CN110483485A - Pyrimidines, preparation method and medical usage - Google Patents
Pyrimidines, preparation method and medical usage Download PDFInfo
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- CN110483485A CN110483485A CN201910806733.7A CN201910806733A CN110483485A CN 110483485 A CN110483485 A CN 110483485A CN 201910806733 A CN201910806733 A CN 201910806733A CN 110483485 A CN110483485 A CN 110483485A
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- compound
- egfr
- cancer
- solvate
- acceptable salt
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- -1 pyrimidine compound Chemical class 0.000 claims abstract description 22
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of pyrimidine compound and its pharmaceutically acceptable salt, stereoisomer, prodrug and solvate, preparation method, pharmaceutical composition and medical usages.Such described compound can generate inhibiting effect to the variation pattern of EGFR protease, therefore the growth of kinds of tumor cells can be effectively inhibited, it can be used for preparing anti-tumor drug, for treatment, combination therapy or the prevention of many different cancers, and the drug resistance of the first generation EGFR inhibitors such as existing drug Gefitinib, Tarceva induction can be overcome.More particularly, such compound can be used for preparing the drug of disease, obstacle, disorder or the patient's condition that the EGF-R ELISA (such as L858R activated mutant body, Exon19 missing activated mutant body and T790M resistant mutants) for treating or preventing by certain variation patterns is mediated.
Description
The application is No. 2015105591784 submitted to China Intellectual Property Office on the 2nd of September in 2015, denomination of invention
For the divisional application of the Chinese invention patent application of " pyrimidines, preparation method and medical usage ".
Technical field
The invention belongs to chemical medicine, more particularly to a kind of pyrimidines and its is pharmaceutically acceptable
Salt, stereoisomer, prodrug and solvate, preparation method, pharmaceutical composition and medical usage.Specifically, this hair
It is bright to be related to some pyrimidine compounds and its pharmaceutically acceptable salt, stereoisomer, prodrug and solvate, preparation side
Method, comprising the compound, its pharmaceutically acceptable salt, stereoisomer, prodrug and/or solvate (especially these
The useful polymorphic of compound and salt) the pharmaceutical composition and compound and its pharmaceutically acceptable salt, three-dimensional different
Structure body, prodrug and solvate are in preparation for treating by various different forms (activated mutant body and/or the resistant mutation bodily form
Formula) EGFR mediate disease drug in purposes.
Background technique
Cancer is becoming the mankind " killer " the most fatal, and in recent years, China dies of the total population of cancer every year, approaches
2000000 people.Although the discovery of various therapy approach and drug brings hope to cancer patient, these routines are controlled
Treatment is there are many drawbacks, and for example side effect is big, and therapeutic effect is bad, tumor post-operation recurrence, transfer etc..There is an urgent need to new treatments
Technology solves the status of the low success rate for the treatment of of cancer.The Individual Chemotherapy and targeted therapy occurred recently gives lung cancer therapy band
Hope newly is carried out.Tumor cells targeted therapy is chemical or biological based on passing through to the closely related key molecule of tumour growth
Learn to do a kind for the treatment of method of section selective killing tumour cell.Targeted therapies have specificity high, and selectivity is strong, and poison is secondary
Act on lighter feature.When targeted therapy and classic chemotherapy, radiotherapy or tumour immunity use in conjunction, curative effect can be greatly reinforced,
Reduce postoperative recurrence.Neoplasm targeted therapy is rapidly developed in recent years, is the emerging field and not of oncotherapy
Carry out development trend.
Protein tyrosine kinase (PTKs) is class protein enzyme, they can be catalyzed the junket ammonia in a variety of key proteins
Thus phenolic hydroxyl group phosphorylation reaction on sour residue activates the bioactivity of functional protein.The letter of this process in the cell
Highly important status is occupied in number conduction path, it adjusts a series of physiochemistries such as cell growth in vivo, differentiation, death
Process.Protein tyrosine kinase functional disturbance can cause a series of intracorporal diseases of biology.Studies have shown that cancer more than half
The activation of protogene and oncogene is all related to protein tyrosine kinase, and the unconventionality expression of protein tyrosine kinase can lead to cell
Proliferation is adjusted and is got muddled, and then leads to tumour.In addition, the unconventionality expression of tyrosine kinase also with the invasion of tumour and turn
It moves, the chemotherapy drug resistance of tumor neovasculature generation, tumour is closely related.Tyrosine kinase has become anti-tumor drug and grinds
The critically important target spot that hair is.
EGF-R ELISA (EGFR) is a kind of receptor tyrosine protein kinase, belongs to one in erbB receptor family
Kind transmembrane protein.
EGFR has regulated and controled the proliferation of cell, survival, adhesion, migration and differentiation, its overactivity in kinds of tumor cells
Or continuous activation, such as lung cancer, breast cancer, in the cells such as prostate cancer.Conversion and growth of the abnormal activation of EGFR in tumour
In play critical effect.Block EGFR activation be clinically proven for effective targeting therapy on tumor cellular processes it
One.EGFR has expression in 50% NSCLC (non-compactness cell lung cancer) case.This becomes EGFR and its family member
The leading candidate of targeted therapy.Gefitinib (gefitinib) and Tarceva (erlotinib) are that the first generation of EGFR is small
Molecule inhibitor is mainly used for treating the drug of advanced NSCLC.Clinical effectiveness shows Gefitinib or Tarceva to about
The asian ancestry NSCLC patient of 10% white man NSCLC and about 35% is effective in cure.Analysis shows majority has EGFR Activating mutations
NSCLC patient is significantly higher than the NSCLC patient of EGFR wild type to the reactivity of EGFR- tyrosine kinase inhibitor (TKI).
