CN105481841A - Compounds possessing kinase inhibition activity, preparation method and uses - Google Patents
Compounds possessing kinase inhibition activity, preparation method and uses Download PDFInfo
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- CN105481841A CN105481841A CN201510769434.2A CN201510769434A CN105481841A CN 105481841 A CN105481841 A CN 105481841A CN 201510769434 A CN201510769434 A CN 201510769434A CN 105481841 A CN105481841 A CN 105481841A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
Compounds possessing kinase inhibition activity, a preparation method and uses are disclosed. The invention discloses the compounds shown as a general formula I, or pharmaceutically-acceptable salts thereof, or enantiomers, diastereomers, tautomerisms, solvates, polymorphic substances or prodrugs thereof, the preparation method of the above compounds, and application of the above compounds to medicines, and the groups in the general formula I are defined as the specification. The compounds possess relatively excellent kinase inhibition activity, and especially EGFR and ALK kinases and mutants thereof possessses relative good medicinal prospect.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly, relate to a class and there is the compound of kinase inhibiting activity, preparation method and purposes.
Background technology
Tumor cells targeted therapy is based on to the closely-related key protein of tumorigenesis, by chemical means selectively acting in signal protein, and a kind of methods for the treatment of of killing tumor cell.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic side effect is low relative to classic chemotherapy medicine; During drug combination, the curative effect of classic chemotherapy can be strengthened; Targeted inhibition agent medicine easily produces resistance clinically and medicine was lost efficacy.
Lung cancer is the malignant tumour that whole world sickness rate and case fatality rate are the highest, and within 5 years, survival rate is only 16.8%, and the sickness rate of lung cancer in 2010 and case fatality rate occupy first of all malignant tumours of China.Nonsmall-cell lung cancer (NSCLC) accounts in all lung cancer histological type 85%, and the nonsmall-cell lung cancer cause of disease is complicated, and polygene, Mutiple Targets regulate and control and easily sudden change produces resistance.Treatment for Non-small Cell Lung medicine mainly contains classic chemotherapy medicine platinum class, taxanes, antibody class, neovascularization inhibitor and targeted inhibition agent etc., but the resistance patient caused along with still there being a large amount of sudden changes clinically occurs, the Treatment for Non-small Cell Lung medicine therefore finding and find overriding resistance is still a popular domain of current industry member.In recent years, U.S. FDA have approved multiple ALK inhibitor in succession, as gram azoles is for Buddhist nun etc. for Buddhist nun, look auspicious, and be in the third generation EGFR inhibitor in clinical late stage at present, as AZD9291, CO1686 etc., but still there is unsatisfactory curative effect in current this kind of medicine, or the problems such as selectivity is not high, therefore have comparatively highly selective in the urgent need to finding and find a class, and medicament-resistant mutation are had to the medicine of the novel mechanism of action of greater activity.
Summary of the invention
One of technical issues that need to address of the present invention are to provide a kind of novel kinase inhibitor, for the preparation of anti-tumor medicine.
The scheme solved the problems of the technologies described above is as follows:
There is the compound shown in formula I, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug,
I
In formula:
R1, R2 are selected from lower group independently of one another: hydrogen, halogen, cyano group, substituted carbonyl, substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl; Preferably, R1 is hydrogen, fluorine, chlorine, trifluoromethyl, cyano group; R2 is hydrogen, fluorine, cyano group;
R3 is selected from lower group: hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl; Be preferably hydrogen;
R4, R5, R6 and R7 are separately selected from hydrogen, halogen, cyano group, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, and wherein any two groups can form the ring system of 3-10 unit; Preferably, R4, R5, R6, R7 independently selected from hydrogen, methyl;
M1, M2 are selected from independently of one another: CRa or N, and wherein have one at least for N; Ra is H, halogen, cyano group, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl; Preferably, Ra is H;
L is selected from lower group: nothing or linking group;
W is selected from lower group: the aromatic base of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl or alkynyl group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 unit heterocyclic radical, 5-10 unit or heteroaryl, substituted carbonyl, substituted sulphonyl, substituted or unsubstituted amino, wherein, described heterocycle comprises the heteroatoms that 1-3 is selected from lower group: N, O, S, P or B; Preferably, W is piperidyl, piperazinyl, pyrazolyl, homopiperazine base etc.;
Above-mentioned arbitrary " replacement " refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: halogen, OH, NH
2, CN, do not replace or halo C1-C8 alkyl, do not replace or halo C3-C8 cycloalkyl, do not replace or halo C1-C8 alkoxyl group, do not replace or halo C2-C6 thiazolinyl, do not replace or halo C2-C6 alkynyl, do not replace or halo C2-C6 acyl group, do not replace or halo 5 ~ 8 yuan of aryl, do not replace or halo 5 ~ 8 yuan of heteroaryls, do not replace or 4 ~ 8 yuan of saturated heterocyclics of halo or carbocyclic ring; Wherein, described heteroaryl comprises the heteroatoms that 1-3 is selected from lower group: N, O or S, and described heterocycle comprises the heteroatoms that 1-3 is selected from lower group: N, O or S.
Another object of the present invention is to provide a kind of pharmaceutical composition for the treatment of tumour.The technical scheme realizing above-mentioned purpose is as follows:
A kind of pharmaceutical composition for the treatment of tumour, it is by the fragrant aminopyridine of the di-substituted aryl shown in above-mentioned general formula (I) or pyrimidines, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug and pharmaceutically acceptable carrier form.
Another object of the present invention is to provide a kind of purposes of above-claimed cpd.The technical scheme realizing above-mentioned purpose is as follows:
The fragrant aminopyridine of di-substituted aryl shown in described general formula (I) or pyrimidines, or its pharmacy acceptable salt or the application in preparation prevention or treatment antitumor drug of its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug.
Described tumour is any one in 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 tumor, leukemia, lymphatic cancer, nasopharyngeal carcinoma etc.
