in the formula (I), its deuterated compound, pharmaceutically may be used
The salt or solvate of receiving are selected from following formula: compound：
“C1-C6Alkyl " refers to the linear chain or branch chain saturated hydrocarbyl on chain with 1 to 6 carbon atom, includes without limitation
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary butyl etc..
“C1-C6Deuteroalkyl " refers to the C that one or more hydrogen atoms on alkyl are replaced by D-atom1-C6Alkyl.
“C1-C6Acyloxy " refers to direct-connected or branch alkyl acyloxy, has 1 to 6 carbon original in moieties
Son, for example, methyl acyloxy, ethyl acyloxy, n-propyl acyloxy, isopropyl acyloxy, normal-butyl acyloxy, isobutyl group acyl
Oxygroup or tertiary butyl acyloxy.
“C1-C6Direct-connected or branch the O- alkyl that alkoxy " refers to contains 1 to 6 carbon atom in moieties,
For example, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
“C3-C6Cycloalkyl " refers to that containing one or more saturations and/or fractional saturation ring, all ring member nitrogen atoms be carbon
The group of atom, including 3 to 6 carbon atoms；For example, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group etc..
“C6-C12Aryl " refers to comprising heteroatomic aromatic series ring group is free of in 6-12 annular atom but annular atom, preferably
For 6-10 members aryl (aryl that i.e. carbon atom number is 6~10), such as phenyl, naphthalene.
" halogen " refers to fluorine, chlorine, bromine and iodine.
Second aspect of the present invention provides the method for preparing -1- carbonats compounds of the indoles shown in general formula (Ι), institute
It states method to include the Formula II compound and acylting agent acylation reaction occurs, obtains logical formula (I) compound represented
Step, shown in following reaction formula：
Wherein, R, R ' define it is identical with the definition in logical formula (I)；
The acylting agent is selected from haloformate XCOOR, two carbonic estersOr carbonic esterWherein X is halogen；
Preferably, haloformate XCOOR is selected from chloro-formate or bromine formic acid esters.
In a preferred embodiment, the method packet of the indoles -1- carbonats compounds shown in the formula (Ι)
Include one of following methods：
Method 1：
Wherein, R, R ' define it is identical with the definition in logical formula (I)；
The Formula II compound under alkaline condition, compound shown in the logical formula (I) of acquisition is reacted with chloro-formate ClCOOR；
The alkali is selected from one or more of sodium hydride, potassium tert-butoxide, potassium carbonate, triethylamine, preferably sodium hydride；
It reacts solvent for use and is selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, dioxane, toluene
One or more of, preferably tetrahydrofuran；
The temperature of the reaction is 0-50 DEG C；
Method 2：
Wherein, R, R ' define it is identical with the definition in logical formula (I)；
The Formula II compound under alkaline condition, with two carbonic estersReaction obtains logical formula (I) institute
Show compound；
The one kind or several of the alkali in sodium hydride, potassium tert-butoxide, potassium carbonate, triethylamine, 4-dimethylaminopyridine
Kind, preferably triethylamine and dimethylamino naphthyridine,
It reacts solvent for use and is selected from tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetonitrile, dioxane, toluene
One or more of, preferably dichloromethane；
The temperature of the reaction is 0-40 DEG C；
Method 3：
Wherein, R, R ' define it is identical with the definition in logical formula (I)；
The Formula II compound and carbonic esterUnder conditions of ionic liquid is catalyst, reaction obtains
Logical formula (I) compound represented；
The ionic liquid is hydroxide 1- butyl -3- methylimidazoles [Bmim] OH or tetrabutylammonium hydroxide；
The temperature of the reaction is 0-90 DEG C.
In a preferred embodiment, the method for preparing the indoles -1- carbonats compounds shown in general formula (Ι)
Include the following steps：
The preparation of intermediate 3：Intermediate 1 reacts under alkaline condition with deuterated iodomethane or iodomethane obtains intermediate 2,
Again intermediate 3 is obtained through acid catalysis removing Boc protecting groups；
The alkali is selected from one or more of sodium hydride, potassium carbonate, triethylamine, preferably potassium carbonate or triethylamine；
The acid is selected from one or more of hydrochloric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid；
In a preferred embodiment, the method for preparing the indoles -1- carbonats compounds shown in general formula (Ι)
Include the following steps 1-5：
Wherein, R, R ' define it is identical with the definition in logical formula (I)；
Step 1：Intermediate 4 obtains intermediate 6 under acid catalysed conditions with intermediate 5 by nucleophilic displacement of fluorine；
The acid is selected from one or more of p-methyl benzenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid, preferably
P-methyl benzenesulfonic acid；
Reaction dissolvent is selected from 2- amylalcohols, the tert-butyl alcohol, Isosorbide-5-Nitrae-one or more of dioxane or tetrahydrofuran, preferably
2- amylalcohols；
Reaction temperature is selected from 80-150 DEG C；
Step 2：Intermediate 6 occurs nucleophilic displacement of fluorine with intermediate 3 and obtains intermediate 7 under alkaline condition；
The alkali is selected from one or more of triethylamine, diisopropylethylamine, potassium carbonate or sodium carbonate, and preferably two
Wopropyl ethyl amine；
The one kind of reaction dissolvent in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or N-Methyl pyrrolidone
Or several, preferably n,N-dimethylacetamide；
Reaction temperature is 80-180 DEG C；
Step 3：7 nitro obtains intermediate 8 by iron powder reducing or metal catalytic hydrogen reducing；
The iron powder reducing is selected from and is sent out in the presence of iron powder and acetic acid or in the presence of iron powder, ammonium chloride and ethyl alcohol
Raw reaction；
The reaction temperature of the iron powder reducing is 60-100 DEG C；
The metal of the metal catalytic hydrogen reducing is selected from Pd/C, Pd (OH)2, Raney's nickel (RaneyNi) or PtO2, preferably
For Pd/C；
The solvent of the metal catalytic hydrogen reducing in ethyl alcohol, ethyl acetate, tetrahydrofuran or dioxane one
Kind is several, preferably ethyl alcohol；
The reaction temperature of the metal catalytic hydrogen reducing is 20-60 DEG C；
Step 4：8 react acquisition intermediate 9 with acryloyl chloride in a solvent；
The solvent of the reaction in dichloromethane, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide one
Kind is several, preferably dichloromethane；
The temperature of the reaction is -10-50 DEG C；
Step 5：Intermediate 9 is reacted with acylting agent, obtains the indoles -1- carbonats compounds shown in formula (Ι),
The solvent of the reaction in dichloromethane, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide one
Kind is several, preferably dichloromethane；
The temperature of the reaction is -10-50 DEG C.
