CN106699810A - Nitrogen-containing heterogeneous ring compound, preparation method thereof and application of nitrogen-containing heterogeneous ring compound in inhibition of kinase activity - Google Patents

Nitrogen-containing heterogeneous ring compound, preparation method thereof and application of nitrogen-containing heterogeneous ring compound in inhibition of kinase activity Download PDF

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CN106699810A
CN106699810A CN201611021938.7A CN201611021938A CN106699810A CN 106699810 A CN106699810 A CN 106699810A CN 201611021938 A CN201611021938 A CN 201611021938A CN 106699810 A CN106699810 A CN 106699810A
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汪舰
别建波
郎明
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Tsinghua University
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Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

The invention discloses a nitrogen-containing heterogeneous ring compound, a preparation method thereof and an application of the nitrogen-containing heterogeneous ring compound in inhibition of kinase activity. The general formula of the nitrogen-containing heterogeneous ring compound is represented as a formula I or a formula I', wherein R1, R2, R3 and R4 in the formula I or the formula I' are selected from any one of hydrogen, halogen, cyanogroup, hydroxyl, amidogen and substituted or unsubstituted C1-C6 alkyl groups independently, and a 3-10-membered ring system can be formed by any two groups in R1, R2, R3 and R4; M1, M2 and M3 are selected from CRa or N independently, and at least one of M1, M2 and M3 is N; W is selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl, unsubstituted or halogenated 4-8-membered alkine groups, substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 4-8-membered heterocyclic groups, 5-10-membered aromatic or heteroaryl groups, substituted carbonyl, substituted sulfonyl and substituted or unsubstituted amidogen. The nitrogen-containing heterogeneous ring compound can inhibit EGFR (epidermal growth factor receptor) mutant kinase activity or ALK (anaplastic lymphoma kinase) activity and is a multi-target tumor therapeutic drug with a brand-new action mechanism.

Description

A kind of nitrogen-containing heterocycle compound and preparation method thereof with suppress kinase activity in Using
Technical field
The present invention relates to a kind of nitrogen-containing heterocycle compound and preparation method thereof and the application in kinase activity is suppressed, belong to Field of pharmaceutical chemistry technology.
Background technology
Tumor cells targeted therapy is based on the key protein closely related to tumorigenesis, by chemical means Selectively acting is in signal protein, a kind for the treatment of method of killing tumor cell.The characteristics of targeted therapy is：It is specific high, choosing Selecting property is strong, and toxic and side effect is low relative to classic chemotherapy medicine；During drug combination, the curative effect of classic chemotherapy can be strengthened；Targeted inhibition Resistance is easily produced on agent clinical drug and medicine is failed.
Lung cancer is the whole world incidence of disease and case fatality rate highest malignant tumour, and survival rate is only 16.8% within 5 years, lung in 2010 The incidence of disease and case fatality rate of cancer are occupied first of all malignant tumours of China.Non-small cell lung cancer (NSCLC) accounts for all lung cancer pathology In type 85%, the non-small cell lung cancer cause of disease is complicated, polygenes, Mutiple Targets regulation and control and easy mutation generation resistance.Non-small cell Remedies for lung cancer thing mainly has classic chemotherapy medicine platinum class, taxanes, antibody class, neovascularization inhibitor and targeted inhibition agent Deng, but with clinically still there is the substantial amounts of resistance patient appearance for being mutated and causing, consequently found that non-with searching overriding resistance Therapy for small cell lung cancer medicine is still a popular domain of current industrial quarters.
In recent years, U.S. FAD have approved multiple ALK inhibitor in succession, and such as gram azoles replaces Buddhist nun, Ceritinib, and at present The third generation EGFR inhibitor in clinical late stage, such as AZD9219, CO1686 etc. are in, but this kind of medicine is still at present There is unsatisfactory curative effect, or selectivity it is not high the problems such as, therefore there is mutant drug-resistant higher in the urgent need to finding and finding a class Selectivity, or the new types of therapeutic agents with multiple target spot inhibitory activity.
The content of the invention
It is an object of the invention to provide a kind of nitrogen-containing heterocycle compound and preparation method thereof with suppress kinase activity in Using the nitrogenous hybrid compounds can be many of the brand-new mechanism of action of a class as the antiblastic of kinds of tumor cells Target tumor medicine.
Nitrogen-containing heterocycle compound, its pharmaceutically acceptable salt, enantiomter, diastereo-isomerism that the present invention is provided Body, dynamic isomer, solvate, polymorph or its prodrug, wherein, formula such as formula I or the formula I ' of nitrogen-containing heterocycle compound It is shown：
In formula I or formula I '：
R1、R2、R3、R4In hydrogen, halogen, cyano group, hydroxyl, amino and substituted or unsubstituted C1-C6 alkyl Any one, and R1、R2、R3、R4In any two group can be formed 3-10 unit ring system；
M1、M2、M3Independently selected from CRa or N, and M1、M2And M3In at least one be N；Ra is hydrogen, halogen, cyano group, takes One kind in generation or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C8 cycloalkyl；
W is selected from any one of following radicals：Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenes Base, unsubstituted or halo 4~8 yuan of alkynyl group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 units Heterocyclic radical, the aromatic radical or heteroaryl, substituted carbonyl, substituted sulphonyl, substituted or unsubstituted amino of 5-10 units, wherein, institute Heterocyclic radical is stated comprising 1-3 selected from the hetero atom in N, O, S, P and B；
At least one substitution base that described one or more groups being substituted by group are selected from the following group is replaced：Halogen Element, hydroxyl, amino, cyano group, unsubstituted or halo C1-C8 alkyl, unsubstituted or halo C3-C8 cycloalkyl, it is unsubstituted or The C1-C8 alkoxyl of halo, unsubstituted or halo C2-C6 alkenyls, unsubstituted or halo C2-C6 alkynyls, unsubstituted or halogen The C2-C6 acyl groups in generation, unsubstituted or halo 5~8 yuan of aryl, unsubstituted or halo 5~8 unit's heteroaryls, unsubstituted or halogen 4~8 yuan of saturated heterocyclics in generation, unsubstituted or halo 4~8 yuan of carbocyclic rings；Wherein, the heteroaryl comprising 1-3 selected from N, O and Hetero atom in S, the heterocycle includes the 1-3 hetero atom selected from N, O and S；
In formula I ', L is selected from any one of following radicals：- CR ' R "-,-O- ,-NR '-and-CR '=, wherein R ' and R " it is each Any one from independently being hydrogen, fluorine, deuterium, C1-C6 alkyl and C1-C6 Heterocyclylalkyls, or wherein adjacent R ' and R " shape Circlewise group.
Compound shown in above-mentioned formula I or its enantiomter, diastereoisomer, dynamic isomer, solvate, polycrystalline Type thing, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic In thing, prodrug or pharmaceutically acceptable salt：R1、R2、R3、R4Concretely hydrogen.
Compound shown in above-mentioned formula I or its enantiomter, diastereoisomer, dynamic isomer, solvate, polycrystalline Type thing, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic In thing, prodrug or pharmaceutically acceptable salt：Compound shown in formula I or compound shown in formula I ' meet it is following 1) and/or 2)：
1) in formula I or formula I ', M1、M2Independently selected from CH or N, and M1And M2In at least one be N；M3Selected from C-F, C- CF3, any one in C-Cl, CH and N；
2) in formula I or formula I ', W is selected from any one in following radicals：Substituted or unsubstituted C1-C6 alkyl or cycloalkanes Base, substituted or unsubstituted 4-10 circle heterocycles, substituted or unsubstituted 4-10 unit's cycloalkyl and substituted or unsubstituted 4-10 units Volution or bridged ring that Heterocyclylalkyl is formed；W is specially any one in substituted or unsubstituted following radicals：Pentamethylene, hexamethylene Alkane, nafoxidine ring, tetrahydrofuran ring, piperidine ring, tetrahydrochysene piperidine ring, piperazine ring, morpholine ring, pyrazole ring, indazole ring, phenyl ring Or pyridine ring；
The substitution refers at least one for replacing base independently selected from following radicals：Halogen, hydroxyl, cyano group, amino, alkane Base, alkyl monosubstituted amino, dialkyl amido), cycloalkyl, heterocyclic radical, alkoxy, hydroxy alkyl, alkoxyalkyl, hydroxy alkoxy base Alkyl, aminoalkyl, dialkyl aminoalkyl, alkoxycarbonylamino, cycloalkyl-alkyl, cycloheteroalkylalkyl, aralkyl, Alkyl-cycloalkyl, naphthene base carbonyl, alkoxy carbonyl, alkoxy carbonyl heterocyclic radical, (alkoxy carbonyl group) (alkyl) amino, (alcoxyl Base alkyl) (alkyl) amino.
