CN104860890A - T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs - Google Patents
T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs Download PDFInfo
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- CN104860890A CN104860890A CN201510214627.1A CN201510214627A CN104860890A CN 104860890 A CN104860890 A CN 104860890A CN 201510214627 A CN201510214627 A CN 201510214627A CN 104860890 A CN104860890 A CN 104860890A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention provides a T790M mutant EGFR inhibitor and an application of the same in preparation of antitumor drugs. The inhibitor is a pyrimidine compound with structural characteristics of a formula (I). The compound can inhibit various tumor cells and particularly can act on EGFR L858R/T790M and EGFR E 745_A750/T790M lung cancer cells selectively, and the IC 50 of the compound is 10 timers and even 100 times higher than that of wild cancer cells. The compound is the protease inhibitor which is capable of overcoming prior EGFR-TKI drug resistance and has selectivity and can be applied to preparation of antitumor drugs. (img file= 'DDAS0000708455660000011. TIF' wi= '716' he= '576'/).
Description
Technical field
The present invention relates to the medicine being used for the treatment of tumour, be specifically related to the inhibitor of T790M mutant egf R and preparing the application in antitumor drug.
Background technology
In the past in 30 years, lung cancer mortality rises 465%, and sickness rate increases by 26.9% every year, has replaced liver cancer to become the first Death Cause for Malignant Tumors of China.A kind of disease that this mortality ratio is the highest, the health of the mankind in serious threat.Wherein nonsmall-cell lung cancer (non-small cell lung cancer, be called for short NSCLC) account for more than 80% of all lung cancer, the NSCLC patient of 1/3rd is only had to there is the chance of operative treatment, the patient of about 70% has belonged to Locally Advanced or has occurred distant metastasis when medical, loses operative treatment chance.In this case, pharmacological agent seems and is even more important.
In traditional cancer treatment procedure, chemotherapy is main treatment means; Chemotherapeutics non-specifically blocks cell fission thus makes necrocytosis, and they are while killing tumour cell, also greatly destroys the growth of human normal cell, brings many untoward reactions.A lot of people makes mood pessimism even abandoning cure because of the serious side effects of worry chemotherapy, add the resistance of chemotherapeutics, the chemotherapy of NSCLC is allowed of no optimist, and the cycle extending chemotherapy merely add toxic side effect, do not increase curative effect.The cancer cells of nonsmall-cell lung cancer is insensitive to chemotherapy, conventional chemotherapy simultaneously, and Overall response rate also only has about 25%; Due to the restriction of these reasons, Patients with Non-small-cell Lung five year survival rate is lower than 20%.
In patient NSCLC of 50%-80%, their EGF-R ELISA (epidermalgrowth factor receptor, EGFR) all overexpressions, thus cause canceration.Targeting EGFR medicine mainly contains two classes: a class is the small molecule tyrosine kinase inhibitors (TKI) acting on acceptor intracellular region; Another kind of is the monoclonal antibody (MAb) acting on receptor extracellular region.Be applied to clinical first-generation EGFR inhibitor as Iressa, erlotinib, lapatinibditosylate etc., they achieve very large success for the treatment of NSCLC lung cancer, and Patients with Non-small-cell Lung five year survival rate improves.Meanwhile, compared with chemotherapy, their advantage is to produce bone marrow depression, feels sick and the side effect such as neurotoxicity; But their drug effects when treating separately are lower, and have the obviously side effect such as fash and diarrhoea, and in use after 1 year, patient occurs resistance to medicine.Research thinks that the sudden change in EGFR gene T790M site is the main inducing of this type of Drug-resistant, and have clinical case data presentation, patient's acquired resistance of nearly 50% all comes from caused by the sudden change in T790M site.Further research confirms, due to EGFR gene T790M sudden change, the Threonine of namely encoding changes methionine(Met) into, thus causes the sterically hindered inhibitor that hinders and be combined with ATP-binding domain and finally result in inhibitor activity and lose.The sudden change having research display T790M site is not at present the affinity directly affecting inhibitor and EGFR yet, but sudden change causes the affinity of EGFR and ATP greatly to increase, and makes greatly reduce (inhibitor and ATP be competitive binding) relative with the affinity of EGFR of inhibitor.S-generation inhibitor as Ah method for Buddhist nun, to reach gram for Buddhist nun (Dacomitinib), the feature that they are better than the first-generation is to increase the identity of EGFR, and can distinguish tumour cell and normal cell, such side effect will reduce; But these molecules are to the poor selectivity of EGFRT790M mutant, cause clinical drug tolerance dose lower, under its maximum tolerated dose (MTD), medicine cannot reach its effective concentration in vivo and make most resistance patient invalid.
In a word, current EGFR tyrosine kinase inhibitor (EGFR-TKI) still can not solve the clinical pressure caused by drug resistance, and mostly existing medicine is that with quinazoline or quinoline amine be the reversible or irreversible inhibitor of the EGFR of basic parent nucleus, it is also inevitable to the toxic side effect that the poor selectivity of wild-type cell is brought.Therefore, exigence novel type, the compound of especially novel skeleton solves the problem such as resistance, poor selectivity.
Summary of the invention
The object of the invention is, the inhibitor of a kind of T790M mutant egf R is provided and is preparing the application in antitumor drug.
For achieving the above object, the invention provides following technical scheme:
An inhibitor of T790M mutant egf R, this inhibitor has the structure of general formula (I):
Wherein, X, Y, Z and U are independently selected from N, CH;
V is selected from CO, CHR
8, wherein R
8be selected from hydrogen, C
1-C
4substituted alkyl;
W is selected from O, NR
9, wherein R
9be selected from hydrogen, C
1-C
4substituted alkyl;
R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl;
R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl;
R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N;
R
5, R
6and R
7independently be selected from hydrogen, halogen, C
1-C
4substituted alkyl.
Preferably, the inhibitor of described T790M mutant egf R has the structure of logical formula V:
Wherein, R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl; R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl; R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N; R
5, R
6and R
7independently be selected from hydrogen, halogen, C
1-C
4substituted alkyl.
Preferably, the inhibitor of described T790M mutant egf R has the structure of general formula (VI):
Wherein, R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl; R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl; R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N.
Preferably, the inhibitor of described T790M mutant egf R is selected from the compound of following structural formula:
The present invention also provides a kind of pharmaceutical composition, this pharmaceutical composition contains at least one inhibitor of T790M mutant egf R or its enantiomorph, diastereomer, resonating body as elucidated before, or described inhibitor pharmacy acceptable salt or its prodrugs, and pharmaceutically acceptable carrier.
The application in antitumor drug prepared by the inhibitor that present invention also offers described T790M mutant egf R.
In one embodiment, this application provides compound and pharmacologically acceptable salts treatment people or other mammal tumors etc. excess proliferative disease or symptom that a kind of utilization has formula I.
In one embodiment, the compound designed by the application and pharmacologically acceptable salts thereof may be used for treatment or control the hyperproliferative diseases such as nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), leukemia, histiocytic lymphatic cancer, nasopharyngeal carcinoma.
Compared with prior art, the present invention has following beneficial effect:
The present invention relates to the pyrimidines with general formula (I) constitutional features, can kinds of tumor cells be suppressed, especially can selectively acting in EGFR L858R/T790M and EGFRE745_A750/T790M lung carcinoma cell.Contrast wild-type cancer cells, the IC50 of this compounds wants high 10 times even order of magnitude difference of 100 times.This compounds is the resistance that can overcome existing EGFR-TKI of a class novelty and has optionally proteinase inhibitor.This compounds can suppress the growth of kinds of tumor cells, and to other protease-producing restraining effect of EGFR, Her family, can be used for preparing antitumor drug, and can overcome existing medicine Gefitinib, the resistance that Tarceva etc. bring out.As understood by those skilled in the art, the compound involved by the application and pharmacologically acceptable salts thereof can be used for preparing antitumor drug, in order to treat the transition proliferative disease such as the mankind and other mammiferous tumours.
Following be in this specification sheets use the definition of term.Unless otherwise noted, the part of initial definition separately or as other group for group provided herein or term is applied in this specification sheets.