The present invention relates to the compound with general formula (I) constitutional features, kinds of tumor cells can be suppressed, especially can selectively acting in the lung carcinoma cell of the sudden change such as EGFRL858R/T790M and the ALK positive, and the strong 10-100 of comparison Wild type EGFR lung carcinoma cell effect doubly, is the lung cancer therapy medicine of the brand-new mechanism of action of a class.
Should understand, within the scope of the present invention in, above-mentioned each technical characteristic of the present invention and can combine mutually between specifically described each technical characteristic in below (eg embodiment) thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
The present inventor, through long-term and deep research, has prepared the compound that a class has structure shown in formula I, and finds that it has good EGFR mutant and ALK kinase inhibiting activity.And described compound is under extremely low concentration (can be low to moderate≤100nmol/L), namely restraining effect is produced to a series of EGFR mutant and ALK kinases, inhibit activities is quite excellent, thus may be used for treating the relative disease that causes with EGFR kinase mutant or ALK fusion rotein as tumour.Based on above-mentioned discovery, contriver completes the present invention.
Term
Unless otherwise defined, otherwise herein the connotation that has of all scientific and technical terminologies is identical with the connotation that claim theme one of ordinary skill in the art understand usually.Except as otherwise noted, all patents quoted in full herein, patent application, open material by reference entirety are incorporated to herein.
Should be understood that above-mentioned summary and being specified as hereafter exemplary and only for explaining, and present subject matter not to be imposed any restrictions.In this application, unless otherwise expressly specified, otherwise use odd number time also comprise plural number.Must be noted that, clearly illustrate unless separately had in literary composition, otherwise singulative used in the present specification and claims comprises the plural form of referents.It shall yet further be noted that unless otherwise stated, "or" used, " or " represent "and/or".In addition, term used " comprises " and other form, such as, " comprise ", " containing " and " containing " non-limiting.
The definition to standard chemistry terms can be found in reference (comprising CareyandSundberg " ADVANCEDORGANICCHEMISTRY4THED. " Vols.A (2000) andB (2001), PlenumPress, NewYork).Unless otherwise stated, adopt the ordinary method within the scope of art technology, as mass spectrum, NMR, IR and UV/VIS spectrography and pharmacological method.Unless proposed concrete definition, otherwise herein analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemical relevant describe in the term of employing be known in the art.At chemosynthesis, chemical analysis, medicine preparation, preparation and can send, and use standard technique in the treatment of patient.Such as, manufacturer can be utilized the operation instruction of test kit, or implement reaction according to mode well known in the art or explanation of the present invention and carry out purifying.Usually according to the description in the multiple summary quoted in this specification sheets and discuss and more concrete document, above-mentioned techniques and methods can be implemented according to ordinary method well known in the art.In this manual, group and substituting group thereof can be selected to provide stable structure part and compound by those skilled in the art.
When describing substituting group by the conventional chemical formulas write from left to right, this substituting group comprise too obtain when writing structural formula from right to left at chemically equivalent substituting group.For example ,-CH2O-is equal to-OCH2-.
Chapter title used herein only for the object of organizational, and should not be interpreted as the restriction to described theme.The all documents quoted in the application or literature department divide and include but not limited to patent, patent application, article, books, operational manual and paper, and entirety is incorporated to herein all by reference.
Some chemical group defined in this article previously by contracted notation to represent the total number of carbon atoms existed in this group.Such as, C1-6 alkyl refer to have 1 to 6 carbon atom altogether as hereafter the alkyl that defines.The total number of carbon atoms in contracted notation does not comprise the carbon in the substituting group that may be present in described group.
Except aforementioned, time in for the specification sheets of the application and claims, unless otherwise specified, otherwise following term has implication as follows.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH group.
" hydroxyalkyl " refer to by hydroxyl (-OH) replace as hereafter the alkyl that defines.
" carbonyl " refers to-C (=O)-group.
" nitro " refers to-NO
2.
" cyano group " refers to-CN.
" amino " refers to-NH
2.
" amino of replacement " refer to by one or two as hereafter the amino that replaces of the alkyl, alkyl-carbonyl, aralkyl, the heteroaralkyl that define, such as, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroaralkyl are amino.
" carboxyl " refers to-COOH.
In this application, as group or a part for other group (being such as used in the groups such as the alkyl of halogen substiuted), term " alkyl " means only to be made up of carbon atom and hydrogen atom, containing unsaturated link(age), have such as 1 to 12 (be preferably 1 to 8, be more preferably 1 to 6) carbon atom and the hydrocarbon chain radical of the straight or branched be connected with the rest part of molecule by singly-bound.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-methyl butyl, 2,2-dimethyl propyls, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl group, nonyl and decyl etc.
In this application, as group or a part for other group, term " thiazolinyl " means only to be made up of carbon atom and hydrogen atom, containing at least one double bond, to have such as 2 to 14 (preferably 2 to 10, be more preferably 2 to 6) carbon atom and the hydrocarbon chain radical of the straight or branched be connected with the rest part of molecule by singly-bound, such as but not limited to vinyl, propenyl, allyl group, but-1-ene base, but-2-ene base, penta-1-thiazolinyl, penta-Isosorbide-5-Nitrae-dialkylene etc.
In this application, as group or a part for other group, term " alkynyl " means only to be made up of carbon atom and hydrogen atom, containing at least one triple bond and optional one or more double bonds, to have such as 2 to 14 (preferably 2 to 10, be more preferably 2 to 6) carbon atom and the hydrocarbon chain radical of the straight or branched be connected with the rest part of molecule by singly-bound, such as but not limited to ethynyl, the third-1-alkynyl, fourth-1-alkynyl, penta-1-alkene-4-alkynyl etc.