Compound shown in above-mentioned formula I or its enantiomter, diastereoisomer, dynamic isomer, solvate, polycrystalline Type thing, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic In thing, prodrug or pharmaceutically acceptable salt：
Concretely in compound shown in the compound to-w of formula I shown in the-a of following formula I any one of compound shown in formula I：
Concretely in the-a of the following formula I ' to-c of formula I ' any one of compound shown in formula I '：
Invention further provides compound shown in a kind of formula I or its enantiomter, diastereoisomer, mutually Tautomeric, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic The method of thing, prodrug or pharmaceutically acceptable salt, comprises the following steps：
(1) by compound shown in formula IV and compound shown in formula V, in transition-metal catalyst and/or acid/base (acid/base Represent acid or alkali) exist under conditions of be coupled, obtain compound shown in formula III；
In formula IV, X and LG is each independently leaving group, and selected from halogen, sulphonic acid ester, boric acid and borate in appoint It is a kind of；
In formula III, the definition of X is with formula IV；M1、M2And M3Definition with formula I or Formulas I '；
(2) compound shown in formula III and compound shown in formula II or compound shown in formula II ' transition-metal catalyst and/ Or acid/base (acid/base represent acid or alkali) exist under conditions of be coupled, obtain compound shown in Formulas I or Formulas I ' shown in chemical combination Thing；
In formula II, the definition of R1, R2, R3, R4, L and W is with formula I；In formula II ', R1、R2、R3、R4, L and W the same formula of definition Ⅰ’。
In above-mentioned preparation method, in step (1) or step (2),
The coupling reaction is carried out in a solvent, and the solvent is selected from water, methyl alcohol, ethanol, isopropanol, ethylene glycol, N- Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, acetonitrile, N, N- dimethyl methyls At least one in acid amides, DMAC N,N' dimethyl acetamide and dioxane；
The transition-metal catalyst is selected from three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium, chlorination Palladium, dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] two At least one in palladium bichloride, double (three adjacent benzyl phosphines) palladium chlorides and 1,2- bis- (diphenylphosphino) ethane palladium chloride； The catalyst ligand is selected from tri-butyl phosphine, tetrafluoro boric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of benzene first At least one in the adjacent benzyl phosphine of base phosphine, tricyclohexyl phosphine and three；
The alkali is inorganic base or organic base；The inorganic base is selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, uncle In butanol potassium, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, saleratus, sodium carbonate and sodium acid carbonate at least It is a kind of；The organic base be selected from pyridine, triethylamine, DIPEA, the carbon of 1,8- diazabicylos [5.4.0] 11- At least one in 7- alkene, the silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two and lutidines；
The acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid and acetic acid at least It is a kind of.
Present invention also offers compound shown in formula I or its enantiomter, diastereoisomer, dynamic isomer, molten Agent compound, polymorph, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic Thing, prodrug or pharmaceutically acceptable salt, are preparing with the work(for suppressing EGFR mutant kinase activities and/or ALK kinase activity Application in the inhibitor of energy.
Invention further provides a kind of kinase inhibitor, it includes compound shown in formula I or its enantiomter, non- Enantiomter, dynamic isomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic Thing, prodrug or pharmaceutically acceptable salt.
Present invention also offers compound shown in formula I or its enantiomter, diastereoisomer, dynamic isomer, molten Agent compound, polymorph, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic Thing, prodrug or pharmaceutically acceptable salt, the application in prevention and/or treatment tumour product is prepared.
In above-mentioned application, the tumour can be non-small cell lung cancer, ED-SCLC, adenocarcinoma of lung, lung squamous cancer, pancreas Cancer, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, leukaemia, lymph cancer and nasopharyngeal carcinoma In any one.
The present invention still further provides a kind of pharmaceutical composition, and it includes：
1) compound or its enantiomter, diastereoisomer, dynamic isomer, solvation shown in the formula I of effective dose Thing, polymorph, prodrug or pharmaceutically acceptable salt；Or
Compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorphic Thing, prodrug or pharmaceutically acceptable salt；
2) pharmaceutically acceptable carrier.
The present invention has the advantages that：
The compound with general structure shown in general structure shown in Formulas I or formula I ' that the present invention is provided, can suppress many Kind of tumour cell, especially can selectively acting in EGFR T790M mutation and the positive lung carcinoma cells of ALK, be that a class is completely newly made With the Mutiple Targets lung cancer therapy medicine of mechanism.
Term in the present invention：
Unless otherwise defined, the connotation that otherwise all scientific and technical terminologies have herein and claim theme art technology The connotation that personnel are generally understood that is identical.Unless otherwise indicated, all patents, patent application, the open material for quoting in full herein It is integrally incorporated by reference herein.
It should be understood that above-mentioned summary and being specified as hereafter are exemplary and be only used for explaining, without appointing to present subject matter What is limited.Additionally, term used " including " and other forms, such as it is "comprising", " containing " and " containing " and non-limiting.
Can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method in the range of art technology, such as mass spectrum, NMR, IR and UV/VIS spectroscopic methodology and Pharmacological method.Unless proposition is specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemistry Relevant description in the term that uses be known in the art.In chemical synthesis, chemical analysis, medicine preparation, preparation and can pass Send, and to using standard technique in the treatment of patient.For example, using manufacturer to the operation instruction of kit, or according to Mode well known in the art or explanation of the invention are implemented to react and are purified.Generally can according in this specification quote and Description in multiple summary and more specific document of discussion, according to conventional method well known in the art implement above-mentioned technology and Method.In this manual, can by those skilled in the art select group and its substitution base with provide stabilization structure division and Compound.
When the conventional chemical formulas by writing from left to right describe substitution base, the substitution base is similarly included from right to left Write substitution base equivalent in chemistry resulting during structural formula.For example ,-CH2O- is equal to-OCH2-。
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme System.The all documents or literature department point quoted in the application include but is not limited to patent, patent application, article, books, manipulator Volume and paper, are integrally incorporated herein by reference.
Some chemical groups of definition represent carbon atom present in the group previously by symbol is simplified herein Sum.For example, C1-6 alkyl refers to have 1 to 6 alkyl as defined below of carbon atom altogether.Simplify the carbon in symbol Total atom number does not include the carbon being likely to be present in the substitution base of the group.
In addition to foregoing, when in the description of the present 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 groups.
" hydroxy alkyl " refers to the alkyl as defined below replaced by hydroxyl (- OH).
" carbonyl " refers to-C (=O)-group.
" nitro " refers to-NO2。
" cyano group " refers to-CN.
" amino " refers to-NH2。
" substituted amino " refers to by one or two alkyl as defined below, alkyl-carbonyl, aralkyl, heteroaryl alkane Base substitution amino, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino, (alkoxy carbonyl group) (alkyl) amino, (alkoxyalkyl) (alkyl) amino.
" carboxyl " refers to-COOH.
In this application, (groups such as the alkyl of halogen substitution are used for example in as a part for group or other groups In), term " alkyl " means only to be made up of carbon atom and hydrogen atom, without unsaturated bond, with such as 1 to 12 (preferably 1 To 8, more preferably 1 to 6) the hydrocarbon chain base of carbon atom and the straight or branched being connected with the remainder of molecule by singly-bound Group.The example of alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, N-pentyl, 2- methyl butyls, 2,2- dimethyl propyls, n-hexyl, heptyl, 2- methylhexyls, 3- methylhexyls, octyl group, nonyl With decyl etc..
In this application, as group or a part for other groups, term " alkenyl " (i.e. " alkenyl ") means only Be made up of carbon atom and hydrogen atom, containing at least one double bond, with such as 2 to 14 (preferably 2 to 10, more preferably 2 To 6) hydrocarbon chain radical of carbon atom and the straight or branched being connected with the remainder of molecule by singly-bound, such as but not limited to Vinyl, acrylic, pi-allyl, but-1-ene base, but-2-ene base, amyl- 1- alkenyls, amyl- 1,4- dialkylenes etc..
In this application, as group or a part for other groups, term " alkynyl " (i.e. " alkynyl group ") means only Be made up of carbon atom and hydrogen atom, containing at least one 3 keys and one or more optional double bonds, with such as 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atom and the straight chain that is connected with the remainder of molecule by singly-bound or branch The hydrocarbon chain radical of chain, such as but not limited to acetenyl, propyl- 1- alkynyls, butyl- 1- alkynyls, amyl- 1- alkene -4- alkynyls etc..
In this application, as group or a part for other groups, term " cycloalkyl " mean only by carbon atom and The non-aromatic monocyclic or multi-ring alkyl of the stabilization of hydrogen atom composition, it may include fused ring system, bridged-ring system or volution body System, with 3 to 15 carbon atoms, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms, and it is saturation Or it is unsaturated and can be connected with the remainder of molecule by singly-bound via any suitable carbon atom.Unless another in this specification Specialize outward, the carbon atom in cycloalkyl can optionally be oxidized.The example of cycloalkyl includes but is not limited to cyclopropyl, ring Butyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cyclooctyl, 1H- indenyls, 2,3- bis- Hydrogenated indenyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6,7,8- tetrahydro-naphthalenyls, 8,9- dihydro -7H- benzo ring heptene -6- bases, 6,7, 8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 5,6,7,8,9,10- hexahydros-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 - 1H- indenyls and octahydro -2,5- methylene-pentalene base etc..
In this application, as group or a part for other groups, term " heterocyclic radical " means by 2 to 14 carbon originals 3 yuan to 20 yuan non-aromatic cyclic groups of the stabilization that son and 1 to 6 hetero atom selected from nitrogen, phosphorus, oxygen and sulphur are constituted.Remove Specialized in addition in non-this specification, otherwise heterocyclic radical can be the member ring systems of monocyclic, bicyclic, three rings or more ring, and it can Including fused ring system, bridged-ring system or spiro ring system；Nitrogen, carbon or sulphur atom in its heterocyclic radical are optionally oxidized；Nitrogen Atom is optionally quaternized；And heterocyclic radical can be partially or completely saturation.Heterocyclic radical can be via carbon atom or miscellaneous original Son is simultaneously connected by singly-bound with molecule remainder.In the heterocyclic radical comprising condensed ring, one or more rings can be hereafter institute The aryl or heteroaryl of definition, it with the tie point of molecule remainder is non-aromatic annular atom that condition is.With regard to mesh of the invention For, heterocyclic radical is preferably comprising 1 to 34 yuan to 11 yuan nonaro-maticity list selected from the heteroatomic stabilization of nitrogen, oxygen and sulphur Ring, bicyclic, bridged ring or spiro-cyclic groups, more preferably comprising 1 to 34 yuan to 8 of the heteroatomic stabilization for being selected from nitrogen, oxygen and sulphur First non-aromatic monocyclic, bicyclic, bridged ring or spiro-cyclic groups.The example of heterocyclic radical is included but is not limited to：Pyrrolidinyl, morpholinyl, Piperazinyl, homopiperazine base, piperidyl, tetrahydrochysene piperidyl, thio-morpholinyl, 2,7- diaza-spiros [3.5] nonane -7- bases, 2- oxygen Miscellaneous -6- aza-spiros [3.3] heptane -6- bases, 2,5- diazas-bicyclic [2.2.1] heptane -2- bases, azetidinyl, pyrans Base, THP trtrahydropyranyl, thiapyran base, tetrahydrofuran base, oxazinyls, dioxy cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, Imidazolinyl, imidazolidinyl, quinolizine base, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indoles Base, octahydro isoindolyl, pyrrolidinyl, pyrazolidinyl, phthaloyl imino etc..