Term " alkyl " refers to straight or branched alkyl, comprises 1-12 carbon atom, especially 1-6 carbon atom.Typically " alkyl " comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, heptyl, 4,4 – dimethyl amyl groups, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.Term " (C
1-C
4) alkyl " refer to straight or branched alkyl, comprise from 1-4 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-." substituted alkyl " refers to that the one or more positions in alkyl are substituted, especially 1-4 substituting group, can replace on any position.Typical replacement includes but not limited to one or more following group: as hydrogen, and (such as, single halogenic substituent or many halogenic substituents, the latter is as trifluoromethyl or comprise Cl for halogen
3alkyl), itrile group, nitro, oxygen (as=O), trifluoromethyl, trifluoromethoxy, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle, aromatic ring, OR
a, SR
a, S (=O) R
e, S (=O)
2r
e, P (=O)
2r
e, S (=O)
2oR
e, P (=O)
2oR
e, NR
br
c, NR
bs (=O)
2r
e, NR
bp (=O)
2r
e, S (=O)
2nR
br
c, P (=O)
2nR
br
c, C (=O) OR
d, C (=O) R
a, C (=O) NR
br
c, OC (=O) R
a, OC (=O) NR
br
c, NR
bc (=O) OR
e, NR
dc (=O) NR
br
c, NR
ds (=O)
2nR
br
c, NR
dp (=O)
2nR
br
c, NR
bc (=O) R
a, or NR
bp (=O)
2r
e, wherein at the R that this occurs
acan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring, R
b, R
cand R
dcan independently represent hydrogen, alkyl, cycloalkyl, heterocycle or aromatic ring, R in other words
band R
cheterocycle can be formed together with atom N; R
ecan independently represent hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituting group, as alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, heterocycle or aromatic ring can optionally replace.
Term " halogen " or " halogen " refer to chlorine, bromine, fluorine, iodine.
Unless otherwise indicated, assuming that the heteroatoms of any discontented valence state has enough hydrogen atoms to supplement its valence state.
The salt that compound in the present invention may be formed also is belong to scope of the present invention.Except as otherwise noted, the compound in the present invention is understood to include its esters.Term " salt " as used herein, refers to the salt forming acid or alkali formula with inorganic or organic bronsted lowry acids and bases bronsted lowry.In addition, when the compound in the present invention is containing a basic moiety, it includes but not limited to pyridine or imidazoles, during containing an acidic moiety, include but not limited to carboxylic acid, the zwitter-ion (" inner salt ") that may be formed is included in the scope of term " salt ".Pharmaceutically acceptable (namely nontoxic, physiology is acceptable) salt is first-selected, although other salts are also useful, such as, can be used in the isolated or purified step in preparation process.Compound of the present invention may form salt, and such as, Compound I and a certain amount of acid as equivalent or alkali reaction, saltout out in media as well, or lyophilize gets in aqueous.
The basic moiety that compound in the present invention contains, includes but not limited to amine or pyridine or imidazole ring, may form salt with organic or inorganic acid.The typical acid of salify can comprise acetate (as with acetic acid or three halogenated acetic acids, as trifluoroacetic acid), adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphor salt, camsilate, cyclopentane propionate, glycol ether hydrochlorate, dodecyl sulfate, ethane sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, isethionate (e.g., 2-isethionate), lactic acid salt, maleate, mesylate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectate, persulphate, phenpropionate (as 3-phenpropionate), phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol (as formed with sulfuric acid), sulfonate, tartrate, thiocyanate-, mesylate is as tosilate, dodecanoate etc.
The acidic moiety that compound of the present invention contains, includes but not limited to carboxylic acid, may form salt with various organic or inorganic alkali.The salt that typical alkali is formed comprises ammonium salt, an alkali metal salt as sodium, lithium, sylvite, alkaline earth salt is as calcium, magnesium salts, with the salt (as organic amine) that organic bases is formed, if benzyl star, dicyclohexyl amine, sea bar amine are (with N, the salt that N-bis-(dehydroabietyl) quadrol is formed), N-methyl-D-glucosamine, N-methyl-D-glucamides, tert-butylamine, and and the salt that formed as arginine, Methionin etc. of amino acid.Basic nitrogen-containing groups can with halogenide quaternary ammonium salt, as lower alkyl halogenide (as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide), dialkyl sulfate (as, methyl-sulfate, diethyl ester, dibutylester and diamyl ester), long chain halide (as the muriate of decyl, dodecyl, tetradecyl and tetradecyl, bromide and iodide), aralkyl halide (as benzyl and pheriyl bromide) etc.
In the present invention, the prodrug of compound and solvate are also within the scope contained.Term " prodrug " refers to a kind of compound herein, when treating relative disease, and the compound, salt or the solvate that produce in the present invention through the chemical conversion of metabolism or chemical process.Compound of the present invention comprises solvate, as hydrate.
Compound in the present invention, salt or solvate, the tautomeric form that may exist (such as acid amides and imines ether).All these tautomers are all parts of the present invention.
The steric isomer of all compounds (such as, those unsymmetrical carbons owing to may exist various replacement), comprises its enantiomeric form and diastereomeric forms, all belongs to imagination scope of the present invention.Compound in the present invention independently steric isomer may not exist (such as with other isomer simultaneously, pure or be in fact that pure optical isomer has special activity as one), or also may be mixture, as raceme, or the mixture formed with every other steric isomer or a part wherein.Chiral centre of the present invention has S or R two kinds of configurations, is defined by International Union of Pure and Applied Chemistry (IUPAC) suggestion in 1974.Racemic form solves by physical method, such as fractional crystallization, or by deriving as diastereomeric separation crystallization, or be separated by chiral column chromatography.Single optical isomer is obtained by racemic modification by suitable method, includes but not limited to traditional method, such as with optical activity acid salify after recrystallize.
Compound in the present invention, its weight content of this compound obtained by preparation, separation and purification is successively equal to or greater than 90%, such as, is equal to or greater than 95%, is equal to or greater than 99% (compound of " very pure "), describes list at text.This " very pure " compound of the present invention is also as a part of the present invention herein.
No matter all configurational isomer of compound of the present invention, all within the scope contained, is mixture, pure or very pure form.Comprise cis (Z) in the definition of the compounds of this invention and return formula (E) two kinds of olefin isomers, and the cis of carbocyclic ring and heterocycle and trans-isomer(ide).
In whole specification sheets, group and substituting group can be selected to provide stable fragment and compound.
Particular functional group and technical term of chemistry definition are all described in detail as follows.For purposes of the invention, chemical element and Periodic Table of the Elements, CAS version, Handbook of Chemistry andPhysics, 75
thed. in, definition is consistent.The definition of particular functional group also describes wherein.In addition, vitochemical fundamental principle and particular functional group and reactive at " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, also has explanation, and its full content includes the row of reference in.
Some compound of the present invention may be present in specific geometry or stereoisomer form.All compounds are contained in the present invention, comprise its cis and trans-isomer(ide), R and S enantiomer, diastereomer, (D) type isomer, (L) type isomer, racemic mixture and other mixture.Unsymmetrical carbon can represent substituting group in addition, as alkyl.All isomer and their mixture, all forgive in the present invention.
According to the present invention, the ratio that the mixture of isomers contains isomer can be various.Such as, can have following combination: 50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1, or 100:0 only having the mixture of two isomer, all ratios of isomer is all within the scope of the invention.The similar ratio of those skilled in the art's easy understand in this specialty, and be that the ratio of mixture of more complicated isomer is also within the scope of the invention.
The present invention also comprises isotope-labeled compound, is equal to original chemical open at this.But in fact the one or more atoms quilt atom different from its nucleidic mass or quality ordinal number is replaced and usually there will be.The isotopic example of compound of the present invention can be classified as and comprise hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively as
2h,
3h,
13c,
11c,
14c,
15n,
18o,
17o,
31p,
32p,
35s,
18f and
36cl.Compound in the present invention, or enantiomorph, diastereomer, isomer, or pharmacy acceptable salt or solvate, the isotropic substance wherein containing above-claimed cpd or other other isotope atoms are all within the scope of the present invention.Some compound isotopically labelled in the present invention, such as
3h and
14the radio isotope of C also wherein, is useful in the tissue distribution experiment of medicine and substrate.Tritium, namely
3h and carbon-14, namely
14c, their preparation and determination methods ratio is easier to.It is the first-selection in isotropic substance.In addition, higher isotope replaces as deuterium, namely
2h, because its good metabolic stability has superiority in some therapy, such as, increases the transformation period in vivo or reduces consumption, therefore, can pay the utmost attention in some cases.Isotope-labeled compound can by general method, by replacing with non isotopic reagent with the isotope labeling reagent be easy to get, with disclose in the diagram and (or) scheme in example can be prepared.
If design the synthesis of a specific enantiomorph of compound of the present invention, it can prepare in asymmetric synthesis, or uses chiral auxiliaries derivatize, is separated by produced mixture of diastereomers, then removes chiral auxiliaries and obtain pure enantiomorph.In addition, if containing a basic functionality in molecule, as amino acid, or acidic functionality, as carboxyl, can with the diastereomeric salt of formation with it of suitable optically active acid or alkali, be separated by the conventional means such as fractional crystallization or chromatogram again, then just obtain pure enantiomorph.
