CN103421010A - Pteridinone derivative as EGFR inhibitor and application thereof - Google Patents

Pteridinone derivative as EGFR inhibitor and application thereof Download PDF

Info

Publication number
CN103421010A
CN103421010A CN2012101489393A CN201210148939A CN103421010A CN 103421010 A CN103421010 A CN 103421010A CN 2012101489393 A CN2012101489393 A CN 2012101489393A CN 201210148939 A CN201210148939 A CN 201210148939A CN 103421010 A CN103421010 A CN 103421010A
Authority
CN
China
Prior art keywords
optional
replaced
alkyl
amino
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2012101489393A
Other languages
Chinese (zh)
Inventor
李洪林
徐玉芳
赵振江
周伟
刘晓峰
薛梦竹
张磊
张友利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China University of Science and Technology
Original Assignee
East China University of Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China University of Science and Technology filed Critical East China University of Science and Technology
Priority to CN2012101489393A priority Critical patent/CN103421010A/en
Priority to US14/400,508 priority patent/US9670213B2/en
Priority to JP2015511908A priority patent/JP6114820B2/en
Priority to DE112013002484.5T priority patent/DE112013002484B4/en
Priority to CN201380003282.4A priority patent/CN103930425B/en
Priority to CN201610325343.4A priority patent/CN106008511B/en
Priority to PCT/CN2013/073612 priority patent/WO2013170671A1/en
Publication of CN103421010A publication Critical patent/CN103421010A/en
Pending legal-status Critical Current

Links

Abstract

The invention relates to a pteridinone derivative as an epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor and an application thereof. Specifically, the invention relates to the compound represented by the following formula I, a pharmaceutical composition containing the compound represented by the following formula I, and the application of the compound in preparation of a drug for treating EGFR mediated diseases or inhibiting EGFR.

