CN106478605A - Pyrimidines, its preparation method and medical usage - Google Patents
Pyrimidines, its preparation method and medical usage Download PDFInfo
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- CN106478605A CN106478605A CN201510559178.4A CN201510559178A CN106478605A CN 106478605 A CN106478605 A CN 106478605A CN 201510559178 A CN201510559178 A CN 201510559178A CN 106478605 A CN106478605 A CN 106478605A
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- 0 CC(C(C1)C1C1(C)CC(C)*C1)C1=CC11C(C)C1 Chemical compound CC(C(C1)C1C1(C)CC(C)*C1)C1=CC11C(C)C1 0.000 description 2
- BCQCIPKWKWDVEZ-UHFFFAOYSA-N CC(C1C)C=Cc2c1cccc2 Chemical compound CC(C1C)C=Cc2c1cccc2 BCQCIPKWKWDVEZ-UHFFFAOYSA-N 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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- 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
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- 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
Abstract
The invention discloses a class pyrimidine compound, and its pharmaceutically acceptable salt, stereoisomer, prodrug and solvate, its preparation method, pharmaceutical composition and medical usage.Such described compound can produce inhibitory action to the variation pattern of EGFR protease, therefore the growth of kinds of tumor cells can effectively be suppressed, can be used to prepare antineoplastic, for the treatment of much different cancers, therapeutic alliance or prevention, it is possible to the drug resistance for overcoming the first generation EGFR inhibitor such as existing medicine Gefitinib, Tarceva to induce.More particularly, such compound can be used to prepare the medicine for treating or preventing the disease, obstacle, disorder or the patient's condition that are mediated by the EGF-R ELISA (such as L858R activated mutant body, Exon19 disappearance activated mutant body and T790M resistant mutants) of some variation patterns.
Description
Technical field
The invention belongs to chemical medicine, more particularly to class pyrimidines and its pharmaceutically acceptable salt,
Stereoisomer, prodrug and solvate, its preparation method, pharmaceutical composition and medical usage.Specifically, this
Bright it is related to some pyrimidine compounds and its pharmaceutically acceptable salt, stereoisomer, prodrug and solvate, its preparation side
Method, (is particularly this comprising the compound, its pharmaceutically acceptable salt, stereoisomer, prodrug and/or solvate
A little compounds and the useful polymorphic of salt) pharmaceutical composition, and the compound and its pharmaceutically acceptable salt, vertical
Body isomers, prodrug and solvate are being prepared for treatment by various multi-forms (activated mutant body and/or resistant mutants
Form) EGFR mediation disease medicine in purposes.
Background technology
Cancer is becoming the mankind " killer " the most fatal, and in recent years, China dies from the total population of cancer every year, is close to
2000000 people.Although the discovery of various therapy approach and medicine brings hope to cancer patient, these routines
There is many drawbacks in treatment, for example large side effects, and therapeutic effect is not good, and tumor post-operation recurs, transfer etc..In the urgent need to new
Treatment technology solving the present situation of the low success rate for the treatment of of cancer.The Individual Chemotherapy for occurring recently and targeted therapy are to lung cancer
Treatment brings new hope.Tumor cells targeted therapy is to pass through chemistry based on the key molecule closely related to tumour growth
Or a kind for the treatment of method of biological means selective killing tumour cell.Targeted therapies have specificity height, selective
By force, the lighter feature of toxic and side effect.When targeted therapy is with classic chemotherapy, radiotherapy or tumour immunity use in conjunction, can be significantly
Strengthen curative effect, reduce postoperative recurrence.Neoplasm targeted therapy was developed rapidly in recent years, was the new of oncotherapy
Emerging field and future developing trend.
Protein tyrosine kinase (PTKs) is class protein enzyme, and they can be catalyzed residual in the tyrosine of multiple key proteins
Phenolic hydroxyl group phosphorylation reaction on base, thus activates the biologically active of functional protein.This process signal in the cell is passed
Highly important status is occupied in guiding path, and it adjusts a series of physiochemistry mistakes such as cell growth in vivo, differentiation, death
Journey.Protein tyrosine kinase functional disturbance can cause a series of biological internal diseases.Research shows, 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 may result in cell
Propagation regulation gets muddled, and then causes tumour to occur.Additionally, the unconventionality expression of EGFR-TK also with the invasion and attack of tumour and
Transfer, tumor neovasculature generation, the chemotherapy resistance to the action of a drug of tumour are closely related.EGFR-TK has become as antineoplastic
The critically important target spot that thing research and development are.
EGF-R ELISA (EGFR) is a kind of receptor tyrosine protein kinase, belongs in erbB receptor family
A kind of transmembrane protein.
EGFR has regulated and controled the propagation of cell, survival, adhesion, migrates and differentiation, and it is excessively lived in kinds of tumor cells
Change or continuous activation, such as lung cancer, breast cancer, in the cell such as prostate cancer.The abnormal activation of EGFR is in the conversion of tumour
With play critical effect in growth.The activation of blocking EGFR has been clinically proven thin for effective targeting therapy on tumor
One of born of the same parents' method.EGFR has expression in 50% NSCLC (non-compactness cell lung cancer) case.This causes EGFR
And its family member becomes the leading candidate of targeted therapy.Gefitinib (gefitinib) and Tarceva (erlotinib) are
The first generation micromolecular inhibitor of EGFR, is mainly used in treating the medicine of advanced NSCLC.Clinical effectiveness shows that Ji is non-to be replaced
Buddhist nun or Tarceva to about 10% white man NSCLC and about 35% asian ancestry NSCLC patient effective in cure.Analytical table
Reactivity of the bright most NSCLC patients with EGFR Activating mutations to EGFR- tyrosine kinase inhibitor (TKI)
It is significantly higher than the NSCLC patient of EGFR wild type.