As described herein, the compound in the present invention can be got with any quantity substituting group or functional group and expand it and forgive scope.Usually, term " replacement " is no matter at term " optional " above or occur below, comprise substituent general formula at the present invention's formula, refer to and use specified structure substituting group, replacement hydroperoxyl radical.When multiple in ad hoc structure are replaced by multiple specific substituting group in position, each position of substituting group can be identical or different.Term used herein " replacement " comprises all permission organic compound and replaces.In broad terms, the substituting group of permission comprise the non-branched of acyclic, ring-type, side chain, carbocyclic ring with heterocycle, aromatic ring with the organic compound of non-aromatic ring.In the present invention, as heteroatoms nitrogen can have the organic compound mentioned above of hydrogen substituting group or any permission to carry out its valence state supplementary.In addition, the present invention is not intended to restriction by any way to allow substituted organic compound.It is considered herein that substituting group and variable groups to be combined in stable compound form be good in the treatment of disease, such as transmissible disease or proliferative disease.Term " is stablized " and is referred to have stable compound herein, detects the integrity being enough to maintain compound structure within the sufficiently long time, preferably within the sufficiently long time all in effect, be used herein to above-mentioned purpose herein.
Compound involved by the application and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug of the structure of the compound that can change in vivo involved by the application and pharmacologically acceptable salts thereof, be also contained in the claim of the application.
Formula I can to known treatment or the other drug coupling improving similar symptom.During Combined Preparation, originally the administering mode & dosage of medicine remains unchanged, and simultaneously or take the compound of formula I subsequently.When formula I and other one or more medicines are taken simultaneously, preferably use the medicinal compositions simultaneously containing one or more known drugs and formula I.The time period that drug combination is also included within overlap takes formula I and other one or more known drugs.When formula I and other one or more medicines carry out drug combination, the dosage that the dosage of formula I or known drug may be than they independent medications is low.
The medicine of drug combination can be carried out or activeconstituents comprises but is not limited to: estrogenic agents with I, androgen receptor is adjusted, retina receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, the medicine of interference cell cycle check and cell death inducer, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, protesome inhibitors, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, ATK inhibitor, integrin retarding agent, Interferon, rabbit, interleukin-I2, cox 2 inhibitor, P53, P53 activator, VEGF antibody, EGF antibody etc.
The present invention also provides a kind of drug regimen, comprises at least one compound described herein or pharmaceutically acceptable salt, solvate or pharmaceutically acceptable carrier.
Here phrase " pharmaceutically acceptable carrier " used refers to material, composition or medium that pharmacy accepts, as liquid or solid filler, thinner, auxiliary material, solvent or packaged material, comprise and carry or transport main pharmaceutical reagent from certain part of an organ or health to certain part of another organ or health.Each carrier must be " can accept ", can become and not damage patient by compatible other forms of medicine.Some examples that can be used as pharmaceutically acceptable carrier comprise: sugar, as lactose, dextrose plus saccharose sugar; Starch, as wheat starch and yam starch starch; Cellulose and its derivates, as CMC (Sodium Carboxymethyl Cellulose) BP/USP, ethyl cellulose, cellulose acetate, powdered gum tragacanth, Fructus Hordei Germinatus, gelatin, talcum powder; Auxiliary material, as cocoa butter and suppository wax; Oil, as peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycol, as butyleneglycol; Polyvalent alcohol, as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Ester, as ethyl oleate and Laurate ethyl; Agar; Buffer reagent, as magnesium hydroxide and aluminium hydroxide; Lalgine; Apirogen water; Physiological saline; Ringer's solution; Ethanol; Phosphate buffered saline buffer, and other nontoxic be applied in pharmaceutical preparation can compatible material.
As described above, some example of this medicament can be presented as the form of pharmaceutically acceptable salt.In this respect, term in the present invention " salt that pharmacy accepts ", refer to relative nontoxic, organic and inorganic acid compound adds the salt of formation.These salts in the present invention can be in the end isolation and purification compound time on-the-spot to produce, or to be formed with the acid of suitable organic or inorganic and free alkali during purifying compounds in single reaction in the present invention, thus separation and form salt.Typical salt comprises hydrobromate, hydrochloric acid, vitriol, hydrosulfate, phosphoric acid salt, nitrate, acetate, valerate, oleate, palmitate, stearate, lauroleate, benzoate, lactic acid salt, tosilate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphtholate, mesylate, gluceptate, Lactobionate and dodecane sulfonate etc.(example see Berge et al., (1977) " Pharmaceutical Salts ", J.Pharm.Sci.66:1-19.)
The main compound of pharmacy acceptable salt comprises salt or the quaternary ammonium salt of traditional non-toxic compound, as the acid of nontoxic organic or inorganic.This nontoxic salt comprises the derivative of mineral acid, example hydrochloric acid salt, hydrobromate, vitriol, sulfamate, phosphoric acid salt, nitrate etc.; Than salt prepared by organic acid, as acetate, butyrates, succinate, glycol hydrochlorate, stearate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, palmitate, maleate, hydroxymaleic acid salt, phenylacetate, glutaminate, benzoate, salicylate, sulfanilate, Aspirin salt, fumarate, tosylate, methane sulfonates, ethane disulfonic acid hydrogen salt, oxalate, isethionate etc.
In other cases, compound of the present invention may comprise one or more acidic functionalities, therefore can be formed and pharmacy acceptable salt with pharmaceutically acceptable alkali.The salt that the inorganic and organic bases that term " salt that pharmacy accepts " refers to the compounds of this invention and relative nontoxic is in this case formed.These salt in the present invention can be equally in the end isolation and purification compound time on-the-spot to produce, or formed with suitable organic or inorganic alkali and free acid during purifying compounds in single reaction in the present invention, as the oxyhydroxide of metallic cation, carbonate or supercarbonate that pharmacy accepts, or organic primary amine, secondary amine or tertiary amine that ammoniacal liquor, pharmacy accept.Typical an alkali metal salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt etc.Organic amine typically for the formation of salt comprises ethamine, diethylamine, quadrol, thanomin, diethanolamine, piperazine etc.(example is see Berge et al., supra.)
Wetting agent, emulsifying agent and lubricant, as the multipolymer of sodium lauryl sulphate, Magnesium Stearate, polyethylene oxide and polybutylene oxide thing, and among the composition that is also present in of tinting material, releasing agent, coating-forming agent, sweeting agent, spices and fumigating agent, sanitas and antioxidant.
Formula of the present invention comprises those suitable oral cavities, nasal cavity, external application (comprise oral cavity and sublingual), rectum, vagina and vein treatment.This formula can become unit dosage form easily, and can by pharmaceutically any known method preparation.The dosage of active ingredient can combine with a solid support material and produce single formulation, can the therapeutic modality of factor receptor, the difference of specific mode of administration and different.The dosage of effective ingredient can combine with solid support material and produce single formulation, generally will produce the dosage for the treatment of as this compound.In general, outside 100%, the active ingredient of this dose is between about between 1%-99%, and preferably from about about 5%-70%, optimum is about about 10%-30%.
Prepare these formulas or the method for Chemical Composition in the present invention to comprise compound and to enter and in conjunction with the step of one or more carrier and assistant agent composition.In the ordinary course of things, formula is prepared into even energy, can be combined by the carrier nearly in the present invention, as liquid vehicle, solid smalls carrier or both have both at the same time.Then, product is fashioned into if necessary.
Applicable oral preparation of the present invention can have following form, as capsule, cachet, pill, tablet, lozenge (normally sucrose and Acacia or tragakanta, have certain taste), pulvis, granule, or as a solution or be suspended in the non-aqueous liquid in water, or as water-in-oil or oil-in-water emulsion liquid, or as elixir or syrup, or granularly (use such as gelatin and glycerine, the inert base of sucrose and Acacia) and/or collutory and so on, eachly comprise the predetermined dose of the compounds of this invention as active ingredient.The compounds of this invention also can be used as bolus, paste or plaster.
Oral solid formulation of the present invention (capsule, tablet, pill, drageeing, powder, particle etc.), its effective ingredient mixes with one or more pharmaceutically acceptable carrier, as Trisodium Citrate or secondary calcium phosphate, and/or any following content: filler or weighting agent, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL; And/or silicic acid, such as tackiness agent, Xylo-Mucine, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or Sudan Gum-arabic, wetting Agent for Printing Inks, as glycerine; Disintegrating agent, as agar, calcium carbonate, potato or tapioca (flour), alginic acid, some silicate, sodium carbonate, ethanol and Starch Sodium; Separate retardant, as paraffin, absorption enhancer, as quarternary ammonium salt compound; Wetting agent, as hexadecanol, Zerol and polyethylene oxide, polyoxygenated multipolymer; Absorption agent, as kaolin clay, wilkinite, lubricant, as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and composition thereof; And tinting material.When capsule, tablet, pill, drug regimen also may comprise sustained release dosage.Similar solids versions composition can use auxiliary material to become soft filling and hard filled capsules, as lactose or caramel, and the weighting material of ultrahigh molecular weight polyethylene(UHMWPE) ethylene glycol and so on.