Description

Pteridinone derivative and application thereof as the EGFR inhibitor
Technical field
The present invention relates to the synthetic of pteridinone compounds and, in the application in pharmaceutical chemistry and pharmacotherapeutics field, specifically, relate to the application of pteridinone compounds in the medicine for preparing the Tumor-assaciated disease of different substituents.This compounds has very high inhibition epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine kinase, EGFR) activity, thereby has potential treatment tumour and the purposes of relative disease.
Background technology
Malignant tumour is the cellularity pathology, is characterized in that the cell proper splitting is out of hand, causes uncontrolled differentiation, propagation, thereby and can invade local organization and cause transfer.Malignant tumour becomes to have become the common disease of serious harm human life health, and according to incompletely statistics, there is nearly new cases of 2,000 ten thousand every year in the whole world.Therefore, the research and development of antitumor drug are to be rich in challenge and far reaching field in current life science.
Traditional antitumor drug is mainly cytotoxicity class medicine, and this class medicine has the toxic side effect that is difficult to avoid, poor selectivity, easily produces the shortcomings such as resistance.Along with the develop rapidly of Life Sci-Tech, in malignant cell, the various basic vital processes such as signal transduction, the adjusting of cell cycle, vasculogenesis are just progressively illustrated.Using the key enzyme of some signal transduction pathway relevant to tumor cell proliferation as the drug screening target spot, and exploitation result for the treatment of antitumor drug good, that toxic side effect is little has become an important directions of current antitumor drug research.Protein tyrosine kinase (protein tyrosine kinase) is that the upper γ-phosphoric acid of a class catalysis ATP is transferred to the albumen on the albumen particular amino acid residue, occupy very important status in the intracellular signal transduction path, and regulating a series of physiological processs such as Growth of Cells, differentiation, death.Existing data shows, surpasses 50% proto-oncogene and product thereof and all has protein tyrosine kinase activity, and their unconventionality expression will cause the disorder of cell life cycle, and then lead oncogenic generation.In addition, the unconventionality expression of Tyrosylprotein kinase is also closely related with the transfer of tumour, chemotherapy resistance etc.
Epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine kinase, EGFR) can mediate many barss Signal Transduction Pathways, extracellular signal is delivered in born of the same parents, propagation, differentiation and the apoptosis of normal cell and tumour cell are all brought into play to important regulating effect (Cell, 2000,100,113-127).Therefore optionally suppress the signal transduction pathway of EGFR mediation, can reach the purpose for the treatment of tumour, for targeting therapy on tumor has been opened up a practical way.The medicine that the EGFR of take is target spot, as Gefitinib, Erlotinib and Laptinib go on the market, for the treatment of nonsmall-cell lung cancer and mammary cancer.Yet clinical experience shows: most of Patients with Non-small-cell Lung, after Reusability Gefitinib or Erlotinib treatment, has produced resistance.Wherein amino acid whose sudden change in the resistance of 50% case and EGFR kinase domain (790 threonine residues sport methionine(Met), T790M) relevant (The New England Journal of Medicine, 2005,352,786-792).In order to overcome the T790M relevant resistance of suddenling change, a series of irreversible ATP competitive inhibitors (as CI-1033, BIBW2992, HKI-272, PF00299804 etc.) have entered clinical study.Irreversible inhibitor contains a michael acceptor fragment, can form covalent linkage with a conservative amino acid residues (Cys797) of the ATP-binding site of EGFR, thereby obtained the EGFR binding affinity stronger than reversible inhibitor (Journal of Medicinal Chemistry, 2009,52,1231-1246).However, the side effect that the toxic action caused due to the effect of missing the target, low selectivity cause, can't realize the reasons such as drug level enough in patient body, the clinical test results of above-mentioned irreversible inhibitor is not ideal enough (Nature, 2009 still, 462,1070-1074).Therefore, the irreversible EGFR inhibitor of development of new has great clinical meaning and application prospect.
Summary of the invention
The inventor adopts the Computer-Aided Drug Design means to set up the virtual screening platform of EGFR specificity micromolecular inhibitor, consider pharmacophore and molecular docking method, the commercial compound database (is comprised ACD-3D (chemical storehouse), ACD-SC, MDDR-3D (pharmaceutical activity data report storehouse) and CNPD) screened, found a collection ofly to have potential EGFR and suppress active material standed for.
The candidate compound obtained is carried out to composition optimizes, designed and synthesized a series of pteridinone compounds that have no bibliographical information, and finished the structure sign.This series compound has been carried out to the active testing of molecular level and cell levels, obtained a collection ofly thering is very high EGFR and suppressing active compound.006 couple of EGF R of compound wherein T790M/L858Kinase inhibiting activity IC 50For 8.4nM, HCC827(non-small cell lung cancer cell, EGFR delE 746-A750) the active IC of cell inhibitory effect 50Be 0.03 μ M.
Involved in the present invention to pteridine ketone EGFR inhibitor can block the phosphorylation process of EGFR, the growth of inhibition tumor cell, propagation and differentiation, thereby can develop and become new antitumor drug.
Pteridinone compounds of the present invention has structure shown in general formula I:
Figure BDA00001635745700031
In formula,
A and B are for being with various substituent phenyl ring or five yuan or hexa-member heterocycle;
C is selected from arbitrary group as follows:
Figure BDA00001635745700032
Wherein, X is selected from O, S and Se; R 1For hydrogen, halogen atom, C1-C6 alkoxyl group (such as methoxyl group, oxyethyl group etc.), the optional C replaced 1-C 6Alkyl (alkyl that for example halogen replaces), the optional aryl replaced (aryl that for example halogen replaces) or the optional aralkyl (for example arylmethyl) replaced;
R 2Independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced; Wherein, R aAnd R bCan be selected from alkyl and alkenyl;
R 3Independently be selected from separately hydrogen, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl, the optional alkoxyl formyl replaced;
M and n respectively do for oneself 0,1,2,3 or 4.
In one embodiment, C is the following formula group:
Figure BDA00001635745700041
In one embodiment, R 1Be selected from H and alkyl.
In one embodiment, A and B are the optional phenyl replaced.
In one embodiment, R 2Independently be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR aR b, amido and formamyl (NH 2C (O)-), wherein, R aAnd R bCan be selected from alkyl and alkenyl.
In one embodiment, R 2Independently be selected from 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-ethylamino, N, N-methyl methylamino and 4-pyridyl.
In one embodiment, R 3Independently be selected from amido, acyloxy and alkoxyl group.
In one embodiment, R 3Independently be selected from following group:
Figure BDA00001635745700042
In one embodiment, R 3Be selected from following group:
Figure BDA00001635745700043
In one embodiment, m is 1 or 2.
In one embodiment, n is 1,2,3 or 4.
In one embodiment, in the group shown in C, containing R 1The waviness of part with C, be connected, and another part is connected with NH.
A preferred version of the present invention is that described compound has structure shown in general formula I I:
Figure BDA00001635745700051
In formula,
Y is selected from N, CH;
Z is selected from N, CR 6
R 1For hydrogen, halogen, C1-C6 alkoxyl group, the optional C replaced 1-C 6Alkyl, the optional aryl replaced, the optional aralkyl replaced;
R 3Independently be selected from acyloxy, amino, the optional amido replaced, the optional C replaced of optional replacement 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl and the optional alkoxyl formyl replaced; R 4, R 5, R 6And R 7Independently be selected from separately hydrogen, halogen, C 1-C 6Alkoxyl group,, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced; Wherein, R aAnd R bCan be selected from alkyl and alkenyl; With
The integer that m is 0-3.
Of the present invention one more preferably scheme be that described compound has structure shown in general formula III:
Figure BDA00001635745700052
In formula,
R 1For hydrogen, halogen, C1-C6 alkoxyl group, the optional C replaced 1-C 6Alkyl, the optional aryl replaced, the optional aralkyl replaced
R 3Independently be selected from acyloxy, amino, the optional amido replaced, the optional C replaced of optional replacement 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl and the optional alkoxyl formyl replaced;
R 5, R 6And R 7Independently be selected from separately hydrogen, halogen, C 1-C 6Alkoxyl group,, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced; Wherein, R aAnd R bCan be selected from alkyl and alkenyl; With
M is 0,1,2 or 3.In a preferred embodiment of formula III, R 1Be selected from H and alkyl.