The present invention also provides a kind of pharmaceutical compositions for the third aspect, above-mentioned it includes being selected from the range of safe and effective amount
One or more works in indoles -1- carbonats compounds, its deuterated compound, pharmaceutically acceptable salt or solvate
Active constituent and pharmaceutically acceptable carrier.
Preferably, which still further comprises other pharmaceutically acceptable therapeutic agents, and particularly other are anti-
Tumour medicine.The therapeutic agent includes but not limited to：The drugs against tumor medicine such as cis-platinum of DNA chemical constitutions is acted on, influences core
The sour antitumor drug such as methotrexate (MTX) (MTX) synthesized, 5 FU 5 fluorouracil (5FU) etc. influence the antitumor drug of transcribed nucleic acid
Such as adriamycin, Epi-ADM, aclacinomycin, mithramycin act on the antitumor drug such as Japanese yew of tubulin synthesis
Alcohol, vinorelbine etc., arimedex such as aminoglutethimide, Lactel is grand, Letrozole, auspicious Ningde etc., cell-signaling pathways suppression
Preparation such as epidermal growth factor receptor inhibitor Imatinib (Imatinib), Gefitinib (Gefitinib), Erlotinib
(Erlotinib), Lapatinib (Lapatinib) etc..
" pharmaceutically acceptable salt " refers to the inorganic acid salt or acylate of relative nontoxic.Suitable inorganic acid includes salt
Acid, hydrobromic acid, sulfuric acid or phosphoric acid, suitable organic acid include trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, citric acid, Malaysia
Acid, fumaric acid, succinic acid or tartaric acid.
Indoles -1- carbonats compounds that fourth aspect is represented the present invention also provides logical formula (I), its deuterated chemical combination
Object, pharmaceutically acceptable salt or solvate are being prepared for selective inhibitory activity EGFR resistant mutations T790M and activation
Property mutation drug in purposes.
The selective inhibitory activity EGFR resistant mutations T790M and activity mutation include：Lung cancer, breast cancer, ovum
Nest cancer, liver cancer, melanoma, prostate cancer, colon and rectum carcinoma, spongiocyte cancer, head and neck cancer, gastric cancer etc.；It is provided by the invention
Logical formula (I) compound and its pharmaceutically acceptable salt, can be administered alone or with other pharmaceutically acceptable compounds
Administering drug combinations, administration route may be selected from taking orally, rectum, parenteral (intravenous, intramuscular or subcutaneous).
Advantageous effect
Logical formula (I) compound provided by the invention innovatively introduces structural carbonate on indole nitrogen in design, obtains
Compound show good activity and selectivity in cellular level, exposed amount in animal body is significantly better than difficult to understand uncommon replace
Buddhist nun has the characteristics that druggability is excellent.In short, this patent innovatively obtains the selective depression of the more brand new of druggability
Active EGFR resistant mutations T790M and the small molecule entity of activity mutation.
The preparation method of logical formula (I) compound provided by the invention, its remarkable advantage is obtained by commercially available
Raw material single step reaction obtain, easy to operate, reaction efficiency is high (part of compounds reaction only needs 10min).This kind of chemical combination simultaneously
The method that object can also use de novo formation carries out, and synthetic route has more preferably flexibility and wider array of applicability.
Description of the drawings
Fig. 1 is compound I-1 to the L858R/T790M EGFR being mutated and its downstream signal AKT and ERK phosphorylation level
It influences.
Specific embodiment
With reference to specific embodiment, the present invention is further explained.These embodiments are merely to illustrate the present invention, and do not have to
In the limitation present invention.Specific experimental method is not specified in specific embodiment, operates usually according to normal condition.
N- (5- ((4- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia
Base) -4- anisyls) raw materials such as acrylamide cross longitude and latitude Information technology (Beijing) Co., Ltd or reference literature purchased from medicine
(J.Med.Chem.2014,57,8249-8267) it prepares；
1H NMR are recorded by Varian Mercury-500 or Varian Mercury-400 types Nuclear Magnetic Resonance, chemical potential
Shifting is represented with δ (ppm)；Mass spectrum is by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECAandMicromass Ultra
Q-TOF (ESI) types mass spectrograph records；Solvent and reagent used is purchased from Sinopharm Chemical Reagent Co., Ltd. and Beijing hundred
Ling Wei Science and Technology Ltd.s.
Described below "1H-NMR(CDCl3, 400MHz) " it refers to measuring by solvent of deuterochloroform under the conditions of 400MHz
The nuclear magnetic resonance of proton, δ are chemical shift, unit ppm.