Tablet can select the compression or shaping of one or more auxiliary ingredients.Compressed tablets can be prepared with binding agent (as gelatin or HBMC), lubricating oil, inert diluent, preservation agent, disintegrating agent (as ethanol or Starch Sodium croscarmellose sodium), surfactivity or dispersion agent.Model tablet can by the mixture of powdered compounds and inert liq diluent, injection molded on a suitable injection moulding machine.
Activeconstituents can with above-mentioned auxiliary material micro encapsulation.The drug regimen of tablet and other solid preparations of the present invention, as drageeing, capsule, pill, granule, selectively can use coating and shell preparation or moulding, as enteric coating layer, and the coating of other known pharmaceutical form.Also may provide slow or the preparation of the active ingredient of Co ntrolled release, such as, HBMC provides required release profiles in different situations, other polymeric matrixs, liposome and/or dermatosome.They may be able to sterilize, and such as, by a filter bacteria gear strainer, or merge anti-microbial agents and aseptic solid content, they dissolve in sterilized water, or in some sterile injectable medium.These compositions also may contain the composition of opacifying agent, or the composition of the active substance of slow releasing, or the preferential mode forming a kind of delay in some part GI.Embed the operable material of composition and comprise polymkeric substance and wax.Activeconstituents also can adopt one or more auxiliary material to be prepared into microencapsulation form.
Pharmaceutically acceptable emulsion is comprised, microemulsion, solution, suspension to compound oral liquid formulation of the present invention, syrup and elixir.Except activeconstituents, the liquid of formulation may containing pharmaceutically conventional inert diluent, such as water or other solvents, solubilising reagent and emulsifying agent, as ethanol, isopropylcarbinol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, methyltrimethylene glycol, 1,3-butyleneglycol, oil (particularly Oleum Gossypii semen, peanut oil, Fructus Maydis oil, sweet oil, Viscotrol C, sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and fatty acid ester sorbyl alcohol and composition thereof.In addition, cyclodextrin, as hydroxyl butyl-beta-cyclodextrin, also can be used for the compound dissolved.
Except inert diluent, oral composition can also comprise as wetting agent, emulsification and suspension agent, sweeting agent, essence, pigment, preservation agent and sanitas.
Except active compound, suspension may contain suspension agent, such as Unimac 5680 ethyl ester, polyoxyethylene sorbitol and sorbitol ester, Microcrystalline Cellulose, aluminum metal oxyhydroxide, wilkinite, agar and tragakanta and composition thereof.
The present invention treats rectum or intravaginal drug composite formula can be suppository, it can comprise preparation by the compound of one or more invention and one or more suitable nonirritant excipient or carrier and sponsor, such as, theobroma oil, polyoxyethylene glycol, a suppository wax or Whitfield's ointment, and be at room temperature solid, but the liquid of body temperature, therefore, will be melted in the invention of rectum or vaginal canal and release active agents.
Formula of the present invention is suitable for treatment vagina class disease, comprises containing known carrier in pharmacy as pessary, cotton balls, paste, gel, paste, foam or spray agent.
Pulvis is comprised, sprays, ointment, ointment, face cream, emulsion, gel, solution, plaster and inhalation for the local of the compounds of this invention or transdermal administration.The carrier accepted with pharmacy under active compound aseptic condition, and any sanitas, buffer reagent, maybe may need mixing.
Except the active ingredient beyond the region of objective existence in the present invention, ointment, ointment, the auxiliary material as animal and plant fat may be comprised, oil, wax in ointment and gel, paraffin, starch, tragakanta, derivatived cellulose, polyoxyethylene glycol, organosilicon, organobentonite active compound, silicic acid, talcum powder, zinc oxide, or their mixture.
Except the active ingredient beyond the region of objective existence in the present invention, the auxiliary material that powder and spray can comprise as lactose, talcum, silicic acid, aluminium hydroxide, calcium-silicate and Silon, or the mixture of these materials.Spray may add conventional, if fluorochlorohydrocarbon and volatility are without the hydrocarbon polymer replaced, as butane and butylene.
In the present invention, the patch of compound is distributed with extra benefit to medicine is controllable in the body.This formulation is formed by the medicament be dissolved or dispersed in buffer medium.Absorption enhancer also can be used for increasing the flux to the medicament in skin the present invention.The rate controlling membranes that this velocity of variation can be provided by either party or be dispersed in polymeric matrix or gel compound is controlled.
Ophthalmic preparation, spongaion, powder, solution etc., also belongs within scope of the present invention.
The drug regimen of one or more compounds that the present invention is suitable is treated outward at intestines and is comprised and one or more pharmaceutically acceptable sterile physiological aqueous solution or non-aqueous solution, dispersion agent, suspension agent or emulsion, or sterilized powder.They may be reassembled as aseptic injection or the preferential dispersion agent used, and may contain antioxidant, snubber, fungistat, and the blood of preparation and expection receiver or suspension agent or thickening material can be made isotonic fused.
When compound of the present invention is treated to human and animal as medicament, they can or the administration as pharmaceutical composition own.Such as, the activeconstituents of 0.1%-99.5% (preferably 0.5%-90%) and pharmaceutically acceptable carrier is comprised.
Compound in the present invention and pharmaceutical composition can be applied to combination treatment, namely compound and pharmaceutical composition can simultaneously before or after, the treatment of one or more required drug use or medical procedure.This specific combination treatment (treatment or program) being applied in combining rule is compatible and/or program and desirable result for the treatment of by the treatment considered needed for realization.The application of this therapy can realize required effect (such as, compound of the present invention may work with another HCV-Ab IgG reagent simultaneously) to identical disease, or likely reaches different effects (as controlled any detrimentally affect).
Compound of the present invention by intravenous injection, intramuscular injection, abdominal injection, subcutaneous injection, external application, oral, or other acceptable ways carry out disease therapy.These compounds can be used for the condition Mammals (such as, the mankind, domestic animal and domestic animal) for the treatment of of arthritis, birds, lizard, and any can these compound other biologicals compatible.
Present invention also offers drug packaging or external member, comprise one or more packagings, wherein containing the drug regimen to composition one or more in the present invention.This type of packaging optional is produced by government organs' specification with the form of bulletin, uses or sell medicine or biological products with the open method of permitting in production regulation, uses or sells the treatment preparation to people.
The shortenings used in the present invention:
ACN: acetonitrile; EA: ethyl acetate; DMF:N, dinethylformamide; PE: sherwood oil; DCM: methylene dichloride; MeOH: methyl alcohol; THF: tetrahydrofuran (THF); K
2cO
3: salt of wormwood; TEA: triethylamine; DIPEA: diisopropyl ethyl amine; DMAP:N, N-dimethyl-4-amido pyridine; TFA: trifluoroacetic acid; NMP:N-methyl-2-pyrrolidone; Boc: tertbutyloxycarbonyl; Tris: Tutofusin tris; BSA: bovine serum albumin; DTT: dithiothreitol (DTT); ATP: adenosine triphyosphate.
Embodiment
Representational example is intended to help to set forth the present invention below, and should not be interpreted as limiting the scope of the invention.In fact, except those occur and described herein except, the full content of file of the present invention, comprises the example according to scientific and technical literature cited herein and patent, and consequent various modification and many further changes are all clear clear to those skilled in the art in this specialty.Example below contains important side information, example and guidance, can be adapted to various change and analogue in the present invention.
The compound contained in the present invention can be synthesized by known conventional art.It is below the general synthetic schemes of compound that the present invention synthesizes.These schemes disclosed herein are descriptive, do not represent the method synthetic compound that restriction those skilled in the art uses other possible.In addition, different synthesis steps can be applied in synthesising target compound in different schemes.Be incorporated to all by way of reference herein at these all documents quoted.
The compound with general formula I can be synthesized by following scheme.Scheme 1 describes the different methods of these intermediates of synthesis, and these methods can be applied in patent of the present invention in the preparation of the compound with general formula I-IV structure.Those skilled in the art can complete the synthesis of analogue compounds described below author by the various modifications of these methods.
The compound with general formula I is prepared as follows shown (scheme 1):
Step 1: take THF/DMF as solvent, benzylalcohol or benzylamine II are obtained by reacting benzyl oxide or benzylamine III under alkali (as NaH) exists or by the pyrimidine of coupling method and replacement.
Step 2: intermediate III de-Boc under TFA effect obtains arylamine IV.
Step 3: intermediate compound IV is obtained by reacting final Compound I with acrylate chloride under alkali (as pyridine) effect.