But clinical research shows many patients (12-14 month) micromolecular inhibitor medicine just to these EGFR quickly
Generate the resistance to the action of a drug, i.e. acquired resistance.Residue (gatekeeper residue) T790M that guards the gate mutation is EGFR
A catastrophe point in 20 extrons, is to cause one of main mechanism of resistance.A new generation for these EGFR mutation
Inhibitor research is coming in be successful.Afatinib (Afatinib) is EGFR and hEGF
Potent, the irreversible double inhibitor of acceptor 2 (HER2) EGFR-TK.Other similar Mutiple Targets, high activity,
Irreversible inhibitor, for example, Canertinib (canertinib), reach and gram also just face in the later stage for Buddhist nun (Dacomitinib)
In bed test.These irreversible inhibitor of new second generation have very strong to the EGFR that L858R and T790M is mutated
Inhibitory action, have significant curative effect to the cancer patient that Gefitinib or Tarceva have developed immunity to drugs.But this
A little second generation EGFR mutant inhibitor similarly have extremely strong inhibition to Wild type EGFR (WT-EGFR).
The verified suppression to Wild type EGFR of clinical research can cause drug toxicity and side effect with most of patient,
Fash or diarrhoea are for example shown as in human body.
Overcome the Side effect of second generation EGFR inhibitor, be necessary for reducing to Wild type EGFR (WT-
EGFR inhibitory action).A new generation EGFR inhibitor should keep to EGFR L858R activated mutant body,
Exon19 disappearance activated mutant body and T790M resistant mutants have stronger suppression, while to WT-EGFR and other junket
Propylhomoserin protein kinase receptor shows relatively low inhibitory action.Such compound can be used for treatment EGFR L858R
Activated mutant body, the treatment of the cancer patient of Exon19 disappearance activated mutant body, and to first generation EGFR inhibitor such as
Gefitinib, Tarceva or Conmana have developed immunity to drugs the cancer patient of EGFR-T790M resistant mutants
Treatment, and without the side effect for worrying that second generation EGFR mutant inhibitor such as Afatinib is brought.
Present invention show many to EGFR mutant (one or more) with high inhibitory activity, but to wild type
EGFR only has the pyrimidine compound of relatively low inhibition.The compound of the present invention have preferable physicochemical properties and
Safe toxicity parameter.Such compound is in the treatment of cancer of the drug-resistant mutation for having EGFR activated mutant body and/or EGFR
In have preferable effect.
The present invention relates to some pyrimidine compounds and its pharmaceutically acceptable salt, which can be used for by the table of some variation patterns
Skin growth factor acceptor (such as L858R activated mutant body, Exon19 disappearance activated mutant body and T790M resistant mutation
Body) disease that mediated or the patient's condition treatment or prevention.Such compound and its pharmaceutically acceptable salt, stereoisomer,
Prodrug and solvate, can be used for treatment or the prevention of much different cancers.The invention further relates to comprising the compound and
Its pharmaceutically acceptable salt, stereoisomer, prodrug and solvate (are particularly the useful many of these compounds and salt
Crystal formation) pharmaceutical composition, useful intermediate and relate to the use of the compound and its medicine in the preparation of the compound
The treatment of acceptable salt on, stereoisomer, prodrug and solvate is by activation and/or resistant mutant forms
The method of the disease mediated by EGFR.
Therefore, in the urgent need to new type, especially the compound of novel skeleton solving drug resistance, ask by poor selectivity etc.
Topic.In documents below list, citation and the patent of the immediate prior art of patent application or non-patent document are (periodical, miscellaneous
Will, handbook and books etc.)：
1st, New England Journal of medicine, volume 2008,358, the 1160-1174 page；
2nd, Chemical and Biophysical Research Communications, volume 2004,319, the 1-11 page；
3rd, Science, volume 2004,304, the 1497-1500 page；
4th, New England Journalof medicine, volume 2004,350, the 2129-2139 page；
5th, Molecular Cancer Therapeutics, volume 2014,13, the 1468-1479 page；
6th, Journal of Medicinal Chemistry, volume 2014,57, the 8249-8267 page；
7th, WO2013014448A1, corresponding 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 representational document, not all about the complete of document
Permutation table.The complete disclosure of above-mentioned patent or non-patent document is incorporated herein by reference herein, there is contradiction or is supporting
In the case of touching, it is defined by description herein.
Current EGFR-TKI can not still solve the clinical problem caused by drug resistance, and mostly existing medicine be
With quinazoline or the reversible or irreversible inhibitor of EGFR that quinoline amine is basic parent nucleus, which is thin to EGFR wild type
The toxic and side effect that the poor selectivity of born of the same parents is brought remains inevitable.Therefore, in the urgent need to new type, especially novel
The problems such as compound of skeleton is to solve drug resistance, poor selectivity.