(1) compound prepares embodiment
Embodiment 1
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- methyl carbonates (I-1)
Synthetic method 1：
By N- (5- ((4- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- anisyls) acrylamide (i.e. AZ5104,3.0g, 6.18mmol) is dissolved in 200mL anhydrous tetrahydro furans, ice bath item
Slow sodium hydride (mineral oil wraps up, content 60%, 740mg, 18.53mmol) is added under part, is slowly dropped into after stirring 2min
The methylchloroformate (1.75g, 18.53mmol) of 50mL tetrahydrofurans is dissolved in, ice bath is removed, slowly falls reaction solution after 10min
Enter 200mL saturated ammonium chloride solutions, add in 200mL ethyl acetate extraction organic phase, saturated sodium-chloride washing, anhydrous sodium sulfate is done
It is dry, solvent is spin-dried for, column chromatography purifying can obtain 2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl)
Amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1H- indoles -1- methyl carbonates, 2.61g, yield 77.0%.
1H NMR(400MHz,CDCl3) δ 10.11 (s, 1H), 9.65 (s, 1H), 8.52 (d, J=5.2Hz, 1H), 8.46
(s, 1H), 8.32 (d, J=7.8Hz, 1H), 8.26 (d, J=8.1Hz, 1H), 7.62 (s, 1H), 7.36 (dt, J=20.0,
7.2Hz, 2H), 7.12 (d, J=5.2Hz, 1H), 6.80 (s, 1H), 6.41 (d, J=16.5Hz, 1H), 6.31 (dd, J=
16.9,10.0Hz, 1H), 5.67 (d, J=10.6Hz, 1H), 4.06 (s, 3H), 3.89 (s, 3H), 2.88 (t, J=5.4Hz,
2H),2.71(s,3H),2.31–2.28(m,2H),2.26(s,6H)。
LR-Mass(ESI)：544.3 (M+1, C29H34N7O4)。
Synthetic method 2：
By N- (5- ((4- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- anisyls) acrylamide (i.e. AZ5104,3.0g, 6.18mmol) is dissolved in 100mL anhydrous methylene chlorides, successively plus
Enter triethylamine (1.88g, 18.53mmol), 4-dimethylaminopyridine (0.15g, 1.24mmol) and two dimethyl carbonates (1.08g,
8.03mmol), 6h is reacted at room temperature, 100mL dichloromethane and the dilution of 100mL water, liquid separation, organic phase nothing are added in into reaction solution
Aqueous sodium persulfate is dried, and is spin-dried for solvent, and column chromatography purifying can obtain 2- (2- ((5- acrylamides -4- ((2- (dimethylamino)
Ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1H- indoles -1- methyl carbonates, 2.40g, yield
71.6%.Nuclear-magnetism and mass spectrum with it is as before.
Synthetic method 3：
By N- (5- ((4- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl)
Amino) -4- anisyls) acrylamide (i.e. AZ5104,3.0g, 6.18mmol) is dissolved in 30mL dimethyl carbonates, it adds in
[Bmim] OH (88mg, 0.618mmol) is heated to 90 DEG C of reaction 1h, it is molten that reaction solution is poured slowly into 200mL saturated ammonium chlorides
Liquid, adds in 200mL ethyl acetate extraction organic phase, saturated sodium-chloride washing, and anhydrous sodium sulfate drying is spin-dried for solvent, column chromatography
Purifying can obtain 2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxybenzenes
Base) amino) pyrimidine-4-yl) -1H- indoles -1- methyl carbonates, 2.12g, yield 63.2%.Nuclear-magnetism and mass spectrum with it is as before.
Embodiment 2
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- ethyl carbonates (I-2)
In addition to methylchloroformate is substituted for ethyl chloroformate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 9.64 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 8.42
(s, 1H), 8.38 (d, J=7.5Hz, 1H), 8.26 (d, J=8.1Hz, 1H), 7.64 (s, 1H), 7.37 (ddd, J=15.1,
14.0,6.7Hz, 2H), 7.14 (d, J=5.2Hz, 1H), 6.81 (s, 1H), 6.41 (d, J=2.8Hz, 2H), 5.72-5.64
(m, 1H), 4.53 (q, J=7.1Hz, 2H), 3.90 (s, 3H), 2.94-2.86 (m, 2H), 2.72 (s, 4H), 2.36 (s, 2H),
2.31 (s, 8H), 1.49 (d, J=7.1Hz, 3H).
LR-Mass(ESI)：558.8 (M+1, C30H36N7O4)。
Embodiment 3
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- propyl carbonates (I-3)
In addition to methylchloroformate is substituted for propyl chlorocarbonate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(500MHz,CDCl3) δ 9.91 (s, 1H), 9.50 (s, 1H), 8.73 (d, J=14.8Hz, 1H), 8.55
(dd, J=14.8,3.1Hz, 1H), 8.11 (dd, J=14.9,3.1Hz, 1H), 7.43-7.06 (m, 4H), 6.43 (s, 1H),
6.17 (ddd, J=26.6,24.4,12.2Hz, 2H), 5.69 (dd, J=33.3,4.6Hz, 1H), 4.69 (s, 1H), 4.21 (t,
J=14.7Hz, 2H), 3.86 (s, 3H), 3.53 (dt, J=21.9,14.6Hz, 2H), 2.75 (s, 3H), 2.50 (t, J=
14.6Hz, 2H), 2.21 (s, 6H), 1.91-1.49 (m, 2H), 1.01 (t, J=13.4Hz, 3H).