Embodiment 1, (R)-N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) acrylamide
Synthesis step:
The preparation of step 1:3-acetylbenzene carbamate (compound 2)
Add (Boc) in dioxane (100mL) solution of 1-(3-aminophenyl) ethyl ketone (compound 1) (8.0g, 59.3mmol)
2o (16.8g, 77.1mmol).Concentrating under reduced pressure after the reaction solution obtained reacts 4 hours at 150 DEG C.Resistates silica gel column chromatography (PE:EA=8:1to 4:1) obtains white solid target product (12.4g, 88.6% productive rate).
1H NMR(400MHz,CDCl
3)δ7.95(s,1H),7.66(d,J＝7.6Hz,1H),7.60(d,J＝7.8Hz,1H),7.37(t,J＝7.9Hz,1H),6.88(s,1H),2.59(s,3H),1.52(s,9H)。
Step 2:(R) preparation of-(3-(1-hydroxyethyl) phenyl) t-butyl carbamate (compound 3)
(+)-DIP-Cl (5.5g, 17.0mmol) is dissolved in anhydrous THF (5mL) and is cooled to-25 DEG C, adds 3-acetylbenzene carbamate (2.0g, 8.5mmol) subsequently.Reaction solution stirring reaction 16 hours at this temperature, then adds acetaldehyde (748mg, 17.0mmol).The reaction solution obtained was raised to room temperature in 30 minutes, then concentrating under reduced pressure.Resistates is dissolved in Et
2o (30mL), then adds diethanolamine (1.9g, 25.5mmol).The mixture obtained stirs until a large amount of white precipitate generates, and then filters.Filter vacuum concentrating under reduced pressure, resistates silica gel column chromatography
1h NMR (400MHz, DMSO-d
6) δ 9.28 (s, 1H), 7.51 (s, 1H), 7.30 – 7.21 (m, 1H), 7.16 (t, J=7.8Hz, 1H), 6.92 (d, J=7.5Hz, 1H), 5.12 (d, J=4.0Hz, 1H), 4.64 (dd, J=6.3,4.2Hz, 1H), 1.47 (s, 9H), 1.29 (d, J=6.4Hz, 3H).
Step 3:(R)-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) preparation of t-butyl carbamate (compound 5)
(R)-(3-(1-hydroxyethyl) phenyl) t-butyl carbamate (237mg, 1mol) be dissolved in dry dioxane (20mL) solution, be cooled to 10 DEG C, add NaH (240mg subsequently in 10 minutes in batches, 60%wt, 6mmol).The mixture obtained, in room temperature reaction half an hour, then adds the insolubles that DMF (5mL) dissolves away bottle wall.Disposablely in above-mentioned solution add 1-(4-(4-((4-chloro-5-(trifluoromethyl) pyrimidin-2-yl) amino)-3-methoxyphenyl) piperazin-1-yl) ethan-1-one (compound 4) (214mg, 0.5mmol), the mixture obtained reacts 2 hours then cool to room temperature at 75 DEG C.In reaction solution, add frozen water (150mL) with vigorous stirring, then use DCM (2x50mL) to extract.Extraction liquid merges, and concentrating under reduced pressure after dry, resistates silica gel column chromatography obtains yellow solid target compound (150mg (AP:70%), 33% thick productive rate).LC-MS:m/z 631(M+H)
+。
Step 4:(R)-1-(4-(4-((4-(1-(3-aminophenyl) oxyethyl group)-5-(trifluoromethyl) pyrimidine-2-base) amino)-3-p-methoxy-phenyl) piperazine-1-base) preparation of ethyl ketone (compound 6)
Compound 5 (150mg, 0.17mmol) is dissolved in DCM (10mL), is cooled to 0 DEG C, is added dropwise to TFA (0.5mL) subsequently.Reaction solution is slowly raised to room temperature and room temperature reaction 2 hours, is slowly added drop-wise to the S.aq.NaHCO in stirring subsequently in 5 minutes
3(30mL) in solution.Mixture DCM (2x10mL) extraction obtained.Extraction liquid merges, and with dry after saturated aqueous common salt (2x15mL) washing, then concentrating under reduced pressure obtains the thick product of yellow solid (130mg, 100% thick productive rate) and is directly used in next step reaction.LC-MS:m/z 531(M+H)
+.
Step 5:(R)-N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) amino)-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) preparation of acrylamide (compound 7)
The compound 6 crude product (130mg that upper step obtains, 0.24mol) be dissolved in dry DCM (10mL) solution, be cooled to-30 DEG C, then pyridine (0.2mL) is added, with DCM (0.5mL) solution of the drying of dropping acrylate chloride (32mg, 0.36mmol).Then the mixture obtained is poured in frozen water (20mL)-30 DEG C of reactions for 15 minutes, then uses DCM (2x10mL) to extract.Extraction liquid merges dry final vacuum concentrating under reduced pressure.Resistates liquid chromatography prepares white solid target product (11mg, 13% productive rate).
1H NMR(400MHz,CDCl
3)δ8.34(s,1H),7.85(m,2H),7.49(m,3H),7.31(t,J＝7.8Hz,1H),7.16(d,J＝7.5Hz,1H),6.57(d,J＝8.7Hz,1H),6.53–6.38(m,2H),6.27(m,2H),5.79(d,J＝10.2Hz,1H),3.86(s,3H),3.80–3.69(m,2H),3.70–3.53(m,2H),3.28–2.96(m,4H),2.15(s,3H),1.61(d,J＝6.6Hz,3H).LC-MS:m/z 585(M+H)
+.
Embodiment 2, (S)-N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) acrylamide
Synthetic method as embodiment 1,
1H NMR(400MHz,CDCl
3)δ8.34(s,1H),7.86(m,2H),7.57(m,3H),7.30(t,J＝7.8Hz,1H),7.16(d,J＝7.4Hz,1H),6.64–6.37(m,3H),6.28(m,2H),5.78(d,J＝10.3Hz,1H),3.87(s,3H),3.80–3.70(m,2H),3.69–3.54(m,2H),3.22–2.98(m,4H),2.19(s,3H),1.66(d,J＝6.6Hz,3H).LC-MS:m/z 585(M+H)
+.
Embodiment 3, N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) acrylamide
Synthetic method as embodiment 1,
1H NMR(400MHz,CDCl
3)δ8.34(s,1H),7.85(m,2H),7.48(m,3H),7.31(t,J＝7.8Hz,1H),7.16(d,J＝7.6Hz,1H),6.64–6.37(m,3H),6.27(m,2H),5.79(d,J＝10.2Hz,1H),3.86(s,3H),3.82–3.70(m,2H),3.68–3.58(m,2H),3.25–2.91(m,4H),2.06(s,3H),1.66(d,J＝6.5Hz,3H).LC-MS:m/z 585(M+H)
+.
Embodiment 4, N-(3-(1-((2-((2-methoxyl group-4-morpholinyl phenyl) is amino)-5-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) acrylamide
Synthetic method as embodiment 1,
1H NMR(400MHz,CDCl
3)δ8.35(s,1H),8.00-7.15(m,7H),6.68-6.61(m,2H),6.48-6.35(m,1H),6.34-6.24(m,2H),5.78(d,J＝4.8Hz,1H),3.92-3.86(m 7H),3.19(m,4H),1.82(d,J＝8.4Hz,3H).LC-MS:m/z 544(M+H)
+.
Embodiment 5, (R)-N-(3-(1-((2-((2-methoxyl group-4-morpholinyl phenyl) is amino)-5-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) propyl group) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.34(s,1H),7.89(s,1H),7.75(s,1H),7.53(d,J＝10.0Hz,1H),7.43(s,1H),7.31(t,J＝7.9Hz,1H),7.26–7.22(m,1H),7.17(d,J＝7.6Hz,1H),6.57(d,J＝8.8Hz,1H),6.53–6.39(m,2H),6.26(m,2H),5.79(d,J＝10.2Hz,1H),3.92–3.83(m,7H),3.20–3.09(m,4H),1.67(d,J＝6.6Hz,3H).LC-MS:m/z 544(M+H)
+.
Embodiment 6, (R)-N-(3-(1-((2-((4-(isopropylamino)-2-p-methoxy-phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,DMSO-d
6)δ10.18(s,1H),8.68(s,1H),8.34(s,1H),7.87–7.62(m,1H),7.57(d,J＝6.4Hz,1H),7.42–6.61(m,3H),6.43(m,1H),6.25(m,2H),6.11(m,1H),5.95(m,1H),5.76(m,1H),5.36(m,1H),3.63(m,3H),3.56(m,1H),1.54(m,3H),1.14(t,J＝6.7Hz,6H).LC-MS:m/z 516(M+H)
+.