In a preferred embodiment of formula III, R 5And R 6Independently be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrrolidyl ,-NR aR b, amido and formamyl (NH 2C (O)-), wherein, R aAnd R bCan be selected from alkyl and alkenyl.
In a preferred embodiment of formula III, R 5Be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR aR b, amido and formamyl (NH 2C (O)-), wherein, R aAnd R bCan be selected from alkyl and alkenyl.
In a preferred embodiment of formula III, R 5Be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR aR b, amido and formamyl (NH 2C (O)-), wherein, R aAnd R bCan be selected from alkyl and alkenyl; R 6For H.
In a preferred embodiment of formula III, R 5Be selected from halogen, 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-diethylamino, N, N-dimethyl methyl amido and 4-pyridyl.
In a preferred embodiment of formula III, R 5And R 6For H, R 7For amido.
In a preferred embodiment of formula III, R 3Independently be selected from amido, acyloxy and alkoxyl group.
In a preferred embodiment of formula III, R 3Independently be selected from following group:
Figure BDA00001635745700061
In a preferred embodiment of formula III, R 3Be selected from following group:
Figure BDA00001635745700071
In a preferred embodiment of formula III, m is 1.
In a preferred embodiment of formula III, m is 1, R 34 of phenyl.
The preferred compound of the present invention is as shown in compound 001-032.
The present invention also comprises that the compounds of this invention is preparing the purposes for the treatment of in the medicine of the disease of epidermal growth factor receptor kinase (EGFR) mediation.
In one embodiment, described disease is cancer.
In one embodiment, described cancer is selected from nonsmall-cell lung cancer, mammary cancer, prostate cancer, neurogliocytoma, ovarian cancer, incidence squama cancer, cervical cancer, the esophageal carcinoma, liver cancer, kidney, carcinoma of the pancreas, colorectal carcinoma, skin carcinoma, leukemia, lymphoma, cancer of the stomach, multiple marrow cancer and solid tumor.
The present invention also comprises the purposes of the compounds of this invention in the medicine of preparation inhibition epidermal growth factor receptor kinase (EGFR).
The present invention is the such use of formula III compound particularly preferably, especially the such use of compound 002-004,006,008-011,013-018,020-027,029-032.
The present invention also comprises the pharmaceutical composition that contains the compounds of this invention, and this pharmaceutical composition also optionally contains pharmaceutically acceptable carrier, vehicle, thinner etc.
Embodiment
Further do following explanation for some terms that relate to herein:
Herein, " alkyl " refers to the saturated branched-chain or straight-chain alkyl that carbon chain lengths is 1-10 carbon atom, the alkyl that preferred alkyl comprises that a long 2-8 carbon atom, 1-6 are individual, a 1-4 carbon atom, a 3-8 carbon atom, a 1-3 carbon atom do not wait.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, heptyl etc.
Alkyl can be replaced by one or more substituting groups, for example by halogen or haloalkyl, is replaced.For example, the alkyl that alkyl can be replaced by 1-4 fluorine atom, or the alkyl alkyl that can be replaced by fluoro-alkyl.
Herein, " alkoxyl group " refers to the oxygen base replaced by alkyl.Preferred alkoxyl group is the alkoxyl group of a long 1-6 carbon atom, more preferably the alkoxyl group of a long 1-4 carbon atom.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-etc.
Herein, " alkenyl " ordinary representation has the univalence hydrocarbyl of at least one two key, usually contains 2-8 carbon atom, preferably contains 2-6 carbon atom, can be straight or branched.The example of alkenyl includes but not limited to vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, hexenyl etc.
Herein, " alkynyl " ordinary representation has the univalence hydrocarbyl of at least one triple bond, usually contains 2-8 carbon atom, preferably contains 2-6 carbon atom, more generally contains 2-4 carbon atom, can be straight or branched.The example of alkenyl comprises ethynyl, proyl, isopropyl alkynyl, butynyl, isobutyl alkynyl, hexin base etc.
Herein, " halogen atom " or " halogen " refers to fluorine, chlorine, bromine and iodine.
" aryl " refers to the monocycle, dicyclo or the three cyclophane family groups that contain 6 to 14 carbon atoms, comprises phenyl, naphthyl, phenanthryl, anthryl, indenyl, Fluorene base, tetrahydro naphthyl, indanyl etc.Aryl optionally for example, is selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replaces: alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, N (CH that the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, halogen replace 3) and C1-4 acyl group etc., heterocyclic radical or heteroaryl etc.
Herein, " aralkyl " refers to the alkyl replaced by aryl, the C1-C6 alkyl for example be substituted by phenyl.The example of aralkyl includes but not limited to arylmethyl, aryl ethyl etc., such as benzyl, styroyl etc.
For example, aryl can be selected from following group by 1-3 and replace: halogen ,-OH, C1-4 alkoxyl group, C1-4 alkyl ,-NO 2,-NH 2,-N (CH 3) 2, carboxyl, and ethoxycarbonyl etc.
" 5 yuan or 6 yuan of heterocycles " used herein include but not limited to contain 1-3 heteroatomic heterocyclic group that is selected from O, S and N, include but not limited to furyl, thienyl, pyrryl, pyrrolidyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidyl, pyrazinyl, piperidyl, morpholinyl etc.
" heteroaryl " used herein refer to and contain 5-14 annular atoms, and have 6, and 10 or 14 electronics share on member ring systems.And contained annular atoms be carbon atom and from oxygen, nitrogen, sulphur optional 1-3 heteroatoms.Useful heteroaryl comprises piperazinyl, morpholinyl, piperidyl, pyrrolidyl, thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, includes, but are not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidyl etc.
Heteroaryl or 5 yuan or 6 yuan of heterocycles optionally for example, are selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replace: alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, N (CH that the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, halogen replace 3) and the C1-4 acyl group.
Herein, " acyloxy " refers to the group that structural formula is " O-C (O)-R ", and wherein, R can be selected from alkyl, alkenyl and alkynyl.Described R optionally is substituted.
Herein, " amido " refers to the group that structural formula is " R '-NH-C (O)-R ", and wherein, R ' can be selected from key or alkyl, and R can be selected from alkyl, alkenyl, alkynyl, by NR aR bThe alkyl replaced, by NR aR bThe alkenyl and the NR that replace aR bThe alkynyl replaced, the alkyl replaced by halogen, the alkenyl replaced by cyano group,
Figure BDA00001635745700091
Wherein, R aAnd R bCan be selected from alkyl and alkenyl.
Herein; " optional replacement " refers to that its substituting group of modifying optionally for example, is selected from following substituting group by 1-5 (, 1,2,3,4 or 5) and replaces: alkoxyl group (for example trifluoromethoxy), carboxyl, C1-4 alkoxyl group, ethoxycarbonyl, N (CH that the alkyl (for example trifluoromethyl) that halogen, C1-4 aldehyde radical, C1-6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, halogen replace, halogen replace 3) and the C1-4 acyl group.
The present invention includes a kind of pharmaceutical composition, said composition contains the formula I of the present invention, the II that treat significant quantity or compound or its pharmacy acceptable salt of III, and pharmaceutically acceptable carrier or vehicle.
The example of the pharmacy acceptable salt of the compounds of this invention includes but not limited to inorganic and organic acid salt, for example hydrochloride, hydrobromate, vitriol, Citrate trianion, lactic acid salt, tartrate, maleate, fumarate, mandelate and oxalate; And with alkali inorganic and organic alkali salt that for example sodium hydroxyl, three (hydroxymethyl) amido methane (TRIS, amine trihydroxybutane) and N-METHYL-ALPHA-L-GLUCOSAMINE form.
Although everyone demand is different, those skilled in the art can determine the optimal dose of every kind of activeconstituents in pharmaceutical composition of the present invention.Generally, compound of the present invention or its pharmacy acceptable salt, to Mammals oral administration every day, dose is according to about 0.0025 to 50 mg/kg of body weight.But preferably the per kilogram oral administration is approximately 0.01 to 10 milligram.For example, the unit oral dosage can comprise approximately 0.01 to 50 milligram, preferably the about the compounds of this invention of 0.1 to 10 milligram.Unitary dose can give one or many, and be one or more pieces every day, and every containing having an appointment 0.1 to 50 milligram, eligibly approximately the compounds of this invention of 0.25 to 10 milligram or its solvate.
Pharmaceutical composition of the present invention can be formulated into the dosage form that is applicable to various route of administration, includes but not limited to be formulated for outside intestines, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, in sheath, encephalic, the form of nasal cavity or external application administration, be used for the treatment of tumour and other diseases.Dosage is effectively to improve or eliminate the dose of one or more illnesss.For the treatment of specified disease, significant quantity is the dose that is enough to improve or alleviate in some mode the symptom relevant with disease.Such dose can be used as single dose and uses, or can be according to effective treatment plan administration.Dosage is also permitted cure diseases, but administration is normally in order to improve the symptom of disease.Generally need repetitively administered to realize required doing well,improving.The dosage of medicine will be according to patient's age, health and body weight, and the kind of concurrent treatment, the frequency for the treatment of, and required treatment benefit decides.