LR-Mass(ESI)：572.8 (M+1, C31H38N7O4)。
Embodiment 4
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- propylene carbonates (I-4)
In addition to methylchloroformate is substituted for isopropyl chlorocarbonate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(400MHz,DMSO-d6) δ 10.08 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.46 (d, J=
8.0Hz, 1H), 8.43-8.35 (m, 2H), 8.15 (d, J=8.3Hz, 1H), 7.43 (d, J=5.3Hz, 1H), 7.38 (t, J=
7.3Hz, 1H), 7.23 (t, J=7.4Hz, 1H), 7.04 (s, 1H), 6.45 (s, 1H), 6.19 (dd, J=16.9,1.9Hz,
1H),5.77–5.69(m,1H),5.29–5.15(m,1H),3.81(s,3H),2.95(s,2H),2.74(s,3H),2.40(s,
2H), 2.28 (s, 6H), 1.45 (d, J=6.2Hz, 6H).
LR-Mass(ESI)：572.8 (M+1, C31H38N7O4)。
Embodiment 5
2- (2- ((5- acrylamides -4- ((2- (deuterated dimethylamino) ethyl) (methyl) amino) -2- methoxybenzenes
Base) amino) pyrimidine-4-yl) -1H- indoles -1- methyl carbonates (I-5)
Step 1：
N- methyl-N- tertbutyloxycarbonyls ethylenediamines (1.74g, 10mmol) are dissolved in 50mL anhydrous methylene chlorides, ice bath item
Potassium carbonate (4.15g, 30mmol) and deuterated iodomethane (CD are sequentially added under part3I, 3.19g, 22mmol), 12h is reacted at room temperature,
Solvent is spin-dried for, column chromatography purifying can obtain N- methyl-N- tertbutyloxycarbonyls-N ', N '-two (deuterated methyl)-ethylenediamine,
1.5g, yield 72%.
1H NMR(500MHz,CDCl3) δ 3.38 (t, J=14.6Hz, 1H), 3.23 (s, 3H), 3.20-3.10 (m, 1H),
2.53 (t, J=14.6Hz, 2H), 1.42 (s, 9H).
LR-Mass(ESI)：209.3 (M+1, C10H17D6N2O2)。
N- methyl-N- tertbutyloxycarbonyls-N ', N '-two (deuterated methyl)-ethylenediamines (1.5g, 7.2mmol) are dissolved in 1M chlorine
Change the dioxane solution 30mL of hydrogen, react at room temperature 1h, be spin-dried for solvent and both obtain product N, N- bis- (deuterated methyl)-N '-methyl-second
The dihydrochloride 1.3g of diamines, yield 100%.
1H NMR(500MHz,CDCl3)δ3.25(s,3H),2.54–2.45(m,2H),2.45–2.33(m,2H)。
LR-Mass(ESI)：109.2 (M+1, C5H9D6N2)。
Step 2：
Intermediate 4 (23g, 100mmol) is dissolved in 500mL 2- amylalcohols, adds in p-methyl benzenesulfonic acid (1.72g, 10mmol),
105 DEG C of reaction 4h are heated, reaction solution is cooled down, there is yellow solid precipitation, filter, filter cake is washed with 50mL 2- amylalcohols, dry both to obtain
Intermediate 635g, yield 92%.
1H NMR(500MHz,CDCl3) δ 8.65-8.50 (m, 2H), 8.23-8.06 (m, 3H), 7.59 (dd, J=11.1,
7.0Hz, 1H), 7.33 (ddd, J=18.1,13.0,5.7Hz, 4H), 5.02 (s, 1H), 3.86 (s, 3H).
LR-Mass(ESI)：380.4 (M+1, C19H15N5O3)。
Intermediate 6 (19g, 50mmol) is dissolved in 200mL trifluoroethanols, sequentially add diisopropylethylamine (25.9g,
200mmol) and intermediate 3 (9g, 50mmol), back flow reaction 12h, is spin-dried for solvent, column chromatography purifying both intermediate 7 (15g,
Light yellow solid, 64%).
1H NMR(500MHz,CDCl3)δ8.65–8.44(m,2H),8.27–8.06(m,2H),7.94(s,1H),7.59
(dd, J=11.1,7.0Hz, 1H), 7.43-7.20 (m, 3H), 6.59 (s, 1H), 5.04 (s, 1H), 3.86 (s, 3H), 3.63
(t, J=14.6Hz, 1H), 3.49 (t, J=14.6Hz, 1H), 2.75 (s, 3H), 2.50 (t, J=14.5Hz, 2H).
LR-Mass(ESI)：468.4 (M+1, C24H22D6N7O3)。
Intermediate 7 (10g, 21.4mmol), iron powder (11.9g, 214mmol) and ammonium chloride (11.44g, 214mmol) is molten
In mixed solution (ethanol/water=3 of 200mL ethanol/waters:1, v/v), heating reflux reaction 4h, reaction solution add in 200mL acetic acid
Ethyl ester dilutes, and diatomite filtering, filtrate is spin-dried for, and column chromatography purifying both obtains intermediate 8 (8.3g, pale yellow viscous liquid, yield
88%).
1H NMR(500MHz,CDCl3) δ 8.64-8.46 (m, 2H), 8.14 (q, J=6.5Hz, 2H), 7.66-7.19 (m,
4H), 6.15 (d, J=20.1Hz, 2H), 5.01 (s, 1H), 3.84 (d, J=22.3Hz, 5H), 3.50 (dt, J=20.7,
14.6Hz, 2H), 2.75 (s, 3H), 2.50 (t, J=14.6Hz, 2H).