Embodiment 7; (R)-N-(3-(1-((2-((4-(6-ethanoyl-2,6-diaza spiroheptane-2-base)-2-p-methoxy-phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,DMSO-d
6)δ10.17(s,1H),8.72(s,1H),8.36(s,1H),7.75(s,1H),7.55(m,1H),7.27-7.15(m,3H),6.48-5.75(m,5H),4.30(s,2H),4.00(s,2H),3.94(s,4H),3.71(s,3H),1.76(s,3H),1.53(s,3H).LC-MS:m/z 597(M+H)
+.
Embodiment 8; (R)-N-(3-(1-((2-((4-(4-ethanoyl-4,7-diaza spiro [2.5] octane-7-base)-2-p-methoxy-phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.33(s,1H),7.82(m,2H),7.50(m,3H),7.31(t,J＝7.6Hz,1H),7.16(d,J＝7.0Hz,1H),6.56–6.37(m,3H),6.27(m,2H),5.80(m,1H),4.06–3.69(m,5H),3.20(m,2H),2.98(s,2H),2.27–1.99(m,4H),1.09(m,4H).LC-MS:m/z 611(M+H)
+.
Embodiment 9, (R)-N-(3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-Methoxyphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl)-4-chloro-phenyl-) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.36(s,1H),7.93(d,J＝7.7Hz,1H),7.39–7.32(m,2H),6.60–6.50(m,3H),6.43(dd,J＝16.8,0.9Hz,1H),6.23(dd,J＝16.8,10.2Hz,1H),5.78(d,J＝11.0Hz,1H),3.86(s,3H),3.82–3.77(m,2H),3.68–3.62(m,2H),3.17–3.09(m,4H),2.16(s,3H),1.66(d,J＝6.5Hz,3H)；LC-MS:m/z 619(M+H)
+.
Embodiment 10, (R)-N-(3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-Methoxyphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl)-5-fluorophenyl) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.35(s,1H),7.67-7.60(m,2H),7.47–7.36(m,2H),6.84(d,J＝8.6Hz,1H),6.59–6.43(m,3H),6.30–6.13(m,2H),5.84–5.77(m,1H),3.86(s,3H),3.81–3.75(m,2H),3.66–3.61(m,2H),3.19–3.09(m,4H),2.16(s,3H),1.65(d,J＝6.6Hz,3H).LC-MS:m/z 603(M+H)
+.
Embodiment 11, N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) is amino) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.14(s,1H),7.79(m,3H),7.49(s,1H),7.38(d,J＝7.5Hz,1H),7.30(t,J＝7.8Hz,1H),7.09(d,J＝7.5Hz,1H),6.56–6.12(m,4H),5.78(d,J＝10.2Hz,1H),5.35(m,2H),3.77(m,5H),3.60(t,J＝4.9Hz,2H),3.10(s,4H),2.14(s,3H),1.58(d,J＝6.6Hz,3H).LC-MS:m/z 584(M+H)
+.
Embodiment 12, (R)-N-(3-(1-((2-((4-(4-acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-5-chloropyrimide-4-base) oxygen) ethyl) propyl group) acrylamide
Synthetic method is as embodiment 1
1H NMR(400MHz,CDCl
3)δ8.11(s,1H),7.92(d,J＝8.7Hz,1H),7.78(s,1H),7.45(d,J＝7.7Hz,1H),7.34(m,3H),7.19(d,J＝7.7Hz,1H),6.59–6.42(m,3H),6.24(m,2H),5.80(m,1H),3.86(s,3H),3.81–3.74(m,2H),3.67–3.61(m,2H),3.19–3.05(m,4H),2.15(s,3H),1.69(d,J＝6.6Hz,3H).LC-MS:m/z 551(M+H)
+.
Embodiment 13, (R)-N-(3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenyl) acrylamide
Synthesis step:
Step 1:(R) preparation of-3-(1-(the chloro-5-iodine pyrimidine of 2--4-base oxygen) ethyl) phenylcarbamate
(R)-3-(1-hydroxyethyl) phenylcarbamate (4.0g, 16.8mmol) be dissolved in THF (100mL) with sodium tert-butoxide, be cooled to-10 DEG C, add 2 subsequently, the chloro-5-iodine pyrimidine (5.1g, 18.5mmol) of 4-bis-.Reaction solution-10 DEG C of reactions 10 minutes, then adds water (100mL) under nitrogen protection.The mixture obtained is extracted with ethyl acetate EA (3x100mL).Organic phase merges after washing, uses anhydrous Na
2sO
4dry final vacuum concentrating under reduced pressure, resistates column chromatography purification obtains yellow oily (R)-3-(1-(the chloro-5-iodine pyrimidine of 2--4-base oxygen) ethyl) phenylcarbamate (7.5g, 93% productive rate).LC-MS:m/z:476(M+H)
+.
Step 2:(R) preparation of-3-(1-(the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate
(R)-3-(1-(the chloro-5-iodine pyrimidine of 2--4-base oxygen) ethyl) phenylcarbamate (7.5g; 15.7mmol) with cuprous iodide (6.0g; 31.5mmol) be dissolved in DMFF (40mL); add methyl 2 subsequently; the fluoro-2-of 2-bis-(fluorosulfonyl) methyl acetate (6.1g, 31.5mmol).Reaction solution 100 DEG C of reactions 3 hours, adds H under nitrogen protection subsequently
2o (200mL).The mixture obtained is extracted with ethyl acetate EA (3x200mL).Organic phase merges after washing, uses anhydrous Na
2sO
4dry final vacuum concentrating under reduced pressure, resistates column chromatography purification obtains colorless oil (R)-3-(1-(the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate (3.1g, 47% productive rate).LC-MS:m/z:418(M+H)
+.
Step 3:(R)-3-(preparation of 1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate
(R)-3-(1-(the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate (200mg, 0.5mol), 1-(4-(4-amino-3-chloro-phenyl-) piperazine-1-base) ethyl ketone (430mg, 1mmol), Pd
2(dba)
3(96.0mg, 0.1mmol) and Xant-phos (58.0mg, 01mmol) are dissolved in toluene (10mL), add Cs subsequently
2cO
3(0.5g, 1.5mmol).Reaction solution reacts 16 hours at 100 DEG C under nitrogen protection, vacuum-concentrcted subsequently.Residue with ethyl acetate washes with water after diluting again, dry final vacuum concentrating under reduced pressure, resistates column chromatography purification obtains yellow solid (R)-3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate (140mg, AP:80%).LC-MS:m/z:635(M+H)
+.
Step 4:(R)-1-(4-(4-((4-(1-(3-aminophenyl) oxyethyl group)-5-(trifluoromethyl) pyrimidine-2-base) amino)-3-chloro-phenyl-) piperazine-1-base) preparation of ethyl ketone
(R)-3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenylcarbamate (140mg, AP:80%) and 2,6-lutidine (250mg, 2.5mmol) be dissolved in dry DCM (10mL), be cooled to 0 DEG C, be added dropwise to TMSOTf (0.55g, 2.5mmol) subsequently.Reaction solution stirs at the same temperature until react end, then goes out with shrend.Organic phase uses anhydrous Na after being separated
2sO
4dry final vacuum concentrating under reduced pressure obtains crude yellow oil (R)-1-(4-(4-((4-(1-(3-aminophenyl) oxyethyl group)-5-(trifluoromethyl) pyrimidine-2-base) is amino)-3-chloro-phenyl-) piperazine-1-base) ethyl ketone (110mg, AP:70%), next step reaction is directly used in without purifying.LC-MS:m/z:535(M+H)
+.
Step 5:(R) preparation of-N-(3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenyl) acrylamide
(R)-1-(4-(4-((4-(1-(3-aminophenyl) oxyethyl group)-5-(trifluoromethyl) pyrimidine-2-base) is amino)-3-chloro-phenyl-) piperazine-1-base) ethyl ketone (110mg, AP:70%) and pyridine (0.4mL) be dissolved in dry DCM (10mL), be cooled to 0 DEG C, be added dropwise to DCM (0.5mL) solution of the drying of acrylate chloride (0.1mL) subsequently.Reaction mixture reacts 15 minutes at the same temperature, then goes out with shrend.The mixture DCM obtained extracts (3x10mL).Organic phase merges after washing, uses anhydrous Na
2sO
4dry final vacuum concentrating under reduced pressure, resistates preparative chromatography purifying obtains white solid (R)-N-(3-(1-(2-(4-(4-acetylpiperazine-1-base)-2-chlorphenylamino)-5-(trifluoromethyl) pyrimidine-4-yl oxygen) ethyl) phenyl) acrylamide (35mg, 29% productive rate).
1H NMR(400MHz,CDCl
3)δ8.35(s,1H),7.84(s,2H),7.66(s,1H),7.39(s,2H),7.30(t,J＝6.8Hz,1H),7.13(d,J＝7.1Hz,1H),6.90(m,2H),6.45(m,1H),6.28(m,1H),6.20(d,J＝6.1Hz,1H),5.79(m,1H),3.76(m,2H),3.62(m,2H),3.23–3.02(m,4H),2.15(s,3H),1.65(d,J＝6.5Hz,3H).LC-MS:m/z:589(M+H)
+.