In this application, as group or a part for other groups, term " aryl " (i.e. " aromatic radical ") means tool There is the conjugated hydrocarbon member ring systems group of 6 to 18 carbon atoms (preferably with 6 to 10 carbon atoms).For purposes of the invention, Aryl can be the member ring systems of monocyclic, bicyclic, three rings or more ring, can also be thick with cycloalkyl defined above or heterocyclic radical Close, condition is that aryl is connected by singly-bound via the atom on aromatic rings with the remainder of molecule.The example of aryl include but It is not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3- dihydro -1H- isoindolyls, 2- benzoxazolinones, 2H-1,4- benzene Bing oxazines -3 (4H) -one -7- bases etc..
In this application, term " aryl alkyl " refers to the alkane defined above replaced by aryl defined above Base.
In this application, as group or a part for other groups, term " heteroaryl " means there is 1 to 15 in ring Individual carbon atom (preferably with 1 to 10 carbon atom) and 1 to 6 heteroatomic 5 yuan to 16 yuan conjugate ring selected from nitrogen, oxygen and sulphur It is group.Unless specialized in addition in this specification, otherwise heteroaryl can be the ring body of monocyclic, bicyclic, three rings or more ring System, can also condense with cycloalkyl defined above or heterocyclic radical, and condition is that heteroaryl passes through via the atom on aromatic rings Singly-bound is connected with the remainder of molecule.Nitrogen, carbon or sulphur atom in heteroaryl are optionally oxidized；Nitrogen-atoms is optionally It is quaternized.For purposes of the invention, heteroaryl is preferably the heteroatomic stabilization selected from nitrogen, oxygen and sulphur comprising 1 to 5 5 yuan to 12 yuan aromatic radicals, more preferably comprising 1 to 45 yuan to 10 of heteroatomic stabilization selected from nitrogen, oxygen and sulphur First aromatic radical or comprising 1 to 3 heteroatomic 5 yuan to 10 yuan aromatic radical selected from nitrogen, oxygen and sulphur.Heteroaryl Example include but is not limited to thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyls, pyridine radicals, Pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazoles base, indyl, furyl, pyrrole radicals, triazolyl, tetrazolium Base, triazine radical, indolizine base, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthyl, naphthalene Piperidinyl, quinoxalinyls, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridinyl, phenazinyl, isothiazolyl, benzene It is benzothiazolyl, benzothienyl, oxatriazoles base, cinnolines base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, different Oxazolyl, phenoxazine groups, phenothiazinyl, 4,5,6,7- tetrahydro benzos [b] thienyl, naphtho- pyridine radicals, [1,2,4] triazol [4,3-b] pyridazine, [1,2,4] triazol [4,3-a] pyrazine, [1,2,4] triazol [4,3-c] pyrimidine, [1,2,4] triazol [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc..
In this application, term " heteroaryl alkyl " refer to by heteroaryl defined above replaced it is defined above Alkyl.
In this application, term " Heterocyclylalkyl " refer to by heterocyclic radical defined above replaced it is defined above Alkyl.
In this application, " optional " or " optionally " represents that the event or situation of then description may be likely to not Occur, and the description includes the situation that the event or situation occur and do not occur simultaneously.For example, " aryl being optionally substituted " Represent that aryl substituted or unsubstituted, and the description includes substituted aryl and unsubstituted aryl simultaneously.
During terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer to molecule Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.
" stereoisomer " refers to be made up of same atoms, is bonded by identical key, but with different three-dimensional structures Compound.The present invention will cover various stereoisomers and its mixture.
When alkene double bond is contained in compound of the invention, unless otherwise stated, compound of the invention is intended to bag Containing E- and Z- geometric isomers.
" dynamic isomer " refers to that proton is formed from an atom transfer of molecule to another atom of identical molecule Isomers.All tautomeric forms of compound of the invention also will be contained in the scope of the present invention.
Compound of the invention or its pharmaceutically acceptable salt may contain one or more asymmetric carbon atoms, and therefore Enantiomter, diastereoisomer and other stereoisomeric forms in any ratio can be produced.Each asymmetric carbon atom can be based on three-dimensional Learn and be defined as (R)-or (S)-.It is contemplated that including all possible isomers, and its racemic modification and optical voidness Form.The preparation of compound of the invention racemic modification, diastereoisomer or enantiomter can be selected as raw material or Intermediate.Optically active isomers can be prepared using chiral synthon or chiral reagent, or be entered using routine techniques Row splits, for example with methods such as crystallization and chiral chromatograms.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or makes With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald is see, for example, Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols, Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.
In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects , the salt formed with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, nitric acid Salt, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2- DCAs, trifluoroacetate, propionic acid Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.
" pharmaceutically acceptable base addition salts " be refer to keep free acid biological effectiveness and without other side effects And salt that inorganic base or organic base are formed.Salt derived from inorganic base includes but is 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 salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium Salt.Salt derived from organic base includes but is not limited to following salt：Primary amine class, secondary amine class and tertiary amines, substituted amine, bag Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three Ethamine, tripropyl amine (TPA), monoethanolamine, diethanol amine, triethanolamine, dimethylethanolamine, DMAE, 2- lignocaine second Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine, Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferred organic base includes isopropyl Amine, diethylamine, monoethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can be by method known in the art Prepare.
" polymorph " refers to some compounds of the invention in the solid state due to there is two or more not The different solid crystal phases produced with molecules align.Some compounds of the invention there may be more than one crystal formation, this hair It is bright to be intended to include various crystal formations and its mixture.
Generally, crystallization effect can produce the solvate of the compounds of this invention.Term " the solvation used in the present invention Thing " refers to the aggregation comprising one or more the compounds of this invention molecules Yu one or more solvent molecules.Solvent can be Water, solvate in this case is hydrate.Or, solvent can be organic solvent.Therefore, compound of the invention can be with Exist with hydrate, including monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., with And corresponding solvation form.The compounds of this invention can form real solvate, but in some cases, it is also possible to only protect Indefinite water or water are stayed plus the mixture of the indefinite solvent in part.Compound of the invention can react in a solvent or from Precipitation or crystallized out in solvent.The solvate of the compounds of this invention is also contained within the scope of the present invention.
Present invention additionally comprises the prodrug of above-claimed cpd.In this application, term " prodrug " expression can be in physiological conditions Compound lower or that bioactive compound of the invention is converted to by solvolysis.Therefore, term " prodrug " refers to The pharmaceutically acceptable metabolic precursor thereof of compound of the invention.When being given in need individual, prodrug can not have Activity, but reactive compound of the invention is converted in vivo.Prodrug generally rapid conversion in vivo, and produce of the invention Parent compound, for example, realized by hydrolyzing in blood.Prodrug compound generally provides molten in mammalian organism The advantage of Xie Du, histocompatbility or sustained release.Prodrug includes known amino protecting group and carboxyl-protecting group.Specific prodrug system Preparation Method can refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990； Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
In this application, " pharmaceutical composition " refers to the generally receiving of the compounds of this invention and this area for biology to be lived Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Medicine The purpose of composition is to promote the administration of organism, absorption beneficial to active component and then plays bioactivity.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influenceing the compounds of this invention Material (such as carrier or diluent), and relative nontoxic, the i.e. material can be applied to individuality without causing bad biological respinse Or interacted with any component included in bad mode and composition.
In this application, " pharmaceutically acceptable carrier " includes but is not limited to any be permitted by related government administration section Can be acceptable adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, the dye used for the mankind or domestic animal Material/colouring agent, flavouring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.
" tumour " of the present invention, " cell proliferative disorder relevant disease " etc. include but is not limited to leukaemia, gastro-intestinal stromal Knurl, histiocytic lymphoma, non-small cell lung cancer, ED-SCLC, cancer of pancreas, lung squamous cancer, adenocarcinoma of lung, breast cancer, prostatitis Gland cancer, liver cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, osteocarcinoma, cancer of the esophagus, melanin The diseases such as knurl, kidney, carcinoma of mouth.
Terms used herein " prevention ", " prevention " and " preventing " includes sufferer is reduced disease or illness generation or evil The possibility of change.
Term " treatment " the used herein synonym similar with other includes following meanings：
I () prevention disease or illness occur in mammal, particularly when this kind of mammal be susceptible to the disease or Illness, but when being not yet diagnosed as having suffered from the disease or illness；
(ii) suppress disease or illness, that is, contain that it develops；
(iii) disease or illness are alleviated, i.e. the state of the disease or illness is disappeared；Or
(iv) disease or the symptom caused by illness are mitigated.
Term " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with certain At least one medicament or the amount of compound of one or more symptoms of the treated disease of alleviation or illness in degree.Its result Can be sign, symptom or the cause of disease abatement and/or alleviation, or biosystem it is any other needed for change.For example, for controlling " effective dose " treated is the composition comprising compound disclosed herein needed for clinically providing significant remission effect Amount.The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.