In this application, as group or a part for other group, term " cycloalkyl " means the stable non-aromatic monocyclic that is only made up of carbon atom and hydrogen atom or multi-ring alkyl, it can comprise fused ring system, bridged-ring system or spiro ring system, there are 3 to 15 carbon atoms, preferably there are 3 to 10 carbon atoms, more preferably there are 3 to 8 carbon atoms, and it is saturated or unsaturated and can be connected with the rest part of molecule by singly-bound via any suitable carbon atom.Unless specialized in addition in this specification sheets, the carbon atom in cycloalkyl can be optionally oxidized.The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, ring octyl group, 1H-indenyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydro-naphthalenyl, 5, 6, 7, 8-tetrahydro-naphthalenyl, 8, 9-dihydro-7H-benzo ring heptene-6-base, 6, 7, 8, 9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5, 6, 7, 8, 9, 10-six hydrogen-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, 7, 7-dimethyl-two ring [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene radical-1H-indenyl and octahydro-2, 5-methylene radical-pentalene base etc.
In this application, as group or a part for other group, 3 yuan to the 20 yuan stable non-aromatic cyclic groups that the heteroatoms that term " heterocyclic radical " means to be selected from nitrogen, phosphorus, oxygen and sulphur by 2 to 14 carbon atoms and 1 to 6 forms.Unless specialized in addition in this specification sheets, otherwise heterocyclic radical can be the member ring systems of monocycle, dicyclo, three rings or more ring, and it can comprise fused ring system, bridged-ring system or spiro ring system; Nitrogen in its heterocyclic radical, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally quaternized; And heterocyclic radical can be partially or completely saturated.Heterocyclic radical can be connected with molecule rest part by singly-bound via carbon atom or heteroatoms.In the heterocyclic radical comprising condensed ring, one or more ring can be hereafter defined aryl or heteroaryl, and condition is non-aromatic annular atoms with the tie point of molecule rest part.With regard to object of the present invention, heterocyclic radical preferably comprises heteroatomic stable 4 yuan to 11 yuan non-aromatic monocyclic, dicyclo, bridged ring or the spiro-cyclic groups that 1 to 3 is selected from nitrogen, oxygen and sulphur, is more preferably and comprises heteroatomic stable 4 yuan to 8 yuan non-aromatic monocyclic, dicyclo, bridged ring or the spiro-cyclic groups that 1 to 3 is selected from nitrogen, oxygen and sulphur.The example of heterocyclic radical includes but not limited to: pyrrolidyl, morpholinyl, piperazinyl, homopiperazine base, piperidyl, thio-morpholinyl, 2, 7-diaza-spiro [3.5] nonane-7-base, 2-oxa--6-aza-spiro [3.3] heptane-6-base, 2, 5-diaza-dicyclo [2.2.1] heptane-2-base, azetidinyl, pyranyl, THP trtrahydropyranyl, thiapyran base, tetrahydrofuran base, oxazinyl, dioxy cyclopentyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidyl, quinolizinyl, thiazolidyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indyl, octahydro pseudoindoyl, pyrrolidyl, pyrazolidyl, phthaloyl imino etc.
In this application, as group or a part for other group, term " aryl " means the conjugated hydrocarbons member ring systems group with 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).With regard to object of the present invention, aryl can be the member ring systems of monocycle, dicyclo, three rings or more ring, can also condense with cycloalkyl defined above or heterocyclic radical, and condition is that aryl is connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.The example of aryl includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1H-pseudoindoyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-one-7-base etc.
In this application, term " arylalkyl " refer to by above the aryl that defines replace above the alkyl that defines.
In this application, as group or a part for other group, term " heteroaryl " means to have in ring heteroatomic 5 yuan to the 16 yuan conjugation ring system groups that 1 to 15 carbon atom (preferably having 1 to 10 carbon atom) and 1 to 6 are selected from nitrogen, oxygen and sulphur.Unless specialized in addition in this specification sheets, otherwise heteroaryl can be the member ring systems of monocycle, dicyclo, three rings or more ring, can also condense with cycloalkyl defined above or heterocyclic radical, condition is that heteroaryl is connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.Nitrogen in heteroaryl, carbon or sulphur atom are optionally oxidized; Nitrogen-atoms is optionally quaternized.With regard to object of the present invention, heteroaryl preferably comprises 5 yuan to the 12 yuan heteroatomic stable aromatic radical that 1 to 5 is selected from nitrogen, oxygen and sulphur, is more preferably to comprise 1 to 4 and be selected from 5 yuan to the 10 yuan heteroatomic stable aromatic radical of nitrogen, oxygen and sulphur or comprise heteroatomic 5 yuan to the 6 yuan aromatic radical that 1 to 3 is selected from nitrogen, oxygen and sulphur.The example of heteroaryl includes but not limited to thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl-, benzopyrazoles base, indyl, furyl, pyrryl, triazolyl, tetrazyl, triazinyl, indolizine base, pseudoindoyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazyl, carbolinyl, phenanthridinyl, phenanthroline base, acridyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole base, cinnolines base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydro benzo [b] thienyl, naphtho-pyridyl, [1,2,4] triazolo [4,3-b] pyridazine, [1,2,4] triazolo [4,3-a] pyrazine, [1,2,4] triazolo [4,3-c] pyrimidine, [1,2,4] triazolo [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc.
In this application, term " heteroarylalkyl " refer to by above the heteroaryl that defines replace above the alkyl that defines.
In this application, " optional " or " optionally " represents that the event that describes subsequently or situation may occur also may not occur, and this description comprises the situation that this event or situation occur and do not occur simultaneously.Such as, " aryl be optionally substituted " represents that aryl is substituted or is not substituted, and this description comprises the aryl and unsubstituted aryl that are substituted simultaneously.
Term used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer to specific fragment in molecule or functional group.Chemical part is considered to the chemical entities embedding or be attached on molecule usually.
" steric isomer " refers to and is made up of same atoms, by identical key bonding, but has the compound of different three-dimensional structure.The present invention will contain various steric isomer and composition thereof.
When containing alkene double bond in compound of the present invention, unless otherwise stated, compound of the present invention is intended to comprise E-and Z-geometrical isomer.
" tautomer " refers to that proton is from an atom transfer of molecule to another atom of same molecular and the isomer formed.All tautomeric forms of compound of the present invention also will within the scope of the present invention.