But clinical research show many patients quickly (12-14 month) just to the micromolecular inhibitor drug of these EGFR
Produce drug resistance, i.e. acquired resistance.Residue (gatekeeper residue) T790M that guards the gate mutation is outside EGFR 20
A catastrophe point in aobvious son, is to cause one of drug resistant main mechanism.It is ground for the inhibitor of new generation of these EGFR mutation
Study carefully and is coming in be successful.Afatinib (Afatinib) is EGFR and human epidermal growth factor receptor 2 (HER2)
Potent, the irreversible double inhibitor of tyrosine kinase.Other similar multiple target points, high activity, irreversible inhibitor, example
Such as, Canertinib (canertinib) replaces Buddhist nun (Dacomitinib) also just in later phase clinical test up to gram.These are novel
The irreversible inhibitor of the second generation has very strong inhibiting effect to the EGFR that L858R and T790M is mutated, to Gefitinib or strategic point
There is significant curative effect in Lip river for the cancer patient that Buddhist nun has developed drug resistance.But these second generations EGFR mutant inhibitor pair
Wild type EGFR (WT-EGFR) similarly has extremely strong inhibition.The verified inhibition to Wild type EGFR of clinical research
It will lead to drug toxicity and side effect with most of patient, for example show as fash or diarrhea in human body.
Overcome the Side effect of second generation EGFR inhibitor, must just reduce to Wild type EGFR (WT-EGFR)
Inhibiting effect.The EGFR inhibitor of a new generation should keep prominent to EGFR L858R activated mutant body, Exon19 missing activation
Variant and T790M resistant mutants have stronger inhibition, while showing phase to WT-EGFR and other receptor tyrosine kinases
To lower inhibiting effect.Such compound, which can be used for treating, EGFR L858R activated mutant body, Exon19 missing activation
The treatment of the cancer patient of mutant, and to first generation EGFR inhibitor such as Gefitinib, Tarceva or Conmana
The treatment of cancer patient through the EGFR-T790M resistant mutants that develop drug resistance, and do not have to worry the suppression of second generation EGFR mutant
Preparation side effect as brought by Afatinib.
Present invention show it is many it is (one or more) to EGFR mutant there is high inhibitory activity, but to Wild type EGFR
The pyrimidine compound of only relatively low inhibition.The compound of the present invention has preferable physicochemical properties and safety poison
Property parameter.Such compound has preferably in the treatment of cancer for the drug-resistant mutation for having EGFR activated mutant body and/or EGFR
Effect.
The present invention relates to certain pyrimidine compounds and its pharmaceutically acceptable salt, can be used for by certain variation patterns
EGF-R ELISA (such as L858R activated mutant body, Exon19 missing activated mutant body and T790M resistant mutants)
The treatment or prevention of the disease or the patient's condition that are mediated.Such compound and its pharmaceutically acceptable salt, stereoisomer, prodrug
And solvate, it can be used for the treatment or prevention of many different cancers.The invention further relates to include the compound and its medicine
Acceptable salt, stereoisomer, prodrug and solvate (the especially useful polymorphics of these compounds and salt) on
Pharmaceutical composition, the compound preparation in useful intermediate and relate to the use of the compound and its pharmaceutically may be used
What salt, stereoisomer, prodrug and the solvate treatment of receiving were mediated by the EGFR of activation and/or resistant mutant forms
The method of disease.
Therefore, there is an urgent need to new type, the especially compounds of novelty skeleton to solve drug resistance, and poor selectivity etc. is asked
Topic.It is cited in following documents list (periodical, miscellaneous with the patent or non-patent document of the immediate prior art of patent application
Will, handbook and books etc.):
1, New England Journal of medicine, volume 2008,358, the 1160-1174 pages;
2, Chemical and Biophysical Research Communications, volume 2004,319,1-
Page 11:
3, Science, volume 2004,304, the 1497-1500 pages;
4, New England Journalof medicine, volume 2004,350, the 2129-2139 pages;
5, Molecular Cancer Therapeutics, volume 2014,13, the 1468-1479 pages;
6, Journal of Medicinal Chemistry, volume 2014,57, the 8249-8267 pages;
7, WO2013014448A1 corresponds to CN103702990A:
8, WO2013108754A1:
9,CN103374000A;
10,CN103804303A;
11, WO2013184766A1:
12、WO2009051822A1。
It is to be understood that above-mentioned patent or non-patent document are representative document, not all related document
Complete list.The complete disclosure of above-mentioned patent or non-patent document is incorporated herein by reference herein, there are contradiction or
In the case where conflict, it is subject to description herein.
Current EGFR-TKI not can solve clinical problem caused by drug resistance still, and existing drug is mostly
With EGFR that quinazoline or quinoline amine are basic parent nucleus is reversible or irreversible inhibitor, the choosing to EGFR wild-type cell
Selecting property difference bring toxic side effect is still inevitable.Therefore, there is an urgent need to new type, the changes of especially novel skeleton
Object is closed to solve drug resistance, the problems such as poor selectivity.
Summary of the invention
It is an object of the present invention to provide pyrimidine compounds shown in formula below one kind (I) and its pharmaceutically acceptable
Salt, stereoisomer, prodrugs or solvate.Such compound can swash EGF-R ELISA (EGFR) albumen
The variation pattern of enzyme generates inhibiting effect, therefore the growth of kinds of tumor cells can be effectively suppressed, and can be used for preparing antineoplastic
Object for the treatment or prevention of many different cancers, and can overcome existing drug Gefitinib, the inductions such as Tarceva
Drug resistance.More particularly, such compound can be used for prepare for treat or prevent by certain variation patterns EGFR (such as
L858R activated mutant body, Exon19 missing activated mutant body, and/or T790M resistant mutants) mediated disease, obstacle,
The drug of disorder or the patient's condition.
It is a further object of the present invention to provide the preparation methods of above compound.
It is yet another object of the invention to provide a kind of pharmaceutical compositions, and it includes be selected from above-mentioned pyrimidine compound, its pharmacy
One of upper acceptable salt, stereoisomer, prodrugs and solvate or a variety of and one or more pharmacy are auxiliary
Material.
It is yet another object of the invention to provide above-mentioned pyrimidine compounds, its pharmaceutically acceptable salt, stereoisomer, preceding
Medicine molecule and/or solvate and aforementioned pharmaceutical compositions are situated between for treating or preventing by the EGFR of variation pattern in preparation
Purposes in the drug of disease, obstacle, disorder or the patient's condition led, especially in preparation for treating or preventing one or more cancers
The purposes of the drug kind of disease.
