CN110526907A - Benzoxazine ketones derivant and its application - Google Patents

Benzoxazine ketones derivant and its application Download PDF

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CN110526907A
CN110526907A CN201810736569.2A CN201810736569A CN110526907A CN 110526907 A CN110526907 A CN 110526907A CN 201810736569 A CN201810736569 A CN 201810736569A CN 110526907 A CN110526907 A CN 110526907A
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benzoxazine
hydrogen
halogen
hydroxyl
compound
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CN110526907B (en
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李锐
魏于全
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Sichuan University
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The present invention relates to benzoxazine ketones derivant and its applications, belong to anti-tumor drug technical field.The technical problem to be solved by the present invention is to provide a kind of new benzoxazine ketone derivatives, and the structural formula of the compound is as shown in formula I.Present invention design has synthesized a series of using benzoxazinone as the noval chemical compound of parent nucleus, which can inhibit PI3K/Akt/mTOR signal path, achieve the effect that preferably to inhibit tumor cell proliferation.

Description

Benzoxazine ketones derivant and its application
Technical field
The present invention relates to benzoxazine ketones derivant and its applications, belong to anti-tumor drug technical field.
Background technique
PI3K/Akt/mTOR signal path mainly includes phosphatidyl-inositol 3-kinase (phosphoinositide-3- Kinase, PI3K), three members of protein kinase B (PKB/Akt) and rapamycin target protein (mTOR).PI3K is a kind of ester Enzyme is primarily present in cytoplasm under quiescent condition；PI3K is fully active rear catalysis substrate PIP2 and is changed into PIP3, PIP3 conduct The Akt in second messenger's activation downstream.Akt is the downstream PI3K key protein, is serine/Soviet Union's ammonia highly conserved in a kind of evolution Pka acid, multidigit is in cytoplasm under quiescent condition；The phosphorylatable formation for inhibiting TSC1/2 of the Akt being activated, in turn Rheb is released, it is final to activate downstream mTORC.MTOR belongs to serine/threonine protein kitase family, possesses mTORC1 With two hypotypes of mTORC2, it is the important regulatory factor of cell growth and proliferation；When cell is by the external nourishment factor or life When long factor signal stimulates, mTOR intracellular can activate some relevant target proteins in downstream, and then metabolism and life to entire cell Length is positively or negatively regulated and controled.PI3K/Akt/mTOR signal path participates in adjusting a variety of life processes of cell, such as: it is thin The growth of born of the same parents and proliferation, the synthesis of albumen, transcription and metabolic process.It is existing studies have shown that PI3K/Akt/mTOR signal path There is vital effect in the occurrence and development of tumour, inhibiting PI3K/Akt/mTOR signal path is considered as that one kind has The anti-cancer therapies of future.
Currently, it is too numerous to enumerate for anti-tumor drug designed by the PI3K/Akt/mTOR signal path, for example, ATP is competing The PI3K and mTOR inhibitors BEZ235 of striving property, the mono- inhibitor rapamycin of multiple target point PI3K inhibitor PI-103, mTOR etc..It can It is, in practical study, it is found that there are some defects for existing compound.For example, the mono- inhibitor of mTOR easily leads to drug and supports Anti-, rapamycin derivative inhibits the feedback activation that Akt can be generated when mTOR, leads to reactivating for PI3K signal path, Therefore rapamycin in vitro inhibiting tumour cells experiment in it is limited to the rejection ability of tumour cell.
Patent US2010/0311736 A1 is disclosed using N-3- pyridyl group -4- fluorobenzenesulfonamide as the compound of parent nucleus, In there are two contain benzoxazinone structure, N-6 pass through methylene linked with phenyl ring.But by the study found that the chemical combination Object is limited to the inhibiting rate of PI3K α or even part inhibitory activity is very low, we are by the research to PI3K alpha-crystal structure, discovery N-6 are directly coupled obtained molecular activity with phenyl ring and are much better than through methylene and phenyl ring coupling.
Summary of the invention
The purpose of the present invention is researching and developing that there is the noval chemical compound for inhibiting PI3K/Akt/mTOR signal path, for controlling Treat and prevent cancer relevant to PI3K/Akt/mTOR abnormal signal.
The technical problem to be solved by the present invention is to provide a kind of new benzoxazine ketone derivatives, which can successfully inhibit PI3K/Akt/mTOR signal path.
Benzoxazine ketone derivatives of the present invention, structural formula is as shown in formula I:
Formula I
Wherein, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6It is selected from Hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkane replaced by hydroxyl, amino, nitro Base；
R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
The present invention also provides the isomers of benzoxazine ketones derivant of the present invention, pharmaceutical salt and hydrations Object.
The present invention also provides benzoxazine ketones derivants of the present invention to inhibit in the mammalian body for producing The purposes of the drug of PI3K/Akt/mTOR signal path.
The present invention also provides the purposes of benzoxazine ketones derivant of the present invention in the preparation of antitumor drugs.
The present invention also provides a kind of pharmaceutical compositions, and the pharmaceutical composition is by effective component and pharmaceutically acceptable auxiliary material Composition, the effective component include therapeutically effective amount benzoxazine ketones derivant or its isomers of the present invention or can Medicinal salt or hydrate.
The present invention also provides the purposes that the benzoxazine ketones derivant is used to prepare DNA-PK inhibitor.
Preferably, the benzoxazine ketones derivant is compound C5-1.
Present invention design has synthesized a series of using benzoxazinone as the noval chemical compound of parent nucleus, which can inhibit PI3K/Akt/mTOR signal path achievees the effect that preferably to inhibit tumor cell proliferation.In addition, the compound of the present invention can There is good inhibitory activity to DNA-PK as DNA-PK inhibitor.
Detailed description of the invention
Fig. 1 is plate clone photo of the compound C5-1 to Hela cell of various concentration.
Fig. 2 is that the compound C5-1 of various concentration counts the plate clone colony number of Hela cell.
Fig. 3 is the variation of Hela Transplanted tumor model administration time and gross tumor volume.
Fig. 4 is the variation of A549 Transplanted tumor model administration time and gross tumor volume.
Fig. 5 is the variation of Hela Transplanted tumor model administration time and mouse weight.
Fig. 6 is the variation of A549 Transplanted tumor model administration time and mouse weight.
Specific embodiment
Benzoxazine ketone derivatives of the present invention, structural formula is as shown in formula I:
Formula I
Wherein, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6It is selected from Hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkane replaced by hydroxyl, amino, nitro Base；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6It is selected from Hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkane replaced by hydroxyl, amino, nitro Base；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For Hydrogen or halogen, X1For C or N.Preferably, R1For C3-C6 naphthenic base, heterocycle orR6It is monosubstituted or take more Dai Ji, R6Replaced selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl, amino, nitro C1-C4 alkyl；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base, heterocycle orR6For Monosubstituted or multi-substituent, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl, The C1-C4 alkyl that amino, nitro replace；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl Base, R5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base, heterocycle orR6It is monosubstituted or polysubstituted Base, R6Replaced selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl, amino, nitro C1-C4 alkyl；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen Element.Preferably, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6Selected from hydrogen, halogen Element, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6It is selected from Hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkane replaced by hydroxyl, amino, nitro Base；R2ForX2For C or N.Further preferred X2For N.