Compound of the present invention or its pharmacy acceptable salt may contain one or more chiral carbon atom, and therefore can produce enantiomer, diastereomer and other stereoisomeric forms in any ratio.Each chiral carbon atom can be defined as based on stereochemistry (R)-or (S)-.The present invention is intended to comprise all possible isomer, and its racemic modification and optical purity form.The preparation of compound of the present invention can select racemic modification, diastereomer or enantiomer as raw material or intermediate.Optically active isomer can use chiral synthon or chiral reagent to prepare, or uses routine techniques to split, such as, adopt the method such as crystallization and chiral chromatography.
The routine techniques of preparation/separation individual isomeric comprises by the chiral synthesize of suitable optical purity precursor, or use such as chiral hplc resolution of racemates (or racemic modification of salt or derivative), such as can see GeraldG ü bitzandMartinG.Schmid (Eds.), ChiralSeparations, MethodsandProtocols, MethodsinMolecularBiology, Vol.243,2004; A.M.Stalcup, ChiralSeparations, Annu.Rev.Anal.Chem.3:341-63,2010; Fumissetal. (eds.), VOGEL'SENCYCLOPEDIAOFPRACTICALORGANICCHEMISTRY5.sup.THED., LongmanScientificandTechnicalLtd., Essex, 1991,809-816; Heller, Acc.Chem.Res.1990,23,128.
In this application, term " pharmacy acceptable salt " comprises pharmaceutically acceptable acid salt and pharmaceutically acceptable base addition salt.
" pharmaceutically acceptable acid salt " refers to the biological effectiveness that can retain free alkali and without other side effect, the salt formed with mineral acid or organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt etc., organic acid salt includes but not limited to formate, acetate, 2, 2-dichloroacetate, trifluoroacetate, propionic salt, hexanoate, octylate, caprate, undecylenate, glycollate, gluconate, lactic acid salt, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, Citrate trianion, palmitate, stearate, oleate, cinnamate, lauroleate, malate, glutaminate, pyroglutamate, aspartate, benzoate, mesylate, benzene sulfonate, tosilate, alginates, ascorbate salt, salicylate, 4-ASA salt, napadisilate etc.These salt are prepared by the method that this specialty is known.
" pharmaceutically acceptable base addition salt " refer to can keep the biological effectiveness of free acid and without other side effect, the salt that formed with mineral alkali or organic bases.Salt derived from mineral alkali includes but not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc.Preferred inorganic salt are ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts.Salt derived from organic bases includes but not limited to following salt: primary amine class, secondary amine class and tertiary amines, the amine be substituted, comprise and natural be substituted amine, cyclic amine and deacidite, such as ammonia, Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, diethanolamine, trolamine, dimethylethanolamine, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, choline, trimethyl-glycine, quadrol, glucosamine, methyl glucose osamine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, versamid 900 etc.Preferred organic bases comprises Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and caffeine.These salt are prepared by the method that this specialty is known.
" polymorphic form " refers to the different solid crystal phases that some compound of the present invention produces owing to there is the arrangement of two or more differing molecular in the solid state.Some compound of the present invention can exist more than a kind of crystal formation, and the present invention is intended to comprise various crystal formation and composition thereof.
Usually, crystallization effect can produce the solvate of the compounds of this invention.The term " solvate " used in the present invention refers to the aggregate comprising one or more the compounds of this invention molecule and one or more solvent molecule.Solvent can be water, and the solvate in this situation is hydrate.Or solvent can be organic solvent.Therefore, compound of the present invention can exist with hydrate, comprises monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., and corresponding solvation form.The compounds of this invention can form real solvate, but in some cases, also only can retain the mixture that indefinite water or water add the indefinite solvent of upper part.Compound of the present invention can react or Precipitation or crystallize out from solvent in a solvent.The solvate of the compounds of this invention is also contained within scope of the present invention.
The present invention also comprises the prodrug of above-claimed cpd.In this application, term " prodrug " is represented and or can be converted to the compound of bioactive compounds of the present invention under physiological conditions by solvolysis.Therefore, term " prodrug " refers to the pharmaceutically acceptable metabolic precursor thereof of compound of the present invention.When being given individuality in need, prodrug can not have activity, but is converted to active compound of the present invention in vivo.Prodrug transforms rapidly usually in vivo, and produces parent compound of the present invention, such as, realize by being hydrolyzed in blood.Prodrug compound provides the advantage of solubleness, histocompatibility or slowly-releasing usually in mammalian organism.Prodrug comprises known amino protecting group and carboxyl-protecting group.Concrete front medicament preparation can refer to Saulnier, M.G., etal., Bioorg.Med.Chem.Lett.1994,4,1985-1990; Greenwald, R.B., etal., J.Med.Chem.2000,43,475.
In this application, " pharmaceutical composition " refers to the preparation of the medium for bioactive compounds being delivered to Mammals (such as people) that the compounds of this invention and this area accept usually.This medium comprises pharmaceutically acceptable carrier.The object of pharmaceutical composition is the administration promoting organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
Term used herein " pharmaceutically acceptable " refers to the material (as carrier or thinner) of biological activity or the character not affecting the compounds of this invention, and relative nontoxic, namely this material can be applied to individuality and not cause bad biological respinse or with any component interaction comprised in bad mode and composition.
In this application, " pharmaceutically acceptable carrier " include but not limited to any by the government administration section license of being correlated with for accepting for the adjuvant of the mankind or domestic animal, carrier, vehicle, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, correctives, tensio-active agent, wetting agent, dispersion agent, suspending agent, stablizer, isotonic agent, solvent or emulsifying agent.
" tumour " of the present invention, " the abnormal relative disease of cell proliferation " etc. include but not limited to the disease such as leukemia, gastrointestinal stromal tumors (GISTs), histiocytic lymphoma, nonsmall-cell lung cancer, small cell lung cancer, carcinoma of the pancreas, lung squamous cancer, adenocarcinoma of lung, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, osteocarcinoma, esophagus cancer, melanoma, kidney, oral carcinoma.
Term used herein " prevention ", " prevention " and " preventing " comprise makes sufferer reduce disease or the generation of illness or the possibility of deterioration.