Content of the invention
It is an object of the present invention to provide pyrimidine compound below a class shown in formula (I) and its pharmaceutically acceptable salt,
Stereoisomer, prodrugs or solvate.Such compound can be to EGF-R ELISA (EGFR) albumen
The variation pattern of kinases produces inhibitory action, therefore can effectively suppress the growth of kinds of tumor cells, can be used to preparing antitumor
Medicine, the treatment for much different cancers or prevention, it is possible to overcome existing medicine Gefitinib, Tarceva etc. is lured
The drug resistance that sends out.More particularly, such compound can be used to prepare for treating or preventing by the EGFR of some variation patterns
The disease mediated by (such as L858R activated mutant body, Exon19 disappearance activated mutant body, and/or T790M resistant mutants)
The medicine of disease, obstacle, disorder or the patient's condition.
It is a further object of the present invention to provide the preparation method of above-claimed cpd.
It is yet another object of the invention to provide a kind of pharmaceutical composition, its include selected from above-mentioned pyrimidine compound, its pharmaceutically
One or more in acceptable salt, stereoisomer, prodrugs and solvate, and one or more pharmacy is auxiliary
Material.
It is yet another object of the invention to provide above-mentioned pyrimidine compound, its pharmaceutically acceptable salt, stereoisomer, front
Medicine molecule and/or solvate and aforementioned pharmaceutical compositions are being prepared for treating or preventing by the EGFR institute of variation pattern
Purposes in the medicine of the disease of mediation, obstacle, disorder or the patient's condition, is especially preparing for treating or preventing one kind or many
Plant the purposes of the medicine kind of cancer.
It is yet another object of the invention to provide a kind for the treatment of or prevention mediated by the EGFR of variation pattern disease, obstacle,
The method of disorderly or the patient's condition, especially one or more cancer.
It is yet another object of the invention to provide a kind of cancer combinational therapeutic methods, will be selected from above-mentioned pyrimidine compound, its medicine
One or more in acceptable salt, stereoisomer, prodrugs and solvate or the medicine according to the present invention
Composition is used in combination with conventional operation, radiotherapy, chemotherapy or tumour immunotherapy.
In a first aspect of the present invention, there is provided the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer,
Prodrugs or solvate：
Wherein:
R1It is C1-C6 alkyl, CD3, or the C1-C6 alkyl that replaced by fluorine；
R2It is
Wherein, R3It is hydrogen, fluorine, chlorine or bromine, n is the integer of 1-3；R4It is halogen substiuted or unsubstituted C2-C6
Alkyl or halogen substiuted or unsubstituted C3-C6 cycloalkyl；
Also, work as R1It is methyl, R2Can not be
Work as R1It is CD3, R2Can not be
In the preferred version of the application, in formula (I),
R1It is C1-C3 alkyl, CD3Or the C1-C3 alkyl replaced by 1 to 3 fluorine；
R2Selected from following group：
Also, work as R1It is methyl, R2Can not be
Work as R1It is CD3, R2Can not be
In another preferred version of the application, in formula (I), R1Methyl or CD3, R2Be selected from following groups：
Wherein, R4It is ethyl, cyclopropyl, bis- fluoro ethyl of 2,2-, 2,2,2- trifluoroethyl.
In another preferred version of the application, in formula (I), R1It is methyl or CD3, R2Be selected from following groups：
In another preferred version of the application, in formula (I), R1It is CD3, R2Be selected from following groups：
In another preferred version of the application, in formula (I), R1It is methyl, R2Be selected from following groups：
In the most preferred embodiment of the application, the compound of formula (I) is selected from：
The second aspect of the application, there is provided prepare the side of compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I)
Method, for example, methods described can with the method shown in following general reaction equation, wherein certain two step or multistep reaction order permissible
Intercourse, be not necessarily intended to just the same with the order 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 commercially availableization
Prepared by compound.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 reacting generating compound
A3.Under conditions of having p-methyl benzenesulfonic acid, compound A-13 and A4 reacting generating compound A5.N, N, N '-trimethyl second
Diamines A6 obtains product A7 in the fluorine atom having under conditions of potassium carbonate in replacement A5.Catalytic hydrogen reduction is by nitro
Benzene changes into aniline A8.After reacting with acrylic anhydride A9, final product A10 is generated.Product A10 adds at methanesulfonic acid
Mesylate A11 can be obtained after reason.Acid is different because of molecule with the ratio of compound A10, and a compound A10 is permissible
Become salt with 1-3 acid molecule, wherein in the majority with diacid salt or trisalt.
A kind of third aspect of the application, there is provided pharmaceutical composition, its include therapeutically effective amount selected from above-mentioned formula (I)
In one or more compound, its pharmaceutically acceptable salt, stereoisomer, prodrugs and/or solvate with
And one or more pharmaceutical excipients.Aforementioned pharmaceutical compositions are for treatment or to prevent by activated mutant body or the resistant mutation bodily form
The disease of formula EGFR mediation, obstacle, disorder or the patient's condition, in particular for treating or preventing the medicine of one or more cancer
Thing.
Said medicine can select multi-medicament dosage form according to therapeutic purposes, generally comprise：Tablet, pill, capsule
Agent, granule, suspension, solution, creme, ointment, pulvis, suppository, aerosol and injection etc..