Terms used herein " taking ", " administration ", " administration " etc. are to refer to be delivered to compound or composition carry out The method in the required site of biological agent.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.This area Can be used for the application technique of Compounds and methods for described herein known to technical staff, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, discuss in Pa Those.In preferred embodiments, the compound and composition being discussed herein are by Orally administered.
Term " drug regimen " used herein, " drug combination ", " drug combination ", " apply other treatment ", " apply it Its therapeutic agent " etc. refers to the drug therapy obtained by mixing or combining more than one active component, and it includes active component Fixation and non-fixed Combination.Term " fixed Combination " refers to be administered simultaneously to patient in the form of single entity or single formulation At least one compound as herein described and at least one collaboration medicament.Term " not fixed Combination " refers to the shape of corpus separatum Formula is administered simultaneously to patient, share or at least one compound as herein described is sequentially applied with variable interval time and at least One kind collaboration preparation.These are also applied in HAART, such as using three or more active component.
It should also be appreciated by one skilled in the art that in method discussed below, midbody compound functional group may need To be protected by appropriate protection group.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group bag Include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, tert-butyl diphenyl first Silylation or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..The protection group of suitable amino, amidino groups and guanidine radicals includes uncle Butoxy carbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " be alkyl, aryl or aralkyl), To methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.
Protection group can be introduced and removed according to standard technique well known by persons skilled in the art and as described herein.Protect The use for protecting base is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., in Wiley.Protection group can also be fluoropolymer resin.
Brief description of the drawings
Fig. 1 is the route map of compound shown in synthesis type II or compound shown in formula II '.
Fig. 2 is the route map of compound shown in synthesis type III.
Fig. 3 is the route map of compound shown in synthesis type I or compound shown in formula I '.
Specific embodiment
Experimental technique used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc. in following embodiments, unless otherwise specified, commercially obtain.
Intermediate in following embodiments is prepared in accordance with the following steps, wherein, compound or formula II ' shown in formula II Shown compound synthesizes according to the route map of Fig. 1；Compound shown in formula III synthesizes according to the route map of Fig. 2；Compound shown in formula I Or compound shown in formula I ' synthesizes according to the route map of Fig. 3.
Intermediate 1：
Bromo- 2, the 3- Dihydrobenzofuranes -7- amine (2.05g, 9.58mmol) of compound 4- are dissolved in 1,2- dichloroethanes In (20mL), after stirring, be slowly dropped into (~30min) to be previously heated to reflux state mCPBA (7.80g, In 1,2- dichloroethanes (60mL) 38.2mmol), continue back flow reaction 2h, raw material disappears.Solvent is evaporated off, EA is added (50mL), saturation Na2S2O3(aq) wash (30mL × 3), 0.5M NaOH (aq) are washed (30mL × 3), column chromatography (P/E=5:1) divide From faint yellow solid 1.60g is obtained, yield is 68%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):7.84 (d, J= 8.8Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 4.92 (t, J=8.8Hz, 2H), 3.35 (t, J=8.8Hz, 2H)
Intermediate 2：
Compound 4- bromine 7- nitro -2,3- Dihydrobenzofuranes (500mg, 2.05mmol) are dissolved in toluene (30mL) In, sequentially add Pd (OAc)2(50mg, 0.21mmol), DavePhos (161mg, 0.41mmol) and K3PO4(1.31g, 6.15mmol,6mL H2O), after stirring, 4- dimethylamino piperidines (789mg, 6.15mmol) is added, under argon gas protection, is returned Stream reaction 20h, raw material disappears.Room temperature is cooled to, solvent is evaporated off, EA (30mL) dissolution residual substance, saturated common salt washing (20mL × 3) (20mL × 2), are washed, column chromatography (D/M=20:1) yellow solid 500mg is isolated and purified to obtain, yield is 84%.Structure verification Data are as follows：1H NMR(CDCl3)δ(ppm):7.92 (d, J=8.8Hz, 1H), 6.42 (d, J=8.8Hz, 1H), 4.81 (t, J =8.4Hz, 2H), 3.71 (d, J=12.0Hz, 2H), 3.20 (t, J=8.4Hz, 2H), 3.04 (m, 1H), 2.90 (t, J= 11.6Hz, 2H), 2.71 (s, 6H), 2.25 (d, J=10.4Hz, 2H), 1.88-1.86 (m, 2H)
Intermediate 3：
Using the identical synthetic method of intermediate 2, with N, N- dimethyl pyrroles are replaced 4- dimethylamino piperidines, are prepared The yellow solid 130mg of intermediate 3, yield is 76%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):7.87(d,J =9.2Hz, 1H), 6.09 (d, J=9.6Hz, 1H), 4.77-4.67 (m, 2H), 3.77-3.40 (m, 6H), 2.81-2.77 (m, 1H),2.31(s,6H),2.23-2.17(m,1H),1.92-1.87(m,1H).
Intermediate 4：
Using the identical synthetic method of intermediate 2,4- dimethylamino piperidines are replaced with N-Boc piperazines, prepare centre The yellow solid 163mg of body 4, yield is 76%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):7.93 (d, J= 9.2Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 4.81 (t, J=8.4Hz, 2H), 3.57 (t, J=4.8Hz, 4H), 3.24- 3.17(m,6H),1.49(s,6H).
Intermediate 5：
Using the identical synthetic method of intermediate 2,4- dimethylamino piperidines are replaced with N methyl piperazine, prepare centre The yellow solid 84mg of body 5, yield is 52%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):7.92 (d, J= 9.2Hz, 1H), 6.43 (d, J=9.2Hz, 1H), 4.80 (t, J=8.8Hz, 2H), 3.27 (t, J=4.8Hz, 4H), 3.21 (t, J=8.8Hz, 2H), 2.55 (t, J=4.8Hz, 4H), 2.36 (s, 3H)
Intermediate 6：
Using the identical synthetic method of intermediate 2, replaced with 1-methyl-4- (piperidin-4-yl) piperazine 4- dimethylamino piperidines, prepare the yellow powdery solid 148mg of intermediate 6, and yield is 69%.Structure verification data are such as Under：1H NMR(CDCl3)δ(ppm):7.90 (d, J=9.2Hz, 1H), 6.41 (d, J=9.2Hz, 1H), 4.79 (t, J= 8.4Hz, 2H), 3.67 (d, J=12.8Hz, 2H), 3.20 (t, J=8.8Hz, 2H), 2.88 (t, J=12.0Hz, 2H), 2.69 (brs, 4H), 2.56 (brs, 4H), 2.49-2.43 (m, 1H), 2.35 (s, 3H), 1.98 (d, J=11.6Hz, 2H), 1.68- 1.58(m,2H).
Intermediate 7：
Intermediate 1 (200mg, 0.82mmol) is dissolved in toluene (10mL), Pd (OAc) is sequentially added2(20mg, 0.08mmol), DavePhos (65mg, 0.16mmol) and K3PO4(520mg, 2.46mmol, 2mL H2O), after stirring, plus Enter tert-butyl4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6- Dihydropyridine-1 (2H)-carboxylate (760mg, 2.46mmol), under argon gas protection, 95 DEG C of reaction 4h, raw material Disappear.Room temperature is cooled to, solvent is evaporated off, EA (30mL) dissolution residual substance, saturated common salt washes (20mL × 3), washing (20mL × 2), column chromatography (D/M=10:1) the yellow powdery solid 250mg of intermediate 7, is obtained, yield is 88%.Structure verification data are such as Under：1H NMR(CDCl3)δ(ppm):7.91 (d, J=8.8Hz, 1H), 6.82 (d, J=8.8Hz, 1H), 5.91 (s, 1H), 4.83 (t, J=8.8Hz, 2H), 4.09 (m, 2H), 3.63 (t, J=8.8Hz, 2H), 3.32 (t, J=8.8Hz, 2H), 2.45 (m, 2H),1.50(s,9H).