It is further preferred that R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkane Base, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2For R3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N. Preferably, R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1- C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For Hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl Base, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For Hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base orR6 For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl, amino, nitre The C1-C4 alkyl that base replaces；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5 For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1- C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R1For C3-C6 naphthenic base orR6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkane Base, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForX2For C or N.Further preferred X2For N.
It is further preferred that R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, the mono-substituted benzene of methyl or methoxy Base, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, the mono-substituted phenyl of methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen Element, X1For C or N.Preferably, R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, the mono-substituted phenyl of methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen Or halogen.Preferably, R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, the mono-substituted phenyl of methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R1For cyclopropyl Base, cyclohexyl, phenyl ring or by halogen, the mono-substituted phenyl of methyl or methoxy, R2For R3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R1For cyclopropyl, cyclohexyl, phenyl ring or By halogen, the mono-substituted phenyl of methyl or methoxy, R2ForR3For chlorine or methoxyl group, R5 For hydrogen or halogen.
Preferably, R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, the mono-substituted phenyl of methyl or methoxy, R2ForX2For C or N.Further preferred X2For N.
As one of preferred embodiment, structural formula is as shown in formula II:
Formula II
Wherein, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or The C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For hydrogen, C1-C4 alcoxyl Base, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro Or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl Base, R4For hydrogen orR5For hydrogen or halogen, X1For C or N.Preferably, R6For monosubstituted base, R6It is selected from Hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkane replaced by hydroxyl, amino, nitro Base；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For Hydrogen or halogen.Preferably, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitre Base or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For hydrogen, C1-C4 alcoxyl Base, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkane Oxygroup, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R6For Monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl, amino, nitro Substituted C1-C4 alkyl；R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro Or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；R2ForX2For C or N.Further preferred X2For N.
It is further preferred that R6For chlorine, bromine, methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N。
Preferably, R6For chlorine, bromine, methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or Hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N.Preferably, R6For chlorine, bromine, methyl or first Oxygroup, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5 For hydrogen or halogen.Preferably, R6For chlorine, bromine, methyl or methoxy, R2ForR3For hydrogen, C1- C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R6For chlorine, bromine, methyl or methoxy, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R6 For chlorine, bromine, methyl or methoxy, R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R6For chlorine, bromine, methyl or methoxy, R2ForX2For C or N.Further preferred X2For N.
Preferred structural formula is as shown in formula III:
Formula III
Group selection in formula III is identical as formula II, is only by the R in formula II6It is limited to para-orientating group.
R as another preferred embodiment, in formula I1For C3-C6 naphthenic base；R2For R3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R1For C3-C6 naphthenic base, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4 For hydrogen orR5For hydrogen or halogen, X1For C or N.Preferably, R1For C3-C6 naphthenic base, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen Element.Preferably, R1For C3-C6 naphthenic base, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or Hydroxyl, R5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R1For C3-C6 naphthenic base, R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R1For C3-C6 naphthenic base, R2ForX2For C or N.Further preferred X2For N.
It is further preferred that R1For cyclopropyl or cyclohexyl, R2ForR3For hydrogen, C1- C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
Preferably, R1For cyclopropyl or cyclohexyl, R2ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl Base, R4For hydrogen orR5For hydrogen or halogen, X1For C or N.Preferably, R1For cyclopropyl or cyclohexyl, R2 ForR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen Element.Preferably, R1For cyclopropyl or cyclohexyl, R2ForR3For hydrogen, C1-C4 alkoxy, halogen Or hydroxyl, R5For hydrogen or halogen.Preferably, R1For cyclopropyl or cyclohexyl, R2ForR3For Hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R5For hydrogen or halogen.Preferably, R1For cyclopropyl or cyclohexyl, R2ForR3For chlorine or methoxyl group, R5For hydrogen or halogen.
Preferably, R1For cyclopropyl or cyclohexyl, R2ForX2For C or N.Further preferred X2For N.
The following are currently preferred structural formulas.
The preparation method of benzoxazine ketones derivant of the present invention, can be used conventional method, and specific preparation method is detailed See embodiment 1.
The invention further relates to the isomers of the compound as shown in general formula I, pharmaceutical salt and hydrates.It wherein, can medicine Salt include but is not limited to generalformulaⅰcompound and inorganic acid for example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid institute at Salt and with various organic acids, as malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, acetic acid, lactic acid, Salt formed by p-methyl benzenesulfonic acid, methanesulfonic acid, palmitinic acid etc..Some compounds in the present invention may use water or various organic solvents Crystallization or recrystallization, in this case it is possible to form various solvates.The present invention includes the solvation of those stoichiometries Object, including hydrate are also included within the compound comprising variable water formed when being prepared with lyophylization.
Benzoxazine ketones derivant of the invention, can be used for producing inhibition, PI3K/Akt/mTOR believes in the mammalian body The drug of number access.
Benzoxazine ketones derivant of the invention, it may also be used for prepare anti-tumor drug.
The compound of the present invention or its pharmaceutical salt can be used alone, can also be with pharmaceutical carrier or excipient one Rise in the form of pharmaceutical composition use, when in the form of pharmaceutical composition in use, usually by the present invention of therapeutically effective amount Compound or pharmaceutically acceptable salt thereof or hydrate and one or more pharmaceutical acceptable carrier or diluent, which combine, is made application appropriate Form or dosage form.Therefore, the present invention also provides pharmaceutical compositions, it includes the benzene of the present invention of therapeutically effective amount And oxazines ketones derivant, its all possible isomers or its pharmaceutical salt or hydrate and at least one pharmaceutical Carrier.
The Pharmaceutical composition of the compounds of this invention can be granted with any way of following aspect: oral, spraying to suck, is straight Enteral administration, nasal-cavity administration, vagina administration, local administration, parenterai administration are as in subcutaneous, vein, intramuscular, peritonaeum, sold interior, ventricle In interior, breastbone or intracranial injection or input, or by a kind of reservoir medication of explant, wherein preferably take orally, intramuscular injection, in peritonaeum or Intravenous administration mode.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition.Form of administration can be liquid Body dosage form, solid dosage forms.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, warm suspension type.Other Dosage form such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, warm suspension, emulsion, granule, suppository, freeze-dried powder Injection, inclusion compound, implants, patch, liniment etc..