The fourth aspect of the application, there is provided compound shown in above-mentioned formula (I), its pharmaceutically acceptable salt, solid are different
Structure body, prodrugs and/or solvate are preparing the EGFR mediation for the treatment of or prevention by activation or resistant mutant forms
Obstacle or disease medicine in purposes.The obstacle or disease are included but is not limited to:Oophoroma, cervical carcinoma, colon are straight
Intestinal cancer (for example, adenocarcinoma of colon), breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate
Cancer, leukaemia, lymthoma, NHL, cancer of the stomach, lung cancer (for example, non-small cell lung cancer), hepatocellular carcinoma,
Gastrointestinal stromal knurl (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, urgency
Acute myeloid leukemia (AML), Huppert's disease 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 disappearance activated mutant body and/or T790M resistant mutants.Therefore, dashed forward by activated mutant body or resistance
The disease of the EGFR mediation of variant form, obstacle, disorder or the patient's condition can be such as L858R activated mutant body,
Disease, obstacle, disorder or the patient's condition that Exon19 disappearance activated mutant body and/or T790M resistant mutants are mediated.
Compound, its pharmaceutically acceptable salt, stereoisomer, prodrugs and solvent according to the formula (I) of the present invention
Compound or the EGFR being particularly useful for according to the pharmaceutical composition of the present invention by activated mutant body or resistant mutant forms
The prevention of the disease of mediation, obstacle, disorder or the patient's condition or treatment, for example, lacked by L858R activated mutant body, Exon19
The prevention of disease, obstacle, disorder or the patient's condition that activated mutant body and/or T790M resistant mutants are mediated or treatment, than
Such as can be used for Gefitinib, the prevention of Tarceva or angstrom cancer patient that can have been developed immunity to drugs for Buddhist nun or treatment.
In still another aspect of the invention, there is provided a kind of cancer combinational therapeutic methods, it include to apply to individuality in need for the treatment of
With the pyrimidine compound selected from the formula (I) according to the present invention of therapeutically effective amount, its pharmaceutically acceptable salt, alloisomerism
One or more in body, prodrugs and solvate or the pharmaceutical composition according to the present invention of therapeutically effective amount, while
Conventional operation or radiotherapy or chemotherapy or immune tumor therapy is used in combination.
Described chemotherapy or immune tumor therapy and the compounds of this invention can side by side, simultaneously, sequentially or divide
It is not administered, and can be including but not limited to one or more of following kind of antitumor agent：Alkylating agent (such as card molybdenum,
Ao Shali molybdenum, suitable molybdenum, endoxan, nitrosoureas, mustargen, melphalan), antimetabolite (such as gemcitabine), and
Antifol (such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methopterin, cytarabine, hydroxycarbamide), topology are different
Structure enzyme inhibitor (such as Etoposide, Hycamtin, camptothecine), antimitotic agent (for example vincristine, vincaleukoblastinum,
Vinorelbine, taxol, taxotere), (for example adriamycin, bleomycin, Doxorubicin, road promise are mould for antitumor antibiotics
Element, mitomycin C, D actinomycin D), antiestrogen (such as TAM, fulvestrant, Toremifene, Lei Luoxi
Fragrant, Droloxifene), antiandrogen (such as Bicalutamide, Flutamide, Nilutamide), lhrh antagonist or
LHRH activator (such as Goserelin, Leuprorelin and Buserelin), aromatase inhibitor (such as Anastrozole,
Bent azoles), CYP17 lyase inhibitors (such as abiraterone), anti-erbB 2 antibody trastuzumab [Trastuzumab], resist
EGFR antibody cetuximab [Erbitux]；EGFR-TK, inhibitor (the such as Imatinib of serine/threonine kinase
Buddhist nun being replaced with AMN107, Sorafenib, trametinib, gram azoles) cell cycle protein dependent kinase inhibitor is (for example
CDK4 inhibitor palbociclib), anti-human vascular endothelial growth factor antibody Avastin (Avastin) and
Vegf receptor tyrosine kinase inhibitor (Ah handkerchief replaces Buddhist nun), immune tumor therapeuticing method, for example 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 the formula (I) of the present invention is illustrated to EGFR activated mutant body or resistant mutant forms (one or more)
With high inhibitory activity, but a class pyrimidine compound relatively low to Wild type EGFR suppression.The compound of the present invention
With preferable physicochemical properties and safe toxicity parameter.Such compound is by EGFR activated mutant and/or the resistance to the action of a drug
The treatment of the disease (including cancer) of mutation mediation has preferable clinical effectiveness.
Specific embodiment
The present invention will be further described for following examples, but the following example is not intended to limit the protection model of the present invention
Enclose.
Embodiment 121
1. the synthesis of intermediate 121-3
Nitrogen protection under, in 100 milliliters of (mL) there-necked flasks at room temperature, by raw material 121-1 (3.0 grams (g), 25.6
MM (mmol)) it is dissolved in 50mL 1,2- dichloroethanes (DCE), mixture is down to 0 DEG C, by first at 0 DEG C
Base magnesium bromide (8.5mL, 25.6mmol) is added dropwise in reaction system, is added rear constant temperature and is continued reaction 30 minutes
(min), again 121-2 (5.4g, 36.3mmol) is added in reaction system at 0 DEG C, reacts overnight after being warming up to room temperature.
After reaction completely, in reactant mixture, add 100 milliliters of frozen water that reaction is quenched, mixture is extracted with 100mL dichloromethane
Take 3 times, organic phase merge after with 100 milliliters of saturated common salt water washings 3 times, with concentration, crude product after anhydrous sodium sulfate drying
(ethyl acetate (EA)/petroleum ether (PE)=1 is purified with silica gel column chromatography:10-1:5), 2.0g product 121-3 is obtained
(34%), it is yellow solid.
Liquid chromatography mass (LCMS)：229.0.