Term used herein " treatment " and other similar synonym comprise following implication:
(i) preventing disease or illness occur in Mammals, particularly when this kind of Mammals easily suffers from this disease or illness, but are not yet diagnosed as when having suffered from this disease or illness;
(ii) suppress disease or illness, namely contain that it develops;
(iii) alleviate disease or illness, that is, make the state of this disease or illness disappear; Or
(iv) alleviate the symptom that this disease or illness cause.
Herein use term " significant quantity ", " treatment significant quantity " or " pharmacy effective dose " refer to and take metapedes with the amount of at least one medicament or compound of alleviating one or more symptoms of treated disease or illness to a certain extent.Its result can be abatement and/or the alleviation of sign, symptom or the cause of disease, or other required change any of biosystem.Such as, " significant quantity " that be used for the treatment of provides the amount comprising the composition of compound of coming into the open herein needed for significant remission effect clinically.The significant quantity that the technical measurement of such as dose escalation trial is suitable in any individual case can be used.
Term used herein " is taken ", " using ", " administration " etc. refer to and compound or composition can be delivered to the method for carrying out site needed for biological action.These methods include but not limited to oral route, through intraduodenal routes, parental injection (comprising intravenously, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical and per rectum administration.Those skilled in the art know the application technique that can be used for Compounds and methods for described herein, such as, at GoodmanandGilman, ThePharmacologicalBasisofTherapeutics, currented.; Pergamon; AndRemington's, PharmaceuticalSciences (currentedition), discuss in MackPublishingCo., Easton, Pa those.In preferred embodiments, the compound discussed herein and composition are by Orally administered.
Herein institute uses term " drug regimen ", " drug combination ", " drug combination ", " using other treatment ", " using other therapeutical agent " etc. to refer to the pharmacological agent obtained by mixing or combine more than a kind of activeconstituents, and it comprises fixing and not fixed Combination of activeconstituents.Term " fixed Combination " refers to uses at least one compound as herein described with the form of single entity or single formulation to patient and at least one works in coordination with medicament simultaneously.Term " not fixed Combination " refers to be used to patient with the form of separate entity simultaneously, to share or to use at least one compound as herein described variable interval time in turn and at least one works in coordination with preparation.These are also applied in drug cocktail therapy (treatment), such as, use three kinds or more kind activeconstituents.
Those skilled in the art it is also understood that in method hereinafter described, and midbody compound functional group may need to be protected by suitable protecting group.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group comprises trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl etc.The protecting group of suitable amino, amidino groups and guanidine radicals comprises tertbutyloxycarbonyl, carbobenzoxy-(Cbz) etc.Suitable sulfhydryl protected base comprises-C (O)-R " (wherein R " is alkyl, aryl or aralkyl), to methoxy-benzyl, trityl etc.Suitable carboxyl-protecting group comprises alkyl, aryl or aralkyl ester class.
Protecting group can be introduced according to standard technique well known by persons skilled in the art and as described herein and remove.The use of protecting group is specified in Greene, T.W. and P.G.M.Wuts, ProtectiveGroupsinOrganiSynthesis, and (1999), in 4thEd., Wiley.Protecting group also can be fluoropolymer resin.
Below in conjunction with specific embodiment, set forth the present invention further.Should understand, these embodiments are only not used in for illustration of the present invention and limit the scope of the invention.Experimental technique, usually conveniently condition or the condition of advising according to manufacturer of unreceipted actual conditions in the following example.Unless otherwise indicated otherwise per-cent and number are weight percent and parts by weight.
Embodiment prepares universal method:
Intermediate 1:
Under nitrogen protection; 3-aminocarbonyl phenyl t-butyl carbamate (2.1 grams; 10 mmoles); triethylamine (1.2 grams; 12 mmoles) be dissolved in THF(20 milliliter), dry ice acetone bath is cooled to-70 DEG C, drips acrylate chloride (0.99 gram; 11 mmoles), mixture is warming up to stirring at room temperature 8 hours naturally.Concentrating under reduced pressure removes most of THF, and resistates adds water (20 milliliters), extracts by ethyl acetate (20 milliliters × 3).By the organic over anhydrous dried over sodium sulfate merged, filter and evaporate, obtaining title compound (light gray solid, 1.6 grams, crude product).LCMS(ESI)m/z:263(M+1).
Intermediate 2:
At 0 DEG C, toward embodiment 1A(1.6 gram, about 6 mmoles) methylene dichloride (20 milliliters) solution in drip trifluoroacetic acid (5 milliliters), after dropwising, mixture stirs 1 hour at 20 DEG C.Remove most of solvent and remaining trifluoroacetic acid under reduced pressure, obtain the trifluoroacetate (brown oil, 2.1 grams, crude product) of title compound.LCMS(ESI)m/z:163(M+1).
Intermediate 3:
At 0 DEG C, solid 2,3-Dihydrobenzofuranes-7-amine (5 grams, 37 mmoles) is dissolved in DMF(60 milliliter) in, add NBS(7.2 gram, 41 mmoles in batches), stir after 10 minutes, naturally heat up 20 ~ 30 DEG C of stirrings 3 hours.Remove most of solvent under reduced pressure, resistates obtains title compound (yellow solid, 6 grams, 76% productive rate) by purification by silica gel column chromatography.LCMS(ESI)m/z:214,216(M+1,M+3).
Intermediate 4:
Under nitrogen protection, embodiment intermediate 3(0.2 gram, 0.94 mmole); 4-(4,4,5; 5-tetramethyl--1; 3,2-dioxy borine-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formate (0.58 gram; 1.88 mmole); Isosorbide-5-Nitrae-the dioxane (10 milliliters) of salt of wormwood (0.26 gram, 1.88 mmoles) and tetrakis triphenylphosphine palladium (20 person of outstanding talent gram) and the mixture of water (1 milliliter) stir 8 hours at 80 ~ 90 DEG C.Remove most of solvent under reduced pressure, resistates adds water (10 milliliters), extracts by ethyl acetate (10 milliliters × 3).By the organic over anhydrous dried over sodium sulfate merged, filter and concentrate, crude product obtains title compound (light yellow solid, 0.18 gram, 60% productive rate) by purification by silica gel column chromatography.LCMS(ESI)m/z:317(M+1).