LR-Mass(ESI)：438.7(M+1,C24H24D6N7O)。
Intermediate 8 (4.4g, 10mmol) is dissolved in 100mL anhydrous methylene chlorides, is slowly dropped into and is dissolved under condition of ice bath
The acryloyl chloride (0.9g, 10mmol) of 50mL anhydrous methylene chlorides, ice bath reaction 2h, the sodium carbonate liquor for adding in 100mL 1M are quenched
Go out reaction, detach organic phase, anhydrous sodium sulfate drying is spin-dried for solvent, column chromatography purifying can obtain intermediate 9 (3.5g, it is pale yellow
Color solid, 71%).
1H NMR(500MHz,CDCl3)δ9.89(s,1H),8.73–8.51(m,2H),8.19–8.03(m,2H),7.59
(dd, J=11.1,7.0Hz, 1H), 7.41-7.24 (m, 3H), 7.12 (s, 1H), 6.49-6.18 (m, 2H), 6.05 (dd, J=
20.0,4.6Hz, 1H), 5.69 (dd, J=33.3,4.6Hz, 1H), 5.15 (s, 1H), 3.86 (s, 3H), 3.56 (dt, J=
28.9,14.7Hz, 2H), 2.75 (s, 3H), 2.50 (t, J=14.7Hz, 2H)
LR-Mass(ESI)：492.8(M+1,C27H26D6N7O2)。
Intermediate 9 and methylchloroformate can be obtained into embodiment 5 using the synthetic method 1 in embodiment 1.
1H NMR(500MHz,CDCl3) δ 9.90 (s, 1H), 9.46 (s, 1H), 8.68-8.38 (m, 2H), 8.10 (dd, J=
15.0,3.1Hz, 1H), 7.41-7.01 (m, 4H), 6.42 (s, 1H), 6.11 (ddd, J=26.4,24.9,12.5Hz, 2H),
5.68 (dd, J=32.8,4.9Hz, 1H), 4.98 (s, 1H), 3.86 (s, 3H), 3.74-3.48 (m, 5H), 2.75 (s, 3H),
2.50 (t, J=14.6Hz, 2H).
LR-Mass(ESI)：550.8(M+1,C29H28D6N7O4)。
Embodiment 6
2- (2- ((5- acrylamides -4- ((2- (deuterated dimethylamino) ethyl) (methyl) amino) -2- methoxybenzenes
Base) amino) pyrimidine-4-yl) -1H- indoles -1- ethyl carbonates (I-6)
In addition to methylchloroformate is changed into ethyl chloroformate, other synthetic routes are the same as embodiment 5.
1H NMR(500MHz,CDCl3) δ 9.83 (s, 1H), 8.80-8.59 (m, 2H), 8.51 (dd, J=14.8,3.1Hz,
1H), 8.07 (dd, J=14.9,3.1Hz, 1H), 7.42-7.01 (m, 4H), 6.40 (s, 1H), 6.10 (ddd, J=26.5,
24.9,12.5Hz, 2H), 5.66 (dd, J=32.9,4.9Hz, 1H), 4.98 (s, 1H), 4.19 (q, J=11.8Hz, 2H),
3.84 (s, 3H), 3.55 (dt, J=38.8,14.3Hz, 2H), 2.74 (s, 3H), 2.49 (t, J=14.1Hz, 2H), 1.26 (t,
J=11.8Hz, 3H).
LR-Mass(ESI)：564.8(M+1,C30H30D6N7O4)。
Embodiment 7
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- plutonium carbonates propyl ester (I-7)
In addition to methylchloroformate to be substituted for chloro-carbonic acid ring propyl ester, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(500MHz,CDCl3) δ 8.80-8.42 (m, 3H), 8.11 (dd, J=14.9,3.0Hz, 1H), 7.48-
7.06 (m, 4H), 6.49-6.24 (m, 2H), 6.05 (dd, J=20.0,4.4Hz, 1H), 5.69 (dd, J=33.3,4.4Hz,
1H), 4.92 (s, 1H), 4.20 (p, J=16.5Hz, 1H), 3.86 (s, 3H), 3.58 (dd, J=45.2,35.1Hz, 2H),
2.75 (s, 3H), 2.50 (t, J=10.1Hz, 2H), 2.21 (s, 6H), 0.93-0.54 (m, 2H), 0.39-0.20 (m, 2H).