Embodiment 14, (R)-N-(3-(1-((2-(4-(4-acetylpiperazine-1-base)-phenyl amino)-5-trifluoromethyl pyrimidine-4-base) oxygen) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 13
1H NMR(400MHz,CDCl
3)δ8.30(s,1H),7.86(s,2H),7.66(s,1H),7.45-7.25(m,4H),7.13(d,J＝6.9Hz,1H),6.93(d,J＝8.8Hz,2H),6.46(m,1H),6.31(m,1H),6.15(q,J＝6.5Hz,1H),5.78(m,1H),3.83–3.71(m,2H),3.68–3.58(m,2H),3.19–3.01(m,4H),2.15(s,3H),1.64(d,J＝6.6Hz,3H).LC-MS:m/z:555(M+H)
+.
Embodiment 15,4-acrylamide-N-(2-((2-methoxyl group-4-morpholine phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-benzamide
Synthesis step:
The preparation of the chloro-N-of step 1:4-(2-methoxyl group-4-morpholine phenyl)-5-(trifluoromethyl) pyrimidine-2-amine
The chloro-5-of 2,4-bis-(trifluoromethyl) pyrimidine (1.6g, 7.37mmol) is dissolved in DCE/tBuOH (1:1,80mL), is cooled to 0 DEG C, is added dropwise to ZnCl under nitrogen protection subsequently
2diethyl ether solution (1M, 8.1mL, 8.1mmol).Dropwise, reaction solution is continuing reaction one hour at 0 DEG C, 2-methoxyl group-4-morpholine aniline (1.6g is added subsequently in order in 15 minutes, DCE/tBuOH solution (1:1 7.37mmol), 15mL) with TEA (8.2g, DCE/tBuOH solution (1:1,5mL) 8.1mmol).The mixture obtained is raised to room temperature reaction and spends the night.Add water and ethyl acetate after reaction solution is concentrated, continue after aqueous phase separation to be extracted with ethyl acetate.Organic phase merges with dry concentrated after saturated common salt water washing.Resistates column chromatography purification obtains target product (1.1g, 38.4% productive rate).LC-MS:m/z 389(M+H)
+.
Step 2:N
2-(2-methoxyl group-4-morpholine phenyl)-N
4the preparation of-methyl 5-(trifluoromethyl) pyrimidine-2,4-diamines
The chloro-N-of 4-(2-methoxyl group-4-morpholine phenyl)-5-(trifluoromethyl) pyrimidine-2-amine (1g) is dissolved in MeOH (10mL), adds NH subsequently
2cH
3/ EtOH solution (10mL).After adding, then reactant concentrates at room temperature reaction for 1 hour.Resistates column chromatography purification obtains target product (950mg, 96.3% productive rate).LC-MS:m/z 384(M+H)
+.
The preparation of step 3:N-(2-((2-methoxyl group-4-morpholine phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-4-nitrobenzamide
N
2-(2-methoxyl group-4-morpholine phenyl)-N
4-methyl-5-(trifluoromethyl) pyrimidine-2,4-diamines (504mg, 1mmol) is dissolved in anhydrous pyridine (5mL), is raised to 60 DEG C, adds 4-nitrobenzoyl chloride (371mg, 2mmol) subsequently.Mixture reacts 4 hours at this temperature, then concentrates and obtains target product, without the need to purifying, is directly used in next step reaction.LC-MS:m/z 533(M+H)
+.
The preparation of step 4:4-amino-N-(2-((2-methoxyl group-4-morpholine phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-benzamide
N-(2-((2-methoxyl group-4-morpholine phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-4-nitrobenzamide (262mg, 0.5mmol) be dissolved in EtOH (5mL), add SnCl subsequently
2.2H
2o (451mg, 2mmol).Reactant uses frozen water cancellation after room temperature reaction 4hr.The mixture obtained is transferred to pH 14, is then extracted with ethyl acetate.Organic phase merges dry rear concentrated, and the resistates column chromatography purification obtained obtains target product (95mg, 37.8% productive rate).LC-MS:m/z 503(M+H)
+.
The preparation of step 5:4-acrylamide-N-(2-((2-methoxyl group-4-morpholine phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-benzamide
4-amino-N-(2-((2-methoxyl group-4-morpholine phenyl) amine)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-benzamide (63mg, 0.125mmol) be dissolved in DCM (5mL), be cooled to 0 DEG C, add pyridine (79mg, 1mmol) and acrylate chloride subsequently.Reaction solution is at room temperature reaction 2 hours final vacuum concentrating under reduced pressure, and the resistates column chromatography purification obtained is separated and obtains target product (10mg, 14.3% productive rate).LC-MS:m/z 557(M+H)
+.
1H NMR(CDCl
3)δ8.17(s,1H),7.66-7.69(d,J＝8.4Hz,2H),7.55-7.57(d,J＝8.4Hz,2H),7.35(s,1H),7.08-7.09(d,J＝9.2Hz,2H),7.44-7.54(m,3H),6.20-6.28(m,1H),5.80-5.82(m,1H),5.03(s,1H),3.84-3.87(m,4H),3.74(s,1H),3.19-3.21(m,1H),2.45-2.46(m,3H).
Embodiment 16,3-acrylamide-N-(2-((2-methoxyl group-4-morpholine phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl)-N-methyl-benzamide
Synthetic method is as embodiment 15
LC-MS:m/z 557(M+H)
+.
1H NMR(CDCl
3)δ8.19(s,1H),7.97-8.00(d,J＝8.4Hz,2H),7.66-7.69(d,J＝8.4Hz,2H),7.25-7.40(m,4H),7.07-7.10(d,J＝9.2Hz,2H),7.52-7.54(m,1H),6.40-6.45(m,1H),5.03-5.04(d,J＝8Hz,1H),4.84-4.85(d,J＝8Hz,1H),3.85-3.87(m,4H),3.74-3.76(d,J＝6.4Hz,3H),3.20-3.22(m,4H),2.40(s,3H).
Embodiment 17, (R)-N-(3-(1-((2-((2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) is amino)-5-(trifluoromethoxy) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthesis step:
Step 1:(R)-(preparation of 3-(1-((2-((2-methoxyl group-4-(4-methyl piperidine-1-base) phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenylcarbamate
(R)-(3-(1-((the chloro-5-trifluoromethyl of 2-) pyrimidine-4-yl) oxygen) ethyl) phenylcarbamate (450mg, 1.08mmol) be dissolved in acetonitrile (10mL) with triethylamine (1mL), add 2-methoxyl group-4-(4-methylpiperazine-1-yl) aniline (477mg, 2.16mmol).Reaction opening is heated to 130 DEG C, stirs 30 minutes again, be as cold as room temperature after solvent evaporates.Column chromatography (sherwood oil: ethyl acetate=1:1 is to methylene dichloride: methyl alcohol=15:1 with 0.5% triethylamine) obtain an oily compound crude product (740mg).
Step 2:(R) preparation of-4-(1-(3-amine phenyl) oxyethyl group)-N-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-5-(trifluoromethoxy) pyrimidine-2-amine
(R)-(3-(1-((2-((2-methoxyl group-4-(4-methyl piperidine-1-base) phenyl) is amino)-5-(trifluoromethyl) pyrimidine-4-yl) oxygen) ethyl) phenylcarbamate (740mg, crude product) and 2,6-lutidine (0.9mL, 8.1mmol) be dissolved in anhydrous methylene chloride (10mL), drop to 0 DEG C, drip TMSOTf (1.5mL, 8.1mmol).React and stir one hour at 0 DEG C, be poured into water (30mL), dichloromethane extraction twice (20mL x 2).Organic layer saturated aqueous common salt (30mL) is washed, anhydrous sodium sulfate drying, and concentrated, column chromatography for separation (sherwood oil: ethyl acetate=1:1 is to methylene dichloride: methyl alcohol=15:1) obtains the thick product of yellow oil (500mg).LC-MS:m/z 503(M+H)
+.
Step 3:(R)-N-(3-(1-((2-((2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl) amino)-5-(trifluoromethoxy) pyrimidine-4-yl) oxygen) ethyl) phenyl) preparation of acrylamide
(R)-4-(1-(3-amine phenyl) oxyethyl group)-N-(2-methoxyl group-4-(4-methylpiperazine-1-yl) phenyl)-5-(trifluoromethoxy) pyrimidine-2-amine (500mg, thick product) be dissolved in anhydrous methylene chloride (100mL), be as cold as-40 DEG C, add pyridine (0.6mL) and acrylate chloride (0.3mL).React and stir 15 minutes at-40 DEG C, be poured into water (50mL), organic layer saturated common salt is washed, anhydrous sodium sulfate drying, and concentrated, preparative HPLC (neutrality) is separated to obtain final product (10mg).