Intermediate 5 and intermediate 6:
Intermediate 2(2.1 gram, about 6 mmoles), Virahol (20 milliliters) mixture of the chloro-5-of 2,4-bis-(trifluoromethyl) pyrimidine (1.3 grams, 6 mmoles) and sodium carbonate (1.3 grams, 12 mmoles) stirs 8 hours at 0 ~ 30 DEG C.Filter, filtrate reduced in volume removes most of solvent, and resistates adds water (20 milliliters), extracts by ethyl acetate (20 milliliters × 3).By the organic over anhydrous dried over sodium sulfate merged, filter and concentrate, obtaining mixture (light gray solid, 2.4 grams, crude product, ratio is about 9:1) .LCMS (ESI) m/z:343 (M+1) of title compound.
Intermediate 7:
By intermediate 4(317,1mmol) be dissolved in methanol(20mL) in, add Pd/C(50mg), catalytic hydrogenation 3h, raw material disappears.Filtering Pd/C, concentrated, obtain intermediate 7: micro-yellow solid, 263 milligrams.
1HNMR(CDCl
3)δ(ppm):6.56-6.54(m,2H),4.59(t,J=8.8Hz,2H),4.23(m,2H),3.48(ts,2H),3.18(t,J=8.8Hz,2H),2.76(m,2H),2.52-2.49(m,1H),1.74(d,J=12.4Hz,2H),1.64-1.55(m,2H).
Intermediate 8:
With intermediate 3 and (1-(piperidin-4-yl)-1H-pyrazoles-4-base) boric acid for raw material, the method synthesis adopting intermediate 4 identical, prepare intermediate 8(light yellow solid, 216 milligrams): LCMS (ESI) m/z:285 (M+1).
Embodiment 1 embodiment 2
Under nitrogen protection, intermediate 4(0.2 gram, 0.58 mmole), intermediate 5 and 6(14.8 gram, 350 mmoles), and tetrahydrofuran (THF) (10 milliliters) solution of trifluoroacetic acid (0.14 gram, 1.2 mmoles) stirs 5 hours at 50 ~ 60 DEG C.Remove most of solvent under reduced pressure, resistates obtains the mixture (white solid, 93 milligrams, 26% productive rate, ratio is about 9:1) of title compound by purification by silica gel column chromatography.LCMS(ESI)m/z:623(M+1).
Embodiment 3 embodiment 4
At 0 DEG C, toward embodiment 1 and embodiment 2(93 milligram, 0.15 mmole) methylene dichloride (20 milliliters) solution in drip trifluoroacetic acid (5 milliliters), after dropwising, mixture stirs 1 hour at 20 DEG C.Remove most of solvent and remaining trifluoroacetic acid under reduced pressure, half resistates obtains trifluoroacetate (embodiment 3, white solid, 10 milligrams of title compound respectively by preparative HPLC purifying; Embodiment 4, white solid, 1 milligram), second half resistates is directly used in the next step.Embodiment 3:
1hNMR (400MHz, MeOD) ppm8.33 (brs, 1H), 7.69 (brs, 1H), 7.55 (brs, 1H), 7.44 (d, J=8.0Hz, 1H), 7.27 (d, J=8.0Hz, 1H), 7.14 (t, J=8.0Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.43-6.45 (m, 2H), 5.93 (brs, 1H), 5.80 (d, J=9.6Hz, 1H), 4.54 (t, J=8.8Hz, 2H), 3.88 (brs, 2H), 3.49 (t, J=6.4Hz, 2H), 3.31 (brs, 2H), 2.76 (brs, 2H). embodiment 4:
1hNMR (400MHz, MeOD) ppm8.31 (brs, 1H), 7.75 (brs, 1H), 7.66 (brs, 1H), (7.54 d, J=8.4Hz, 1H), (7.37 t, J=8.4Hz, 1H), (7.18 d, J=8.0Hz, 1H), 6.56 (brs, 1H), 6.48-6.35 (m, 2H), 5.85 (brs, 1H), (5.80 d, J=9.2Hz, 1H), (4.58 t, J=8.4Hz, 2H), 3.84 (brs, 2H), 3.45 (t, J=6.4Hz, 2H), 3.31 (brs, 2H), 2.70 (brs, 2H) .LCMS (ESI) m/z:523 (M+1).
Embodiment 5 embodiment 6
Under nitrogen protection, embodiment 3 and embodiment 4(about 0.07 mmole) be dissolved in methyl alcohol (10 milliliters), add paraformaldehyde (4.2 milligrams; 0.14 mmole) and sodium cyanoborohydride (8.7 milligrams; 0.14 mmole), stir after 10 minutes, this mixture stirs 8 hours at 50 ~ 60 DEG C.Remove most of solvent under reduced pressure, resistates adds water (10 milliliters), extracts by ethyl acetate (10 milliliters × 3).By the organic over anhydrous dried over sodium sulfate merged, filter and concentrate, crude product obtains trifluoroacetate (embodiment 5, white solid, 10 milligrams of title compound respectively by preparative HPLC purifying; Embodiment 6, white solid, 1 milligram).Embodiment 5:
1hNMR (400MHz, MeOD) ppm8.31 (s, 1H), 7.76-7.71 (m, 2H), 7.41 (d, J=7.6Hz, 1H), 7.34 (d, J=8.0Hz, 1H), 7.14 (t, J=8.0Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 6.47-6.34 (m, 2H), 5.92 (brs, 1H), 5.79 (d, J=9.6Hz, 1H), 4.59 (t, J=8.8Hz, 2H), 3.88 (brs, 2H), 3.50 (brs, 2H), 3.31 (brs, 2H), 3.05 (s, 3H), 2.85 (brs, 2H). embodiment 6:
1hNMR (400MHz, MeOD) ppm8.34 (s, 1H), 7.75-7.67 (m, 2H), 7.54 (d, J=7.6Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.17 (d, J=7.6Hz, 1H), 6.57 (brs, 1H), 6.49-6.35 (m, 2H), 5.83-5.79 (m, 2H), 4.58 (t, J=8.4Hz, 2H), 4.06-4.02 (m, 2H), 5.82-3.70 (m, 2H), 3.31 (m, 2H), 3.03 (s, 3H), 2.72 (m, 2H) .LCMS (ESI) m/z:537 (M+1).