It is yet another object of the invention to provide a kind of diseases that treatment or prevention are mediated by the EGFR of variation pattern, barrier
Hinder, disorder or the patient's condition, the method for especially one or more cancers.
It is yet another object of the invention to provide a kind of cancer combinational therapeutic methods, i.e., will selected from above-mentioned pyrimidine compound, its
One of pharmaceutically acceptable salt, stereoisomer, prodrugs and solvate be a variety of or medicine according to the present invention
Compositions are used in combination with conventional operation, radiotherapy, chemotherapy or tumour immunotherapy.
In the first aspect of the present invention, the compound or its pharmaceutically acceptable salt, alloisomerism of formula (I) are provided
Body, prodrugs or solvate:
Wherein:
R1It is C1-C6 alkyl, CD3Or by fluorine-substituted C1-C6 alkyl;
R2It is
Wherein, R3It is hydrogen, fluorine, chlorine or bromine, n is the integer of 1-3;R4Be the substituted or unsubstituted C2-C6 alkyl of halogen or
The substituted or unsubstituted C3-C6 naphthenic base of halogen:
Also, work as R1It is methyl, R2Cannot be
Work as R1It is CD3, R2Cannot be
In the preferred embodiment of the application, in formula (I),
R1It is C1-C3 alkyl, CD3Or by 1 to 3 fluorine-substituted C1-C3 alkyl;
R2Selected from following group:
Also, work as R1It is methyl, R2Cannot be
Work as R1It is CD3, R2Cannot be
In another preferred embodiment of the application, in formula (I), R1Methyl or CD3, R2It is selected from following groups:
Wherein, R4It is ethyl, cyclopropyl, 2,2- bis-fluoro ethyls, 2,2,2- trifluoroethyls.
In another preferred embodiment of the application, in formula (I), R1It is methyl or CD3, R2It is selected from following groups:
In another preferred embodiment of the application, in formula (I), R1It is CD3, R2It is selected from following groups:
In another preferred embodiment of the application, in formula (I), R1It is methyl, R2It is selected from following groups:
In the most preferred embodiment of the application, the compound of the formula (I) is selected from:
The second aspect of the application provides and prepares compound shown in above-mentioned formula (I) or its pharmaceutically acceptable salt
Method, for example, the method can the method shown in following general reaction equation, wherein certain two step or multistep reaction sequence can be with
It intercourses, is not necessarily intended to just the same with sequence shown in following reaction equation.Compound A1 in following general reaction equation,
A2, A4, A6, A9 etc. can be commercially available, or can be according to procedures known in the art by from other commercial compound systems
It is standby.Preparation method is described later in detail in embodiment.
Wherein, n, R1、R3、R4As previously defined and preferably,
In above-mentioned general reaction sequence, 2,4- dichloro pyrimidine compound A1 and benzazolyl compounds A2 reaction generate compound
A3.Under conditions of having p-methyl benzenesulfonic acid, compound A-13 and A4 reaction generate compound A-45.N, N, N '-trimethyl ethylenediamine A6
Replace the fluorine atom in A5 under conditions of having potassium carbonate and obtains product A7.Nitrobenzene is converted to aniline by catalytic hydrogen reduction
A8.With after acrylic anhydride A9 reaction, final product A10 is generated.Available mesylate after product A10 adds methanesulfonic acid to handle
A11.Acid is different because of molecule with the ratio of compound A10, and a compound A10 can be with 1-3 acid molecule at salt, wherein with two
Hydrochlorate or trisalt are in the majority.
The third aspect of the application provides a kind of pharmaceutical composition, is selected from above-mentioned formula (I) it includes therapeutically effective amount
One of or multiple compounds, its pharmaceutically acceptable salt, stereoisomer, prodrugs and/or solvate and
One or more pharmaceutical excipients.Aforementioned pharmaceutical compositions are for treating or preventing by activated mutant body or resistant mutant forms
Disease, obstacle, disorder or the patient's condition that EGFR is mediated, in particular for treating or preventing the drug of one or more cancers.
Said medicine can choose a variety of pharmaceutical preparation forms according to therapeutic purposes, generally comprise: tablet, pill, capsule
Agent, granule, suspension, solution, creme, ointment, pulvis, suppository, aerosol and injection etc..
It is different to provide compound shown in above-mentioned formula (I), its pharmaceutically acceptable salt, solid for the fourth aspect of the application
Structure body, prodrugs and/or solvate are treated or prevented in preparation by the EGFR of activation or resistant mutant forms mediation
Purposes in obstacle or the drug of disease.The obstacle or disease include but is not limited to: oophoroma, cervical carcinoma, colorectal cancer
(for example, adenocarcinoma of colon), breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, leaching
Bar tumor, non-Hodgkin lymphoma, gastric cancer, lung cancer (for example, non-small cell lung cancer), hepatocellular carcinoma, gastrointestinal stromal tumor (GIST),
It is thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia (AML), multiple
Property myeloma or celiothelioma.
In the present invention, the EGFR of the activated mutant body or resistant mutant forms can be prominent for such as L858R activation
Variant, Exon19 missing activated mutant body and/or T790M resistant mutants.Therefore, by activated mutant body or the resistant mutation bodily form
Disease, obstacle, disorder or the patient's condition that the EGFR of formula is mediated can be prominent for the missing activation of such as L858R activated mutant body, Exon19
Disease, obstacle, disorder or the patient's condition that variant and/or T790M resistant mutants are mediated.
The compound of formula (I) according to the present invention, its pharmaceutically acceptable salt, stereoisomer, prodrugs and molten
Object is closed in agent or pharmaceutical composition according to the present invention is particularly useful for the EGFR by activated mutant body or resistant mutant forms
Disease, obstacle, disorder or the prevention of the patient's condition or treatment of mediation, for example, it is prominent by L858R activated mutant body, Exon19 missing activation
The prevention or treatment of disease, obstacle, disorder or the patient's condition that variant and/or T790M resistant mutants are mediated, for example can be used for
Prevention or treatment to Gefitinib, Tarceva or angstrom cancer patient that Buddhist nun can be replaced to have developed drug resistance.