Pharmaceutical preparation of the present invention can give any Mammals, as long as they can obtain the result for the treatment of of the compounds of this invention.The most importantly mankind in these Mammalss.
Compound of the present invention or its pharmaceutical composition can be used for treating the various diseases by epidermal growth factor receptor kinase (EGFR) mediation.Herein, the disease by the EGFR mediation is various cancers.Described cancer includes but not limited to nonsmall-cell lung cancer, mammary cancer, prostate cancer, neurogliocytoma, ovarian cancer, incidence squama cancer, cervical cancer, the esophageal carcinoma, liver cancer, kidney, carcinoma of the pancreas, colorectal carcinoma, skin carcinoma, leukemia, lymphoma, cancer of the stomach, multiple marrow cancer and solid tumor.
Should be understood that in the present invention, EGFR comprises its wild-type and can cause the various varients of disease.These varients include but not limited to the varient that comprises following sudden change: T790M, L858R, L861Q or L858R/T790M.The present invention also comprises the clipped form that can cause disease of EGFR.Therefore, the compounds of this invention or its pharmaceutical composition can be used for treatment by EGFR wild-type or its various diseases that can cause the various varients of disease to mediate, comprise various cancers as described above, or suppress the EGFR wild-type or it can cause the biologic activity of the various varients of disease.
Pharmaceutical preparation of the present invention can be manufactured in a known manner.For example, by traditional mixing, granulate, ingot processed, dissolve, or the freezing dry process manufacture.While manufacturing oral preparations, can be in conjunction with solid adjuvant material and active compound, the selectivity grinding mixture.If after need to or adding appropriate amount of addition agent in case of necessity, the processing granular mixture, obtain tablet or lozenge core.
Suitable auxiliary material is filler particularly, and for example carbohydrate is as lactose or sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation or calcium phosphate, for example tricalcium phosphate or secondary calcium phosphate; And binding agent, for example starch paste, comprise W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragacanth, methylcellulose gum, Vltra tears, Xylo-Mucine, or polyvinylpyrrolidone.If necessary, can increase disintegrating agent, such as starch above-mentioned, and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salt, as sodium alginate. auxiliary is flowing regulator and lubricant particularly, for example, silica, talcum, stearates, as the magnesium calcium stearate, stearic acid or polyoxyethylene glycol.If necessary, Ke Yi Give lozenge core core provides the suitable dressing that can resist gastric juice.For this reason, can apply concentrated saccharide solution.This solution can contain Sudan Gum-arabic, talcum, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture.In order to prepare the dressing of resistant to gastric juice, can use suitable cellulose solution, for example cellulose acetate phthalic acid or Vltra tears phthalic acid.Can add dyestuff or pigment to the dressing of tablet or lozenge core core.For example,, for identification or in order to characterize the combination of activeconstituents dosage.
Therefore, the present invention also provides a kind of disease of the EGFR for the treatment of mediation or suppresses the method for EGFR activity, and the method comprises that the object needed is with compound of the present invention or pharmaceutical composition.
Medication includes but not limited to the various medications that this area is known, can be determined according to patient's practical situation.These methods include but not limited to outside intestines, subcutaneous, vein, and muscle, intraperitoneal, transdermal, oral cavity, in sheath, encephalic, nasal cavity or external application administration.
The present invention also comprises the disease that the compounds of this invention mediates at preparation treatment EGFR or the purposes in the medicine that suppresses the active use of EGFR.
EGFR inhibitor composite part
To further illustrate the present invention in following embodiment.These embodiment are only for the present invention is described, but do not limit the present invention in any way.
Figure BDA00001635745700111
Reagent and condition: (a) ArNH 2, DIPEA, Isosorbide-5-Nitrae-dioxane, r.t.; (b) ArNH 2, DIPEA, Isosorbide-5-Nitrae-dioxane, r.t.; (c) Pd/C, H 2, EtOH; (d) R 2COCOOEt, HOAc, EtOH, reflux; (e) trifluoroacetic acide, CH 2Cl 2, 0 ° of C to r.t.; (f) acyl chloride, Et 3N, CH 2Cl 2, 0 ° of C to r.t.or acyl chloride, 1-Methyl-2-pyrrolidinone, CH 3CN, 0 ° of C to r.t.
In above-mentioned preparation flow, R 1-R 4Civilian described as defined above.Those skilled in the art can be according to the actual needs that prepare, and adopting the conventional various initial compounds that obtain in this area is raw material, prepares compound of the present invention.
Embodiment 1
The concrete synthetic method of above-mentioned steps a-f is as follows:
Synthetic (the step a) of (4-(the chloro-5-nitro-pyrimidine of 2--4-amino) phenyl) t-butyl carbamate
Figure BDA00001635745700121
Take the chloro-5-nitro-pyrimidine of 2,4-bis-(95mg, 0.49mmol) and be placed in the 10mL round-bottomed flask, add 3mL Isosorbide-5-Nitrae-oxygen six rings, stir under room temperature, separately get (4-aminophenyl) t-butyl carbamate (100mg, 0.48mmol), DIPEA (69mg, 0.53mmol) be dissolved in 2mL 1, the 4-dioxane, and be added drop-wise in above-mentioned reaction solution, after being added dropwise to complete, continue at room temperature to stir 0.5 hour, TLC tracks to raw material and transforms fully.Rotary evaporation is except desolventizing, and crude product separates through silica gel column chromatography (petrol ether/ethyl acetate=10:1, v/v), obtains (4-(the chloro-5-nitro-pyrimidine of 2--4-amino) phenyl) t-butyl carbamate orange solids 144mg, productive rate 82%. 1H?NMR(400MHz,DMSO-d 6):δ10.38(s,1H),9.46(s,1H),9.12(s,1H),7.49(d,J=8.6Hz,2H),7.39(d,J=8.6Hz,2H),1.49(s,9H)。
Synthetic (the step b) of (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate
Figure BDA00001635745700122
Take (4-(the chloro-5-nitro-pyrimidine of 2--4-amino) phenyl) t-butyl carbamate (50mg, 0.14mmol), P-nethoxyaniline (17mg, 0.14mmol), N, N-sec.-propyl ethamine (18mg, 0.18mmol) be placed in the 10mL round-bottomed flask, add 5mL Isosorbide-5-Nitrae-dioxane, under room temperature, stir 4 hours, TLC tracks to raw material and transforms fully.Rotary evaporation is except desolventizing, crude product is through silica gel column chromatography (petrol ether/ethyl acetate=4:1, v/v) purifying, obtain (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate yellow solid 51mg, productive rate 82%. 1H?NMR(400MHz,DMSO-d 6):δ10.30(s,1H),10.26(s,1H),9.45(s,1H),9.04(s,1H),7.49(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,2H),7.40(d,J=8.6Hz,2H),6.75(d,J=8.6Hz,2H),3.73(s,3H),1.50(s,9H)。
Synthetic (the step c) of (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate
Take (4-(2-(4-p-methoxy-phenyl amino)-5-nitro-pyrimidine-4-amino) phenyl) t-butyl carbamate (45mg, 0.10mmol) be placed in the 50mL round-bottomed flask, add 20mL ethanol, 5mg palladium carbon (10%Pd), pass into hydrogen, under room temperature, stir and spend the night.After reaction finishes, suction filtration, be spin-dried for filtrate, crude product is through silica gel column chromatography (methylene chloride/methanol=5:1, v/v) purifying, obtain (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate pale pink solid 30mg, productive rate 83%. 1H?NMR(400MHz,DMSO-d 6):δ9.23(s,1H),8.42(s,1H),8.10(s,1H),7.62(d,J=9.2Hz,2H),7.56(s,1H),7.53(d,J=9.2Hz,2H),7.40(d,J=8.8Hz,2H),6.77(d,J=8.8Hz,2H),3.70(s,3H),1.48(s,9H)。
Synthetic (the step d) of (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate
Figure BDA00001635745700132
Take (4-(5-amino-2-(4-p-methoxy-phenyl amino) pyrimidine-4-amino) phenyl) t-butyl carbamate (30mg, 0.07mmol) be placed in the 10mL round-bottomed flask, add 0.29mL Glacial acetic acid, 5mL dehydrated alcohol, then add glyoxylic acid ethyl ester (50% toluene solution) (16mg, 0.08mmol), be heated to return stirring and spend the night.After reaction finishes, there is solid to separate out, suction filtration, ethanol, ammoniacal liquor, deionized water wash for filter cake, drying.Obtain (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate yellow solid 18mg, productive rate 76%. 1H?NMR(400MHz,DMSO-d 6):δ10.08(s,1H),9.64(s,1H),8.84(s,1H),8.03(s,1H),7.65(d,J=8.4Hz,2H),7.30-7.28(m,4H),6.61(br,2H),3.67(s,3H),1.52(s,9H)。
Synthetic (the step e) of 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 001)
Figure BDA00001635745700133