2. the synthesis of intermediate 121-5
Under nitrogen protection, 121-4 (10g, 63.7mmol), 100mL nothing are sequentially added in 250mL there-necked flask
Water DMF (DMF), K2CO3(1.3g, 9.34mmol), and deuterated iodomethane (11g, 75.9
Mmol), react after then 50 DEG C being heated in oil bath 2 hours (h).Reaction is cooled to room temperature, uses 100mL frozen water
It is quenched, 100mL EA is extracted three times, filters, organic phase is washed 3 times with 200mL saturated common salt.Anhydrous sodium sulfate is done
Dry, concentrate drying, 9.7g product 121-5 (88%) is obtained, is yellow solid.
3. the synthesis of intermediate 121-6
121-5 (9.7g, 55.7mol), 240mL methyl alcohol, palladium carbon (12 is sequentially added in 500mL single port bottle
G, 5%), replace three hydrogen, reaction overnight under room temperature.Filter out palladium carbon, filtrate concentrate drying, obtain 7.2g product
121-6 (90%), is light color liquid.
LCMS：145.1.
4. the synthesis of intermediate 121-7
Under nitrogen protection, 121-6 (7.2g, 49.9mmol) is sequentially added in 250mL there-necked flask, 64mL is dense
Sulfuric acid, is dividedly in some parts red fuming nitric acid (RFNA) (HNO after being cooled to 0-10 DEG C3) (5.05g, 50.0mmol), added with 15 minutes.
React overnight under room temperature.Reactant mixture being added in 500mL frozen water reaction being quenched, it is 10 pH to be adjusted with ammoniacal liquor, uses
100mL EA is extracted three times, then is washed 3 times with 200mL saturated common salt.After anhydrous sodium sulfate drying, concentrate drying,
5.1g product 121-7 (54%) is obtained, is yellow 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 under room temperature
In milliliter DMF, reaction system is cooled to 0 DEG C after finishing by charging, is then dividedly in some parts sodium hydride
(NaH) (786mg, 18.5mmol), at 0 DEG C react 0.5 hour after add TFMS trifluoro ethyl ester 121-8 (3.65g,
15mmol), charging is finished and is back to room temperature reaction 2 hours, and detection reaction is completely.Reactant liquor is poured in 200mL frozen water
It is quenched, has red solid to separate out, gained mixture is filtered, solid is collected, 4.2g product 121-9 is dried to obtain, is red
Color solid.LCMS：312.0.
6. the synthesis of intermediate 121-10
Under nitrogen protection, in 250mL there-necked flask, raw material 121-9 (1.8g, 5.77mmol) is dissolved under room temperature
In 50mL isopropanol (i-PrOH), then successively by 121-7 (1.1g, 5.82mmol), and p-methyl benzenesulfonic acid (1.3g, 7.55
Mmol) it is added in reaction system, reaction system is warming up to 105 DEG C after finishing and reacts 6 hours by charging.Detection has been reacted
Reaction system is dropped to room temperature after complete, mixture is filtered, filter cake is collected, solid dries to obtain 3g crude product 121-10, be yellow
Color solid.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 in 30 under room temperature
In mL N- methyl cyclohexane acid amides (NMP), then successively by N, N, N '-trimethyl ethylenediamine (860mg, 8.42mmol), no
Aqueous carbonate potassium (2.7g, 19.5mmol) is added in reaction system, and reaction system is warmed up to 100 DEG C after finishing by charging.Instead
After answering 2 hours, detection reaction completely, reaction system is down to room temperature, reactant liquor is poured into and is quenched in 100mL frozen water, will
Mixture suction filtration, collects filter cake and dries, obtain 1.7g (48%) product 121-11, be red solid.LCMS：
547.2.
8. the synthesis of intermediate 121-12
Under nitrogen protection, in 250mL single port bottle, under room temperature, methyl alcohol 50mL, dichloromethane (DCM) is sequentially added
50mL, raw material 121-11 (1.7g, 3.11mmol), aqueous palladium carbon (1.7g, 10%), ammonium formate (1.7g), feed
By system room temperature reaction 3 hours after finishing, detection reaction is completely.Reaction system suction filtration, collects filtrate, is concentrated to dryness.Gained
Residue 200mL dichloromethane dissolves, 200mL NaHCO3Aqueous solution backwash 1 time, then eaten with 200mL saturation
Salt is washed 1 time, obtains 0.8g (50%) product 121-12 after organic phase anhydrous sodium sulfate drying after being concentrated to dryness, and is yellow
Color 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 under room temperature
In 50mL chloroform, reactant mixture is cooled to 0 DEG C, acrylic anhydride (195mg, 1.55mmol) is added drop-wise to
In reaction system, react about 1 hour at 0 DEG C after adding.After detection reaction completely, directly reactant mixture is concentrated to dryness,
Gained residue preparative chromatography column chromatography (chromatographic column：Silica gel, mobile phase：CHCl3/ EtOH, 20-60% ethanol；
20min；Detection wavelength：254nm) purify.Products obtained therefrom organic phase is concentrated to dryness, obtains 300mg compound
121.