In still another aspect of the invention, a kind of cancer combinational therapeutic methods are provided comprising give individual in need for the treatment of
Apply pyrimidine compound, its pharmaceutically acceptable salt, alloisomerism selected from formula according to the present invention (I) of therapeutically effective amount
One of body, prodrugs and solvate or a variety of or therapeutically effective amount pharmaceutical compositions according to the present invention, simultaneously
Conventional operation or radiotherapy or chemotherapy or immune tumor therapy is used in combination.
The chemotherapy or immune tumor therapy and the compounds of this invention can side by side, simultaneously, sequentially or point
It is not administered, and may include but be not limited to the one or more of following kind of antitumor agent: alkylating agent (such as card molybdenum,
Ao Shali molybdenum, suitable molybdenum, cyclophosphamide, nitrosoureas, mustargen, melphalan), antimetabolite (such as gemcitabine), He Kangye
Sour agent (such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methopterin, cytarabine, hydroxycarbamide), topoisomerase inhibit
Agent (such as Etoposide, Hycamtin, camptothecine), antimitotic agent (such as vincristine, vincaleukoblastinum, vinorelbine, it is purple
China fir alcohol, taxotere), antitumor antibiotics (such as adriamycin, bleomycin, Doxorubicin, daunomycin, mitomycin C, put
Line rhzomorph), antiestrogen (such as tamoxifen, fulvestrant, Toremifene, Raloxifene, Droloxifene), antiandrogen
Medicine (such as Bicalutamide, Flutamide, Nilutamide), lhrh antagonist or LHRH agonist are (such as Goserelin, bright third auspicious
Woods and Buserelin), aromatase inhibitor (such as Anastrozole, Letrozole), CYP17 lyase inhibitors (such as Ah's bit
Dragon), anti-erbB 2 antibody trastuzumab [Trastuzumab], anti-egfr antibodies Cetuximab [Erbitux];Tyrosine kinase, silk
Propylhomoserin/threonine kinase inhibitor (such as Imatinib and nilotinib, Sorafenib, trametinib, gram azoles replace Buddhist nun)
Cell cycle protein dependent kinase inhibitor (such as CDK4 inhibitor palbociclib), anti-human vascular endothelial cell growth
Factor antibody Avastin (Avastin) and vegf receptor tyrosine kinase inhibitor (Ah pa replaces Buddhist nun), immune tumour is controlled
Treatment method, for example, it is anti-PD-1 antibody (pembrolizumab, nivolumab), anti-PD-L1 antibody, anti-lag-3 antibody, anti-
CTLA-4 antibody, anti-4-1BB antibody, anti-GITR antibody, anti-ICOS antibody, interleukin 2.
Beneficial effect
The compound of formula (I) of the invention illustrates (a kind of or more to EGFR activated mutant body or resistant mutant forms
Kind) there is high inhibitory activity, but relatively low a kind of pyrimidine compound is inhibited to Wild type EGFR.The compound of the present invention tool
There are preferable physicochemical properties and safe toxicity parameter.Such compound is by EGFR activated mutant and/or drug-resistant mutation
The treatment of the disease (including cancer) of mediation has preferable clinical effectiveness.
Specific embodiment
The present invention will be further described for following embodiment, but the following example is not intended to limit protection of the invention
Range.
Embodiment 121
1. the synthesis of intermediate 121-3
Under nitrogen protection, at room temperature into 100 milliliters of (mL) there-necked flasks, by raw material 121-1, (3.0 grams (g), 25.6 in the least
Mole (mmol)) it is dissolved in 50mL 1, in 2- dichloroethanes (DCE), mixture is down to 0 DEG C, by methyl-magnesium-bromide at 0 DEG C
(8.5mL, 25.6mmol) is added dropwise in reaction system, again will at adding rear constant temperature the reaction was continued 30 minutes (min), 0 DEG C
121-2 (5.4g, 36.3mmol) is added in reaction system, is reacted overnight after being warming up to room temperature.It is mixed to reaction after fully reacting
It closes and 100 milliliters of ice water quenching reactions is added in object, mixture is extracted 3 times with 100mL methylene chloride, with 100 after organic phase merging
Milliliter saturated common salt water washing 3 times, with being concentrated after anhydrous sodium sulfate drying, crude product purifies (ethyl acetate with silica gel column chromatography
(EA)/petroleum ether (PE)=1: 10-1: 5), 2.0g product 121-3 (34%) is obtained, is yellow solid.
Liquid chromatography mass (LCMS): 229.0.
2. the synthesis of intermediate 121-5
Under nitrogen protection, it is sequentially added into 250mL there-necked flask 121-4 (10g, 63.7mmol), 100mL anhydrous N, N-
Dimethylformamide (DMF), K2CO3(1.3g, 9.34mmol), deuterated iodomethane (11g, 75.9mmol) then add in oil bath
Heat is to reacting 2 hours (h) after 50 DEG C.Reaction is cooled into room temperature, is quenched with 100mL ice water, 100mL EA is extracted three times, mistake
Filter, organic phase are washed 3 times with 200mL saturated common salt.Anhydrous sodium sulfate is dry, is concentrated and dried, obtains 9.7g product 121-5
It (88%), is yellow solid.
3. the synthesis of intermediate 121-6
It is sequentially added into 500mL single port bottle 121-5 (9.7g, 55.7mmol), 240mL methanol, palladium carbon (12g, 5%),
Hydrogen three times is replaced, at room temperature reaction overnight.Palladium carbon is filtered out, filtrate is concentrated and dried, obtains 7.2g product 121-6 (90%), be
Light color liquid.
LCMS:145.1.
4. the synthesis of intermediate 121-7
Under nitrogen protection, it is sequentially added into 250mL there-necked flask 121-6 (7.2g, 49.9mmol), the 64mL concentrated sulfuric acid,
Concentrated nitric acid (HNO is added portionwise after being cooled to 0-10 DEG C3) (5.05g, 50.0mmol), it was added with 15 minutes.It reacted at room temperature
Night.Reaction mixture is added to quenching reaction in 500mL ice water, is 10 with ammonium hydroxide tune pH, three times with 100mL EA extraction, then
It is washed 3 times with 200mL saturated common salt.It after anhydrous sodium sulfate is dry, is concentrated and dried, obtains 5.1g product 121-7 (54%), for Huang
Color solid.
