CN110437149A - Natural naphthyl-isoquinolines compound of anti-tumor activity and combinations thereof, application - Google Patents
Natural naphthyl-isoquinolines compound of anti-tumor activity and combinations thereof, application Download PDFInfo
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- CN110437149A CN110437149A CN201910769844.5A CN201910769844A CN110437149A CN 110437149 A CN110437149 A CN 110437149A CN 201910769844 A CN201910769844 A CN 201910769844A CN 110437149 A CN110437149 A CN 110437149A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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Abstract
The invention belongs to biomedicine fields, are related to natural naphthyl-isoquinolines compound of anti-tumor activity and combinations thereof, application.Compound, by the 1 of general formula I, 3,8 and general formula II 5 connections, or by 1,3,6,8 and general formula II 7 connections of general formula I;The general formula I, general formula II structure be respectively as follows:
Description
Technical field
The present invention relates to natural naphthyl-isoquinolines compounds of anti-tumor activity and combinations thereof, application, belong to biology
Pharmaceutical technology field.
Background technique
Protein tyrosine kinase (protein tyrosine kinase, PTKs) is logical by the signal transduction of control cell
Road adjusts a series of physiological and biochemical procedures such as growth, differentiation, the apoptosis of cell.Receptor type tyrosine kinase is one kind across cell
The relatively large kinases of film, extracellular domain, transmembrane domain and zymogenesis-with ligand binding are in phosphorylation
Specific tyrosine residue and the intracellular domain for thus influencing cell Proliferation.(such as lung cancer, mammary gland in general human cancer
Cancer, gastric cancer, oophoroma, lymthoma) it has been found that the kinases unconventionality expression.Protein tyrosine kinase has become anti-tumor drug
One of the important target spot of research and development.
Epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine
Kinase, EGFR) it is one of the protein tyrosine kinase found earliest, the intracellular region of EGFR has ATP-binding site, and EGFR inhibits
Agent competitive can be combined with ATP-binding site, to inhibit the Phosphorylation events of EGFR, block the conduction of downstream signal,
And then inhibit growth, differentiation and the transfer of tumour cell.Presently found EGFR tyrosine kinase (EGFR-TK) can be catalyzed
The energy-rich phosphate bond of ATP is transferred to several tyrosine sites of EGFR, makes its phosphorylation, thus activate the PI3K/Akt in downstream,
The signal paths such as Ras/MAPK promote proliferation, the metabolism of cell, inhibit Apoptosis.EGFR overexpression and mutation in cell
When, meeting block cell programmed cell death keeps the growth regulating of cell out of control, and obtains infinite multiplication and invasive ability, that is, develops into
For malignant cell.EGFR-TKI is prevented by competing the binding site of tyrosine kinase intracellular with ATP by internal tyrosine
Autophosphorylation, inhibit EGFR tyrosine kinase activation, thus inhibit growth of tumour cell, accelerate apoptosis of tumor cells, suppression
Angiogenesis and tumor cell invasion processed, transfer.Small molecule EGFR-TKI's is divided into: 1) invertibity TKI mainly has: Ji Fei is replaced
Buddhist nun (gefitinib), Tarceva (erlotinib), Lapatinib (lapatinib);2) irreversibility TKI mainly has: Ah
Method replaces Buddhist nun (afatinib), and Buddhist nun (dacomitinib) can be replaced by reaching.Currently, invertibity and irreversibility EGFR-TKI are to mutation
There is significant curative effect in the EGFR non-small cell lung cancer short time, but finally treatment is caused to be lost because generating acquired resistance
It loses, is not obviously prolonged the life cycle of patient.Therefore, developing and develop has the novel of stronger, more longlasting anti-tumor activity
EGFR-TKI will likely bring life for mutation EGFR Patients with Non-small-cell Lung.
Contain numerous unique structures, the significant compound of EGFR-TKI effect in Chinese medicine or natural drug, such as from snakegourd
Belong to Cucurbitacin B obtained in the medicinal materials such as Chinese medicine snakegourd, Oridonin, turmeric obtained in a variety of medicinal plants of Rabdosia
Curcumin obtained in Traditional Chinese medicine Rhizoma curcumae, turmeric etc. is the active area of modern medicine study.Natural EGFR-TKI is not only medicine
The discovery of object is laid a good foundation, and the synthesis that more synthetic organic chemist carries out class natural products is provided beyond mankind's imagination
Excellent template.
Summary of the invention
An object of the present invention is to provide a kind of naphthyl-isoquinolines compound, such compound has good anti-swollen
Tumor activity.