By 300mg compound 121 in 20mL acetonitrile, by methanesulfonic acid (297.7mg, 2.00equiv, 2.0eq)
It is added drop-wise in system, reactant mixture was concentrated to dryness after 1 hour by insulated and stirred at low temperature, gained residue is added water again
The mesylate of 466mg (39%) 121 is obtained after new dissolving 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)：δ9.50(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, in 500mL there-necked flask, 5- fluoro indole (10g, 74.0mmol) is added, 100mL steams again
Anhydrous tetrahydro furan, cools the temperature to 0 DEG C, dropping 37.1mL methyl-magnesium-bromide diethyl ether solution (3.0M), completion of dropping
Afterwards, 0 DEG C of reaction about 30min is kept, 2,4- dichloro pyrimidine (16.5g, 111mmol) at 0 DEG C, is dividedly in some parts, charging is finished
Afterwards reaction system is returned to room temperature reaction overnight naturally.After detection reaction completely, 100mL chlorination is dripped in reaction system
Reaction is quenched by aqueous ammonium, is extracted 2 times to gained mixture with 100mL ethyl acetate, is merged organic phase, is used 100
ML saturated aqueous common salt backwash 1 time, is concentrated to dryness after anhydrous sodium sulfate drying, and gained solid 100mL acetonitrile is washed 1 time,
Suction filtration, collects filter cake drying and obtains 6g (33%) product 122-1, be yellow solid.LCMS：248.0.
2. the synthesis of intermediate 122-2
Under nitrogen protection, in 100mL there-necked flask, raw material 122-1 (2.0g, 8.08mmol) is dissolved in 50 under room temperature
In mL dry DMF, then it is cooled to 0 DEG C and NaH (65%, 445mg, 12.1mmol) is dividedly in some parts, charging is finished
Afterwards reaction system is kept 0 DEG C of reaction 30min.Then drip at 0 DEG C TFMS trifluoro ethyl ester (2.8g, 12.1
Mmol), system is kept for 0 DEG C react 1 hour after completion of dropping, after detection reaction completely, reactant mixture is poured into
Reaction is quenched in 100mL frozen water, is separated out solid, mixture is filtered, collect filter cake and dry to obtain 3g crude product 122-2,
For yellow solid.LCMS：330.0.
3. the synthesis of intermediate 122-4
Under nitrogen protection, 122-3 (100g, 709mmol) and 800mL is sequentially added in 2000mL there-necked flask
The concentrated sulfuric acid (H2SO4), 0 DEG C is cooled to, and maintains temperature potassium nitrate (KNO to be dividedly in some parts between 0-10 DEG C3) (71.6g,
708mmol), used time 1 hour, finally reacts overnight at room temperature.After reaction terminates, 2 liters (L) is added in there-necked flask
Frozen water is to be quenched reaction.It is 10 reactant mixture ammoniacal liquor to be transferred to pH under low temperature, is extracted with 1L dichloromethane (DCM)
Take 3 times.After organic phase merges, with 3L saturated aqueous common salt backwash 3 times, with anhydrous sodium sulfate drying, it is spin-dried for.Gained is thick
Product is through silica gel column chromatography (eluant ethyl acetate (EA):Petroleum ether (PE)=1:4-1:After 1), eluent is spin-dried for
To 79g 122-4 (yield：60%), it is yellow solid.
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 30 under room temperature
In mL isopropanol, then successively by 122-4 (1.7g, 9.13mmol), p-methyl benzenesulfonic acid (2g, 11.6mmol) is added to
In reaction system, reaction system is warming up to 105 DEG C of reaction 6h after finishing by charging.By reaction system after detection reaction completely
Room temperature is dropped to, mixture is filtered, filter cake is collected, 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 30 under room temperature
In mL NMP, then successively by N, N- trimethyl ethylenediamine (770mg, 7.54mmol), Anhydrous potassium carbonate (2.1g,
15.2mmol) it is added in reaction system, reaction system is warmed up to 100 DEG C after finishing by charging.After reaction 2h, detection is anti-
Reaction system should be down to room temperature, reactant liquor is poured into and is quenched in 100mL frozen water completely, mixture suction filtration is collected
Filter cake is simultaneously dried, and is obtained 1.5g (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, under room temperature, methyl alcohol 50mL, dichloromethane 50mL is sequentially added,
Raw material 122-6 (1.5g, 2.67mmol), aqueous palladium carbon (10%, 1.5g), ammonium formate (1.5g), feed by body after finishing
It is room temperature reaction 3h, detection reaction is completely.Reaction system suction filtration, collects filtrate, is concentrated to dryness.Gained residue is used
200mL dichloromethane dissolves, 200mL sodium bicarbonate aqueous solution backwash 1 time, then washes 1 with 200mL saturated common salt
Secondary, 1.1g (77%) product 122-7 is obtained after being concentrated to dryness after organic phase anhydrous sodium sulfate drying, is 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 30 under room temperature
In mL chloroform, reactant mixture is cooled to 0 DEG C, acrylic anhydride (260mg, 2.06mmol) is added drop-wise to reaction
In system, react about 1 hour at 0 DEG C after adding.After detection reaction completely, it is directly thickened to do, gained residue silicon
Plastic column chromatography (chromatographic column：Silica gel, mobile phase：CHCl3/EtOH)；20-60% ethanol；20min；Detection wavelength：
254nm) purify.Products obtained therefrom organic phase is concentrated to dryness, obtains 590mg compound 122.
By 960mg compound 122 in 10mL acetonitrile, methanesulfonic acid (96mg, 1.00mmol, 1.0eq) is dripped
It is added in system, reactant mixture was concentrated to dryness after 1 hour by insulated and stirred at low temperature, gained residue is added water again
The mesylate of 629.4mg (45%) 122 is obtained after dissolving after freeze-drying, is yellow solid.
LRMS (parent molecule) C29H31F4N7O2:(ES,m/z):586.2[M+H]+.