Take (4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) t-butyl carbamate (18mg, 0.04mmol) be placed in the 5mL round-bottomed flask, add the 2mL methylene dichloride, stir under 0 ° of C, add the 0.5mL trifluoroacetic acid.Then continue to stir 1 hour under 0 ° of C, stir 1 hour under room temperature.Reaction adds saturated sodium bicarbonate solution to be neutralized to the solution meta-alkalescence after finishing, with dichloromethane extraction (3 * 50mL), and deionized water, saturated nacl aqueous solution washing for organic phase, anhydrous sodium sulfate drying, be spin-dried for solvent.Obtain 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinone yellow solid 14mg, productive rate 99%. 1H NMR (400MHz, DMSO-d 6): δ 10.04 (br, 1H), 8.81 (s, 1H), 8.00 (s, 1H), 7.40 (d, J=7.6Hz, 2H), 6.98 (d, J=8.4Hz, 2H), 6.73 (d, J=8.4Hz, 2H), 6.67 (b r, 2H), 5.44 (s, 2H), 3.70 (s, 3H). 13C NMR (100MHz, DMSO-d 6): δ 159.19,158.53,157.17,154.95,151.76,149.66,146.68,133.17,129.22,122.66,121.04,120.70,114.37,113.87,55.55.HRMS (ESI) calculated value C 19H 17N 6O 2[M+H] +361.1413, experimental value 361.1414.
Synthetic (the step f) of N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 002)
Figure BDA00001635745700141
Take 8-(4-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinone (100mg, 0.28mmol) be placed in the 100mL round-bottomed flask, add 50mL methylene dichloride, triethylamine (28mg, 0.28mmol), stir under 0 ° of C, separately get acrylate chloride (29mg, 0.31mmol) and be dissolved in the 5mL methylene dichloride, and be added drop-wise in above-mentioned reaction solution, be added dropwise to complete under rear room temperature and stir and spend the night.Rotary evaporation is except desolventizing, crude product is through silica gel column chromatography (dichloromethane/ethyl acetate=5:1, v/v) purifying, obtain N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide yellow solid 34mg, productive rate 30%. 1H NMR (400MHz, DMSO-d 6): δ 10.42 (s, 1H), 10.07 (br, 1H), 8.84 (s, 1H), (8.04 s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.38 (d, J=8.8Hz, 2H), 7.30 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.0,10.0Hz, 1H), (6.33 dd, J=17.0,1.8Hz, 1H), 5.82 (dd, J=10.0,1.8Hz, 1H), 3.62 (s, 3H). 13C NMR (100MHz, DMSO-d 6): δ 163.90,159.28,158.51,156.68,155.02,151.44,146.65,139.72,133.00,130.18,129.50,127.72,121.02,120.61,113.77,55.40.HRMS (ESI) calculated value C 22H 19N 6O 3[M+H] +415.1519, experimental value 415.1515.
Following compound all obtains according to the method for above-mentioned steps a-f is synthetic:
N-(4-(2-(4-morpholinyl phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 003)
Figure BDA00001635745700151
1H NMR (400MHz, DMSO-d 6): δ 10.44 (s, 1H), 10.00 (s, 1H), 8.82 (s, 1H), (8.02 s, 1H), 7.88 (d, J=8.0Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.22 (br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.2,10.2Hz, 1H), (6.33 d, J=17.2Hz, 1H), 5.85 (d, J=10.2Hz, 1H), 3.67 (br, 4H), 2.92 (br, 4H) .HRMS (ESI) calculated value C 25H 24N 7O 3[M+H] +470.1941, experimental value 470.1932.
N-(4-(2-(4-p-methoxy-phenyl amino)-6-methyl-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 004)
1H NMR (400MHz, DMSO-d 6): δ 10.44 (s, 1H), 9.90 (br, 1H), 8.77 (s, 1H), (7.87 d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), (7.29 br, 2H), 6.59 (br, 2H), 6.52 (dd, J=17.0,10.0Hz, 1H), 6.33 (dd, J=17.0,1.9Hz, 1H), 5.82 (dd, J=10.0,1.9Hz, 1H), 3.61 (s, 3H), 2.42 (s, 3H) .HRMS (ESI) calculated value C 23H 21N 6O 3[M+H] +429.1675, experimental value 429.1671.
8-(3-aminophenyl)-2-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 005)
Figure BDA00001635745700153
1H NMR (400MHz, DMSO-d 6): δ 10.06 (br, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 7.22 (t, J=8.0Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 6.67 (br, 2H), 6.53 (s, 1H), 6.48 (d, J=7.6Hz, 1H), (5.35 s, 2H), 3.69 (s, 3H) .HRMS (ESI) calculated value C 19H 17N 6O 2[M+H] +361.1413, experimental value 361.1413.
N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 006)
Figure BDA00001635745700161
1H NMR (400MHz, DMSO-d 6): δ 10.42 (s, 1H), 10.10 (br, 1H), (8.85 s, 1H), 8.05 (s, 1H), (7.84 d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.56 (t, J=8.0Hz, 1H), (7.31 br, 2H), 7.13 (d, J=8.0Hz, 1H), 6.58 (br, 2H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H), 3.65 (s, 3H) .HRMS (ESI) calculated value C 22H 19N 6O 3[M+H] +415.1519, experimental value 415.1516.
N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) propionic acid amide (compound 007)
Figure BDA00001635745700162
1H NMR (400MHz, DMSO-d 6): δ 10.13 (s, 1H), 10.09 (s, 1H), 8.85 (s, 1H), (8.04 s, 1H), 7.74 (d, J=8.0Hz, 1H), (7.71 s, 1H), 7.53 (t, J=8.0Hz, 1H), (7.31 br, 2H), 7.07 (d, J=8.0Hz, 1H), (6.59 br, 2H), 3.67 (s, 3H), 2.33 (q, J=7.6Hz, 2H), 1.07 (t, J=7.6Hz, 3H) .HRMS (ESI) calculated value C 22H 21N 6O 3[M+H] +417.1675, experimental value 417.1678.
N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) propionic acid amide (compound 008)
1H NMR (400MHz, DMSO-d 6): δ 10.15 (s, 1H), 10.08 (br, 1H), (8.85 s, 1H), 8.04 (s, 1H), (7.80 d, J=8.4Hz, 2H), 7.35-7.33 (m, 4H), 6.61 (br, 2H), 3.67 (s, 3H), 2.41 (q, J=7.6Hz, 2H), (1.14 t, J=7.6Hz, 3H) .HRMS (ESI) calculated value C 22H 21N 6O 3[M+H] +417.1675, experimental value 417.1674.
4-(dimethylamino)-N-(4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 009)
Figure BDA00001635745700171
1H NMR (400MHz, DMSO-d 6): δ 10.45 (s, 1H), 10.10 (br, 1H), 8.85 (s, 1H), (8.05 s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 7.30 (br, 2H), 6.82 (td, J=15.4,6.0Hz, 1H), 6.60 (br, 2H), (6.40 d, J=15.4Hz, 1H), 3.63 (s, 3H), (3.27 d, J=5.2Hz, 2H), 2.33 (s, 6H) .HRMS (ESI) calculated value C 25H 26N 7O 3[M+H] +472.2097, experimental value 472.2095.
4-(dimethylamino)-N-(3-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 010)
Figure BDA00001635745700172
1H NMR (400MHz, DMSO-d 6): δ 10.33 (s, 1H), 10.08 (br, 1H), (8.86 s, 1H), 8.05 (s, 1H), (7.83 d, J=8.0Hz, 1H), 7.78 (s, 1H), 7.55 (t, J=8.0Hz, 1H), (7.32 br, 2H), 7.11 (d, J=8.0Hz, 1H), 6.74 (td, J=15.2,5.6Hz, 1H), 6.59 (br, 2H) 6.30 (d, J=15.2Hz, 1H), 3.66 (s, 3H), 3.06 (d, J=5.6Hz, 2H), 2.17 (s, 6H) .HRMS (ESI) calculated value C 25H 24N 7O 3[M+H] +472.2097, experimental value 472.2094.
Vinylformic acid 4-(2-(4-p-methoxy-phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl ester (compound 011)
Figure BDA00001635745700173
1H NMR (400MHz, DMSO-d 6): δ 10.15 (s, 1H), 8.87 (s, 1H), 8.06 (s, 1H), 7.51 (d, J=8.8Hz, 2H), 7.45 (d, J=8.8Hz, 2H), 7.31 (br, 2H), 6.69 (br, 2H), 6.60 (dd, J=17.2,1.6Hz, 1H), (6.51 dd, J=17.2,9.9Hz, 1H), 6.22 (dd, J=9.9,1.6Hz, 1H), 3.67 (s, 3H) .HRMS (ESI) calculated value C 22H 18N 5O 4[M+H] +416.1359, experimental value 416.1359.
4-(dimethylamino)-N-(4-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 012)
Figure BDA00001635745700181
1H NMR (400MHz, DMSO-d 6): δ 10.37 (s, 1H), 10.19 (br, 1H), (8.90 s, 1H), 8.08 (s, 1H), (7.87 d, J=8.4Hz, 2H), 7.42 (d, J=7.6Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.03 (br, 1H), (6.88 t, J=7.6Hz, 1H), 6.82 (td, J=15.4,5.6Hz, 1H), 6.37 (d, J=15.4Hz, 1H), 3.14 (d, J=5.6Hz, 2H), 2.24 (s, 6H) .HRMS (ESI) calculated value C 24H 24N 7O 2[M+H] +442.1991, experimental value 442.1989.
4-(dimethylamino)-N-(3-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl)-2-butylene acid amides (compound 013)
Figure BDA00001635745700182
1H NMR (400MHz, DMSO-d 6): δ 10.32 (s, 1H), 10.17 (s, 1H), (8.90 s, 1H), 8.08 (s, 1H), (7.81-7.79 m, 2H), 7.55 (t, J=8.0Hz, 1H), 7.41 (d, J=7.2Hz, 2H), (7.12 d, J=8.0Hz, 1H), 7.01 (br, 2H), 6.87 (t, J=7.2Hz, 1H), 6.73 (td, J=15.2,5.6Hz, 1H), 6.28 (d, J=15.2Hz, 1H), 3.05 (d, J=5.6Hz, 2H), 2.16 (s, 6H) .HRMS (ESI) calculated value C 24H 24N 7O 2[M+H] +442.1991, experimental value 442.1996.
N-(4-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl) acrylamide (compound 014)
Figure BDA00001635745700183
1H NMR (400MHz, DMSO-d 6): δ 10.44 (s, 1H), 10.19 (br, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.88 (d, J=8.4Hz, 2H), 7.41-7.38 (m, 4H), 7.03 (br, 2H), (6.88 t, J=7.2Hz, 1H), 6.53 (dd, J=16.8,10.4Hz, 1H), 6.35 (dd, J=16.8,1.6Hz, 1H), 5.84 (dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C 21H 17N 6O 2[M+H] +385.1413, experimental value 385.1405.
N-(3-(7-oxo-2-(phenyl amino)-8 (7H)-pteridyl) phenyl) acrylamide (compound 015)
Figure BDA00001635745700191
1H NMR (400MHz, DMSO-d 6): δ 10.42 (s, 1H), 10.19 (s, 1H), (8.91 s, 1H), 8.09 (s, 1H), (7.84-7.81 m, 2H), 7.57 (t, J=8.0Hz, 1H), 7.41 (br, 2H), 7.15 (d, J=7.6Hz, 1H), 7.02 (br, 2H), (6.87 t, J=7.6Hz, 1H), 6.45 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.6Hz, 1H), 5.77 (dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C 21H 17N 6O 2[M+H] +385.1413, experimental value 385.1413.
N-(4-(2-(4-chloro-phenyl-amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 016)
Figure BDA00001635745700192
1H NMR (400MHz, DMSO-d 6): δ 10.46 (s, 1H), 10.34 (s, 1H), 8.92 (s, 1H), 8.11 (s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.41-7.36 (m, 4H), 7.06 (br, 2H), (6.53 dd, J=16.8,10.4Hz, 1H), (6.36 dd, J=16.8,1.6Hz, 1H), (5.84 dd, J=10.4,1.6Hz, 1H) .HRMS (ESI) calculated value C 21H 16N 6O 2Cl[M+H] +419.1023, experimental value 419.1031.
N-(3-(2-(4-chloro-phenyl-amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 017)
1H NMR (400MHz, DMSO-d 6): δ 10.44 (s, 1H), 10.34 (br, 1H), 8.93 (s, 1H), (8.11 s, 1H), 7.84 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.43 (d, J=7.2Hz, 2H), 7.15 (d, J=7.6Hz, 1H), 6.46 (dd, J=16.8,10.4Hz, 1H), 6.26 (dd, J=16.8,1.8Hz, 1H), 5.77 (dd, J=10.12,1.8Hz, 1H) .HRMS (ESI) calculated value C 21H 16N 6O 2Cl[M+H] +419.1023, experimental value 419.1027.
N-(3-(2-(4-morpholinyl phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 018)
Figure BDA00001635745700201
1H?NMR(400MHz,DMSO-d 6):δ10.43(s,1H),10.06(s,1H),8.84(s,1H),8.03(s,1H),7.92(br,1H),7.72(s,1H),7.56(t,J=7.6Hz,1H),7.27(br,2H),7.12(d,J=7.2Hz,1H),6.58(br,2H),6.45(dd,J=16.8,10.4Hz,1H),6.26(d,J=16.8Hz,1H),5.78(d,J=10.4Hz,1H),3.71(br,4H),2.94(br,4H)。