LCMS:190.1.
5. the synthesis of intermediate 121-9
Under nitrogen protection, in 100mL there-necked flask, raw material 121-3 (3.0g, 13.0mmol) is dissolved in 30 milliliters at room temperature
In n,N-Dimethylformamide, reaction system is cooled to 0 DEG C after charging, sodium hydride (NaH) is then added portionwise
Trifluoromethanesulfonic acid trifluoro ethyl ester 121-8 (3.65g, 15mmol) is added after reacting 0.5 hour at 0 DEG C in (786mg, 18.5mmol),
Charging, which finishes, is back to room temperature reaction 2 hours, detects fully reacting.Reaction solution is poured into 200mL ice water and is quenched, there is red solid
It is precipitated, gained mixture is filtered, collect solid, dry to obtain 4.2g product 121-9, be red solid.LCMS:312.0.
6. the synthesis of intermediate 121-10
Under nitrogen protection, in 250mL there-necked flask, it is different that raw material 121-9 (1.8g, 5.77mmol) is dissolved in 50mL at room temperature
In propyl alcohol (i-PrOH), then successively by 121-7 (1.1g, 5.82mmol), p-methyl benzenesulfonic acid (1.3g, 7.55mmol) is added to instead
It answers in system, reaction system is warming up to 105 DEG C after charging and is reacted 6 hours.Reaction system is dropped after detection fully reacting
To room temperature, it is yellow solid that filter cake is collected in mixture filtering, and solid dries to obtain 3g crude product 121-10.LCMS:465.1.
7. the synthesis of intermediate 121-11
Under nitrogen protection, in 100mL there-necked flask, raw material 121-10 (3.0g, 6.46mmol) is dissolved at room temperature
In 30mLN- methyl cyclohexane amide (NMP), then successively by N, N, N '-trimethyl ethylenediamine (860mg, 8.42mmol), anhydrous carbon
Sour potassium (2.7g, 19.5mmol) is added in reaction system, and reaction system is warming up to 100 DEG C after charging.Reaction 2 hours
After detect fully reacting, reaction system is down to room temperature, reaction solution is poured into 100mL ice water and is quenched, mixture is filtered, receive
Collection filter cake is simultaneously dried, and 1.7g (48%) product 121-11 is obtained, and is red solid.LCMS:547.2.8. intermediate 121-12's
Synthesis
Under nitrogen protection, in 250mL single port bottle, at room temperature, methanol 50mL, methylene chloride (DCM) 50mL are sequentially added,
Raw material 121-11 (1.7g, 3.11mmol), aqueous palladium carbon (1.7g, 10%), ammonium formate (1.7g), by system room after charging
Temperature reaction 3 hours, detects fully reacting.Reaction system filters, and collects filtrate, is concentrated to dryness.Gained residue 200mL dichloro
Methane dissolution, 200mL NaHCO3Aqueous solution backwash 1 time, then washed 1 time with 200mL saturated common salt, organic phase anhydrous slufuric acid
0.8g (50%) product 121-12 is obtained after being concentrated to dryness after sodium is dry, is yellow solid.LCMS:517.3.
9. the synthesis of compound 121
Under nitrogen protection, in 100mL there-necked flask, raw material 121-12 (800mg, 1.55mmol) is dissolved in 50mL at room temperature
In chloroform, reaction mixture is cooled to 0 DEG C, acrylic anhydride (195mg, 1.55mmol) is added drop-wise in reaction system,
It is reacted about 1 hour after adding at 0 DEG C.After detecting fully reacting, directly reaction mixture is concentrated to dryness, gained residue system
Standby column chromatography (chromatographic column: silica gel, mobile phase: CHCl3/ EtOH, 20-60% ethyl alcohol;20min;Detection wavelength:
254nm) purify.Products obtained therefrom organic phase is concentrated to dryness, 300mg compound 121 is obtained.
By 300mg compound 121 in 20mL acetonitrile, methanesulfonic acid (297.7mg, 2.00equiv, 2.0eq) is added drop-wise to
In system, reaction mixture is concentrated to dryness at low temperature after insulated and stirred 1 hour, after adding water to re-dissolve gained residue
The mesylate that 466mg (39%) 121 is obtained after freeze-drying is yellow solid.
LRMS (parent molecule) C29H29D3F3N7O2: (ES, m/z): 571.3 [M+H]+。
1H-NMR (mesylate): 1H-NMR:(300MHz, DMSO-D6, ppm): 89.50 (s, 1H), 9.26 (br s,
1H), 8.75 (s, 1H), 8.47 (m, 1H), 8.36-8.34 (m, 2H), 7.76 (d, J=8.1Hz, 1H), 7.43 (d, J=
6.0Hz, 1H), 7.36-7.31 (m, 1H), 7.24-7.18 (m, 1H), 7.07 (s, 1H), 6.75-6.66 (m, 1H), 6.33-
6.27 (m, 1H), 5.80 (d, J=11.7Hz, 1H), 5.41-5.32 (m, 2H), 3.33 (m, 4H), 2.84 (d, J=4.8Hz,
6H), 2.67 (s, 3H), 2.35 (s, 5H)
Embodiment 122
1. the synthesis of intermediate 122-1
Under nitrogen protection, 5- fluoro indole (10g, 74.0mmol) is added into 500mL there-necked flask, 100mL steams anhydrous four again
Hydrogen furans cools the temperature to 0 DEG C, is added dropwise 37.1mL methyl-magnesium-bromide diethyl ether solution (3.0M), and after being added dropwise, 0 DEG C of holding anti-
Should about 30min, 2,4- dichloro pyrimidine (16.5g, 111mmol) is added portionwise at 0 DEG C, returns reaction system naturally after charging
Overnight to room temperature reaction.After detecting fully reacting, 100mL aqueous ammonium chloride solution is added dropwise into reaction system, reaction is quenched, to
Gained mixture is extracted 2 times with 100mL ethyl acetate, merges organic phase, with 100mL saturated salt solution backwash 1 time, anhydrous slufuric acid
It is concentrated to dryness after sodium is dry, obtained solid is washed 1 time with 100mL acetonitrile, is filtered, and is collected filter cake and is dried to obtain 6g (33%) product
122-1 is yellow solid.LCMS:248.0.