1H-NMR (mesylate):(300MHz,DMSO-D6,ppm):δ9.45(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=5.4
Hz, 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, 1
), H 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, in 100mL there-necked flask, raw material 122-1 (2.5g, 10.1mmol) is dissolved in 50 under room temperature
In mL dry DMF, then it is cooled to 0 DEG C and NaH (65%, 560mg, 15.2mmol) is dividedly in some parts, charging is finished
Afterwards reaction system is maintained at 0 DEG C to react 30 minutes.Then drip at 0 DEG C the fluoro- 2- bromoethane of 1,1- bis- (2.9g, 20.0
Mmol), system is returned to room temperature reaction overnight after completion of dropping.After detection reaction completely, reactant mixture is poured into
Reaction is quenched in 200mL frozen water, is separated out solid, mixture is filtered, collect filter cake, washed 1 time with 50mL acetonitrile,
And 1.6g (51%) product 123-1 is dried to obtain, it is yellow solid.LCMS：312.0.
2. the synthesis of compound 123
Synthesize experimental procedure and reaction condition and above-described embodiment of compound 123 and its mesylate from intermediate 123-1
In 122, the 4th step is identical to the chemical reaction of the 7th step.Except for the difference that embodiment 122 instead of with intermediate 123-1 here
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):δ9.43(br s,2H),8.79(s,1H),8.60
(s,2H),8.35-8.26(m,2H),8.00(br s,1H),7.75-7.71(m,1H),7.19-7.13(m,1H),7.09(s,1
H),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), 100mL anhydrous four is added in 250mL there-necked flask
Hydrogen furans, cools the temperature to 0 DEG C, dropping 18.5mL methyl-magnesium-bromide diethyl ether solution (3.0M), after completion of dropping, protects
Hold 0 DEG C to react about 30 minutes, 2,4- dichloro pyrimidine (8.28g, 55.6mmol) at 0 DEG C, is dividedly in some parts, charging will after finishing
Reaction system returns to room temperature reaction overnight naturally.After detection reaction completely, 100mL ammonium chloride water is dripped in reaction system
Reaction is quenched by solution, is extracted 2 times to gained mixture with 100mL ethyl acetate, is merged organic phase, is used 100mL
Saturated aqueous common salt backwash 1 time, is concentrated to dryness after anhydrous sodium sulfate drying, and gained solid 50mL acetonitrile is washed 1 time, is taken out
Filter, collects filter cake drying and obtains 6.1g (67%) 124-1, be yellow solid.LCMS：248.0.
2. the synthesis of intermediate 124-2
Under nitrogen protection, in 250mL there-necked flask, raw material 124-1 (6.1g, 24.6mmol) is dissolved in 100 under room temperature
In mL dry DMF, then it is cooled to 0 DEG C and NaH (65%, 1.4g, 37.9mmol) is dividedly in some parts, after charging is finished
Reaction system is kept for 0 DEG C react 30 minutes.Then drip at 0 DEG C TFMS trifluoro ethyl ester (8.6g, 37.1
Mmol), system is kept for 0 DEG C react 2 hours after completion of dropping, after detection reaction completely, reactant mixture is poured into
Reaction is quenched in 200mL frozen water, is separated out solid, mixture is filtered, collect filter cake and dry to obtain 3g (37%) product
124-2, is yellow solid.LCMS：330.0.
3. the synthesis of compound 124
Synthesize experimental procedure and reaction condition and above-described embodiment of compound 124 and its mesylate from intermediate 124-2
In 122, the 4th step is identical to the chemical reaction of the 7th step.Except for the difference that embodiment 122 instead of with intermediate 124-2 here
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)：δ9.70(br s,1H),8.67(br s,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, in 100mL there-necked flask, raw material 124-1 (2.5g, 10.1mmol) is dissolved in 50 under room temperature
In mL dry DMF, then it is cooled to 0 DEG C and NaH (65%, 560mg, 15.2mmol) is dividedly in some parts, after charging is finished
Reaction system is kept for 0 DEG C react 30 minutes.Then drip at 0 DEG C the fluoro- 2- bromoethane of 1,1- bis- (2.9g, 20.0
Mmol), system is returned to room temperature reaction overnight after completion of dropping.After detection reaction completely, reactant mixture is poured into
Reaction is quenched in 100mL frozen water, is separated out solid, mixture is filtered, collect filter cake, washed 1 time with 50mL acetonitrile,
1.5g (48%) product 125-1 is dried to obtain, is yellow solid.LCMS：312.0.
2. the synthesis of compound 125
Synthesize experimental procedure and reaction condition and above-described embodiment of compound 125 and its mesylate from intermediate 125-1
In 122, the 4th step is identical to the chemical reaction of the 7th step.Except for the difference that embodiment 122 instead of with intermediate 125-1 here
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):δ9.55(s,2H),9.26(br s,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, 1
H),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：
Method with the growth for determining cell identifying the EGFR being preferentially targeted for some variation patterns, and to wild type
The relatively weak compound of the activity of EGFR.NCI-H1975 cell line is mutated containing T790M and L858R EGFR
Human non-small cell lung cancer's cell, the cell growth containing 10% hyclone (FBS) RPMI-1640 culture medium
(GIBCO) in.LoVo cell line is the human colon adenocarcinoma cell of a Wild type EGFR, and the cell growth is containing 10%
In the F-12K culture medium (GIBCO) of FBS.The growth speed of NCI-H1975 and LoVo cell is sent out by Cell Titer-Glo
Light vitality test method (Promega company #G7572) is detecting.