N-(4-(2-(4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 019)
Figure BDA00001635745700202
1H?NMR(400MHz,DMSO-d 6):δ10.51(s,1H),10.06(s,1H),8.83(s,1H),8.03(s,1H),7.89(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.17(d,J=6.4Hz,1H),6.56-6.49(m,3H),6.34(d,J=16.8Hz,1H),5.85(d,J=10.8Hz,1H),2.94(br,4H),2.37(br,4H),2.20(s,3H)。
N-(3-(2-(4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 020)
Figure BDA00001635745700203
1H?NMR(400MHz,DMSO-d 6):δ10.45(s,1H),10.06(s,1H),8.84(s,1H),8.04(s,1H),7.93(br,1H),7.73(s,1H),7.56(t,J=8.0Hz,1H),7.25(br,2H),7.12(d,J=8.0Hz,1H),6.57(br,2H),6.46(dd,J=16.8,10.4Hz,1H),6.27(dd,J=16.8,1.8Hz,1H),5.78(dd,J=10.4,1.8Hz,1H),2.98(br,4H),2.42(br,4H),2.22(s,3H)。
N-(3-(7-oxo-2-(4-(piperidino) phenyl amino)-8 (7H)-pteridyls) phenyl) acrylamide (compound 021)
Figure BDA00001635745700211
1H?NMR(400MHz,DMSO-d 6):δ10.44(s,1H),10.03(s,1H),8.83(s,1H),8.02(s,1H),7.94(br,1H),7.73(s,1H),7.55(t,J=8.0Hz,1H),7.24(br,2H),7.11(d,J=8.0Hz,1H),6.57(br,2H),6.46(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,1.8Hz,1H),5.77(dd,J=10.2,1.8Hz,1H),2.95(br,4H),1.57(br,4H),1.49(br,2H)。
N-(3-(7-oxo-2-(4-(1-pyrrolidyl) phenyl amino)-8 (7H)-pteridyls) phenyl) acrylamide (compound 022)
Figure BDA00001635745700212
1H?NMR(400MHz,DMSO-d 6):δ10.40(s,1H),9.92(s,1H),8.79(s,1H),7.99(s,1H),7.90(br,1H),7.74(br,1H),7.54(t,J=8.0Hz,1H),7.20(br,2H),7.10(d,J=8.0Hz,1H),6.46(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,1.8Hz,1H),6.20(br,2H),5.77(dd,J=10.2,1.8Hz,1H),3.10(br,4H),1.91(br,4H)。
N-(3-(2-(4-(diethylamino) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 023)
Figure BDA00001635745700213
1H?NMR(400MHz,DMSO-d 6):δ10.42(s,1H),9.92(s,1H),8.80(s,1H),8.00(s,1H),7.92(br,1H),7.73(s,1H),7.53(t,J=8.0Hz,1H),7.19(br,2H),7.09(d,J=8.0Hz,1H),6.46(dd,J=17.0,10.2Hz,1H),6.32(br,2H),6.27(dd,J=17.0,1.8Hz,1H),5.76(dd,J=10.2,1.8Hz,1H),3.20(br,4H),1.00(t,J=6.8Hz,6H)。
N-(3-(2-(4-(kharophen) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 024)
Figure BDA00001635745700221
1H?NMR(400MHz,DMSO-d 6):δ10.43(s,1H),10.16(br,1H),9.78(s,1H),8.87(s,1H),8.06(s,1H),7.82(d,J=8.0Hz,1H),7.79(s,1H),7.56(t,J=8.0Hz,1H),7.32(br,2H),7.23(br,2H),7.15(d,J=8.0Hz,1H),6.46(dd,J=17.0,10.2Hz,1H),6.25(dd,J=17.0,1.8Hz,1H),5.76(dd,J=10.2,1.8Hz,1H),1.98(s,3H)。
4-(8-(3-acrylamide phenyl)-7-oxo-7,8-dihydropteridine-2-amino) benzamide (compound 025)
Figure BDA00001635745700222
1H?NMR(400MHz,DMSO-d 6):δ10.43(s,1H),10.40(s,1H),8.95(s,1H),8.13(s,1H),7.86(s,1H),7.79(d,J=8.0Hz,1H),7.71(br,1H),7.61(t,J=8.0Hz,1H),7.55(d,J=7.6Hz,2H),7.47(br,2H),7.18(d,J=7.6Hz,2H),6.44(dd,J=17.0,10.2Hz,1H),6.25(dd,J=17.0,1.8Hz,1H),5.76(dd,J=10.2,1.8Hz,1H)
N-(3-(2-(4-p-methoxy-phenyl amino)-6-methyl-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 026)
Figure BDA00001635745700223
1H?NMR(400MHz,DMSO-d 6):δ10.42(s,1H),9.93(br,1H),8.78(s,1H),7.83(d,J=8.0Hz,1H),7.77(s,1H),7.56(t,J=8.0Hz,1H),7.31(br,2H),7.11(d,J=8.0Hz,1H),6.58(br,2H),6.45(dd,J=17.0,10.2Hz,1H),6.26(d,J=17.0Hz,1H),5.77(d,J=10.2Hz,1H),3.65(s,3H),2.42(s,3H)。
N-(3-(8-(4-p-methoxy-phenyl)-7-oxo-7,8-dihydropteridine-2-amino) phenyl) acrylamide (compound 027)
Figure BDA00001635745700231
1H?NMR(400MHz,DMSO-d 6):δ10.17(s,1H),10.01(s,1H),8.89(s,1H),8.07(s,1H),7.63(br,1H),7.33(d,J=8.8Hz,2H),7.27(d,J=8.0Hz,1H),7.23(d,J=8.0Hz,1H),7.11(d,J=8.8Hz,2H),6.89(br,1H),6.46(dd,J=17.0,10.2Hz,1H),6.25(dd,J=17.0,1.8Hz,1H),5.74(dd,J=10.2,1.8Hz,1H),3.85(s,3H)。
2-(3-aminophenyl amino)-8-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 028)
Figure BDA00001635745700232
1H?NMR(400MHz,DMSO-d 6):δ9.91(s,1H),8.85(s,1H),8.04(s,1H),7.35(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),6.68-6.65(m,3H),6.16(d,J=7.2Hz,1H),4.63(s,2H),3.86(s,3H)。
N-(4-(8-(4-p-methoxy-phenyl)-7-oxo-7,8-dihydropteridine-2-amino) phenyl) acrylamide (compound 029)
Figure BDA00001635745700233
1H?NMR(400MHz,DMSO-d 6):δ10.19(br,1H),10.03(s,1H),8.87(s,1H),8.05(s,1H),7.36-7.34(m,6H),7.16(d,J=8.4Hz,2H),6.41(dd,J=17.0,10.2Hz,1H),6.23(dd,J=17.0,1.6Hz,1H),5.72(dd,J=10.2,1.6Hz,1H),3.92(s,1H)。
2-(4-aminophenyl amino)-8-(4-p-methoxy-phenyl)-7 (8H)-pteridinones (compound 030)
Figure BDA00001635745700241
1H?NMR(400MHz,DMSO-d 6):δ9.87(s,1H),8.77(s,1H),7.97(s,1H),7.32(d,J=8.8Hz,2H),7.13(d,J=8.8Hz,2H),7.08(br,2H),6.24(br,2H),4.84(s,2H),3.88(s,3H)。
N-(4-(2-(2-methoxyl group)-4-(4-methoxyl group-1-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 031)
Figure BDA00001635745700242
1H?NMR(400MHz,DMSO-d 6):δ10.43(s,1H),8.80(s,1H),8.42(s,1H),8.03(s,1H),7.85(d,J=8.6Hz,2H),7.34(d,J=8.6Hz,2H),7.25(d,J=8.8Hz,1H),6.54-6.48(m,2H),6.33(dd,J=17.0,1.6Hz,1H),6.02(br,1H),5.84(dd,J=10.2,1.6Hz,1H),3.76(s,3H),3.02(br,4H),2.43(br,4H),2.23(s,3H)。
N-(3-(2-(2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl amino)-7-oxo-8 (7H)-pteridyl) phenyl) acrylamide (compound 032)
Figure BDA00001635745700243
1H?NMR(400MHz,DMSO-d 6):δ10.41(s,1H),8.80(s,1H),8.44(br,1H),8.02(s,1H),7.86(br,1H),7.71(s,1H),7.52(t,J=8.0Hz,1H),7.30(d,J=7.6Hz,1H),7.09(d,J=8.0Hz,1H),6.53(s,1H),6.46(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.0,1.8Hz,1H),6.02(br,1H),5.78(dd,J=10.2,1.8Hz,1H),3.76(s,3H),3.04(br,4H),2.44(br,4H),2.23(s,3H)。
Embodiment 2
The biological activity test part
Compound provided by the invention carries out as follows to the extracorporeal extracorporeal suppression experiment of EGFR kinase activity:
The vitro enzyme activation analysis: wild-type and various saltant type (T790M, L858R, L861Q, L858R/T790M) EGFR, Z '-Lyte Kinase Assay Kit is all purchased from Invitrogen.For all compounds to be tested are provided with from 5.1 * 10 -11Mol/L to 1.0 * 10 -610 concentration gradients of mol/L.
Different kinase whose concentration is determined by optimization experiment, corresponding concentration is: EGFR (PV3872, Invitrogen) 0.287 μ g/ μ L, EGFR-T790M (PV4803, Invitrogen) 0.174 μ g/ μ L, EGFR-L858R (PV4128, Invitrogen) 0.054 μ g/ μ L, EGFR-L858R/T790M (PV4879, Invitrogen) 0.055 μ g/ μ L.Compound in DMSO from 5.1x10 -9M is to 1x10 -4Three times of M dilutions.4 μ L compounds are dissolved in 96 μ L water, obtain the compound solution of 4x.40 μ M ATP are dissolved in 1.33x kinase buffer liquid, and kinases/peptide mixt comprises the 2x kinases, 4 μ M trorsine 14 peptides are ready to stand-by.10 μ L kinase reactions comprise 2.5 μ L compound solutions, 5 μ L kinases/peptide mixts, 2.5 μ L ATP solution.5 μ L phosphorylated peptide solution replace kinases/peptide mixt as 100% phosphorylation contrast.2.5 μ L 1.33x kinase buffer liquid replaces ATP solution to suppress contrast as 100%, 2.5 μ L 4%DMSO replace compound solution to suppress contrast as 0%.In plate, solution is at room temperature cultivated 1.5 hours after fully mixing.Every hole continues at room temperature to cultivate 1 hour after adding 5 μ LDevelopmentSolution, and the non-phosphorylating peptide is interior cleaved at this moment.Finally, add 5 μ L Stop Reagent to finish reaction.EnVision Multilabel Reader(Perkin Elmer for orifice plate) measured.Experimental data is used GraphPad Prism version 4.0 to be calculated.Each experiment all repeats more than 3 times.
Cell proliferation and growth-inhibiting analysis: H1975(non-small cell lung cancer cell, EGFR L858R/T790M), the HCC827(non-small cell lung cancer cell, EGFR Del E746-A750), the A549(non-small cell lung cancer cell, the EGFR wild-type), the BT474(breast cancer cell, cross expression Her2), the SK-BR-3(breast cancer cell, cross expression Her2), the MCF-7(breast cancer cell, cross expression Her2) cell all obtains from ATCC.Cell-proliferation activity adopts the MTS analytical method to be assessed.Cell is exposed to treatment condition lower 72 hours, and the cell count that the each experiment of each clone is used is adjusted according to absorbance (absorbance at 490nm place is 1.3-2.2).For compound to be tested is provided with 6 concentration gradients (0.1nM-10 μ M), each concentration value is at least used 6 groups of parallel controls.
H1975, HCC827, A549, BT474, MCF-7, SK-BR-3 cell are cultivated in corresponding substratum, and cell at least goes down to posterity twice after recovery, then for testing use.The cell trypsinize of logarithmic phase also suspends in substratum again.The every hole of H1975(1000 cells), the every hole of BT474(1500 cells), the every hole of MCF-7(1500 cells), the every hole of HCC827(2000 cells), the every hole of SK-BR-3(2000 cells), the every hole of A549(2000 cells) be seeded in 96 orifice plates volume 100 μ L; 6 groups of parallel and 7 row are set.Orifice plate is put in the incubator of 37 ° of C 5% carbonic acid gas and spends the night.Compound is dissolved in to DMSO, and compound concentration is every liter of 10 μ M, subsequently compound concentration is progressively diluted to the compound concentration obtained and is respectively every liter of 10 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, 0.001 μ M, 0.0001 μ M.2 μ L compound solutions are added in the substratum of 998 μ L, and mixture is through fully mixing.The mixture of 100 μ L adds in 96 orifice plates.2 μ L DMSO replace compound solution to suppress contrast as 0%.After cultivating 68 hours, add 20 μ L MTT(5mg/mL).4 as a child, abandons supernatant liquor and add 150 μ L DMSO.After shake 10 minutes, Synergy HT(Bio TeK for orifice plate) (OD490) reading of data.Data are used GraphPad Prism version 4.0 to be calculated, IC 50Value obtains by the nonlinear regression model (NLRM) adjustment of using dosage response curve.
Test result is as shown in following table 1 and 2.
Figure BDA00001635745700271
Table 2
Figure BDA00001635745700281