2. the synthesis of intermediate 122-2
Under nitrogen protection, into 100mL there-necked flask at room temperature by raw material 122-1 (2.0g, 8.08mmol) be dissolved in 50mL without
In water DMF, then it is cooled to 0 DEG C and NaH (65%, 445mg, 12.1mmol) is added portionwise, protect reaction system after charging
Hold 0 DEG C of reaction 30min.Then trifluoromethanesulfonic acid trifluoro ethyl ester (2.8g, 12.1mmol) is added dropwise at 0 DEG C, by body after being added dropwise
System is kept for 0 DEG C react 1 hour, and after detecting fully reacting, reaction mixture is poured into quenching reaction in 100mL ice water, is precipitated solid
Body filters mixture, collects filter cake and dries to obtain 3g crude product 122-2, is yellow solid.LCMS:330.0.
3. the synthesis of intermediate 122-4
Under nitrogen protection, 122-3 (100g, 709mmol) and the 800mL concentrated sulfuric acid are sequentially added into 2000mL there-necked flask
(H2SO4), it is cooled to 0 DEG C, maintains temperature that potassium nitrate (KNO is added portionwise between 0-10 DEG C3) (71.6g, 708mmol), the used time
1 hour, finally reaction was stayed overnight at room temperature.After reaction, 2 liters of (L) ice water are added to quench the reaction into there-necked flask.Low temperature
It is lower by reaction mixture with ammonium hydroxide be transferred to pH be 10, with 1L methylene chloride (DCM) extract 3 times.After organic phase merges, it is saturated with 3L
It is saline solution backwash 3 times, dry with anhydrous sodium sulfate, it is spin-dried for.Gained crude product is through silica gel column chromatography (eluant ethyl acetate (EA)
: petroleum ether (PE)=1: 4-1: 1), eluent obtains 79g 122-4 after being spin-dried for (yield: being yellow solid 60%).
LCMS:187.0.
4. the synthesis of intermediate 122-5
Under nitrogen protection, in 100mL there-necked flask, raw material 122-2 (3g, 9.10mmol) is dissolved in 30mL isopropyl at room temperature
In alcohol, then successively by 122-4 (1.7g, 9.13mmol), p-methyl benzenesulfonic acid (2g, 11.6mmol) is added in reaction system, adds
Reaction system is warming up to 105 DEG C of reaction 6h after material.Reaction system is dropped into room temperature, mixture mistake after detection fully reacting
Filter cake is collected in filter, and solid dries to obtain 2.4g (55%) product 122-5, is yellow solid.
LCMS:480.1.
5. the synthesis of intermediate 122-6
Under nitrogen protection, in 100mL there-necked flask, raw material 122-5 (2.4g, 5.01mmol) is dissolved in 30mL at room temperature
In NMP, then successively by N, N- trimethyl ethylenediamine (770mg, 7.54mmol), Anhydrous potassium carbonate (2.1g, 15.2mmol) addition
Into reaction system, reaction system is warming up to 100 DEG C after charging.Fully reacting is detected after reaction 2h, by reaction system
It is down to room temperature, reaction solution is poured into 100mL ice water and is quenched, mixture is filtered, collect filter cake and is dried, 1.5g is obtained
(53%) product 122-6 is red solid.LCMS:562.2.6. the synthesis of intermediate 122-7
Under nitrogen protection, in 250mL single port bottle, at room temperature, methanol 50mL, methylene chloride 50mL, raw material are sequentially added
122-6 (1.5g, 2.67mmol), aqueous palladium carbon (10%, 1.5g), ammonium formate (1.5g) are anti-by system room temperature after charging
3h is answered, fully reacting is detected.Reaction system filters, and collects filtrate, is concentrated to dryness.Gained residue is molten with 200mL methylene chloride
Solution, 200mL sodium bicarbonate aqueous solution backwash 1 time, then washed 1 time with 200mL saturated common salt, organic phase is dry with anhydrous sodium sulfate
After be concentrated to dryness after obtain 1.1g (77%) product 122-7, be yellow solid.
LCMS:532.2.
7. the synthesis of compound 122
Under nitrogen protection, in 100mL there-necked flask, raw material 122-7 (1.1g, 2.07mmol) is dissolved in 30mL tri- at room temperature
In chloromethanes, reaction mixture is cooled to 0 DEG C, acrylic anhydride (260mg, 2.06mmol) is added drop-wise in reaction system, is added
It is reacted about 1 hour after complete at 0 DEG C.After detecting fully reacting, it is directly thickened to do, gained residue silica gel column chromatography (chromatography
Column: silica gel, mobile phase: CHCl3/EtOH);20-60% ethyl alcohol: 20min;Detection wavelength: 254nm) purifying.By gained
Product organic phase is concentrated to dryness, and obtains 590mg compound 122.
By 960mg compound 122 in 10mL acetonitrile, methanesulfonic acid (96mg, 1.00mmol, 1.0eq) is added drop-wise to system
In, reaction mixture is concentrated to dryness at low temperature after insulated and stirred 1 hour, is freezed after adding water to re-dissolve gained residue
The mesylate that 629.4mg (45%) 122 is obtained after drying is yellow solid.
LRMS (parent molecule) C29H31F4N7O2: (ES, m/z): 586.2 [M+H]+。
1H-NMR (mesylate): (300MHz, DMSO-D6, ppm): δ 9.45 (s, 1H), 9.39 (br s, 1H), 8.60
(s, 2H), 8.35-8.34 (m, 2H), 8.11 (d, J=8.7Hz, 1H), 7.74-7.71 (m, 1H), 7.25 (d, J=5.4Hz,
1H), 7.19-7.12 (m, 1H), 7.03 (s, 1H), 6.78-6.70 (m, 1H), 6.27 (dd, J=1.8Hz, 17.1Hz, 1H),
5.79-5.75 (m, 1H), 5.37-5.28 (m, 2H), 3.87 (s, 3H), 3.30 (s, 4H), 2.82 (d, J=4.5Hz, 6H),
2.68 (s, 3H), 2.33 (s, 3H).