LR-Mass(ESI)：570.7(M+1,C31H36N7O4)。
Embodiment 8
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- carbonic acid phenyl esters (I-8)
In addition to methylchloroformate is substituted for phenyl chloroformate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(400MHz,CDCl3) δ 9.97 (s, 1H), 9.63 (s, 1H), 8.60 (s, 1H), 8.53 (d, J=5.2Hz,
1H), 8.40-8.34 (m, 1H), 8.34-8.29 (m, 1H), 7.67 (s, 1H), 7.47 (ddd, J=5.5,2.9,1.3Hz, 2H),
7.40 (td, J=7.4,1.5Hz, 2H), 7.37-7.30 (m, 4H), 7.17 (d, J=5.2Hz, 1H), 6.79 (s, 1H), 6.42
(dd, J=16.5,9.3Hz, 1H), 6.32 (dd, J=16.9,1.9Hz, 1H), 5.58 (dd, J=9.8,2.0Hz, 1H), 3.89
(s,3H),3.00–2.89(m,2H),2.70(s,3H),2.45(s,2H),2.33(s,7H)。
LR-Mass(ESI)：606.7(M+1,C34H36N7O4)。
Embodiment 9
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- carbonic acid benzyl esters (I-9)
In addition to methylchloroformate is substituted for benzyl chloroformate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(400MHz,CDCl3) δ 10.08 (s, 1H), 9.63 (s, 1H), 8.54 (d, J=5.2Hz, 1H), 8.39
(dd, J=9.7,2.0Hz, 2H), 8.26 (d, J=8.0Hz, 1H), 7.64 (s, 1H), 7.57-7.50 (m, 2H), 7.48-7.33
(m, 5H), 7.12 (d, J=5.2Hz, 1H), 6.82 (s, 1H), 6.48-6.29 (m, 2H), 5.68 (dd, J=9.3,2.6Hz,
1H),5.51(s,2H),3.91(s,3H),2.95–2.89(m,2H),2.73(s,3H),2.36(s,2H),2.31(s,6H)。
LR-Mass(ESI)：620.7(M+1,C35H38N7O4)。
Embodiment 10
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- carbonic acid -2 '-methyl benzyl ester (I-10)
In addition to methylchloroformate to be substituted for chloro-carbonic acid neighbour's methyl benzyl ester, synthetic method is the same as the synthetic method in embodiment 1
1。
1H NMR(500MHz,CDCl3) δ 9.88 (s, 1H), 8.78-8.69 (m, 2H), 8.55 (dd, J=14.8,3.1Hz,
1H), 8.11 (dd, J=14.9,3.0Hz, 1H), 7.47-6.99 (m, 8H), 6.43 (s, 1H), 6.12 (dd, J=53.0,
19.0Hz, 2H), 5.69 (dd, J=33.0,4.9Hz, 1H), 5.13 (s, 2H), 4.92 (s, 1H), 3.86 (s, 3H), 3.55
(dt, J=25.1,14.6Hz, 2H), 2.75 (s, 3H), 2.50 (t, J=14.6Hz, 2H), 2.29 (s, 3H), 2.21 (s, 6H).
LR-Mass(ESI)：634.8(M+1,C36H40N7O4)。
Embodiment 11
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- carbonic acid -2 '-acetoxyl group benzyl ester (I-11)
In addition to methylchloroformate to be substituted for chloro-carbonic acid neighbour's acetoxyl group benzyl ester, synthetic method is the same as the synthesis in embodiment 1
Method 1.
1H NMR(500MHz,CDCl3) δ 9.81 (s, 1H), 9.10 (s, 1H), 8.80-8.37 (m, 2H), 8.11 (dd, J=
15.0,3.1Hz, 1H), 7.42-7.01 (m, 8H), 6.43 (s, 1H), 6.30-5.95 (m, 2H), 5.69 (dd, J=33.2,
4.8Hz, 1H), 5.13 (s, 2H), 4.94 (s, 1H), 3.86 (s, 3H), 3.53 (dt, J=16.1,14.5Hz, 2H), 2.75 (s,
3H),2.55–2.26(m,5H),2.21(s,6H)。
LR-Mass(ESI)：678.8(M+1,C37H40N7O6)。
Embodiment 12
2- (2- ((5- acrylamides -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) ammonia
Base) pyrimidine-4-yl) -1H- indoles -1- allyl carbonates (I-12)
In addition to methylchloroformate is substituted for allyl chlorocarbonate, synthetic method is the same as the synthetic method 1 in embodiment 1.
1H NMR(400MHz,CDCl3) δ 9.56 (s, 1H), 9.54-9.40 (m, 1H), 8.52 (d, J=5.2Hz, 1H),
8.42 (s, 1H), 8.38 (d, J=6.8Hz, 1H), 8.27 (d, J=8.3Hz, 1H), 7.63 (s, 1H), 7.46-7.35 (m,
2H), 7.15 (d, J=5.2Hz, 1H), 6.74 (s, 1H), 6.42 (dd, J=16.9,1.9Hz, 1H), 6.18-6.05 (m, 1H),
6.20-6.05 (m, 1H), 5.72 (d, J=12.0Hz, 1H), 5.51 (dd, J=17.1,1.3Hz, 1H), 5.40 (d, J=
10.3Hz, 1H), 4.98 (d, J=5.9Hz, 2H), 3.92 (s, 3H), 3.25 (s, 2H), 2.75 (s, 4H), 2.72 (s, 4H).
LR-Mass(ESI)：570.8(M+1,C31H36N7O4)。
(2) bioactivity detection embodiment
Test example one：Cellular level Inhibition test
Experimental method：
People epidermal carcinoma A431 cell strain and high expression EGFRT790M/L858R of the detection compound to high expression EGFR WT
The in-vitro multiplication inhibiting effect of the Non-small cell lung carcinoma NCI-H1975 cell strains of mutation.A431 cells and NCI-H1975 cells
Strain is purchased from Unite States Standard biology product collecting center (ATCC).Using sulphonyl rhodamine B (sulforhodamine B, SRB) methods into
Row detection, it is specific as follows：Certain amount is in the different tumor cell inoculations of exponential phase in 96 well culture plates, culture
After cell is adherent for 24 hours, the test-compound of the present invention of various concentration is added in, each concentration sets three wells, and sets corresponding dense
The DMSO solution control of degree and acellular zeroing hole.After treated with medicaments cell 72h, incline culture solution, adds in the precooling of 100 μ L ice
10% solution of trichloroacetic acid fix cell, 4 DEG C place 1h after be washed with distilled water 5 times, spontaneously dried in air.Then plus
Enter 100 μ L SRB (4mg/mL) (Sigma, St Louis, MO, USA) solution, dye 15min in room temperature, dyeing liquor is removed, with 1%
Glacial acetic acid washs 5 times, is air-dried.It is eventually adding the Tris solution (pH 10.5) of 150 μ L 10mM, wavelengthtunable declines orifice plate
Microplate reader (VERSAmaxTM, Molecular Device Corporation, Sunnyvale, CA, USA) and under 515nm wavelength
Measure OD values.Inhibiting rate of the drug to cell growth is calculated with following equation：Inhibiting rate (%)=(OD control-OD dosings)/OD
Control × 100%.