Common carrier can also be contained in pharmaceutical composition of the invention, pharmaceutical acceptable carrier described here includes but not office It is limited to: ion-exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin such as human albumin, buffer substance such as phosphate, Glycerol, sorbic acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as sulfuric acid fish Protamine, phosphoric acid hydrogen two are received, and potassium hydrogen phosphate, oxidation is received, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, fine Tie up plain substance, polyethylene glycol, carboxymethylcellulose sodium, polyacrylate, beeswax, wool grease etc..Carrier is in pharmaceutical composition Content (weight ratio) can be 1~98%, generally about account for 80%.For convenience, local anesthetic, preservative delay Electuary etc. can be directly dissolved in carrier.
The present invention also provides the purposes that the benzoxazine ketones derivant is used to prepare DNA-PK inhibitor.
Preferably, the benzoxazine ketones derivant is compound C5-1.
In the present invention, " C1-C6 alkyl " refers to the linear or branched alkyl group with 1~6 carbon atom, such as methyl, second Base, propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3- Hexyl etc.." C1-C4 alkyl " refers to the linear or branched alkyl group with 1~4 carbon atom, such as methyl, ethyl, propyl, different Propyl, normal-butyl, sec-butyl, tert-butyl etc..
" C1-C4 alkoxy " refers to the straight or branched alkoxyl with 1~4 carbon atom, such as methoxyl group, ethoxy Base, propoxyl group, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy etc..
" monosubstituted " refers to that only one hydrogen atom is substituted.
" polysubstituted ", which refers to, has at least two hydrogen atoms to be substituted, and substituent group can be the same or different.
A specific embodiment of the invention is further described below with reference to embodiment, is not therefore limited the present invention System is among the embodiment described range.
The synthesis of 1 compound of embodiment
1, the synthesis of intermediate
The preparation of the chloro- N- hexamethylene yl acetamide (a1) of intermediate 2-
Raw material cyclohexylamine (3g, 30mmol) is dissolved in 25mL acetonitrile, is added potassium carbonate (6.2g, 45mmol).Under ice bath Stirring 20min mixes well it.Chloracetyl chloride (3mL, 36mmol) is slowly added dropwise again, generates a large amount of white cigarettes, continues to stir White cigarette disappears after 30min, and solution is in faint yellow.3h is reacted in continuation at room temperature, and TLC is monitored until fully reacting.Processing method: Most of acetonitrile first is removed with vacuum distillation, adds 100mL water, extracts (4 × 25mL) with EA, collected organic layer, with saturation Salt is washed three times, and anhydrous sodium sulfate is dry, and vacuum distillation concentration obtains white crude, is recrystallized to give powder with PE/EA system White needle-like crystals, about 3.5g, yield 67%.ESI-MS:198.1[M+Na]+.
The synthesis of intermediate (the bromo- 2- chlorophenoxy of 5-)-N- hexamethylene yl acetamide (b1)
The bromo- 2- chlorophenol (2.9g, 14.3mmol) of 5- is that raw material is dissolved in 50mL acetonitrile, addition potassium carbonate (2.5g, 30min 17.1mmol) is stirred, intermediate a1 is added in reaction solution, then move into 80 DEG C of oil bath pans and be heated to reflux 4 hours, is mixed Close liquid is become muddy (having white solid precipitation) from clarifying, and TCL monitors extent of reaction.Processing method: reaction is cooled to room temperature, first Rotation removes partial acetonitrile, adds water removing potassium carbonate, is extracted 4 times with EA, collected organic layer washes three with water and saturated salt solution respectively Secondary, vacuum distillation obtains pink solid, is recrystallized to give white solid 4.7g, yield about 80% with PE/EA system.1H NMR (400MHz, DMSO) δ 7.88 (s, 1H), 7.40 (d, J=8.4Hz, 1H), 7.26-7.11 (m, 2H), 4.64 (s, 2H), 3.67-3.54 (m, 1H), 1.81-1.61 (m, 4H), 1.55 (d, J=12.5Hz, 1H), 1.40-1.07 (m, 5H) .ESI-MS: 346.1,348.1[M+H]+.
The synthesis of the chloro- N- cyclopropyl-acetamide (a2) of intermediate 2-
The preparation method of the intermediate is identical as the preparation manipulation method of intermediate a1, and raw material is only changed to cyclopropylamine.Have Light yellow oil is obtained after the vacuum distillation of machine layer, PE/EA system is recrystallized to give white crystal, yield 53.9%.ESI- MS:134.1[M+H]+.
The synthesis of intermediate (the bromo- 2- chlorophenoxy of 5-)-N- cyclopropyl-acetamide (b2)
The operation of the reaction is with intermediate b1, and the raw material used is a2, and PE/EA system is recrystallized to give white powder solid, Yield is 88.2%.1H NMR (400MHz, DMSO) δ 8.12 (s, 1H), 7.40 (d, J=8.3Hz, 1H), 7.26-7.13 (m, 2H),4.61(s,2H),2.67(s,1H),0.79–0.55(m,2H),0.55–0.35(m,2H).ESI-MS:342.3,344.2 [M+K]+.
The synthesis of intermediate N (the bromo- 2- chloropyridine -3 of 5-) -4- fluorobenzenesulfonamide (h)
The bromo- 2- chlorine-3-aminopyridine (f, 530mg, 2.57mmol) of raw material 5- is dissolved in 8mL pyridine, in condition of ice bath Under, the pyridine solution of the 4- fluorophenylsulfonyl chloride (4g, 19.4mmol) of about 5mL is slowly added dropwise, then a small spoon is added into solution DMAP as catalyst, reacted after dripping at room temperature the reaction was continued overnight, solution be in yellowish-brown.TCL monitors extent of reaction. Processing method: into reaction solution plus water 200mL, solution generates a large amount of precipitating, filtering, cake layer is washed with water to non-pyridine taste, It is washed once with ethyl alcohol, obtains milky solid powder g, 940mg after dry, intermediate g is taken to be dissolved in the methanol of 10mL, then About 3mL wet chemical is added.It is stirred to react 5-6h at room temperature, TCL is monitored to fully reacting.Processing method: to reaction solution Middle addition water, then extracted 4 times with EA, merge organic layer, washed 2 times with saturated common salt aqueous solution, then is dry with anhydrous sodium sulfate, Column chromatography is carried out with EA/PE eluent system after reduced pressure, obtains faint yellow solid, PE/EA system is recrystallized to give white powder End.Yield is about 75%.ESI-MS:363.1[M-H]-.