Embodiment 123
1. the synthesis of intermediate 123-1
Under nitrogen protection, into 100mL there-necked flask at room temperature by raw material 122-1 (2.5g, 10.1mmol) be dissolved in 50mL without
In water DMF, then it is cooled to 0 DEG C and NaH (65%, 560mg, 15.2mmol) is added portionwise, protect reaction system after charging
It holds and is reacted 30 minutes at 0 DEG C.Then the fluoro- 2- bromoethane (2.9g, 20.0mmol) of 1,1- bis- is added dropwise at 0 DEG C, it will after being added dropwise
System returns to room temperature reaction overnight.After detecting fully reacting, reaction mixture is poured into quenching reaction in 200mL ice water, is precipitated
Solid filters mixture, collects filter cake, is washed 1 time with 50mL acetonitrile, and dry to obtain 1.6g (51%) product 123-1, is yellow
Solid.LCMS:312.0.
2. the synthesis of compound 123
The experimental procedure and reaction condition and above-mentioned implementation of compound 123 and its mesylate are synthesized from intermediate 123-1
The chemical reaction of the 4th step to the 7th step is identical in example 122.The difference is that here with intermediate 123-1 instead of embodiment 122
In intermediate 122-2.
The data of compound 123:
LRMS (parent molecule) C29H32F3N7O2: (ES, m/z): 568.3 [M+H]+。
1H-NMR (mesylate): (300MHz, DMSO-D6, ppm): δ 9.43 (br s, 2H), 8.79 (s, 1H), 8.60
(s, 2H), 8.35-8.26 (m, 2H), 8.00 (brs, 1H), 7.75-7.71 (m, 1H), 7.19-7.13 (m, 1H), 7.09 (s,
1H), 7.03 (s, 1H), 6.50-6.21 (m, 2H), 5.78-5.74 (m, 1H), 4.91-4.81 (m, 2H), 3.84 (s, 3H),
3.33 (s, 4H), 2.82 (d, J=4.8Hz, 6H), 2.67 (s, 3H), 2.34 (s, 6H).
Embodiment 124
1. the synthesis of intermediate 124-1
Under nitrogen protection, 6- fluoro indole (5g, 37.0mmol) is added into 250mL there-necked flask, the anhydrous tetrahydro furan of 100mL
It mutters, cools the temperature to 0 DEG C, be added dropwise 18.5mL methyl-magnesium-bromide diethyl ether solution (3.0M), after being added dropwise, keep 0 DEG C of reaction about
2,4- dichloro pyrimidine (8.28g, 55.6mmol) is added portionwise at 30 minutes, 0 DEG C, returns to reaction system naturally after charging
Room temperature reaction is overnight.After detecting fully reacting, 100mL aqueous ammonium chloride solution is added dropwise into reaction system, reaction is quenched, to institute
It obtains mixture to be extracted 2 times with 100mL ethyl acetate, merges organic phase, with 100mL saturated salt solution backwash 1 time, anhydrous sodium sulfate
It being concentrated to dryness after drying, obtained solid is washed 1 time with 50mL acetonitrile, is filtered, and it collects filter cake and dries to obtain 6.1g (67%) 124-1,
For yellow solid.LCMS:248.0.
2. the synthesis of intermediate 124-2
Under nitrogen protection, into 250mL there-necked flask at room temperature by raw material 124-1 (6.1g, 24.6mmol) be dissolved in 100mL without
In water DMF, then it is cooled to 0 DEG C and NaH (65%, 1.4g, 37.9mmol) is added portionwise, keep reaction system after charging
0 DEG C is reacted 30 minutes.Then trifluoromethanesulfonic acid trifluoro ethyl ester (8.6g, 37.1mmol) is added dropwise at 0 DEG C, by system after being added dropwise
It is kept for 0 DEG C react 2 hours, after detecting fully reacting, reaction mixture is poured into quenching reaction in 200mL ice water, solid is precipitated,
Mixture is filtered, filter cake is collected and dries to obtain 3g (37%) product 124-2, is yellow solid.LCMS:330.0.
3. the synthesis of compound 124
The experimental procedure and reaction condition and above-mentioned implementation of compound 124 and its mesylate are synthesized from intermediate 124-2
The chemical reaction of the 4th step to the 7th step is identical in example 122.The difference is that here with intermediate 124-2 instead of embodiment 122
In intermediate 122-2.
The data of compound 124:
LRMS (parent molecule) C29H31F4N7O2: (ES, m/z): 586.2 [M+H]+。
1H-NMR (mesylate): (300MHz, DMSO-D6, ppm): δ 9.70 (br s, 1H), 8.67 (brs, 1H), 8.55
(s, 1H), 8.39-8.34 (m, 2H), 8.11 (s, 1H), 7.65 (dd, J=2.1Hz, 9.9Hz, 1H), 7.26 (d, J=5.4Hz,
1H), 7.06-6.99 (m, 2H), 6.72-6.63 (m, 1H), 6.32-6.22 (m, 1H), 5.78-5.77 (m, 1H), 5.37-5.25
(m, 2H), 3.89 (s, 3H), 3.31-3.07 (m, 4H), 2.65-2.56 (m, 8H), 2.32 (s, 3H).
Embodiment 125
1. the synthesis of intermediate 125-1
Under nitrogen protection, into 100mL there-necked flask at room temperature by raw material 124-1 (2.5g, 10.1mmol) be dissolved in 50mL without
In water DMF, then it is cooled to 0 DEG C and NaH (65%, 560mg, 15.2mmol) is added portionwise, protect reaction system after charging
0 DEG C is held to react 30 minutes.Then the fluoro- 2- bromoethane (2.9g, 20.0mmol) of 1,1- bis- is added dropwise at 0 DEG C, by body after being added dropwise
System returns to room temperature reaction overnight.After detecting fully reacting, reaction mixture is poured into quenching reaction in 100mL ice water, is precipitated solid
Body filters mixture, collects filter cake, is washed 1 time with 50mL acetonitrile, dry to obtain 1.5g (48%) product 125-1, solid for yellow
Body.LCMS:312.0.