Intermediate 8：
Intermediate 7 (190mg, 0.55mmol) is dissolved in DCM (15mL), TFA (625mg, 5.50mmol), room temperature is added Reaction 3h, raw material disappears.Concentration, obtains the pale yellow powder shape solid 188mg of intermediate 8, and yield is 100%.Structure verification data It is as follows：1H NMR(CDCl3)δ(ppm):9.07 (brs, 1H), 7.94 (d, J=8.4Hz, 1H), 6.80 (d, J=8.8Hz, 1H), 6.63 (s, 1H), 5.89 (s, 1H), 4.84 (t, J=8.8Hz, 2H), 3.94 (brs, 2H), 3.53 (brs, 2H), 3.31 (t, J =8.8Hz, 2H), 2.76 (brs, 2H)
Intermediate 9：
Intermediate 8 (170mg, 0.50mmol) is dissolved in THF (10mL) and MeOH (10mL), formalin is added (120mg, 37%, 1.50mmol) and sodium triacetoxy borohydride (555mg, 2.50mmol), room temperature reaction 2h, raw material disappears Lose.Concentration, adds EA (30mL), washes (20mL × 3), column chromatography (D/M=20:1) the pale yellow powder shape of intermediate 9, is obtained to consolidate Body 120mg, yield is 92%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):7.90 (d, J=8.8Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 5.91 (m, 1H), 4.81 (t, J=8.8Hz, 2H), 3.33 (t, J=8.8Hz, 2H), 3.16- (s, the 3H) of 3.15 (m, 2H), 2.69 (t, J=5.6Hz, 2H), 2.53 (m, 2H), 2.44
Intermediate 10：
Using the identical synthetic method of intermediate 2,4- is replaced with 1-Boc-4- (piperidin-4-yl) piperazine Dimethylamino piperidine, prepares the yellow powdery solid 156mg of intermediate 10, and yield is 58%.Structure verification data are as follows ：1H NMR(CDCl3)δ(ppm):7.90 (d, J=9.2Hz, 1H), 6.41 (d, J=9.6Hz, 1H), 4.79 (t, J=8.8Hz, 2H), 3.67 (d, J=12.4Hz, 2H), 3.45 (m, 4H), 3.20 (t, J=8.8Hz, 2H), 2.87 (t, J=12.0Hz, 2H), 2.53 (m, 4H), 2.46 (m, 2H), 1.94 (d, J=12.0Hz, 2H), 1.66-1.59 (m, 2H)
Intermediate 11：
Intermediate 2 (463mg, 1.59mmol) is dissolved in methanol (20mL), Pd/C (60mg), catalytic hydrogenation is added 3h, raw material disappears.Pd/C is filtered, is concentrated, obtain the off-white powder 410mg of intermediate 11, yield is 99%.Structure verification data are such as Under：1H NMR(DMSO-d6)δ(ppm):6.38 (d, J=8.0Hz, 1H), 6.24 (d, J=8.4Hz, 1H), 4.45 (t, J= 8.4Hz, 2H), 4.23 (brs, 2H), 3.16 (d, J=12.0Hz, 2H), 3.04 (t, J=8.4Hz, 2H), 2.45-2.50 (m, 2H), 2.31 (m, 7H), 1.85 (d, J=11.6Hz, 2H), 1.55-1.47 (m, 2H)
Intermediate 12：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 3, obtain the off-white color of intermediate 12 and consolidate Body 68mg, yield is 96%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.51 (d, J=8.4Hz, 1H), 6.06 (d, J=8.4Hz, 1H), 4.58-4.50 (m, 2H), 3.41-3.18 (m, 6H), 2.82 (t, J=7.2Hz, 1H), 2.29 (s,6H),2.12-2.11(m,1H),1.88-1.83(m,1H).
Intermediate 13：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 4, obtain the off-white color of intermediate 13 and consolidate Body 87mg, yield is 92%.Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):6.41 (d, J=8.4Hz, 1H), 6.25 (d, J=8.0Hz, 1H), 4.55 (brs, 2H), 4.46 (t, J=8.4Hz, 2H), 3.40 (m, 4H), 3.07 (t, J= 8.4Hz, 2H), 2.75 (t, J=4.8Hz, 4H), 1.41 (s, 9H)
Intermediate 14：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 5, obtain the off-white color of intermediate 14 and consolidate Body 58mg, yield is 100%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.55 (d, J=8.4Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 4.61 (t, J=8.4Hz, 2H), 3.32 (m, 6H), 3.16 (t, J=8.4Hz, 2H), 2.79 (s,3H),1.28(m,4H).
Intermediate 15：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 6, obtain the off-white color of intermediate 15 and consolidate Body 64mg, yield is 78%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.51 (d, J=8.4Hz, 1H), 6.33 (d, J=8.4Hz, 1H), 4.57 (t, J=8.4Hz, 2H), 3.28 (d, J=12.0Hz, 2H), 3.14 (t, J=8.4Hz, 2H), 2.67-2.52 (m, 10H), 2.37-2.34 (m, 1H), 2.32 (s, 3H), 1.92 (d, J=12.4Hz, 2H), 1.71- 1.61(m,2H).
Intermediate 16：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 7, obtain the slightly yellow color of intermediate 16 Solid 48mg, yield is 77%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.85 (d, J=8.4Hz, 1H), 6.54 (d, J=8.0Hz, 1H), 5.71 (s, 1H), 4.55 (t, J=8.8Hz, 2H), 3.55 (brs, 2H), 3.26 (t, J= 8.8Hz, 2H), 3.09-3.07 (m, 2H), 2.63 (t, J=5.6Hz, 2H), 2.51 (m, 2H), 2.40 (s, 3H)
Intermediate 17：
Intermediate 16 (70mg, 0.27mmol) is dissolved in methanol (10mL), Pd/C (15mg), catalytic hydrogenation is added 3h, raw material disappears.Pd/C is filtered, is concentrated, obtain slightly yellow color solid 49mg, yield is 79%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.59 (d, J=8.4Hz, 1H), 6.54 (d, J=8.0Hz, 1H), 5.71 (s, 1H), 4.58 (t, J =8.8Hz, 2H), 3.46 (brs, 2H), 3.18 (t, J=8.8Hz, 2H), 2.98-2.95 (m, 2H), 2.38-2.33 (m, 1H), 2.31(s,3H),2.05-1.98(m,2H),1.81-1.68(m,4H).
Intermediate 18：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 9, obtains slightly yellow color solid 90mg, Yield is 90%.Structure verification data are as follows：1H NMR(CDCl3)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 19：
Using the identical synthetic method of intermediate 11, intermediate 2 is replaced with intermediate 10, obtains off-white powder 55mg, Yield is 74%.Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):6.51 (d, J=8.4Hz, 1H), 6.33 (d, J= 8.4Hz, 1H), 4.57 (t, J=8.4Hz, 2H), 3.55 (brs, 4H), 3.30 (d, J=11.6Hz, 2H), 3.14 (t, J= 8.4Hz,2H),2.64-2.58(m,7H),1.90(m,2H),1.71(m,2H),1.47(s,9H).
Intermediate 20：
By compound 4,6- dichloro pyrimidines (100mg, 0.60mmol) and 2- (aminophenyl) dimethyl phosphine oxide (51mg, 0.30mmol) it is dissolved in n-butanol (5mL), adds DIEA (116mg, 0.90mmol), back flow reaction 12h, raw material to disappear substantially. Column chromatography (P/E=1:6) white solid 50mg, is obtained, yield is 56%.Structure verification data are as follows：1H NMR(CDCl3)δ (ppm):11.02(s,1H),6.62(dd,J1=8.4Hz, J2=4.4Hz, 1H), 8.54 (s, 1H), 7.57-7.52 (m, 1H), 7.29-7.23(m,1H),7.14-7.09(m,1H),6.74(s,1H),1.85(s,3H),1.82(s,3H).
Intermediate 21：
Using the identical synthetic method of intermediate 20,4 are replaced with the chloro- 5-FUs (100mg, 0.60mmol) of 2,4- bis-, 6- dichloro pyrimidines, obtain the white solid 50mg of intermediate 21, and yield is 56%.Structure verification data are as follows：1H NMR(CDCl3)δ (ppm):11.84(s,1H),8.80(dd,J1=8.4Hz, J2=4.4Hz, 1H), 8.08 (d, J=2.8Hz, 1H), 7.62- 7.58(m,1H),7.29-7.24(m,1H),7.19-7.14(m,1H),1.87(s,3H),1.84(s,3H).
Intermediate 22：
Using the identical synthetic method of intermediate 20,4,6- dichloros are replaced with 2,4- dichloro pyrimidines (352mg, 2.36mmol) Pyrimidine, obtains intermediate 22 and obtains white solid 120mg, and yield is 36%.Structure verification data are as follows：1H NMR(CDCl3)δ (ppm):11.22(s,1H),8.69(dd,J1=8.4Hz, J2=4.4Hz, 1H), 8.14 (d, J=5.6Hz, 1H), 7.59- 7.55 (m, 1H), 7.27-7.25 (m, 1H), 7.14-7.10 (m, 1H), 6.58 (d, J=5.6Hz, 1H), 1.85 (s, 3H), 1.82(s,3H).
Intermediate 23 and 24：
Using the identical synthetic method of intermediate 20, with the chloro- 5- trifluoromethyl pyrimidines (386mg, 1.78mmol) of 2,4- bis- 4,6- dichloro pyrimidines are replaced, the mixture of intermediate 23 and 24 is obtained：White solid 210mg, yield is 68%.Structure verification data It is as follows：1H NMR(CDCl3)δ(ppm):11.67(s,1H),11.28(s,0.5H),8.65-8.62(m,1H),8.59(s,1H), 8.49-8.46(m,1H),7.61-7.54(m,1.5H),7.34-7.22(m,2H),7.15-7.12(m,1H),1.86(s,3H), 1.85(s,1.5H),1.83(s,3H),1.81(s,1.5H).
Intermediate 25：
Using the identical synthetic method of intermediate 20, replaced with the chloro-1,3,5-triazines of 2,4- bis- (267mg, 1.78mmol) 4,6- dichloro pyrimidines, obtain intermediate 25：White solid 150mg, yield is 60%.Structure verification data are as follows：1H NMR (DMSO-d6)δ(ppm):11.81(brs,1H),8.63(dd,J1=8.4Hz, J2=4.4Hz, 1H), 8.57 (s, 1H), 7.60 (t, J=8.0Hz, 1H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H)
Intermediate 26：
Using the identical synthetic method of intermediate 20,4,6- bis- is replaced with 2,4,5- trichloropyrimidines (866mg, 4.72mmol) Chlorine pyrimidine, obtains intermediate 26：Off-white powder 483mg, yield is 65%.Structure verification data are as follows：1H NMR(DMSO-d6)δ (ppm):11.55(brs,1H),8.67(dd,J1=8.4Hz, J2=4.4Hz, 1H), 8.22 (s, 1H), 7.60 (t, J= 8.4Hz,1H),7.32-7.28(m,1H),7.20-7.18(m,1H),1.86(s,3H),1.83(s,3H).