1H NMR(400MHz,CDCl
3)8.33(s,1H),7.80-7.90(m,1H),7.68(s,1H),7.48-7.52(m,2H),7.26-7.31(m,2H),7.15(d,J＝7.6Hz,1H),6.42-6.58(m,3H),6.23-6.30(m,2H),5.78(d,J＝10.0Hz,1H),3.85(s,3H),3.20(t,J＝5.2Hz,4H),2.60(t,J＝4.8Hz,4H),2.37(s,3H),1.66(d,J＝6.8Hz,3H).LC-MS:m/z 557(M+H)
+.
Embodiment 18, (R)-N-(3-(1-((the chloro-2-of 5-((2-methoxy-4-(4-methylpiperazine-1-yl) phenyl) is amino) pyrimidine-4-yl) oxygen) ethyl) phenyl) acrylamide
Synthetic method is as embodiment 17
1H NMR(400MHz,CDCl
3)8.10(s,1H),7.86(d,J＝8.8Hz,1H),7.73(s,1H),7.47-7.52(m,2H),7.28-7.34(m,2H),7.17(d,J＝7.6Hz,1H),6.42-6.55(m,3H),6.27-6.35(m,1H),6.18-6.21(m,2H),5.77-5.80(m,1H),3.84(s,3H),3.25(t,J＝4.4Hz,4H),2.75(t,J＝4.4Hz,4H),2.47(s,3H),1.69(d,J＝6.4Hz,3H).LC-MS:m/z 523(M+H)
+.
The Bioexperiment test of embodiment 1-18
The kinases IC50 of this compounds to EGFR wild-type and EGFR-T790M sudden change tests: EGFR (WT) is wild-type egf acceptor, EGFR (T790M) is the EGF-R ELISA being sported methionine(Met) with the 790th amino acids by Threonine, EGFR (L858R) is for sport arginic EGF-R ELISA with the 858th amino acids by leucine, EGFR (L858R/T790M) simultaneously sports by leucine arginine and the 790th amino acids to be sported methionine(Met) EGF-R ELISA by Threonine with the 858th amino acids.
Kinase activity detects: this test uses Kinase-Glo Plus luminescence kinaseassay kit (purchased from Promega company).After it swashs enzymatic reaction by quantitative analysis, residual ATP content detects kinase activity.Fluorescent signal in test is relevant to existing ATP content.The reaction solution of configuration 50uL, comprises 40mM Tris, pH 7.4,10mM MgCl
2, 0.1mg/ml BSA, 1mM DTT, 0.2mg/ml Poly (Glu, Tyr) substrate, 10M ATP and EGFR.Testing compound is made into 10%DMSO solution, gets 5uL and be diluted in the above-mentioned reaction solution of 50uL that to obtain final DMSO concentration be the reaction solution of 1%.All enzymic catalytic reactions all carry out 35 minutes at 30 DEG C.For pre-incubated reaction in 30 minutes, enzyme first and inhibitor hatch 30 minutes, then add ATP and substrate starts to react.After enzymic catalytic reaction terminates, in reaction solution, add 50uL Kinase-Glo Plus Luminescence kinase assaysolution, continue incubation at room temperature 5 minutes.Measured by BioTek Synergy 2microplatereader during fluorescent signal.
IC50 calculates with GraphPadPrism5.00 (four parameter logistic equation).In following table, data are bioassay data of the corresponding compound of embodiment 1-18, record by above-described method.
* NA: do not test
Containing in the competition experiments of benzyl oxide, benzylamine or aryl amide compound and ATP, form irreversible Michael reaction, so all embody higher inhibit activities to kinases owing to existing with protein cysteine site.
Claims (7)
1. an inhibitor of T790M mutant egf R, this inhibitor has the structure of general formula (I):
Wherein,
X, Y, Z and U are independently selected from N, CH;
V is selected from CO, CHR
8, wherein R
8be selected from hydrogen, C
1-C
4substituted alkyl;
W is selected from O, NR
9, wherein R
9be selected from hydrogen, C
1-C
4substituted alkyl;
R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl;
R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl;
R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N;
R
5, R
6and R
7independently be selected from hydrogen, halogen, C
1-C
4substituted alkyl.
2. inhibitor as claimed in claim 1, it has the structure of logical formula V:
Wherein,
R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl;
R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl;
R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N;
R
5, R
6and R
7independently be selected from hydrogen, halogen, C
1-C
4substituted alkyl.
3. inhibitor as claimed in claim 1, it has the structure of general formula (VI):
Wherein,
R
1be selected from hydrogen, halogen, C
1-C
4substituted alkyl;
R
2be selected from hydrogen, halogen, C
1-C
4alkoxyl group, C
1-C
4substituted alkyl;
R
3and R
4independently be selected from hydrogen, C
1-C
4substituted alkyl; Or, R
3, R
4the monocycle of replacement, volution or bridged ring is formed together with atom N.
4. inhibitor as claimed in claim 1, is characterized in that: described inhibitor is selected from the compound of following structural formula,
5. a pharmaceutical composition, this pharmaceutical composition contains at least one inhibitor as described in any one of claim 1-4 or its enantiomorph, diastereomer, resonating body, or described inhibitor pharmacy acceptable salt or its prodrugs, and pharmaceutically acceptable carrier.
6. the application in antitumor drug prepared by the inhibitor described in any one of claim 1-4.
7. the application in antitumor drug prepared by inhibitor as claimed in claim 6, it is characterized in that: described tumour is nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs), white leukemia, histiocytic lymphatic cancer, at least one in nasopharyngeal carcinoma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461640A (en) * | 2015-12-02 | 2016-04-06 | 芷威（上海）化学科技有限公司 | Preparation method of tyrosine kinase inhibitor |
| WO2017049992A1 (en) * | 2015-09-25 | 2017-03-30 | 浙江博生医药有限公司 | Egfr kinase inhibitor and preparation method and use thereof |
| WO2017071419A1 (en) * | 2015-10-26 | 2017-05-04 | 苏州明锐医药科技有限公司 | Method for preparing rociletinib |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101902911A (en) * | 2007-10-19 | 2010-12-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN102083800A (en) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2014124230A2 (en) * | 2013-02-08 | 2014-08-14 | Celgene Avilomics Research, Inc. | Erk inhibitors and uses thereof |
| CN104130265A (en) * | 2014-04-29 | 2014-11-05 | 苏州景泓生物技术有限公司 | Spiral ring or bridged ring containing pyrimidine compound |
| WO2015006492A1 (en) * | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
-
2015
- 2015-04-29 CN CN201510214627.1A patent/CN104860890B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101902911A (en) * | 2007-10-19 | 2010-12-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN102083800A (en) * | 2008-06-27 | 2011-06-01 | 阿维拉制药公司 | Heteroaryl compounds and uses thereof |
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and uses thereof |
| WO2014124230A2 (en) * | 2013-02-08 | 2014-08-14 | Celgene Avilomics Research, Inc. | Erk inhibitors and uses thereof |
| WO2015006492A1 (en) * | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
| CN104130265A (en) * | 2014-04-29 | 2014-11-05 | 苏州景泓生物技术有限公司 | Spiral ring or bridged ring containing pyrimidine compound |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017049992A1 (en) * | 2015-09-25 | 2017-03-30 | 浙江博生医药有限公司 | Egfr kinase inhibitor and preparation method and use thereof |
| JP2018536698A (en) * | 2015-09-25 | 2018-12-13 | ジェジャン ボサン ファーマシューティカル カンパニー リミテッドＺｈｅｊｉａｎｇ Ｂｏｓｓａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ． Ｌｔｄ． | EGFR kinase inhibitors and methods of making and using the same |
| US10710979B2 (en) | 2015-09-25 | 2020-07-14 | Zhejiang Bossan Pharmaceutical Co. Ltd. | EGFR kinase inhibitor and preparation method and use thereof |
| WO2017071419A1 (en) * | 2015-10-26 | 2017-05-04 | 苏州明锐医药科技有限公司 | Method for preparing rociletinib |
| US10138224B2 (en) | 2015-10-26 | 2018-11-27 | Suzhou Miracpharma Technology Co., Ltd. | Preparation method of rociletinib |
| CN105461640A (en) * | 2015-12-02 | 2016-04-06 | 芷威（上海）化学科技有限公司 | Preparation method of tyrosine kinase inhibitor |
| CN105461640B (en) * | 2015-12-02 | 2017-11-21 | 芷威（上海）化学科技有限公司 | A kind of preparation method of tyrosine kinase inhibitor |
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