The synthesis of intermediate N (the bromo- 2- methoxypyridine -3- base of 5-) -4- fluorobenzenesulfonamide (j)
It is dissolved in 20mL dioxane with the bromo- 2- chlorine-3-aminopyridine (f, 500mg, 2.42mmol) of raw material 5- first, then It is added sodium methoxide (300mg, 5.55mmol), is warming up to 100 DEG C of reflux, react about 10h, TCL detects extent of reaction.Processing side Method: being added water quenching reaction, EA extraction, and collected organic layer is concentrated, and EA/PE eluent system crosses column, and the bromo- 2- methoxyl group-of 5- is made 3- aminopyridine (i).It takes intermediate i (500mg, 2.45mmol) to be dissolved into 10mL pyridine, is slowly added under condition of ice bath The pyridine solution 8mL of 4- fluorophenylsulfonyl chloride (4g, 19.4mmol), and a small amount of DMAP catalysis is added.The reaction was continued at room temperature 5-6h. Fully reacting post-processing approach is the same as intermediate h.White solid 720mg is obtained after drying, yield is about 81%.ESI-MS:259.2 [M-H]-.
Intermediate 3- (4- fluorobenzene ylsulfonylamino) phenylboric acid (k)
3- amino phenyl boric acid (1g, 7.3mmol) and 4- fluorophenylsulfonyl chloride (2g, 9.7mmol) are dissolved in 10mL methylene chloride In, triethylamine 1.5mL is added, overnight, solution turns yellow clear solution, processing reaction by suspension for reaction at room temperature Liquid: being evaporated under reduced pressure to reaction solution and remove DCM, add water, and alkene HCl is added dropwise and adjusts PH to acidity, is extracted 3 times, is collected organic with EA Layer, dry, concentration.Brown oil is obtained, is recrystallized with PE/EA system, obtains yellow solid powder about 1.88g, yield is about It is 92%.ESI-MS:294.1[M-H]-.
The synthesis of intermediate N (5- borate -2- methoxypyridine -3- base) -4- fluorobenzenesulfonamide (l)
Take N- (the bromo- 2- methoxyl group -3- pyridyl group of 5-) -4- fluorobenzenesulfonamide (j, 400mg, 1.12mmol), connection boric acid frequency That alcohol ester (340mg, 1.32mmol), PdCl2 (dppf) (60mg, 0.084mmol), potassium acetate (328mg, 3.46mmol) mixing It in 10mL1,4- dioxane, vacuumizes, is filled with nitrogen protection, be placed in 100 DEG C of oil bath pans and react 5h.TCL monitoring reaction Progress.Processing reaction: the reaction is cooled to room temperature, being added 30mL water, then extract (4 × 20mL) with EA, merge organic layer, anhydrous Sodium sulphate is dry, and vacuum distillation carries out column chromatography with EA/PE (1:5) eluent system, recrystallizes after obtaining crude product, obtain white Solid powder 360mg, yield 79.6%.ESI-MS:409.0[M+H]+,431[M+Na]+.
2, the synthesis of benzoxazin ketone compound
The preparation of bromo- 2H-1,4- benzoxazine -3 (4H) -one (C0) of 6-
Under ice bath, chloracetyl chloride (4.7ml, 60mmol) is dissolved in 25mL THF solution, which is added dropwise to 2- In the THF solution of amino-4-bromophenol (9g, 48mmol).Add NaHCO3(6g, 72mmol) continues to stir under ice bath React 1h.TCL detection reaction adds potassium carbonate (10g, 72mmol) when completing, and reaction solution is heated to 80 DEG C of reaction 3h, room The reaction was continued under temperature overnight.Processing reaction: reaction solution is diluted with water, with EA extract 4 times, collected organic layer, respectively with dilute hydrochloric acid, It is saturated NaHCO3, saturated common salt aqueous solution respectively washes once, and anhydrous sodium sulfate is dry, and vacuum distillation concentration is recrystallized to give brown Solid 6.9g, yield are about 63%.1H NMR (400MHz, DMSO) δ 10.82 (s, 1H), 7.07 (dd, J=8.5,2.4Hz, 1H), 7.03 (d, J=2.3Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 4.59 (s, 2H) ppm.HRMS (DART-TOF) calculated for C8H6BrNO2Na[M+Na]+m/z 249.9480,251.9459,found 249.9448, 251.9419.
The preparation of the bromo- 4- of 6- (3- methoxyphenyl) -2H- benzoxazine -3 (4H) -one (C1)
C1 prepare raw material be the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0) and 3- methoxyphenylboronic acid, other Raw material and the same C2 of operation, yield is about 19.2%.1H NMR (400MHz, DMSO) δ 7.51 (t, J=8.1Hz, 1H), 7.18 (dd, J=8.5,2.3Hz, 1H), 7.11 (dd, J=8.4,3.4Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 6.99-6.96 (m, 1H), 6.92 (d, J=8.7Hz, 1H), 6.36 (d, J=2.3Hz, 1H), 4.83 (s, 2H), 3.79 (s, 3H) ppm.HRMS (DART-TOF)calculated for C15H12BrNO3Na[M+Na]+m/z 355.9898,357.9878,found 355.9861,357.9856.
The preparation of bromo- 4- phenyl -2H-1,4- benzoxazine -3 (4H) -one (C2) of 6-
By the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0,350mg, 1.54mmol) is used as reaction raw materials, raw material C0 Be dissolved in 20mL THF, be added under stirring at room temperature phenyl boric acid (400mg, 3.28mmol) and copper acetate (420mg, 2.31mmol), it then is added dropwise to triethylamine (0.5mL, 4.62mmol), it is a little that 4 molecules of interest sieve is finally added in reaction solution.It moves Enter and react about 6h in 60 DEG C of oil bath pans, TCL monitors fully reacting.It handles reaction solution: reaction solution being evaporated under reduced pressure and removes part THF adds water filtering, and filtrate is extracted 4 times with EA, and collected organic layer is dry, concentration, and dry method loading is eluted with PE/EA (6:1) System carries out column chromatography, collects target compound, is recrystallized to give white crystal 102mg, yield about 22%.1H NMR (400MHz, DMSO) δ 7.63-7.58 (m, 1H), 7.53 (t, J=7.4Hz, 1H), 7.37 (d, J=7.1Hz, 1H), 7.18 (dd, J=8.5,2.3Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 6.31 (d, J=2.3Hz, 1H), 4.85 (s, 1H) ppm.HRMS(DART-TOF)calculated for C14H10BrNO2Na[M+Na]+m/z 325.9793,327.9772found 325.9771,327.9762.
The preparation of the bromo- 4- of 6- (4- chlorphenyl) -2H- benzoxazine -3 (4H) -one (C3)
The raw material for preparing of C3 is the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0) and 4- chlorophenylboronic acid, other raw materials With the same C2 of operation, yield is about 19.8%.1H NMR(400MHz,CDCl3) δ 7.53 (d, J=8.7Hz, 2H), 7.22 (d, J= 8.6Hz, 2H), 7.11 (dd, J=8.6,2.2Hz, 1H), 6.93 (d, J=8.6Hz, 1H), 6.55 (s, 1H), 4.75 (s, 2H) ppm.HRMS(DART-TOF)calculated for C14H9BrClNO2Na[M+Na]+m/z 336.9505, 338.9485found 336.9501,338.9481.