In brief, digest the cell in exponential phase with trypsase, and with 5000, every hole Lovo or
3000 NCI-H1975 cells are inoculated in 96 orifice plates, and are incubated in 37 DEG C, have 5%CO2Moistening incubator in,
While setting the blank control wells that not inoculating cell only adds nutrient solution.After 24 hours, by the DMSO solution of different compounds
Variable concentrations are diluted to from high to low with cell culture medium liquid, diluted with 3.16 times every time, have 8 differences dense
Degree.In NCI-H1975 cell the concentration of testing drug from 0.03nM-100nM, LoVo cell testing drug dense
Degree is from 3nM-10 μM.Then the cell culture medium liquid of different compounds is added in 96 porocyte plates of cell,
While setting the cell control well of the cell culture medium liquid only containing DMSO.After drug-treated 72 hours, will be thin
Born of the same parents' plate takes out from incubator and places 30 minutes at room temperature.Then plus Cell Titer-Glo reagent is in hole, and by 96
Porocyte plates are rocked 10 minutes at room temperature, with inducing cell lysis.Again 96 porocyte plates are placed on experimental bench upper 2 minute,
Make luminous signal stable.Finally 96 porocyte plates are put in EnVision multiple labeling micropore board detector (PerkinElmer),
The time of integration with 0.5 second is come read signal.
Computing formula is：
Cell growth inhibition percentage %=(peak signal compound signal)/(peak signal-minimum signal) * 100%
Peak signal is obtained by the cell control well of the DMSO control treatment without compound；
Compound signal is obtained by the cell hole of the drug-treated for adding compound
Minimum signal is obtained only in the blank control wells of nutrient solution by without cell.
Cell growth inhibition curve is calculated by GraphPad Prism V5.0 software, and acquisition is calculated based on this data
Compound concentration needed for 50% inhibition, i.e. compound IC50.
Acquired results are arranged in table 1 below.
Table 1：Compound activity experimental result
Claims (10)
1. pyrimidine compound or its pharmaceutically acceptable salt, stereoisomer, prodrug of the class as shown in following formula (I)
Molecule or solvate：
Wherein:
R1It is C1-C6 alkyl, CD3, or the C1-C6 alkyl that replaced by fluorine；
R2It is
Wherein, R3It is hydrogen, fluorine, chlorine or bromine, n is the integer of 1-3；R4It is halogen substiuted or unsubstituted C2-C6
Alkyl or halogen substiuted or unsubstituted C3-C6 cycloalkyl；
Also, work as R1It is methyl, R2Can not be
Work as R1It is CD3, R2Can not be
2. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, front
Medicine molecule or solvate, wherein,
R1It is C1-C3 alkyl, CD3Or the C1-C3 alkyl replaced by 1 to 3 fluorine；
R2Be selected from following group：
Also, work as R1It is methyl, R2Can not be
Work as R1It is CD3, R2Can not be
3. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, prodrug
Molecule or solvate, wherein,
R1It is methyl or CD3, R2Be selected from following groups：
Wherein, R4It is ethyl, cyclopropyl, bis- fluoro ethyl of 2,2-, 2,2,2- trifluoroethyl.
4. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, prodrug
Molecule or solvate, wherein,
R1It is methyl or CD3, R2Be selected from following groups：
5. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, prodrug
Molecule or solvate, wherein,
R1It is CD3, R2Be selected from following groups：
6. pyrimidine compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, prodrug
Molecule or solvate, wherein,
R1It is methyl, R2Be selected from following groups：
7. a class pyrimidine compound or its pharmaceutically acceptable salt, stereoisomer, prodrugs or solvate,
Wherein, the pyrimidine compound is as follows compound：
8. a kind of pharmaceutical composition, its include one or more of therapeutically effective amount selected from any one in claim 1～7
Described compound, its pharmaceutically acceptable salt, stereoisomer, prodrugs and/or solvate and a kind of or
Multiple pharmaceutical excipients.
9. compound in claim 1～7 described in any one, its pharmaceutically acceptable salt, stereoisomer, front
Medicine molecule and/or solvate prepare treatment or prevention by activation or resistant mutant forms EGFR mediation obstacle or
Purposes in the medicine of disease.
10. purposes according to claim 9, wherein, the EGFR mediation by activation or resistant mutant forms
Obstacle or disease be oophoroma, cervical carcinoma, colorectal cancer, breast cancer, cancer of pancreas, glioma, glioblast
Knurl, melanoma, prostate cancer, leukaemia, lymthoma, NHL, cancer of the stomach, lung cancer, hepatocellular carcinoma,
Gastrointestinal stromal knurl, thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type, acute marrow are thin
Born of the same parents' leukaemia, Huppert's disease or celiothelioma.
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| WO2023011415A1 (en) * | 2021-08-02 | 2023-02-09 | 贝达药业股份有限公司 | Pharmaceutical composition of egfr inhibitor and use thereof |
| CN115925687A (en) * | 2022-12-29 | 2023-04-07 | 广东省人民医院 | EGFR (epidermal growth factor receptor) -targeting compound, PET (polyethylene terephthalate) molecular probe and preparation method and application thereof |
| CN115925687B (en) * | 2022-12-29 | 2024-04-02 | 广东省人民医院 | EGFR-targeting compound, PET molecular probe and preparation method and application thereof |
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