2. the synthesis of compound 125
The experimental procedure and reaction condition and above-mentioned implementation of compound 125 and its mesylate are synthesized from intermediate 125-1
The chemical reaction of the 4th step to the 7th step is identical in example 122.The difference is that here with intermediate 125-1 instead of embodiment 122
In intermediate 122-2.
The data of compound 125:
LRMS (parent molecule) C29H32F3N7O2: (ES, m/z): 568.3 [M+H]+。
1H-NMR (mesylate): (300MHz, DMSO-D6, ppm): 89.55 (s, 2H), 9.26 (brs, 1H), 8.72 (s,
1H), 8.32-8.30 (m, 3H), 7.64 (d, J=9.9Hz, 1H), 7.42 (d, J=6.3Hz, 1H), 7.08 (s, 1H), 7.05-
6.99 (m, 1H), 6.73-6.26 (m, 3H), 5.82-5.78 (m, 1H), 4.89-4.78 (m, 2H), 3.87 (s, 3H), 3.34 (m,
4H), 2.84 (d, J=4.8Hz, 6H), 2.68 (s, 3H), 2.34 (s, 7H)
EXPERIMENTAL EXAMPLE
Cell growth inhibition test:
The EGFR being preferentially targeted for certain variation patterns is identified with the method for the growth of measurement cell, and to wild type
The relatively weak compound of the activity of EGFR.NCI-H1975 cell strain is that the mankind containing T790M and L858R EGFR mutation are non-
Small cell lung cancer cell, the cell are grown in the RPMI-1640 culture medium (GIBCO) containing 10% fetal calf serum (FBS).LoVo
Cell strain is the human colon adenocarcinoma cell of a Wild type EGFR, which is grown in the F-12K culture medium containing 10%FBS
(GIBCO) in.The growth speed of NCI-H1975 and LoVo cell is by Cell Titer-Glo luminescent sank measuring method (Promega
Company #G7572) it detects.
In brief, the cell in logarithmic growth phase is digested, and with trypsase with 5000, every hole Lovo or 3000
A NCI-H1975 cell inoculation is incubated in 37 DEG C into 96 orifice plates, there is 5%CO2Wet incubator in, while setting not
The blank control wells of nutrient solution are only added in inoculating cell.After 24 hours, by the DMSO solution cell culture medium of different compounds
Liquid is diluted to various concentration from high to low, is diluted every time with 3.16 times, shares 8 various concentrations.It is surveyed in NCI-H1975 cell
The concentration of the concentration of reagent object testing drug from 0.03nM-100nM, LoVo cell is from 3nM-10 μM.Then by different chemical combination
The cell culture medium liquid of object is added in 96 porocyte plates of cell, while setting one only containing the cell culture medium of DMSO
The cell control well of liquid.After drug-treated 72 hours, cell plates are removed and placed to 30 points at room temperature from incubator
Clock.Then plus Cell Titer-Glo reagent is into hole, and 96 porocyte plates are rocked 10 minutes at room temperature, with inducing cell
Cracking.96 porocyte plates are placed on experimental bench 2 minutes again, luminous signal is allowed to stablize.Finally 96 porocyte plates are put into
In EnVision multiple labeling micropore board detector (PerkinElmer), signal was read with 0.5 second time of integration.
Calculation formula are as follows:
Cell growth inhibition percentage %=(peak signal-compound signal)/(peak signal-minimum signal) * 100%
Peak signal obtains in the cell control well by the DMSO control treatment of not compound;
Compound signal obtains in the cell hole by the drug-treated of addition compound
Minimum signal is only obtained in the blank control wells of nutrient solution by not cell.
Cell growth inhibition curve is calculated by GraphPad Prism V5.0 software, and is calculated based on this data
Compound concentration needed for obtaining 50% inhibitory effect, i.e. compound IC50。
Acquired results arrange in table 1 below.
Table 1: compound activity experimental result
Claims (6)
1. a kind of pyrimidine compound as shown in following formula (I) or its pharmaceutically acceptable salt, stereoisomer, prodrugs
Or solvate:
Wherein:
R1It is methyl or CD3, R2It is selected from following groups:
2. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, prodrugs
Or solvate, wherein
R1It is methyl, R2It is selected from following groups:
3. a kind of pyrimidine compound or its pharmaceutically acceptable salt, stereoisomer, prodrugs or solvate,
In, the pyrimidine compound is as follows compound:
4. a kind of pharmaceutical composition, it includes the one or more selected from any one of claims 1 to 3 institute of therapeutically effective amount
Compound, its pharmaceutically acceptable salt, stereoisomer, prodrugs and/or the solvate stated and one or more
Pharmaceutical excipients.
5. compound described in any one of claims 1 to 3, its pharmaceutically acceptable salt, stereoisomer, prodrug point
Son and/or solvate are treated or prevented in preparation by the EGFR of the activation or resistant mutant forms obstacle mediated or disease
Purposes in drug.
6. purposes according to claim 5, wherein the obstacle mediated by the EGFR of activation or resistant mutant forms
Or disease be oophoroma, cervical carcinoma, colorectal cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma,
Prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid gland
Cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute myelocytic leukemia, Huppert's disease or
Celiothelioma.
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Address after: 201203 building 63, Lane 1000, zhangheng Road, Pudong New Area, Shanghai Applicant after: Yifang Biotechnology (Shanghai) Co.,Ltd. Applicant after: BETTA PHARMACEUTICALS Co.,Ltd. Address before: Room 210, No. 4, Lane 67, Li Bing Road, Pudong New Area, Shanghai, 201203 Applicant before: Yifang Biotechnology (Shanghai) Co.,Ltd. Applicant before: BETTA PHARMACEUTICALS Co.,Ltd. |
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Application publication date: 20191122 |
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