The preparation of the bromo- 4- of 6- (4- aminomethyl phenyl) -2H- benzoxazine -3 (4H) -one (C4)
The raw material for preparing of C4 is the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0) and 4- methylphenylboronic acid, other are former Expect and operate same C2, yield is about 21.6%.1H NMR(400MHz,CDCl3) δ 7.35 (d, J=8.1Hz, 2H), 7.14 (d, J =8.2Hz, 2H), 7.08 (dd, J=8.5,2.2Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 6.56 (d, J=2.2Hz, 1H), 4.75(s,2H),2.44(s,3H)ppm.HRMS(DART-TOF)calculated for C15H12BrNO2Na[M+Na]+m/z 339.9949,341.9929,found 339.9931,341.9906.
The preparation of the bromo- 4- of 6- (4- methoxyphenyl) -2H- benzoxazine -3 (4H) -one (C5)
C5 prepare raw material be the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0) and 4- methoxyphenylboronic acid, other Raw material and the same C2 of operation, yield is about 21.6%.Yield is 25.2%.1H NMR (400MHz, DMSO) δ 7.28 (d, J= 8.9Hz, 2H), 7.16 (dd, J=8.5,2.3Hz, 1H), 7.12 (d, J=8.9Hz, 2H), 7.03 (d, J=2.3Hz, 1H), 6.35 (d, J=2.3Hz, 1H), 4.82 (s, 2H), 3.84 (s, 3H) ppm.HRMS (DART-TOF) calculated for C15H12BrNO3Na[M+Na]+m/z 355.9898,357.9878,found 355.9876,357.9855.
The preparation of the bromo- 4- of 6- (4- fluorophenyl) -2H- benzoxazine -3 (4H) -one (C6)
The raw material for preparing of C6 is the bromo- 2H-1 of 6-, 4- benzoxazine -3 (4H) -one (C0) and 4- first fluorobenzoic boric acid, other are former Expect and operate same C2, yield is about 18.7%.1H NMR (400MHz, DMSO) δ 7.47-7.40 (m, 4H), 7.19 (dd, J= 8.5,2.3Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 6.34 (d, J=2.2Hz, 1H), 4.84 (s, 2H) ppm.HRMS (DART-TOF)calculated for C14H9BrFNO2Na[M+Na]+m/z 343.9698,345.9678,found 343.9612,345.9655.
The preparation of bromo- 4- cyclohexyl -2H- benzoxazine -3 (4H) -one (C7) of 6-
Intermediate (the bromo- 2- chlorophenoxy of 5-)-N- hexamethylene yl acetamide (b1) be raw material, take b1 (220mg, 0.64mmol), cesium carbonate (500mg, 1.53mmol) is placed in microwave reaction pipe, and 3mL DMF dissolution is added.Reaction tube is set It is reacted in microwave instrument, microwave condition is set as 150 DEG C of temperature, power 50W, time 60min.TCL monitoring is anti-after reaction It should be complete.Processing reaction, water is added into reaction, is extracted, is washed with water three times with EA, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, dry method Loading carries out column chromatography with PE/EA (10:1) eluent system, collects target compound, be concentrated to get yellow oil, PE is tied again Crystalline substance obtains light yellow crystal 80mg, and yield is about 50.6%.1H NMR (400MHz, CDCl3) δ 7.25 (d, J=1.9Hz, 1H), 7.08 (d, J=10.5Hz, 1H), 6.86 (d, J=8.5Hz, 1H), 4.45 (s, 2H), 4.12-4.01 (m, 1H), 2.40-2.25 (m,2H),1.98–1.67(m,5H),1.47–1.20(m,3H)ppm.HRMS(DART-TOF)calculated for C14H17BrNO2[M+H]+m/z 310.0443,312.0422,found 310.0436,312.0415.
The preparation of bromo- 4- cyclopropyl -2H- benzoxazine -3 (4H) -one (C8) of 6-
Intermediate 2- (the bromo- 2- chlorophenoxy of 5-)-N- cyclopropyl-acetamide (b2)
For raw material, the preparation of other raw materials and operation with C7.Yield is about 43.6%.1H NMR(400MHz,CDCl3)δ 7.44 (d, J=2.2Hz, 1H), 7.10 (dd, J=8.5,2.2Hz, 1H), 6.84 (d, J=8.5Hz, 1H), 4.54 (s, 2H), 2.76–2.65(m,1H),1.22–1.16(m,2H),0.82–0.75(m,2H)ppm.HRMS(DART-TOF)calculated for C11H11BrNO2[M+H]+m/z 267.9973,269.9953,found 267.9952,269.9932.
3, the synthesis of target compound
The synthesis of target compound C1-1
By the bromo- 4- of raw material 6- (3- methoxyphenyl) -2H- benzoxazine -3 (4H) -one (C1,60mg, 0.18mmol), in Mesosome l (80mg, 0.21mg), catalyst PdCl2(dppf) (10mg, 0.013mmol) and alkali potassium acetate (60mg, 0.6mmol) It is added in reaction tube, the dissolution of 4mL dioxane is added.It vacuumizes, is filled with nitrogen, move into 80 DEG C of oil bath pans and react 5h, TCL Monitor extent of reaction.Processing reaction solution: being cooled to room temperature, add water, extracted with EA, merges organic layer, is washed with saturation NaCl solution Twice, anhydrous sodium sulfate is dry, and vacuum distillation, dry method loading carries out TLC separation with PE/EA (4:1) solvent and purifies, Target product is collected, white powder 40mg is recrystallized to give.Yield is 41.7%.1H NMR(400MHz,DMSO)δ10.06(s, 1H), δ 8.29 (d, J=2.3Hz, 1H), 7.89 (dd, J=9.0,5.0Hz, 2H), 7.61 (d, J=2.3Hz, 1H), 7.55- 7.48 (m, 3H), 7.28 (dd, J=8.3,2.1Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 7.11 (dd, J=8.1,2.7Hz, 1H), 7.01 (t, J=2.1Hz, 1H), 6.97 (d, J=7.8Hz, 1H), 6.53 (d, J=2.0Hz, 1H), 4.87 (s, 2H), 3.79(s,3H),3.47(s,3H)ppm.HRMS(DART-TOF)calculated for C27H22FN3O6S[M+H]+m/z 535.1213,found 535.1211.
The synthesis of target compound C1-2
The raw material for preparing of compound C1-2 is compound C1, intermediate k, other raw materials and the same C1-1 of operation.PE/EA system It is recrystallized to give faint yellow solid 56mg.Yield is 61.5%.1H NMR(400MHz,DMSO)δ10.41(s,1H),7.72 (dd, J=8.9,5.2Hz, 2H), 7.53 (t, J=8.1Hz, 1H), 7.33 (t, J=8.8Hz, 2H), 7.21 (t, J=7.9Hz, 1H), 7.17-7.11 (m, 2H), 7.06 (s, 1H), 7.04-6.99 (m, 2H), 6.96 (d, J=8.7Hz, 2H), 6.42 (s, 1H),4.84(s,2H),3.80(s,3H)ppm.HRMS(DART-TOF)calculated for C27H21FN2O5S[M+H]+m/z 504.1155,found 504.1149.