Claims (10)

1. the compound that there is structure shown in general formula I:
In formula,
A and B are for being with various substituent phenyl ring or five yuan or hexa-member heterocycle;
C is selected from arbitrary group as follows:
Figure FDA00001635745600012
Wherein, X is selected from O, S and Se; R 1For hydrogen, halogen atom, C1-C6 alkoxyl group, the optional C replaced 1-C 6Alkyl, the optional aryl replaced or the optional aralkyl replaced;
R 2Independently be selected from separately hydrogen, halogen, C1-C6 alkoxyl group, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced;
R 3Independently be selected from separately hydrogen, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl, the optional alkoxyl formyl replaced;
R aAnd R bIndependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
2. compound as claimed in claim 1, is characterized in that, described compound has structure shown in general formula I I:
Figure FDA00001635745600021
In formula,
Y is selected from N, CH;
Z is selected from N, CR 6
R 1For hydrogen, halogen, C1-C6 alkoxyl group, the optional C replaced 1-C 6Alkyl, the optional aryl replaced, the optional aralkyl replaced;
R 3Independently be selected from acyloxy, amino, the optional amido replaced, the optional C replaced of optional replacement 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl and the optional alkoxyl formyl replaced;
R 4, R 5, R 6And R 6Independently be selected from separately hydrogen, halogen, C 1-C 6Alkoxyl group,, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced;
R aAnd R bIndependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
3. compound as claimed in claim 1, is characterized in that, described compound has structure shown in general formula III:
Figure FDA00001635745600031
In formula,
R 1For hydrogen, halogen, C1-C6 alkoxyl group, the optional C replaced 1-C 6Alkyl, the optional aryl replaced, the optional aralkyl replaced;
R 3Independently be selected from acyloxy, amino, the optional amido replaced, the optional C replaced of optional replacement 1-C 4Alkyl, CN, sulfonic group, amino-sulfonyl, carboxyl and the optional alkoxyl formyl replaced;
R 5, R 6And R 7Independently be selected from separately hydrogen, halogen, C 1-C 6Alkoxyl group,, hydroxyl, the optional acyloxy replaced, amino, the optional amido replaced, the optional C replaced 1-C 6The pyrrolidyl of the phenyl of alkyl, CN, sulfonic group, amino-sulfonyl, formamyl, carboxyl, the optional alkoxyl formyl replaced, optional replacement, the optional N-alkylpiperazinyl replaced, the optional morpholinyl replaced, the piperidyl optionally replaced, the optional pyrryl replaced, optional replacement ,-NR aR b, the optional pyridyl replaced;
R aAnd R bIndependently be selected from separately alkyl and alkenyl; With
M and n respectively do for oneself 0,1,2,3 or 4.
In a preferred embodiment of formula III, R 1Be selected from H and alkyl.
4. compound as claimed in claim 3, is characterized in that,
R 1Be selected from H and C1-C6 alkyl;
R 3Be selected from amido, acyloxy and alkoxyl group;
R 5Be selected from H, alkoxyl group, morpholinyl, halogen, N-alkyl-piperazinyl, piperidyl, pyrryl, pyrrolidyl, pyridyl ,-NR aR b, amido and formamyl, wherein, R aAnd R bCan be selected from alkyl and alkenyl;
R 6Be selected from H; With
R 7Be selected from H or amido.
5. compound as claimed in claim 4, is characterized in that,
R 5Be selected from halogen, 4-N-methylpiperazine base, N-morpholinyl, N-piperidyl, N-pyrryl, N-pyrrolidyl, N, N-ethylamino, N, N-methyl methylamino and 4-pyridyl;
R 3Be selected from any in following group:
Figure FDA00001635745600041
R 7For H.
6. be selected from following compound:
Figure FDA00001635745600042
Figure FDA00001635745600051
Figure FDA00001635745600061
7. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains the described compound of any one or its pharmacy acceptable salt in claim 1-6, and pharmaceutically acceptable carrier or vehicle.
8. the purposes in the disease that in claim 1-6, the described compound of any one is mediated by epidermal growth factor receptor kinase in the preparation treatment or the medicine that suppresses epidermal growth factor receptor kinase.
9. purposes as claimed in claim 8, is characterized in that, described disease is cancer.
10. purposes as claimed in claim 9, is characterized in that, described cancer is selected from nonsmall-cell lung cancer, mammary cancer, prostate cancer, neurogliocytoma, ovarian cancer, incidence squama cancer, cervical cancer, the esophageal carcinoma, liver cancer, kidney, carcinoma of the pancreas, colorectal carcinoma, skin carcinoma, leukemia, lymphoma, cancer of the stomach, multiple marrow cancer and solid tumor.
CN2012101489393A 2012-05-14 2012-05-14 Pteridinone derivative as EGFR inhibitor and application thereof Pending CN103421010A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN2012101489393A CN103421010A (en) 2012-05-14 2012-05-14 Pteridinone derivative as EGFR inhibitor and application thereof
US14/400,508 US9670213B2 (en) 2012-05-14 2013-04-02 Pteridine ketone derivative and applications thereof as EGFR, BLK, and FLT3 inhibitor
JP2015511908A JP6114820B2 (en) 2012-05-14 2013-04-02 Pteridinone derivatives and applications as inhibitors of EGFR, BLK, FLT3
DE112013002484.5T DE112013002484B4 (en) 2012-05-14 2013-04-02 Pteridine ketone derivative and applications of the same as EGFR, BLK and FLT3 inhibitor
CN201380003282.4A CN103930425B (en) 2012-05-14 2013-04-02 Pteridinone derivative and the application as EGFR, BLK, FLT3 inhibitor thereof
CN201610325343.4A CN106008511B (en) 2012-05-14 2013-04-02 Pteridine ketone derivatives and its application as EGFR, BLK, FLT3 inhibitor
PCT/CN2013/073612 WO2013170671A1 (en) 2012-05-14 2013-04-02 Pteridine ketone derivative and applications thereof as egfr, blk, and flt3 inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2012101489393A CN103421010A (en) 2012-05-14 2012-05-14 Pteridinone derivative as EGFR inhibitor and application thereof