It is a further object of the present invention to provide naphthyl-isoquinolines compounds to promote the application in apoptosis of tumor cells,
Mechanism is as epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TKI).
Another object of the present invention is to provide the derivative and its optical isomer of the naphthyl-isoquinolines compound, and
The purposes of its composition.
Thus, on the one hand, the present invention provides a kind of compound by 1,3,8 and general formula II 5 connections of general formula I, or
Person is by 1,3,6,8 and general formula II of general formula I 7 connection;
The general formula I, general formula II structure be respectively as follows:
General formula I
General formula II
Wherein: R1、R2、R3、R4Selected from hydroxyl or methoxyl group;Isoquinoline structure be selected from tetrahydroisoquinoline, dihydro-isoquinoline or
Isoquinolin.
Further, the structure of the compound is as follows:
As a kind of specific embodiment of the invention, the preferably following derivative of the present invention and its optical isomer, but this
A little compounds are not meant to any limitation of the invention, and the compound has structural formula shown in I-1~I-12:
Structural compounds as shown above are naphthyl-isoquinolines compound.Antitumor activity screening of the invention shows, this
Class compound has stronger inhibition non-small cell lung cancer (NSCLC) ability of cell proliferation.As special natural of a class formation
Small molecule, the present invention in compound have exploitation at new and effective EGFR inhibitor potentiality, to treatment-related tumour disease
Sick especially non-small cell lung cancer, Small Cell Lung Cancer has biggish application value.
Structure shown in aforementioned I-1~I-12 is respectively provided with following title:
(I-1) (1R, 3S, 5S)-5- (4- hydroxy-5-methyl oxygroup-2- methyl-1-naphthalene)-1,2,3,4- tetrahydro-8- methoxy
Base -1,2,3- trimethyl -6- isoquinolinol;
(I-2) (1S, 3S, 5R)-5- (4,5- dimethoxy-2- methyl-1-naphthalene)-1,2,3,4- tetrahydro-6- methoxyl group-
1,3- dimethyl -8- isoquinolinol;
(I-3) (3S, 5S)-3,4- dihydro-5- (4- hydroxy-5-methyl oxygroup-2- methyl-1-naphthalene)-8- methoxyl group-1,3-
Dimethyl -6- isoquinolinol;
(I-4) 5- (4,5- dimethoxy-2- methyl-1-naphthalene)-1,2,3,4- tetrahydro-8- methoxyl group-1,2,3- front three
Base -6- isoquinolinol;
(I-5) (3S, 5R)-5- (5- hydroxyl-4- methoxyl group-2- methyl-1-naphthalene)-3,4- dihydro-8- methoxyl group-1,3-
Dimethyl -6- isoquinolinol;
(I-6) (2S, 5S)-5- (4,5- dimethoxy-2- methyl-1-naphthalene) dimethoxy-1-3,4- dihydro-6,8-,
3- dimethylisoquinoline;
(I-7) 8- methoxyl group -3- methyl -2- [(1R, 3S) -1,2,3,4- tetrahydro -6,8- dimethoxy -1,2,3- front three
Base -5- isoquinolyl] -1- hydroxyl naphthalene;
(I-8) 5- [(3S) -3,4- dihydro -6,8- dimethoxy -1,3- dimethyl -5- isoquinolyl] -4,5- dimethoxy
Base -2,7- dimethyl -1- naphthalene;
(I-9) (1S, 3S, 7S)-1,2,3,4- tetrahydro-8- methoxyl group-7- (4,5- dimethoxy-2- methyl-1-naphthalene)-
1,3- dimethyl -6- hydroxy-isoquinolin;
(I-10) 8- methoxyl group -3- methyl -2- [(1R, 3S) -1,2,3,4- tetrahydro -6,8- dimethoxy -1,2,3- front three
Base -7- isoquinolyl] -1- hydroxyl naphthalene;
(I-11) 7- (1- hydroxyl-6- methyl-8- methoxyl group-2- naphthalene) dimethoxy-1-1,2,3,4- tetrahydro-6,8-,
2,3- trimethyl-isoquinolin;
(I-12) 7- (4,5- dimethoxy-7- methyl-1-naphthalene)-1,2,3,4- tetrahydro-6,8- dimethoxy-1,2,3-
Trimethyl-isoquinolin.
On the other hand, the present invention provides a kind of pharmaceutical composition, shown in the general formula I of the present invention containing effective dose
Compound derivative, optical isomer and pharmaceutical carrier.