The synthesis of target compound C1-3
The raw material for preparing of compound C1-3 is compound C1, intermediate h and connection boric acid pinacol ester, other raw materials and operation Same C7-3.TLC separation purifying, collects target compound.It is recrystallized to give Off-white solid, yield 16.5%.1H NMR (400MHz, DMSO) δ 10.56 (s, 1H), 8.60 (d, J=2.3Hz, 1H), 7.96 (dd, J=9.0,5.0Hz, 2H), 7.69 (d, J=2.3Hz, 1H), 7.61-7.47 (m, 3H), 7.35 (dd, J=8.3,2.1Hz, 1H), 7.26 (d, J=8.3Hz, 1H), 7.10 (dd, J=8.7,2.9Hz, 1H), 7.01 (t, J=2.1Hz, 1H), 6.96 (d, J=10.3Hz, 1H), 6.62 (d, J=2.1Hz, 1H), 4.90 (s, 2H), 3.78 (s, 3H) ppm.HRMS (DART-TOF) calculated for C25H17ClF2N3O4S[M+H]+m/z 528.0596,found 528.0579.
The synthesis of target compound C1-4
The raw material for preparing of compound C1-4 is compound C1 and 3- quinoline boronic acid.Other raw materials and the same C1-1 of operation.It obtains White solid.Yield is about 39.6%.1H NMR (400MHz, DMSO) δ 8.91 (d, J=2.3Hz, 1H), 8.33 (d, J= 2.3Hz, 1H), 7.99 (d, J=9.4Hz, 2H), 7.74 (t, J=8.3Hz, 1H), 7.61 (t, J=8.0Hz, 1H), 7.56- 7.47 (m, 2H), 7.28 (d, J=8.3Hz, 1H), 7.10 (dd, J=8.1,2.8Hz, 1H), 7.05-6.97 (m, 2H), 6.70 (d, J=2.1Hz, 1H), 4.90 (s, 2H), 3.79 (s, 3H) ppm.HRMS (DART-TOF) calculated for C24H18N2O3[M+H]+m/z 382.1317,found 382.1309.
The synthesis of target compound C1-5
The raw material for preparing of compound C1-5 is compound C1 and 4- hydroxyl phenyl boric acid.Other raw materials and the same C1-1 of operation. To white solid.Yield is about 15.8%.1H NMR (400MHz, DMSO) δ 9.69 (s, 1H), 7.49 (t, J=8.1Hz, 1H), 7.20-7.07 (m, 5H), 7.00-6.92 (m, 2H), 6.75 (d, J=8.6Hz, 2H), 6.43 (d, J=2.0Hz, 1H), 4.82 (s,2H),3.78(s,3H)ppm.HRMS(DART-TOF)calculated for C20H15FNO3[M+H]+m/z 336.1036, found 336.1029.
The synthesis of target compound C2-1
Weigh bromo- -3 (4H) -one (C2,50mg, 0.17mmol) of 4- phenyl -2H-1,4- benzoxazine of 6- and intermediate l (80mg, 0.20mmol), catalyst PdCl2(dppf) (9mg, 0.012mmol), alkali potassium acetate (50mg, 0.49mmol) are added In 3mL Isosorbide-5-Nitrae-dioxane, it is heated to 80 DEG C of reactions 5h, TCL and detects fully reacting.Processing method: after reaction solution is cooling, add Water is extracted 4 times with EA, and collected organic layer is washed twice with saturation NaCl solution, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, thin layer Analysis isolates and purifies, and PE/EA (4:1) system is collected target product band, eluted with EA as solvent, is evaporated under reduced pressure, PE/EA It is recrystallized to give yellow powder 15mg, yield 18.1%.1H NMR(400MHz,DMSO)δ10.02(s,1H),7.93(s,1H), 7.70 (dd, J=7.9,4.1Hz, 2H), 7.63 (t, J=7.5Hz, 2H), 7.58-7.52 (m, 1H), 7.45 (d, J=2.3Hz, 1H), 7.42 (d, J=7.1Hz, 2H), 7.37 (t, J=8.9Hz, 2H), 7.23 (dd, J=8.3,2.0Hz, 1H), 7.18 (d, J =8.3Hz, 1H), 6.36 (d, J=2.0Hz, 1H), 4.87 (s, 2H), 3.64 (s, 3H) ppm.HRMS (DART-TOF) calculated for C26H20FN3O5S[M+H]+m/z 505.1108,found 505.1101.
The synthesis of target compound C2-2
The raw material for preparing of compound C2-2 is C2 and other raw materials of intermediate k and operation with compound C2-1.Yield 61.5%.1H NMR (400MHz, DMSO) δ 10.40 (s, 1H), 7.71 (dd, J=8.9,5.1Hz, 2H), 7.63 (t, J= 7.4Hz, 2H), 7.56 (t, J=6.7Hz, 1H), 7.41 (d, J=7.0Hz, 2H), 7.35 (t, J=8.8Hz, 2H), 7.22 (t, J=7.9Hz, 1H), 7.16 (s, 2H), 7.07-7.00 (m, 2H), 6.98 (d, J=8.1Hz, 1H), 6.37 (s, 1H), 4.86 (s,2H)ppm.HRMS(DART-TOF)calculated for C26H19FN2O4S[M+H]+m/z 474.1050,found 474.1025.
The synthesis of target compound C2-3
Raw material used in the synthesis of compound C2-3 is C2 (60mg, 0.2mmol), intermediate h (87mg, 0.24mmol) and connection Boric acid pinacol ester (76,0.3mmol), using " one kettle way ", other raw materials and the same C1-3 of operating method, yield 11.8%.1H NMR (400MHz, DMSO) δ 10.41 (s, 1H), 8.19 (s, 1H), 8.03 (dd, J=8.9,4.9Hz, 1H), 7.96 (d, J =9.2Hz, 1H), 7.87 (d, J=2.2Hz, 1H), 7.70 (dd, J=8.8,5.2Hz, 2H), 7.65-7.60 (m, 2H), 7.55 (s, 2H), 7.44-7.38 (m, 2H), 7.22 (d, J=8.3Hz, 1H), 6.43 (s, 1H), 4.86 (s, 2H) .HRMS (DART- TOF)calculated for C25H17ClFN3O4S[M+H]+m/z 509.0612,found 509.0611.