Embodiment 1：
Intermediate 11 (25mg, 0.10mmol) and intermediate 20 (35mg, 0.12mmol) are dissolved in iPrOH (1mL), plus Enter concentrated hydrochloric acid (24mg, 0.25mmol), microwave reaction (250w, 130 DEG C, 120min, 300psi).Room temperature is cooled to, EA is added (20mL), saturated sodium bicarbonate (aq) is washed (20mL × 3), saturated common salt washing (20mL × 3), column chromatography (D/M/Et3N=10: 1:0.02) embodiment 1, is obtained：Off-white powder 48mg, yield is 71%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.01(s,1H),8.46(dd,J1=8.4Hz, J2 =4.4Hz, 1H), 8.35 (s, 1H), 7.47 (t, J=7.6Hz, 1H), 7.23-7.15 (m, 2H), 7.02-6.98 (m, 1H), 6.45 (d, J=8.8Hz, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 4.60 (t, J=8.8Hz, 2H), 3.40 (d, J= 12.0Hz, 2H), 3.20 (t, J=8.8Hz, 2H), 2.67 (t, J=12.0Hz, 2H), 2.33 (s, 6H), 2.29-2.23 (m, 1H), 1.93 (d, J=12.0Hz, 2H), 1.80 (s, 3H), 1.74 (s, 3H), 1.68-1.58 (m, 2H) .HRMS (ESI):m/z, calcd for C27H36N6O2P[M+H+]:507.2637,found 507.2646.
Embodiment 2：
With intermediate 11 (50mg, 0.19mmol) and intermediate 21 (71mg, 0.24mmol) for raw material, using embodiment 1 Identical method synthesizes, and prepares embodiment 2：Off-white powder 84mg, yield is 84%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):11.51(s,1H),8.66(m,1H),8.24(s, 1H), 8.02 (d, J=3.2Hz, 1H), 7.54 (dd, J1=13.6Hz, J2=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.08 (t, J=7.2Hz, 1H), 6.44 (d, J=8.8Hz, 1H), 4.49 (t, J=8.4Hz, 2H), 3.41-3.39 (m, 2H), 3.16 (t, J=8.0Hz, 2H), 3.01 (m, 1H), 2.64 (t, J=12.0Hz, 2H), 2.53 (s, 6H), 2.01 (d, J=10.0Hz, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 1.80-1.65 (m, 2H) .HRMS (ESI): m/z,calcd for C27H35N6O2PF[M+H+]:525.2543,found 525.2557.
Embodiment 3：
With intermediate 11 (40mg, 0.15mmol) and intermediate 22 (54mg, 0.19mmol) for raw material, using embodiment 1 Identical method synthesizes, and prepares embodiment 3：Off-white powder 35mg, yield is 45%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):10.95(s,1H),8.51-8.50(m,1H), 8.11 (s, 1H), 7.95 (d, J=5.6Hz, 1H), 7.52 (d, J1=12.8Hz, J2=6.4Hz, 1H), 7.31 (t, J= 7.6Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 6.43 (d, J=8.8Hz, 1H), 5.96 (d, J=5.6Hz, 1H), 4.49 (t, J=8.4Hz, 2H), 3.39 (m, 2H), 3.17-3.13 (m, 3H), 2.63 (t, J=12.0Hz, 2H),2.43(s,6H),1.97-1.94(m,2H),1.78(s,3H),1.75(s,3H),1.62-1.59(m,2H).HRMS (ESI):m/z,calcd for C27H36N6O2P[M+H+]:507.2637,found 507.2634.
Embodiment 4 and embodiment 5：
With intermediate 11 (65mg, 0.25mmol) and intermediate 23,24 (108mg, 0.31mmol) for raw material, using implementation The identical method of example 1 synthesizes, and prepares embodiment compound 4 and 5：Off-white powder 60mg.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.81(s,1H),10.36(s,0.5H),8.49- 8.48 (m, 1H), 8.35-8.32 (m, 2H), 7.90 (d, J=7.6Hz, 1H), 7.79 (d, J=7.6Hz, 0.5H), 7.46- 7.34 (m, 1.5H), 7.27-7.17 (m, 1.5H), 7.06-7.05 (m, 1.5H), 6.95 (s, 1.5H), 6.49 (d, J= 8.4Hz,1H),6.37(brs,0.5H),4.65-4.61(m,3H),3.49-3.43(m,3H),3.21-3.17(m,3H),3.00 (m, 1.5H), 2.77-2.72 (m, 12H), 2.25 (d, J=10.8Hz, 3H), 1.91-1.89 (m, 3H), 1.84 (s, 4.5H), 1.81(s,4.5H).HRMS(ESI):m/z,calcd for C28H35N6O2PF3[M+H+]:575.2511,found 575.2527.
Embodiment 6：
With intermediate 11 (40mg, 0.15mmol) and 25 (54mg, 0.19mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment compound 6：Off-white powder 13mg, yield is 17%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):11.17(s,1H),9.14(brs,1H),8.41 (brs,1H),8.23(s,1H),7.53(m,1H),7.24(m,1H),7.09-7.07(m,2H),6.46(m,1H),4.50(t,J =8.4Hz, 2H), 3.33 (m, 2H), 3.17 (m, 3H), 3.05 (m, 1H), 2.65 (t, J=11.2Hz, 2H), 2.50 (s, 6H), 1.97(m,2H),1.78(s,3H),1.75(s,3H),1.64-1.61(m,2H).HRMS(ESI):m/z,calcd for C26H35N7O2P[M+H+]:508.2590,found 508.2596.
Embodiment 7：
With intermediate 11 (50mg, 0.19mmol) and 26 (75mg, 0.24mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment compound 7：Off-white powder 74mg, yield is 72%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.84(s,1H),8.63(dd,J1=8.4Hz, J2 =4.4Hz, 1H), 8.08 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.29-7.24 (m, 1H), 7.11 (d, J=6.8Hz, 1H), 6.81 (s, 1H), 6.43 (d, J=8.4Hz, 1H), 4.60 (t, J=8.8Hz, 2H), 3.38 (d, J=12.0Hz, 2H), 3.21 (t, J=8.4Hz, 2H), 2.66 (t, J=12.0Hz, 2H), 2.33 (s, 6H), 2.30-2.23 (m, 1H), 1.93 (d, J=11.6Hz, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.69-1.60 (m, 2H) .HRMS(ESI):m/z,calcd for C27H35N6O2PCl[M+H+]:541.2248,found 541.2257.
Embodiment 8：
With intermediate 14 (40mg, 0.17mmol) and 26 (67mg, 0.21mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 8：Off-white powder 40mg, yield is 46%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.86(s,1H),8.62(dd,J1=8.0Hz, J2 =4.4Hz, 1H), 8.08 (s, 1H), 7.84 (d, J=8.4Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.30-7.27 (m, 1H), 7.11 (d, J=6.4Hz, 1H), 6.83 (s, 1H), 6.46 (d, J=8.8Hz, 1H), 4.61 (t, J=8.8Hz, 2H), 3.20 (d, J=8.4Hz, 2H), 3.12-3.07 (m, 4H), 2.45 (s, 3H), 1.85 (s, 3H), 1.82 (s, 3H), 1.41 (t, J =7.2Hz, 2H) .HRMS (ESI):m/z,calcd for C25H31N6O2PCl[M+H+]:513.1935,found 513.1924.
Embodiment 9：
With intermediate 13 (40mg, 0.12mmol) and 26 (47mg, 0.15mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 9：White solid 14mg, yield is 22%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):11.21(s,1H),8.53(brs,1H),8.47 (s,1H),8.07(s,1H),7.53(dd,J1=14.0Hz, J2=8.4Hz, 1H), 7.29 (m, 1H), 7.17 (d, J=8.8Hz, 1H), 7.10-7.08 (m, 1H), 6.45 (d, J=8.4Hz, 1H), 5.76 (s, 1H), 4.49 (t, J=8.0Hz, 2H), 3.30 (m,4H),3.19-3.12(m,6H),1.78(s,3H),1.75(s,3H).HRMS(ESI):m/z,calcd for C24H29N6O2PCl[M+H+]:499.1778,found 499.1779.
Embodiment 10：
With intermediate 12 (35mg, 0.14mmol) and 26 (55mg, 0.18mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 10：White solid 60mg, yield is 81%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):11.19(s,1H),8.56(brs,1H),8.31 (s,1H),8.03(s,1H),7.51(dd,J1=14.0Hz, J2=7.2Hz, 1H), 7.28 (m, 1H), 7.77 (t, J=6.8Hz, 1H), 6.98 (d, J=8.4Hz, 1H), 6.09 (d, J=8.4Hz, 1H), 4.46-4.35 (m, 2H), 3.52-3.24 (m, 6H), 2.90(m,1H),2.29(s,6H),2.13-2.09(m,1H),1.78(m,1H),1.75(s,3H),1.74(s,3H).HRMS (ESI):m/z,calcd for C26H33N6O2PCl[M+H+]:527.2091,found 527.2104.
Embodiment 11：
With intermediate 15 (40mg, 0.13mmol) and 26 (50mg, 0.16mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 11：Off-white powder 35mg, yield is 46%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.85(s,1H),8.63(dd,J1=8.0Hz, J2 =4.0Hz, 1H), 8.08 (s, 1H), 7.81 (d, J=8.8Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 7.30-7.25 (m, 1H), 7.11 (d, J=7.6Hz, 1H), 6.81 (s, 1H), 6.42 (d, J=8.8Hz, 1H), 4.61 (t, J=8.4Hz, 2H), 3.40 (d, J=13.6Hz, 2H), 3.19 (t, J=8.0Hz, 2H), 2.92-2.51 (m, 13H), 2.01 (m, 2H), 1.85 (s, 3H),1.81(s,3H),1.79-1.75(m,2H).HRMS(ESI):m/z,calcd for C30H40N7O2PCl[M+H+]: 596.2670,found 596.2673.