Pharmaceutical composition of the invention is not limited to containing a kind of the compounds of this invention, can contain have more than it is one or more
The compound of the present invention.In addition, pharmaceutical composition of the invention can also optionally include one or more other pharmaceutical active chemical combination
Object.
It has been found that the compounds of this invention has anti-EGFR in vitroWTHighly expressed A549 cell, EGFRT790MHigh table
The proliferation activity of the HCC827 cell of the H1975 cell, EGFR sensitizing mutation that reach, it may be used as preparation treatment and/or prevention
The drug of non-small cell lung cancer.
By in vitro to EGFRWTAnd EGFRT790MThe test experiments of kinase inhibiting activity, the compounds of this invention have significant
Inhibition EGFR kinase activity, to the highly expressed non-small cell lung cancer cell of EGFR have stronger inhibiting effect, it is especially useful in
The drug of preparation treatment and/or prevention non-small cell lung cancer.
The invention has the advantages that: the present invention provides a kind of novel molecular targeted EGFR-TKI, i.e. natural small molecule
Application of the object naphthalene morphinane alkaloid in non-small cell lung cancer is closed, new E GFR-TKI can be developed into, is had extensive
Application prospect.
Specific embodiment
Further description of the technical solution of the present invention combined with specific embodiments below, but the present invention is not with any shape
Formula is limited to embodiment content.
Test method described in the embodiment of the present invention is conventional method unless otherwise specified, or according to raw material or commodity
Condition proposed by manufacturer;Unless otherwise specified, the reagent and biomaterial, commercially obtain.
The preparation of 1 naphthalene isoquinoline compound molecule of embodiment
(1) alcohol extracting step: hook branch rattan (Ancistrocladus tectorius) branches and leaves after taking fresh dried crush,
It is extracted 3 times, each 0.5h with 10 times of 95% ethanol solutions of amount, extracting solution is concentrated under reduced pressure at 50 DEG C or less, medicinal extract is made, recycles
Hook branch rattan branches and leaves alcohol extract is made in etoh solvent;
(2) extraction step: the water of 0.3 times of weight of addition in the medicinal extract of hook branch rattan branches and leaves alcohol extract, dispersing and dissolving, then
It is successively extracted 2 times respectively with hexamethylene and methylene chloride extraction, obtains hexamethylene extraction position and methylene chloride extraction position;
(3) Diol primary colours compose column chromatography steps: taking methylene chloride to extract position, be loaded on the Diol primary colours of its 30 times of weight
It composes on chromatographic column, successively with hexamethylene/methylene chloride (9:1) of 3 times of column volumes, dichloromethane/ethyl acetate (20:1), acetic acid
Ethyl ester, ethyl acetate/methanol (5:1) and methanol elution gradient, are prepared each separated part.Collect methylene chloride/acetic acid
Ethyl ester (20:1) elutes position, and naphthalene isoquinoline compound is carried out after concentrate drying isolates and purifies preparation.
(4) ODS and preparative HPLC purify naphthalene isoquinoline compound molecule: by methylene chloride/second after concentrate drying
Acetoacetic ester (20:1) eluate, upper ODS column chromatography, 70% methanol, 80% methanol, 90% methanol and methanol elution gradient, TLC inspection
Know, improvement bismuth potassium iodide colour developing, merges the flow point of identical colour developing spot, obtain flow point 1~14 after concentration and recovery solvent.It takes above-mentioned
Flow point, using C18 preparative HPLC chromatographic column, with 70% methanol-water~100% methanol, 80% acetonitrile water~100% acetonitrile and
Its gradient elution mode (containing 0.5% trifluoroacetic acid) is mobile phase, gradually purifying be prepared naphthalene isoquinoline compound I-1~
I-12。
(5) identification of naphthalene isoquinoline compound: by above-mentioned isolated monomeric compound, it is tested respectively1H-
NMR、13C-NMR and MS, and obtained data are compareed with document, it is identified respectively as N-methylancistectorine A1
(I-1)、5-epi-ancistectorine A2(I-2)、ancistectorine A3(I-3)、(+)-ancistrocline(I-
4)、5′-O-demethylhamatinine(I-5)、ancistrocladinine(I-6)、ancistrotectorine C(I-
7)、ancistrotanzanine B(I-8)、ancistectorine B1(I-9)、ancistrotectorine(I-10)、
ancistrotectoriline C(I-11)、ancistrocyclinone B(I-12)。
The preparation of 2 naphthalene isoquinolin pharmaceutical composition of embodiment
Above-mentioned two target molecule of equimolar amounts (1mmol) (5mL) in anhydrous methanol is taken, is stirred at room temperature 10 minutes,
Solvent is evaporated off to get the mixture of target molecule in room temperature.(I-1)-(I -2), (I-3)-(I-8), (I- are prepared for by this method
7)-mixture of (I-10) three.