According to the growth inhibition effect of compound on intracellular, its half-inhibition concentration (IC is calculated50) value, it is shown in Table 1.
The analysis result of the growth inhibition effect of 1 compound on intracellular of table
Experiment conclusion：In parallel laboratory test, part indoles -1- carbonats compounds (cross longitude and latitude with AZD9291 purchased from medicine
Information technology (Beijing) Co., Ltd) there is comparable IC to the cell strain NCI-H1975 of EGFR saltant types50, while all embody
Go out good selectivity, there may be preferable safety in animal body.
Test example two：Influences of the I-1 and I-12 to EGFR and its downstream signal phosphorylation
Experimental method：
It is detected using routine immunization blotting (Western Blot).It is respectively that the A431 in exponential phase is thin
Born of the same parents and NCI-H1975 cells press certain amount kind after adhere-wall culture in 6 orifice plates, incubator is stayed overnight, and change serum-free medium famine
It starves for 24 hours, adds in certain density compound effects 2h, add in EGF stimulating factors 50ng/mL effect 10min, cracked with lysate
Cell receives sample.Then appropriate amount of sample is taken to carry out SDS-PAGE electrophoresis, with half-dried electrotransfer system by protein delivery after electrophoresis
To nitrocellulose filter, nitrocellulose filter is placed in confining liquid, and (5% skimmed milk power is diluted in the polysorbas20 containing 0.1wt.%
TBS room temperature closes 2h in), and film then is respectively placed in primary antibody solution (1：500 are diluted in the TBS of the polysorbas20 containing 0.1wt.%) in
4 DEG C of overnight incubations.It is washed three times with the triethanolamine buffered saline solution (TBS) of the polysorbas20 containing 0.1wt.%, each 15min.
By film be placed in two corresponding anti-solution (IgG of horseradish peroxidase-labeled goat-anti rabbit, 1：2000 are diluted in the polysorbas20 containing 0.1wt.%
TBS room temperature reaction 1h in).It is washed three times with the TBS of the polysorbas20 containing 0.1wt.%, after each 15min, is sent out with ECLplus reagents
Color, Image Quant LAS 4000 take pictures, and see Fig. 1.
Experiment conclusion：In parallel laboratory test, I-1 can significantly inhibit EGFR under 10nM and 100nM concentration conditions
The phosphorylation of the bis- mutation of L858R/T790M, while also there is significant suppression to the phosphorylation of the AKT and ERK of downstream signaling pathway
It makes and uses, overall effect is similar with AZD9291.
Test example three：Pharmacokinetics tests of the I-1 in beasle dog
Administering mode：Single oral gavage is administered.
Dosage：2 milligrams/5 ml/kgs.
Preparation prescription：Suspension is configured to 0.5%CMC-Na.
Experimental animal：Strain：Beasle dog；Gender：It is male；Weight：8-11Kg；Fasting 12h before experiment, free water.Administration
4h is unified afterwards feeds.
Sample collection：It 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and is taken for 24 hours through limb vein before administration and after administration
Blood 0.6mL.
Before blood specimen collection, the esterase inhibitor of the 1M of 20 μ L is added in the EDTA anticoagulant tubes of label in advance
(BNPP), 4 DEG C of refrigerator storages are placed in.During sample collection, the esterase inhibitor of 600 μ L whole bloods of acquisition to the 1M for having added in 20 μ L
In anticoagulant tube (BNPP), test tube is gently overturned to mixing as early as possible 5-6 times (it does not shake acutely, in order to avoid cause haemolysis) after, 1h
Within complete 4 DEG C of centrifugation 10min (3500rpm) and obtain blood plasma, preserved in -70 DEG C of refrigerators.(remarks：1M dinitrophenol phosphoric acid
The preparation method of diester (BNPP) solution：After the BNPP for weighing 1.36g, it is completely dissolved in the acetonitrile of 4mL：Water (1：1, v/v), i.e.,
.)
Plasma sample pre-processes：25.0 μ L inner mark solution (50.0ng/mL Verapamils are added in into 25.0 μ L plasma samples
Inner mark solution) and 150 μ L acetonitriles, 1min is vortexed, centrifugation 5min (14000rpm, 4 DEG C) takes supernatant to carry out LC-MS/MS points
Analysis.
Liquid phase-mass spectral analysis：
1. instrument
Liquid chromatographic system：WatersACQUITYI Class system, Waters companies
Autosampler WatersACQUITYFTN autosamplers, Waters companies
MS/MS systems：5500 type triple quadrupole bar tandem mass spectrometers of Triple Quad are equipped with electron spray ionisation source (ESI
Source), AppliedBiosystems companies, the U.S.
Data processing：Analyst 1.6.2 quantitative Treatments software (AppliedBiosystems companies, the U.S.)
2. chromatographic condition and Mass Spectrometry Conditions
Chromatographic condition
Analytical column：YMC-Triat C18Column, 2.0 × 50mm, 5.0 μM, Japanese YMC companies
Pre-column：C18Guard column, 4.0 × 3.0mm I.D., U.S.'s phenomenex company
Column temperature：40℃
Mobile phase：A phases：5mM ammonium acetate aqueous solutions (contain 0.1% formic acid)；B phases：Acetonitrile
Flow velocity：0.600mL/min
Sample size：2μL
Gradient elution：
Mass Spectrometry Conditions
Ion source be electron spray ionisation source (ESI sources), positive ion detection；Ion spray voltage 5500V；Ion source temperature
500℃；1 (N of ion source gas2)50psi；2 (N of ion source gas2)50psi；Curtain gas (N2)30psi。
Dynamic metabolism interpretation of result of 2 compound of table in beasle dog body
Experiment conclusion：Beasle dog pharmacokinetics test result shows that when 20mg is administered, I-1 is in the blood of beasle dog
Slurry exposed amount Cmax is 1.7 times of AZD9291, and AUC is 1.6 times of AZD9291, and half-life period 7h, medicine is shown in Table for Rational Parameters
2.It is more excellent compared to the druggability of AZD9291.