Publications (1)

Publication Number Publication Date
CN103421010A true CN103421010A (en) 2013-12-04

Family

ID=49646431

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2012101489393A Pending CN103421010A (en) 2012-05-14 2012-05-14 Pteridinone derivative as EGFR inhibitor and application thereof

Country Status (1)

Country Link
CN (1) CN103421010A (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965120A (en) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CN106467540A (en) * 2015-08-21 2017-03-01 华东理工大学 Pteridine ketone derivatives are as the application of FLT3 inhibitor
CN107129506A (en) * 2016-02-26 2017-09-05 华东理工大学 It is used as pyrimido [4,5-d] [1,3] oxazine -2- ketone derivatives and its application of EGFR inhibitor
WO2017148440A1 (en) * 2016-03-04 2017-09-08 华东理工大学 Pteridinone derivative serving as flt3 inhibitor, and uses
CN107922417A (en) * 2015-05-29 2018-04-17 华东理工大学 Application of the pteridine ketone derivatives as EGFR inhibitor
WO2018192536A1 (en) * 2017-04-19 2018-10-25 华东理工大学 Pyrimido-heterocyclic compound serving as bruton tyrosine kinase inhibitor and applications thereof
CN110698443A (en) * 2019-10-28 2020-01-17 成都中医药大学 SHP2 small-molecule selective inhibitor and application thereof in preparation of anti-lung cancer drugs
WO2021249558A1 (en) * 2020-06-12 2021-12-16 华东理工大学 Pteridone derivative as rsk inhibitor and application thereof

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965120A (en) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CN103965120B (en) * 2013-01-25 2016-08-17 上海医药集团股份有限公司 Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application
CN107922417A (en) * 2015-05-29 2018-04-17 华东理工大学 Application of the pteridine ketone derivatives as EGFR inhibitor
CN106467540A (en) * 2015-08-21 2017-03-01 华东理工大学 Pteridine ketone derivatives are as the application of FLT3 inhibitor
CN106467540B (en) * 2015-08-21 2021-03-16 华东理工大学 Application of pteridinone derivative as FLT3 inhibitor
CN107129506A (en) * 2016-02-26 2017-09-05 华东理工大学 It is used as pyrimido [4,5-d] [1,3] oxazine -2- ketone derivatives and its application of EGFR inhibitor
CN107129506B (en) * 2016-02-26 2019-10-22 华东理工大学 As pyrimido [4,5-d] [1,3] oxazines -2- ketone derivatives of EGFR inhibitor and its application
WO2017148440A1 (en) * 2016-03-04 2017-09-08 华东理工大学 Pteridinone derivative serving as flt3 inhibitor, and uses
WO2018192536A1 (en) * 2017-04-19 2018-10-25 华东理工大学 Pyrimido-heterocyclic compound serving as bruton tyrosine kinase inhibitor and applications thereof
CN110698443A (en) * 2019-10-28 2020-01-17 成都中医药大学 SHP2 small-molecule selective inhibitor and application thereof in preparation of anti-lung cancer drugs
WO2021249558A1 (en) * 2020-06-12 2021-12-16 华东理工大学 Pteridone derivative as rsk inhibitor and application thereof
CN113801118A (en) * 2020-06-12 2021-12-17 华东理工大学 Pteridinone derivatives as RSK inhibitors and application thereof

Similar Documents

Publication Publication Date Title
CN103930425B (en) Pteridinone derivative and the application as EGFR, BLK, FLT3 inhibitor thereof
CN103421010A (en) Pteridinone derivative as EGFR inhibitor and application thereof
KR101839915B1 (en) Arylamino purine derivatives, preparation method and pharmaceutical use thereof
EP3170825B1 (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
EP3434676B1 (en) Substituted pyrrolopyrimidine cdk inhibitor, pharmaceutical composition containing same and use thereof
EP3312180B1 (en) Use of pteridinone derivative serving as egfr inhibitor
EP3392245A1 (en) Novel egfr and alk dual inhibitor
JP6321821B2 (en) 2,3,4,6-4-substituted benzene-1,5-diamine derivatives, their production and use in pharmaceuticals
CN107428763B (en) Pyrimidopyrimidinedione derivatives as EGFR inhibitors and uses thereof
CN114656482A (en) Macrocyclic heterocyclic compound as EGFR inhibitor and application thereof
CN103833759A (en) Pteridinone derivatives as BLK and FLT3 inhibitors and applications thereof
ES2872775T3 (en) Pyrropyrimidine compounds as MNK inhibitors
CN106467540B (en) Application of pteridinone derivative as FLT3 inhibitor
CN106892922A (en) As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application
CN109384788A (en) Purine series derivates and its preparation method and application
EP3896059B1 (en) Pan-kit kinase inhibitor having quinoline structure and application thereof
CN113801118A (en) Pteridinone derivatives as RSK inhibitors and application thereof
CN113801139A (en) Pyrimido-oxazine derivatives as RSK inhibitors and uses thereof
CN110452243B (en) Pyrrolopyrimidine derivative epidermal growth factor inhibitor and preparation method and application thereof
CN110483523B (en) Pyrazolopyrimidine derivative epidermal growth factor inhibitor and preparation method and application thereof
CN115894486B (en) Hydrogenated pyridoquinazoline compound, composition and application thereof
CN113527215B (en) Quinazoline compound, preparation method and application thereof
CN116354964A (en) 7 (8H) -pteridinone derivatives as BTK inhibitors and uses thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20131204