3 naphthalene isoquinoline compound antiproliferation of embodiment
Using mtt assay, naphthalene isoquinolin monomeric compound anti-cell proliferation of NSCLC activity in vitro is measured.It selects
EGFRWTHighly expressed A549 cell, EGFRT790MThe HCC827 cell progress of highly expressed H1975 cell, EGFR sensitizing mutation
Proliferation inhibition activity test.Using PBS as blank control when measurement, Gefitinib, Luo Le are positive control for Buddhist nun.
(1) cell culture: Non-small cell lung carcinoma cell strain (A549, H1975, HCC827) with containing 10% fetal calf serum and
1% dual anti-1640 culture medium of RPMI, in 37 DEG C, 5%CO2Incubator in cultivate.
(2) cell inoculation: taking in exponential phase of growth, cell in good condition, collects cell centrifugation, abandons supernatant.With containing
RPMI 1640 (or DMEM) culture solution of 10% fetal calf serum is made into cell suspension, then counts.Take cell suspension inoculation in 96
On orifice plate, 100 holes μ L/ (every hole contains 7000 tumour cells).Culture plate is transferred to constant temperature CO2In incubator, in 37 DEG C, 5%
CO2And it is cultivated for 24 hours under the conditions of saturated humidity.
(3) it is administered: untested compound being configured to 4mmol/L mother liquor with DMSO in advance and is stored in 4 DEG C of refrigerators.Before administration,
Mother liquor is taken to preheat in thermostat water bath, be then diluted to 40 with the culture medium (RPMI 1640 or DMEM) for not containing serum,
20,10,5,2.5 μm of ol/L solution are used for primary dcreening operation.Culture solution in above-mentioned adherent inoculating cell is toppled over and is thrown away, is separately added into
The untested compound of 100 μ L various concentrations, every group sets 3 multiple holes, remaining blank well is supplied with PBS.Negative control is isometric
Culture medium, while the DMSO Vehicle controls of respective concentration are set, blank control is free of cell and drug.Jointly in 37 DEG C, 5%CO2
Incubator in cultivate 72h.
(4) colour generation: 10 μ L MTT solution (5mg/mL) are added in administration cell every hole after cultivating 72h, are placed in incubator
After being incubated for 4 hours, 100 μ L, tri- liquid is added in every hole, is placed in incubator overnight.
(5) colorimetric: measuring each hole shading value (OD value) on enzyme-linked immunosorbent assay instrument, wavelength 570nm is selected, with cell-free
I.e. blank culture solution blank well zeroing, survey the absorbance value in each hole.Experiment is repeated 3 times.
Test result is as shown in table 1.
Antiproliferative activity (IC of the 1 naphthyl-isoquinolines compound of table to non-small cell lung cancer cell50,μmol)
4 naphthalene isoquinoline compound of embodiment is to EGFRWTAnd EGFRT790MThe inhibitory activity of kinases
The test of kinase inhibiting activity uses ADP-GloTMKinase reagent box.The kit test when in two steps:
Firstly, a and isometric ADP-Glo of kinase reaction system is added thereto after kinase reactionTMReagent makes reaction eventually
Only, and remaining ATP is run out of.In second step, kinase assay reagent is added, it is while making ADP be converted to ATP, also
Newly synthesized ATP is detected using the luciferase of coupling/luciferin reaction.
(1) it prepares kinase assay buffer: melting kinase assay buffer in room temperature, seen whether precipitating.If gone out
It now precipitates, be just incubated for 15 minutes at 37 DEG C and often shake, dissolution precipitating.Or supernatant is carefully absorbed, removal precipitating.
(2) kinase assay reagent is prepared: using preceding in equilibrium at room temperature kinase assay buffer and kinase assay substrate.It will swash
Enzyme detection buffer is all poured into the brown bottle equipped with kinase assay substrate, is dissolved freeze-dried powder substrate, is thus made
Kinase assay reagent.It gently shakes or is vortexed and mix, become homogeneous solution, substrate should dissolve in 1 minute.Kinase assay reagent
It should be used immediately after preparing, or packing is stored in -20 DEG C.
(3) production ATP is converted to the standard curve of ADP
A. 900 μ L 50 μm of ol/L ATP and 500 μ L are respectively prepared in Ultra the Pure ATP and ADP kit provided
50μmol/L ADP。
B. prepare 50 μm of ol/L ATP and 50 μM of ol/L ADP solution are mixed in the hole A1-A12 of 384 orifice plates, is used
To simulate the concentration of the ATP and ADP of each conversion percentages, it is uniformly mixed.