Embodiment 12：
With intermediate 16 (30mg, 0.13mmol) and 26 (50mg, 0.16mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 12：Off-white powder 25mg, yield is 38%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.85(s,1H),8.61(m,1H),8.10(s, 1H),7.97(m,1H),7.48(m,1H),7.26(m,1H),7.13(m,1H),7.00(s,1H),6.74(m,1H),5.79(s, 1H),4.59(m,2H),3.32-3.11(m,4H),2.66-2.34(m,7H),1.85(s,3H),1.82(s,3H).HRMS (ESI):m/z,calcd for C26H30N5O2PCl[M+H+]:510.1826,found 510.1830.
Embodiment 13：
With intermediate 17 (40mg, 0.17mmol) and 26 (67mg, 0.21mmol) for raw material, using the identical of embodiment 1 Method synthesizes, and prepares embodiment 13：Off-white powder 28mg, yield is 38%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.84(s,1H),8.61-8.60(m,1H),8.09 (s, 1H), 7.94 (d, J=8.0Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 7.30-7.26 (m, 1H), 7.14 (t, J= 6.4Hz, 1H), 6.93 (s, 1H), 6.72 (t, J=7.2Hz, 1H), 4.62 (t, J=8.4Hz, 2H), 3.24 (t, J=8.4Hz, 2H), 3.02 (d, J=10.0Hz, 2H), 2.44-2.36 (m, 4H), 2.08-2.05 (m, 2H), 1.89-1.82 (m, 10H) .HRMS(ESI):m/z,calcd for C26H32N5O2PCl[M+H+]:512.1982,found 512.1970.
Embodiment 14：
Intermediate 18 (30mg, 0.09mmol) is dissolved in toluene (4mL), Pd is sequentially added2(dba)3(8mg, 0.009mmol), DavePhos (8mg, 0.018mmol) and K3PO4(40mg, 0.018mmol, 0.4mL H2O), stir Afterwards, intermediate 26 (34mg, 0.11mmol) is added, under argon gas protection, 90 DEG C of reaction 1h, raw material disappears.Room temperature is cooled to, is evaporated off Solvent, EA (30mL) dissolution residual substance, saturated common salt washing (20mL × 3) is washed (20mL × 2), column chromatography (D/M=10: 1) embodiment 14, is obtained：White powdery solids 36mg, yield is 64%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.86(s,1H),8.61(dd,J1=8.4Hz, J2 =4.4Hz, 1H), 8.10 (s, 1H), 7.94 (d, J=8.0Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.31-7.26 (m, 1H), 7.16-7.12 (m, 1H), 6.93 (s, 1H), 6.65 (d, J=8.8Hz, 1H), 4.63 (t, J=8.4Hz, 2H), 4.27 (m, 2H), 3.25 (t, J=8.4Hz, 2H), 2.79 (t, J=12.4Hz, 2H), 2.62-2.56 (m, 1H), 1.85 (s, 3H), 1.82(s,3H),1.79-1.63(m,4H),1.50(s,9H).
Embodiment 15：
Intermediate 19 (40mg, 0.13mmol) is dissolved in toluene (6mL), Pd is sequentially added2(dba)3(11mg, 0.013mmol), DavePhos (10mg, 0.025mmol) and K3PO4(53mg, 0.25mmol, 1mL H2O), after stirring, Compound 26 (58mg, 0.15mmol) is added, under argon gas protection, 90 DEG C of reaction 4h, raw material disappears.Room temperature is cooled to, is evaporated off molten Agent, EA (30mL) dissolution residual substance, saturated common salt washing (20mL × 3) is washed (20mL × 2), column chromatography (D/M=20:1), Obtain embodiment 16：White powdery solids 70mg, yield is 81%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.83(s,1H),8.62(dd,J1=8.0Hz, J2 =4.4Hz, 1H), 8.08 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 7.26 (m, 1H), 7.13-7.11 (m, 1H), 6.82 (s, 1H), 6.42 (d, J=8.8Hz, 1H), 4.60 (t, J=8.0Hz, 2H), 3.53-3.38 (m, 6H), 3.19 (t, J=8.4Hz, 2H), 2.70-2.64 (m, 7H), 1.97 (brs, 2H), 1.85 (s, 3H), 1.81 (s, 3H),1.64(m,2H),1.47(s,9H).
Embodiment 16：
Embodiment 14 (28mg, 0.05mmol) is dissolved in DCM (4mL), TFA (0.5mL), room temperature reaction 3h is added, it is former Material disappears.Room temperature is cooled to, solvent is evaporated off, obtain embodiment 16：White powdery solids 136mg, yield is 57%.
Structure verification data are as follows：1H NMR(CDCl3)δ(ppm):10.02(s,1H),10.73(brs,1H),9.82(s, 1H), 9.37 (s, 1H), 8.47 (s, 1H), 7.41 (d, J=7.6Hz, 1H), 7.26-7.21 (m, 3H), 6.74 (d, J= 8.0Hz, 1H), 4.61 (t, J=8.0Hz, 2H), 3.59 (d, J=9.2Hz, 2H), 3.24 (t, J=8.0Hz, 2H), 3.07 (m, 2H), 2.79 (m, 1H), 2.19-2.15 (m, 2H), 2.01 (d, J=12.8Hz, 2H) .1.87 (s, 3H), 1.84 (s, 3H) .HRMS(ESI):m/z,calcd for C25H30N5O2PCl[M+H+]:498.1826,found 498.1826.
Embodiment 17：
Embodiment 15 (40mg, 0.06mmol) is dissolved in DCM (4mL), TFA (0.5mL), room temperature reaction 3h is added, it is former Material disappears.Room temperature is cooled to, solvent is evaporated off, obtain embodiment 17：White powdery solids 40mg, yield is 78%.
Structure verification data are as follows：1H NMR(DMSO-d6)δ(ppm):11.38(s,1H),9.16(brs,2H),8.73 (s,1H),8.52(s,1H),8.10(s,1H),7.56-7.52(m,1H),7.30(s,1H),7.16-7.11(m,2H),6.46 (d, J=8.4Hz, 2H), 4.50 (t, J=8.0Hz, 2H), 3.75 (m, 4H), 3.49-3.40 (m, 6H), 3.19-3.08 (m, 3H), (m, the 5H) .HRMS of 2.70 (t, J=11.6Hz, 2H), 2.12 (d, J=10.0Hz, 2H), 1.79 (s, 3H), 1.76 (ESI):m/z,calcd for C29H38N7O2PCl[M+H+]:582.2513,found 582.2516.
Test case 1, the compounds of this invention is to ALKwt/ALKL1196MThe measure of kinase activity
Embodiment compound 12000g is centrifuged 5min, adds DMSO to be configured to 10-2M liquid storages, be vortexed uniform rear ultrasound 10min Stand-by, -40 DEG C preserve (compound for having special storage requirement is changed according to concrete condition).During test by compound with DMSO from Liquid storage is diluted to 100 times (DMSO concentration is 1% in system) of institute's test concentrations.
Method of testing：
1st, enzyme reaction substrate Poly (Glu, Tyr) 4：1 with PBS (10mM sodium phosphate buffers, 150mM without potassium ion NaCl, pH7.2-7.4) 20 μ g/mL are diluted to, 125 μ L/ holes coated elisa plates are put 37 DEG C and are reacted 12-16 hours.In discarding hole Liquid.Board-washing, with T-PBS (PBS without potassium ion containing 0.1%Tween-20,200 μ L/ holes) board-washing three times, every time 5 minutes. Dried in 37 DEG C of baking ovens ELISA Plate 1-2 hours；
2nd, added with reaction buffer (50mM HEPES pH 7.4,50mM MgCl per hole2,0.5mM MnCl2,0.2mM Na3VO4, 1mM DTT) dilution the μ L of ATP solution 49, add 1 μ L compounds to be tested per in hole, 50 μ L are added to react slow The ALK of fliud flushing dilutionwt/ALKL1196MKinase domain recombinant protein starts reaction, and experiment every time need to be set without ATP control wells holes.Put 37 DEG C shaking table (100rpm) reacts 1 hour.Discard liquid in hole, T-PBS board-washings three times；
3rd, antibody PY99 dilutions (T-PBS 1 of the antibody containing BSA 5mg/mL is added:500 dilutions), 100 μ L/ holes, 37 DEG C shaking table reacts 0.5 hour.Discard liquid in hole, T-PBS board-washings three times；
4th, the sheep anti mouse secondary antibody dilution (T-PBS of the antibody containing BSA 5mg/ml of horseradish peroxidase-labeled is added 1:2000 dilutions), 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS board-washings three times；
5th, the μ L/ holes of OPD nitrite ions 100 of 2mg/ml are added【With containing 0.03%H2O20.1M citric acid-sodium citrates Buffer solution (pH=5.4) dilutes】, 25 DEG C of lucifuges react 1-10 minutes；
6th, 2M H are added2SO450 μ L/ holes stopped reactions, are declined orifice plate ELIASA VERSAmax readings, ripple with wavelengthtunable A length of 490nm；
7th, interpretation of result, IC50Value is used the random bundled software of ELIASA to be returned with four parametric methods and tried to achieve.
0<IC50<100nM, is designated as " +++ "；100nM<IC50<500nM, is designated as " ++ "；IC50>500nM, is designated as "+". Experimental result is as shown in table 1.