Embodiment 7 embodiment 8
With intermediate 7 and intermediate 5,6 for raw material, the method synthesis adopting embodiment 1 identical with embodiment 2, prepares embodiment 7 and embodiment 8.Embodiment 7(off-white color solid, 9 milligrams):
1hNMR (400MHz, MeOD) ppm8.38 (brs, 1H), 7.84-7.62 (m, 2H), 7.39 (brs, 1H), 7.21-7.16 (m, 2H), 6.45-6.38 (m, 3H), 5.82 (m, 1H), 4.61 (brs, 2H), 3.52 (m, 2H), 3.32-3.15 (m, 4H), 2.91 (m, 1H), 2.01-1.88 (m, 4H) .LCMS (ESI) m/z:525 (M+1). embodiment 8(off-white color solid, 1 milligram): LCMS (ESI) m/z:525 (M+1).
Embodiment 9 embodiment 10
With embodiment 7 and embodiment 8 for raw material, the method synthesis adopting embodiment 5 identical with embodiment 6, prepares embodiment 9 and embodiment 10.Embodiment 9(off-white color solid, 3 milligrams): LCMS (ESI) m/z:539 (M+1). embodiment 10:(off-white color solid, 0.8 milligram): LCMS (ESI) m/z:539 (M+1).
Embodiment 11 embodiment 12
With intermediate 5 and intermediate 6 and intermediate 8 for raw material, adopt the synthetic method that embodiment 1 is identical, prepare embodiment 11 and embodiment 12. embodiment 11(white solid, 7 milligrams):
1hNMR (400MHz, MeOD) ppm8.37 (brs, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.63 (brs, 1H), 7.46 (d, J=7.6Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.11 (d, J=8.4Hz, 2H), 6.28 (d, J=5.6Hz, 2H), 5.70 (t, J=6.0Hz, 1H), 4.68-4.60 (m, 1H), 4.47 (t, J=0.8Hz, 2H), 3.65-3.61 (m, 2H), 3.34-3.23 (m, 4H), 2.42-2.31 (m, 4H). embodiment 12(white solid, 2 milligrams):
1hNMR (400MHz, MeOD) ppm8.44 (brs, 1H), 7.97-7.62 (m, 4H), 7.48 (brs, 1H), 7.23-7.13 (m, 2H), 6.82 (brs, 1H), 6.33 (brs, 2H), 5.74 (brs, 1H), 4.66-4.58 (m, 3H), 3.63-3.60 (m, 2H), 3.32-3.22 (m, 4H), 2.38-2.32 (m, 4H) .LCMS (ESI) m/z:591 (M+1).
Test case 1 the compounds of this invention is to the mensuration of different EGFR kinase activity
This experiment is adopted and is determined embodiment compound with the following method to different CDK kinases: CDK1/CyclinB (invitrogen), CDK4/CyclinD1(invitrogen), the inhibit activities of CDK6/CyclinD1 (invitrogen).
Testing method: test-compound is dissolved in methyl-sulphoxide, and need to be diluted to each concentration gradient with damping fluid (50mMHEPES, 10mMMgCl2,1mMEGTA, 2mMDTTand0.01%Tween20) according to test, dimethyl sulfoxide concentration is 4%; Being mixed with concentration with damping fluid dilution ATP and substrate ULight-4E-BP1 is again that the mixture of 800 μMs of ATP and 200nM substrate solutions is stand-by; In reacting hole, add 2.5 μ L substrates and ATP mixed solution, then add the damping fluid (negative control hole) of 2.5 μ L compounds or 4% methyl-sulphoxide, finally add 5 μ L enzymes or damping fluid (negative control hole), room temperature lucifuge hatches 60 minutes.Every hole adds 5 μ L1xdetectionbuffer(LANCEDetectionBuffer, 10x, PerkinElmer) the EDTA stop buffer (final concentration 6mM) diluted, then antibody (final concentration 2nM) the room temperature lucifuge adding 1xdetectionbuffer dilution hatches 60 minutes.With PerkinElmerEnVision TRFRETmode(excitation wavelength: 320nm, emission wavelength: 615nm and 665nm) drafting board.IC
50value adopts the random bundled software of microplate reader to return with four parameter methods and tries to achieve.
Test-compound is tried to achieve by following formula the inhibiting rate of different kinase activity:
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (7)
1. the compound as shown in general formula I, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug,
I
In formula:
R1, R2 are selected from lower group independently of one another: hydrogen, halogen, cyano group, substituted carbonyl, substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl;
R3 is selected from lower group: hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
R4, R5, R6 and R7 are separately selected from hydrogen, halogen, cyano group, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, and wherein any two groups can form the ring system of 3-10 unit;
M1, M2 are selected from independently of one another: CRa or N, and wherein have one at least for N;
Ra is H, halogen, cyano group, substituted or unsubstituted C1-C6 alkyl and C3-C8 cycloalkyl;
L is selected from lower group: nothing or linking group;
W is selected from lower group: the aromatic base of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl or alkynyl group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 unit heterocyclic radical, 5-10 unit or heteroaryl, substituted carbonyl, substituted sulphonyl, substituted or unsubstituted amino, wherein, described heterocycle comprises the heteroatoms that 1-3 is selected from lower group: N, O, S, P or B;
Above-mentioned arbitrary " replacement " refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: halogen, OH, NH
2, CN, do not replace or halo C1-C8 alkyl, do not replace or halo C3-C8 cycloalkyl, do not replace or halo C1-C8 alkoxyl group, do not replace or halo C2-C6 thiazolinyl, do not replace or halo C2-C6 alkynyl, do not replace or halo C2-C6 acyl group, do not replace or halo 5 ~ 8 yuan of aryl, do not replace or halo 5 ~ 8 yuan of heteroaryls, do not replace or 4 ~ 8 yuan of saturated heterocyclics of halo or carbocyclic ring; Wherein, described heteroaryl comprises the heteroatoms that 1-3 is selected from lower group: N, O or S, and described heterocycle comprises the heteroatoms that 1-3 is selected from lower group: N, O or S.