The synthesis of target compound C2-4
Compound C2-4 prepare raw material be C2 (45mg, 0.15mmol) and 3- quinoline boronic acid (31mg, 0.18mmol), His raw material and operation are the same as from compound C2-1, yield 36.6%.1H NMR (400MHz, DMSO) δ 8.89 (d, J=2.4Hz, 1H), 8.32 (d, J=2.2Hz, 1H), 7.98 (d, J=8.3Hz, 2H), 7.77-7.70 (m, 1H), 7.64-7.57 (m, 3H), 7.56-7.47 (m, 2H), 7.44 (d, J=7.0Hz, 2H), 7.29 (d, J=8.3Hz, 1H), 6.65 (d, J=2.1Hz, 1H), 4.92(s,2H)ppm.HRMS(DART-TOF)calculated for C23H16N2O2[M+H]+m/z 352.1212,found 352.1210.
The synthesis of target compound C2-5
Compound C2-5 prepare raw material be C2 (45mg, 0.15mmol) and 4- hydroxyl phenyl boric acid (30mg, 0.22mmol), Other raw materials and operation are the same as from compound C2-1, yield 21.5%.1H NMR(400MHz,DMSO)δ9.56(s,1H),7.59 (t, J=7.9Hz, 2H), 7.52 (t, J=7.4Hz, 1H), 7.39 (d, J=7.0Hz, 2H), 7.18 (dd, J=8.3,2.1Hz, 1H), 7.12 (d, J=8.5Hz, 3H), 6.74 (d, J=8.6Hz, 2H), 6.38 (d, J=2.0Hz, 1H), 4.83 (s, 2H) ppm.HRMS(DART-TOF)calculated for C20H15NO3[M+H]+m/z 317.1052,found 317.1041.
The synthesis of target compound C3-1
By the bromo- 4- of 6- (4- chlorphenyl) -2H- benzoxazine -3 (4H) -one (C3) and intermediate l for synthesizing C3-1, The operation of his raw material is recrystallized to give pale yellow powder, yield 24.2% with from C2-1.1H NMR(400MHz,DMSO)δ 10.04 (s, 1H), 7.96 (d, J=2.3Hz, 1H), 7.75-7.66 (m, 4H), 7.51 (d, J=2.3Hz, 1H), 7.47 (d, J =8.7Hz, 2H), 7.38 (t, J=8.9Hz, 2H), 7.24 (dd, J=8.3,2.0Hz, 1H), 7.19 (d, J=8.3Hz, 1H), 6.40 (d, J=2.0Hz, 1H), 4.86 (s, 2H), 3.65 (s, 3H) ppm.HRMS (DART-TOF) calculated for C26H19ClFN3O5S[M+H]+m/z 539.0718,found 539.0713.
The synthesis of target compound C3-2
The raw material for preparing of compound C3-2 is C3 and intermediate k, other raw materials and the same C2-1 of operation.White powder is obtained, Yield is about 34.7%.1H NMR (400MHz, DMSO) δ 10.42 (s, 1H), 7.76-7.65 (m, 4H), 7.47 (d, J= 8.7Hz, 2H), 7.36 (t, J=8.8Hz, 2H), 7.24 (t, J=7.9Hz, 1H), 7.17 (d, J=1.1Hz, 2H), 7.10- 7.03 (m, 2H), 7.00 (d, J=10.0Hz, 1H), 6.38 (s, 1H), 4.86 (s, 2H) ppm.HRMS (DART-TOF) calculated for C26H18ClFN2O4S[M+H]+m/z 508.0660,found 508.0645.
The synthesis of target compound C3-3
The raw material for preparing of compound C3-3 is C3, intermediate h and connection boric acid pinacol ester, and using " one kettle way ", other are former Material and the same C1-3 of operating method, yield 15.6%.1H NMR (400MHz, DMSO) δ 10.49 (s, 1H), 8.30 (d, J= 2.3Hz, 1H), 7.72 (dd, J=8.9,5.1Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.64 (d, J=2.3Hz, 1H), 7.58 (t, J=8.8Hz, 1H), 7.47 (d, J=8.7Hz, 2H), 7.41 (dd, J=10.9,6.8Hz, 2H), 7.33 (dd, J= 8.3,2.1Hz, 1H), 7.24 (d, J=8.3Hz, 1H), 6.50 (d, J=2.1Hz, 1H), 4.89 (s, 2H) ppm.HRMS (DART-TOF)calculated for C25H16Cl2FN3O4S[M+H]+m/z 543.0223,found 543.0221.
The synthesis of target compound C3-4
Compound C3-4 prepare raw material be C3 (45mg, 0.13mmol) and 3- quinoline boronic acid (30mg, 0.16mmol), His raw material and operation obtain white solid 20mg, yield 39.2% with from compound C2-1.1H NMR(400MHz,DMSO)δ 8.95 (d, J=2.4Hz, 1H), 8.36 (d, J=2.2Hz, 1H), 8.00 (d, J=8.6Hz, 2H), 7.74 (t, J=7.6Hz, 1H), 7.66 (d, J=8.7Hz, 2H), 7.61 (t, J=7.0Hz, 1H), 7.55-7.44 (m, 3H), 7.29 (d, J=8.3Hz, 1H), 6.73 (d, J=2.1Hz, 1H), 4.91 (s, 2H) ppm.HRMS (DART-TOF) calculated for C23H15ClN2O2 [M+H]+m/z 386.0822,found 386.0816.
The synthesis of target compound C3-5
Compound C3-5 prepare raw material be C3 (45mg, 0.13mmol) and 4- hydroxyl phenyl boric acid (30mg, 0.22mmol), Other raw materials and operation are the same as from compound C2-1, yield 19.4%.1H NMR(400MHz,DMSO)δ9.65(s,1H),7.65 (d, J=8.7Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 7.17 (ddd, J=22.2,11.0,5.2Hz, 4H), 6.76 (d, J =8.6Hz, 2H), 6.41 (d, J=2.0Hz, 1H), 4.83 (s, 2H) ppm.HRMS (DART-TOF) calculated for C20H14ClNO3[M+H]+m/z 351.0662,found 351.0639.
The synthesis of target compound C4-1
By the bromo- 4- of 6- (4- aminomethyl phenyl) -2H- benzoxazine -3 (4H) -one (C4) and intermediate l for synthesizing C4-1, With from C2-1, PE/EA system is recrystallized to give white powder, yield 39.2% for the operation of other raw materials.1H NMR (400MHz, DMSO) δ 10.03 (s, 1H), 7.91 (d, J=2.3Hz, 1H), 7.71 (dd, J=8.9,5.2Hz, 2H), 7.47 (d, J=2.3Hz, 1H), 7.42 (d, J=8.1Hz, 2H), 7.37 (t, J=8.8Hz, 2H), 7.28 (d, J=8.2Hz, 2H), 7.21 (dd, J=8.3,2.0Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 6.38 (d, J=1.9Hz, 1H), 4.85 (s, 2H), 3.65(s,3H),2.40(s,3H)ppm.HRMS(DART-TOF)calculated for C27H22FN3O5S[M+H]+m/z 519.1264,found 519.1243.