The computing formula of inhibiting rate is as follows：
Table 1, embodiment 1-18 compounds are to ALKwt/ALKL1196MThe inhibitory activity of kinases
Test case 2：Inhibitory activity of the compound to other kinases
ALK is tested using the kinases screening technique similar with test case 1L1152, ALKG1202, ALKF1245, ALKC1156, ALKG1269, ALKS1206, EGFRwt,EGFR TT90M,EGFR T790M/L858R, the inhibitory activity of the kinases such as ROS.As a result display portion The embodiment compound such as grade of embodiment 7,8,9,12,13,16 is to ALKL1152, ALKG1202, ALKF1245, ALKC1156, ALKG1269, ALKS1206, the inhibitory activity IC50 of ROS kinases is respectively less than 100nM, it is shown that preferable inhibitory activity；Meanwhile, above-claimed cpd To EGFRwt,EGFR TT90M,EGFR T790M/L858RInhibitory activity IC50 Deng kinases is less than 500nM, equally also show higher Activity.
Test case 3：Compound on intracellular proliferation inhibition activity
By the work of the single Solution Cell Proliferation experimental evaluation embodiment compound on intracellular Proliferation Abilities of Cell Titer 96 Property.After inoculation 24 hours, using embodiment compound treatment cell, grow 72 hours.It is thin in zero moment (process time) correction Born of the same parents are counted, and growth of the Microsoft Excel draftings relative to control group (DMSO) is carried out using XLfit version 4.2.2 Percentage data, determines the concentration (GI50 values) for suppressing 50% growth.Result shows, embodiment compound 7,8,9,12,13,16 Deng to NCI-H3122 and EML4-ALKG1202There is stronger proliferation inhibition activity Deng cell line, IC50 is less than 100nM；Meanwhile, To H1975, the cell line such as A431, SK-N-SH also has preferable inhibitory activity to above-claimed cpd, and IC50 is less than 500nM.

Claims (10)

1. compound shown in formula I, its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, molten Agent compound, polymorph or its prodrug；Or
Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；
In formula I or formula I '：
R1、R2、R3、R4Appointing in hydrogen, halogen, cyano group, hydroxyl, amino and substituted or unsubstituted C1-C6 alkyl One kind, and R1、R2、R3、R4In any two group can be formed 3-10 unit ring system；
M1、M2、M3Independently selected from CRa or N, and M1、M2And M3In at least one be N；Ra be hydrogen, halogen, cyano group, substitution or One kind in unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C8 cycloalkyl；
W is selected from any one of following radicals：Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyls, Unsubstituted or halo 4~8 yuan of alkynyl group, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 units are miscellaneous Ring group, the aromatic radical or heteroaryl, substituted carbonyl, substituted sulphonyl, substituted or unsubstituted amino of 5-10 units, wherein, it is described Heterocyclic radical is comprising 1-3 selected from the hetero atom in N, O, S, P and B；
The substitution base that described one or more groups being substituted by group are selected from the following group is replaced：Halogen, hydroxyl, amino, Cyano group, unsubstituted or halo C1-C8 alkyl, unsubstituted or halo C3-C8 cycloalkyl, unsubstituted or halo C1-C8 alkane Epoxide, unsubstituted or halo C2-C6 alkenyls, unsubstituted or halo C2-C6 alkynyls, unsubstituted or halo C2-C6 acyl groups, Unsubstituted or halo 5~8 yuan of aryl, unsubstituted or halo 5~8 unit's heteroaryls, unsubstituted or halo 4~8 yuan of saturations Heterocycle, unsubstituted or halo 4~8 yuan of carbocyclic rings；Wherein, the heteroaryl includes the 1-3 hetero atom being selected from N, O and S, institute State heterocycle and include the 1-3 hetero atom selected from N, O and S；
In formula I ', L is selected from any one of following radicals：- CR ' R "-,-O- ,-NR '-and-CR '=, wherein R ' and R " each solely It is on the spot hydrogen, fluorine, deuterium, C1-C6 alkyl or Heterocyclylalkyl, or adjacent R ' and R " form cyclic group.
2. compound shown in formula according to claim 1 I or its enantiomter, diastereoisomer, dynamic isomer, Solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt, it is characterised in that：
Compound shown in formula I or compound shown in formula I ' meet it is following 1) and/or 2)：
1) in formula I or formula I ', M1、M2Independently selected from CH or N, and M1And M2In at least one be N；M3Selected from C-F, C-CF3、 Any one in C-Cl, CH and N；
2) in formula I or formula I ', W is selected from any one in following radicals：Substituted or unsubstituted C1-C6 alkyl or cycloalkyls, take Generation or unsubstituted 4-6 circle heterocycles, substituted or unsubstituted 4-10 unit's cycloalkyl and substituted or unsubstituted 4-10 circle heterocycles alkane Volution or bridged ring that base is formed；
It is described substitution refer to substitution base independently selected from：Halogen, hydroxyl, cyano group, amino, alkyl, alkyl monosubstituted amino, dialkyl amino Base, cycloalkyl, heterocyclic radical, alkoxy, hydroxy alkyl, alkoxyalkyl, hydroxy alkoxy alkyl, aminoalkyl, dialkyl amino Base alkyl, alkoxycarbonylamino, cycloalkyl-alkyl, cycloheteroalkylalkyl, aralkyl, alkyl-cycloalkyl, naphthene base carbonyl, Alkoxy carbonyl, alkoxy carbonyl heterocyclic radical, (alkoxy carbonyl group) (alkyl) amino, (alkoxyalkyl) (alkyl) amino.
3. compound shown in formula according to claim 1 and 2 I or its enantiomter, diastereoisomer, tautomerism Body, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt, it is characterised in that：
Compound shown in formula I is any one in compound shown in the compound to-w of formula I shown in the-a of following formula I：
Concretely in the-a of the following formula I ' to-c of formula I ' any one of compound shown in formula I '：
4. prepare compound shown in the formula I any one of claim 1-3 or its enantiomter, diastereoisomer, Dynamic isomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding The method of medicine or pharmaceutically acceptable salt, comprises the following steps：
(1) by compound shown in formula IV and compound shown in formula V, in the condition that transition-metal catalyst and/or acid/base are present Under be coupled, obtain compound shown in formula III；
In formula IV, X and LG is each independently leaving group, and selected from any in halogen, sulphonic acid ester, boric acid and borate Kind；
In formula III, the definition of X is with formula IV；M1、M2And M3Definition with formula I；
(2) compound shown in formula III and compound shown in formula II or compound shown in formula II ' in transition-metal catalyst and/or Acid/base is coupled under conditions of existing, and obtains compound shown in Formulas I；
In formula II, R1、R2、R3、R4Definition with W is with formula I；In formula II ', R1、R2、R3、R4, L and W definition with formula I '.
5. method according to claim 4, it is characterised in that：In step (1) or step (2),
The coupling reaction is carried out in a solvent, and the solvent is selected from water, methyl alcohol, ethanol, isopropanol, ethylene glycol, N- methyl Pyrrolidones, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, acetonitrile, N, N- dimethyl formyls At least one in amine, DMAC N,N' dimethyl acetamide and dioxane；
The transition-metal catalyst be selected from three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium, palladium, palladium bichloride, Dichloro two (triphenylphosphine) palladium, trifluoracetic acid palladium, triphenylphosphine palladium acetate, [double (diphenylphosphino) ferrocene of 1,1'-] dichloro Change at least one in palladium, double (three adjacent benzyl phosphines) palladium chlorides and 1,2- bis- (diphenylphosphino) ethane palladium chloride；Institute State catalyst ligand and be selected from tri-butyl phosphine, tetrafluoro boric acid tri-butyl phosphine, tri-n-butyl phosphine, triphenylphosphine, three pairs of benzyls At least one in the adjacent benzyl phosphine of phosphine, tricyclohexyl phosphine and three；
The alkali is inorganic base or organic base；The inorganic base is selected from sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, the tert-butyl alcohol In potassium, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, saleratus, sodium carbonate and sodium acid carbonate at least one Kind；The organic base is selected from pyridine, triethylamine, DIPEA, the carbon -7- of 1,8- diazabicylos [5.4.0] 11 At least one in alkene, the silicon substrate lithium of hexamethyl two, the silicon substrate sodium of hexamethyl two and lutidines；
The acid is selected from least one in hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.
6. compound shown in the formula I any one of claim 1-3, its pharmaceutically acceptable salt, enantiomter, non- Enantiomter, dynamic isomer, solvate, polymorph or its prodrug；Or
Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；
Preparing the application having in the inhibitor of the function of suppressing EGFR mutant kinase activities and/or ALK kinase activity.
7. a kind of kinase inhibitor, compound or its enantiomerism shown in the formula I that it includes any one of claim 1-3 Body, diastereoisomer, dynamic isomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt；Or
It is compound shown in formula I ' or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph, preceding Medicine or pharmaceutically acceptable salt.
8. compound shown in the formula I any one of claim 1-3, its pharmaceutically acceptable salt, enantiomter, non- Enantiomter, dynamic isomer, solvate, polymorph or its prodrug；Or
Compound shown in formula I ', its pharmaceutically acceptable salt, enantiomter, diastereoisomer, dynamic isomer, solvent Compound, polymorph or its prodrug；
Application in prevention and/or treatment tumour product is prepared.
9. application according to claim 8, it is characterised in that：The tumour is non-small cell lung cancer, ED-SCLC, lung Gland cancer, lung squamous cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, white blood Any one in disease, lymph cancer and nasopharyngeal carcinoma.
10. a kind of pharmaceutical composition, it is characterised in that：It includes：
1) compound, its pharmaceutically acceptable salt, mapping shown in the formula I any one of the claim 1-4 of effective dose Isomers, diastereoisomer, dynamic isomer, solvate, polymorph or its prodrug；With
2) pharmaceutically acceptable carrier.
CN201611021938.7A 2015-11-17 2016-11-16 Nitrogen-containing heterogeneous ring compound, preparation method thereof and application of nitrogen-containing heterogeneous ring compound in inhibition of kinase activity Pending CN106699810A (en)

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