It is described according to the above, under the premise of basic fundamental thought of the present invention is not departed from, according to the common skill in this field
Art knowledge or customary means, to the embodiment of foregoing invention can also there are many modifications and replacement modified.
Claims (10)
1. indoles -1- carbonats compounds, its pharmaceutically acceptable salt, deuterated compound or solvent shown in logical formula (I)
Close object,
Wherein,
R is selected from substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C6-C12
Aryl, substituted or unsubstituted benzyl；The substituted substituent group is selected from halogen, nitro, cyano, C1-C6Alkyl, C1-C6Acyl-oxygen
Base, C1-C6Alkoxy or C2-C6Alkenyl；
R ' is selected from C1-C6Alkyl or C1-C6Deuteroalkyl.
2. indoles -1- carbonats compounds, its pharmaceutically acceptable salt shown in general formula (I) as described in claim 1,
Deuterated compound or solvate, wherein, R ' is methyl or deuterated methyl.
3. indoles -1- carbonats compounds, its pharmaceutically acceptable salt shown in general formula (I) as described in claim 1,
Deuterated compound or solvate, be the phthalazines ketones derivant represented by below formula (I-A), its geometric isomer and
Pharmaceutically acceptable salt,
R defines identical with the definition in claim 1.
4. indoles -1- carbonats compounds shown in general formula (I) as described in any one of claim 1-3, its pharmaceutically
Acceptable salt, deuterated compound or solvate, wherein,
R is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, methylbenzyl, acyloxybenzyl or allyl
Base；Further preferably methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, benzyl, adjacent methylbenzyl, adjacent acetoxyl group benzyl
Base or 2- pi-allyls；
R ' is methyl or deuterated methyl.
5. indoles -1- carbonats compounds, its pharmaceutically acceptable salt shown in general formula (I) as described in claim 1,
Deuterated compound or solvate, wherein, indoles -1- carbonats compounds shown in the general formula (I), it pharmaceutically may be used
Salt, deuterated compound or the solvate of receiving are in following compounds：
6. prepare the indoles -1- carbonats compounds shown in general formula (Ι), its pharmaceutically acceptable salt, deuterated compound or
The method of solvate, the method includes making the Formula II compound and acylting agent that acylation reaction occur to obtain general formula
It the step of (Ι) compound represented, is shown below：
Wherein, R, R ' define it is identical with the definition in claim 1；
The acylting agent is selected from haloformate XCOOR, two carbonic estersOr carbonic esterWherein X is halogen.
7. a kind of pharmaceutical composition is selected from Yin according to any one of claims 1 to 5 containing therapeutically effective amount
One or more conducts in diindyl -1- carbonats compounds, its deuterated compound, pharmaceutically acceptable salt or solvate
Active constituent and optional pharmaceutically acceptable carrier.
8. a kind of pharmaceutical composition is selected from Yin according to any one of claims 1 to 5 it includes therapeutically effective amount
One or more conducts in diindyl -1- carbonats compounds, its deuterated compound, pharmaceutically acceptable salt or solvate
Active constituent and other pharmaceutically acceptable therapeutic agents and optional pharmaceutically acceptable carrier.
9. indoles -1- carbonats compounds according to any one of claims 1 to 5, its deuterated compound, pharmaceutically
Acceptable salt or solvate or pharmaceutical composition according to claim 7 or 8 are being prepared for selective depression work
Property EGFR resistant mutations T790M and activity mutation drug in purposes.
10. purposes according to claim 9, wherein, the selective inhibitory activity EGFR resistant mutations T790M and swash
Activating mutations include lung cancer, breast cancer, oophoroma, liver cancer, melanoma, prostate cancer, colon and rectum carcinoma, spongiocyte cancer,
Head and neck cancer, gastric cancer.
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| US20090149467A1 (en) * | 2005-09-15 | 2009-06-11 | Merck & Co., Inc. | Tyrosine Kinase Inhibitors |
| CN104109161A (en) * | 2011-07-27 | 2014-10-22 | 阿斯利康(瑞典)有限公司 | 2 - (2, 4, 5 - substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN104761544A (en) * | 2014-01-03 | 2015-07-08 | 南京波尔泰药业科技有限公司 | Selectivity inhibitor of EGFR tyrosine kinase clinic important mutant |
| WO2017096095A1 (en) * | 2015-12-03 | 2017-06-08 | Shanghai Aeon Biotech Co., Ltd. | Thieno-pyrimidine derivatives and uses thereof |
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| CN111303123A (en) * | 2020-03-31 | 2020-06-19 | 南京雷正医药科技有限公司 | 2- (2,4, 5-substituted anilino) pyrimidine compound and application thereof |
| CN111303123B (en) * | 2020-03-31 | 2021-08-31 | 南京雷正医药科技有限公司 | 2- (2,4, 5-substituted anilino) pyrimidine compound and application thereof |
| WO2021244560A1 (en) * | 2020-06-03 | 2021-12-09 | InventisBio Co., Ltd. | Aminopyrimidine compounds, preparation methods and uses thereof |
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