C. 5 μ L ADP-Glo are added in every holeTMReagent terminates kinase reaction.Room temperature is protected from light incubation 40 minutes.
D. every hole is added 10 μ L kinase assay reagents and ADP is converted to ATP, and introduces luciferase and luciferin to detect
The ATP being converted to by ADP.
E. it under dark surrounds, is incubated at room temperature 30~60 minutes, measures fluorescent with multi-function microplate reader later and record firefly
Light value.
F. the standard curve that ATP is converted to ADP is drawn.
(4) IC of kinase inhibitor naphthalene isoquinoline compound is measured50Value
Illustrate preparation kinase reaction buffer, 50ng/ μ L kinases and 0.5 μ g/ μ L substrate and 125 μ according to kit
mol/L ATP.3 μ L kinase reaction buffers, 2 μ L, 0.5 125 μm of ol/L ATP of μ g/ μ L substrate are added in no enzyme control wells.
1 μ L kinase reaction buffer, 2 μ L 50ng/ μ L kinases, 2 μ L, 0.5 μ g/ μ L substrate and 125 μ are added in negative control hole
mol/L ATP.1 μ L untested compound, 2 μ L 50ng/ μ L kinases, 2 μ L, 0.5 μ g/ μ L substrate and 125 μ are added in instrument connection
mol/L ATP.Plate is mixed, is incubated at room temperature 60 minutes in the dark.After the completion of incubation, 5 μ L ADP-GloTM examination is added in every hole
Agent terminates kinase reaction.It is incubated for 40 minutes under the same conditions again.Every hole is added 10 μ L kinase assay reagents and turns ADP later
It is melted into ATP, and introduces luciferase and luciferin to detect ATP.Incubation is protected from light 30~60 minutes in room temperature, with multifunctional enzyme mark
Instrument measurement fluorescent simultaneously records fluorescent value, calculates IC50Value.
Test result is as shown in table 2.
2 naphthyl-isoquinolines compound of table is to EGFR kinase inhibitor activity (IC50,nmol)
The result shows that naphthalene isoquinoline compound is to EGFRWTAnd EGFRT790MHave compared with high inhibition effect, part of compounds energy
Reach the active rank of nanomolar range, effective inhibition concentration IC of part of compounds50Value is less than 20nMol/L, is higher than guideization
It closes object Luo Le and replaces Buddhist nun (the drug resistant third generation EGFR-TKI of T790M can be reversed);Inhibition of the part of compounds to T790M mutant kinase
Effect is tens times stronger than marketed drug Gefitinib, even as high as hundreds of times.It can be confirmed that naphthyl-isoquinolines compound
The inhibitor that can be used as EGFR target spot implies that such compound can for showing the treatment of highly expressed disease to EGFR
Exploitation is the therapeutic agent of non-small cell lung cancer.
The above is only preferred embodiments of the invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, some improvements and modifications can also be made, these improvement and modification
Also it should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of compound, which is characterized in that by 5 of the 1 of general formula I, 3,8 and general formula II connections, or by general formula I 1,
3,6,8 and general formula II 7 connections;The general formula I, general formula II structure be respectively as follows:
Wherein: R1、R2、R3、R4Selected from hydroxyl or methoxyl group;Isoquinoline structure is selected from tetrahydroisoquinoline, dihydro-isoquinoline or isoquinoline
Quinoline.
2. a kind of compound according to claim 1, which is characterized in that structure is as follows:
3. the optical isomer of compound according to claim 1 or combinations thereof object.
4. compound according to claim 1, which is characterized in that have structure shown in I-1~I-12:
5. compound according to any one of claims 1 to 4 or its optical isomer are in preparation EGFR skin factor receptor egg
Application in white tyrosine kinase inhibitor.
6. a kind of pharmaceutical composition, the compound according to any one of claims 1 to 4 containing effective dose or its is medicinal
Carrier.
7. compound according to any one of claims 1 to 4 or its optical isomer are in the drug of preparation treatment tumour
Using.
8. application according to claim 7, which is characterized in that the tumour is selected from non-small cell lung cancer, Small Cell Lung Cancer
One of or it is a variety of.
9. application according to claim 7, which is characterized in that the tumour is non-small cell lung cancer.
10. application according to claim 7 or 8, which is characterized in that the application is by inhibiting EGFR, EGFRT790MMutation
Type skin factor receptor protein tyrosine kinase is realized.
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