2. compound as claimed in claim 1, it is characterized in that, R1 is preferably hydrogen, chlorine, F, trifluoromethyl, cyano group; And/or
R2 is preferably H, F, Cl, cyano group or CH
3; And/or
R3 is preferably H, F, Cl, cyano group, alkyl or substituted alkyl; And/or
M1, M2 are separately selected from CH or N, and wherein have one at least for atom N; And/or
L is selected from :-CR ' R "-,-O-,-NR '-and-CR '=, wherein R ' and R " be H, F, deuterium (D), C1-C6 alkyl or Heterocyclylalkyl or adjacent R ' and R independently of one another " form cyclic group; And/or
W is selected from: volution, bridged ring etc. that substituted or unsubstituted C1-C6 alkyl and cycloalkyl, substituted or unsubstituted 4-6 unit's heterocycle or cycloalkyl, Heterocyclylalkyl etc. are formed, more preferably W is pentamethylene, hexanaphthene, Pyrrolidine ring, tetrahydrofuran (THF) ring, piperidine ring, piperazine ring, morpholine ring, pyrazole ring, indazole ring, phenyl ring, pyridine ring etc.:
Substituting group described on W ring is independently selected from halogen,-OH,-CN,-NH2, alkyl, alkyl monosubstituted amino, dialkyl amido, cycloalkyl, heterocyclic radical, alkoxyl group, hydroxyalkyl, alkoxyalkyl, hydroxy alkoxy alkyl, aminoalkyl group, dialkyl aminoalkyl, alkoxycarbonylamino, cycloalkylalkyl, cycloheteroalkylalkyl, aralkyl, alkyl-cycloalkyl, naphthene base carbonyl, alkoxy carbonyl, alkoxy carbonyl heterocyclic radical, (carbalkoxy) (alkyl) is amino, (alkoxyalkyl) (alkyl) is amino.
3. the compound as described in claim 1,2, is characterized in that, described nitrogen-containing heterocycle compound has the structure shown in general formula I I, III:
II
III,
Wherein, the definition of each group as described above.
4. the compound as described in claim 1,2,3, is characterized in that, described compound has following structure:
。
5. a method for preparation I compound, is characterized in that, described method comprises step:
A1) by formula (1) compound and formula (2) compound, under the reaction conditions that transition-metal catalyst or acid/alkali exist, carry out coupling, thus form intermediate (3); With
A2) carry out coupling under reaction conditions intermediate (3) and formula (4) compound existed at transition-metal catalyst or acid/alkaline catalysts, obtain formula I;
，
In various,
X and LG is leavings group independently of one another, and is selected from lower group: halogen, sulphonate, boric acid, boric acid ester;
FG is selected from lower group: boric acid, boric acid ester, boron salt, organotin, organic zinc etc.;
The definition of other each radicals R 1, R2, R3, R4, R5, R6, R7, M1, M2, L, W is described above;
In another preference, described step a1), a2) carry out in a solvent separately, and described solvent is selected from lower group: water, methyl alcohol, ethanol, Virahol, ethylene glycol, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene, methylene dichloride, 1,2-ethylene dichloride, acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, dioxane, or its composition;
In another preference, described metal catalyst is selected from lower group: three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), palladium, Palladous chloride, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride, two (three adjacent phenmethyl phosphines) palladium chloride, 1,2-bis-(diphenylphosphino) ethane palladium chloride, or its composition; Described catalyst ligand is selected from lower group: tri-butyl phosphine, Tetrafluoroboric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of phenmethyl phosphines, tricyclohexyl phosphine, three adjacent phenmethyl phosphines, or its composition;
In another preference, described mineral alkali is selected from lower group: sodium hydride, potassium hydroxide, sodium-acetate, Potassium ethanoate, potassium tert.-butoxide, sodium tert-butoxide, Potassium monofluoride, cesium fluoride, potassiumphosphate, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, or its composition; Described organic bases is selected from lower group: pyridine, triethylamine, DIPEA, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU), the silica-based lithium of hexamethyl two, the silica-based sodium of hexamethyl two, lutidine, or its composition;
In another preference, described acid is selected from lower group: hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, toluenesulphonic acids, trifluoroacetic acid, formic acid, acetic acid, or its composition.
6. the purposes of the formula I as described in claim 1,2,3,4,5, is characterized in that, for the preparation for the treatment of and EGFR and mutant kinase thereof, and the medicine, particularly anti-tumor medicine of the disease that ALK and mutant kinase activity thereof or expression amount are correlated with; Described tumour is independently selected from nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cancer of the stomach, intestinal cancer, leukemia, lymphatic cancer, nasopharyngeal carcinoma etc.
7. comprise the pharmaceutical composition of the formula I composition as described in claim 1,2,3,4,5,6, it is characterized in that, described pharmaceutical composition comprises:
The formula I of (i) significant quantity, or its pharmacy acceptable salt or its enantiomer, diastereomer, tautomer, solvate, polymorphic form or prodrug; With
(ii) pharmaceutically acceptable carrier.
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| CN106243044A (en) * | 2016-06-30 | 2016-12-21 | 浙江大学 | Pyridine derivatives containing halo acrylamide side chain and preparation and application |
| CN106565612A (en) * | 2016-10-25 | 2017-04-19 | 大连医科大学 | Diphenyl vinyl pyridine compound, composition and application thereof |
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| CN106243044A (en) * | 2016-06-30 | 2016-12-21 | 浙江大学 | Pyridine derivatives containing halo acrylamide side chain and preparation and application |
| CN106565612A (en) * | 2016-10-25 | 2017-04-19 | 大连医科大学 | Diphenyl vinyl pyridine compound, composition and application thereof |
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