The synthesis of target compound C4-2
The raw material for preparing of compound C4-2 is C4 and intermediate k, other raw materials and the same C2-1 of operation.Obtain milky white toner End, yield are about 30.3%.1H NMR (400MHz, DMSO) δ 10.41 (s, 1H), 7.72 (dd, J=8.9,5.1Hz, 2H), 7.42 (d, J=8.0Hz, 2H), 7.34 (t, J=8.8Hz, 2H), 7.27 (d, J=8.2Hz, 2H), 7.22 (t, J=7.9Hz, 1H), 7.15 (d, J=2.7Hz, 2H), 7.06 (s, 1H), 7.01 (d, J=7.8Hz, 1H), 6.97 (d, J=8.1Hz, 1H), 6.40(s,1H),4.84(s,2H),2.40(s,3H)ppm.HRMS(DART-TOF)calculated for C27H21FN2O4S[M +H]+m/z 488.1206,found 488.1206.
The synthesis of target compound C4-3
The raw material for preparing of compound C4-3 is C4, intermediate h and connection boric acid pinacol ester, and using " one kettle way ", other are former Material and the same C1-3 of operating method, yield 12.2%.1H NMR(400MHz,DMSO)δ10.49(s,1H),8.16(s,1H), 8.03 (dd, J=10.5,3.4Hz, 1H), 7.70 (dd, J=8.9,5.2Hz, 2H), 7.61-7.52 (m, 2H), 7.41 (t, J= 7.6Hz, 3H), 7.36 (d, J=8.8Hz, 2H), 7.28 (d, J=8.3Hz, 3H), 7.21 (d, J=8.3Hz, 1H), 6.44 (d, J=2.0Hz, 1H), 4.87 (s, 2H), 2.40 (s, 3H) ppm.HRMS (DART-TOF) calculated for C26H19ClFN3O4S[M+H]+m/z 523.0769,found 523.0761.
The synthesis of target compound C4-4
Compound C4-4 prepare raw material be C4 (50mg, 0.16mmol) and 3- quinoline boronic acid (41mg, 0.24mmol), His raw material and operation obtain white solid 16mg, yield 28.1% with from compound C2-1.1H NMR(400MHz,DMSO)δ 8.89 (d, J=2.4Hz, 1H), 8.33 (d, J=2.2Hz, 1H), 7.99 (d, J=8.5Hz, 2H), 7.77-7.71 (m, 1H), 7.66-7.53 (m, 1H), 7.49 (dd, J=8.3,2.1Hz, 1H), 7.40 (d, J=8.1Hz, 2H), 7.29 (dd, J=12.6, 8.3Hz, 3H), 6.67 (d, J=2.1Hz, 1H), 4.90 (s, 2H), 2.40 (s, 3H) ppm.HRMS (DART-TOF) calculated for C24H18N2O2[M+H]+m/z 351.0662,found 351.0649.
The synthesis of target compound C4-5
Compound C4-5 prepare raw material be C4 (50mg, 0.16mmol) and 4- hydroxyl phenyl boric acid (35mg, 0.25mmol), Other raw materials and operation are the same as from compound C2-1, yield 27%.1H NMR(400MHz,DMSO)δ9.72(s,1H),7.37 (t, J=8.9Hz, 2H), 7.25 (d, J=8.2Hz, 2H), 7.19-7.08 (m, 3H), 6.77 (dd, J=16.6,8.6Hz, 3H), 6.41 (d, J=2.0Hz, 1H), 4.81 (s, 2H), 2.40 (s, 3H) ppm.HRMS (DART-TOF) calculated for C21H17NO3[M+H]+m/z 331.1208,found 331.1202.
The synthesis of target compound C5-1
By the bromo- 4- of 6- (4- methoxyphenyl) -2H- benzoxazine -3 (4H) -one (C5) and intermediate l for synthesizing C5- 1, with from C2-1, PE/EA system is recrystallized to give pale yellow powder, yield 39.5% for the operation of other raw materials.1H NMR (400MHz, DMSO) δ 10.04 (s, 1H), 7.92 (d, J=2.3Hz, 1H), 7.71 (dd, J=8.9,5.2Hz, 2H), 7.48 (d, J=2.3Hz, 1H), 7.38 (d, J=8.8Hz, 2H), 7.35-7.30 (m, 2H), 7.21 (dd, J=8.3,2.0Hz, 1H), 7.16 (dd, J=8.6,1.9Hz, 3H), 6.40 (s, 1H), 4.85 (s, 2H), 3.83 (s, 3H), 3.65 (s, 3H) ppm.HRMS (DART-TOF)calculated for C27H22FN3O6S[M+H]+m/z 535.1213,found 535.1201.
The synthesis of target compound C5-2
The raw material for preparing of compound C5-2 is C5 and intermediate k, other raw materials and the same C2-1 of operation.White powder is obtained, Yield is about 33.8%.1H NMR (400MHz, DMSO) δ 10.42 (s, 1H), 7.72 (dd, J=8.9,5.1Hz, 2H), 7.39- 7.28 (m, 4H), 7.23 (t, J=7.9Hz, 1H), 7.15 (d, J=6.9Hz, 4H), 7.08 (s, 1H), 7.03 (d, J= 7.8Hz, 1H), 6.98 (d, J=8.1Hz, 1H), 6.41 (s, 1H), 4.84 (s, 2H), 3.83 (s, 3H) ppm.HRMS (DART- TOF)calculated for C27H21FN2O5S[M+H]+m/z 504.1155,found 504.1142.
The synthesis of target compound C5-3
The raw material for preparing of compound C5-3 is C5, intermediate h and connection boric acid pinacol ester, and using " one kettle way ", other are former Material and the same C1-3 of operating method, yield 16.7%.1H NMR(400MHz,DMSO)δ10.53(s,1H),8.44(s,1H), 8.19 (s, 1H), 7.88 (d, J=2.2Hz, 1H), 7.83 (dd, J=8.9,5.2Hz, 2H), 7.71 (dd, J=8.9,5.2Hz, 1H), 7.59 (d, J=2.3Hz, 1H), 7.40 (t, J=8.4Hz, 2H), 7.32 (d, J=8.9Hz, 1H), 7.20 (d, J= 8.3Hz, 1H), 7.15 (d, J=8.9Hz, 1H), 6.47 (s, 1H), 4.87 (s, 2H), 3.83 (s, 3H) ppm.HRMS (DART- TOF)calculated for C26H19ClFN3O5S[M+H]+m/z 539.0718,found 539.0703.
The synthesis of target compound C5-4
The raw material for preparing of compound C5-4 is C5 and 3- quinoline boronic acid, other raw materials and operation are obtained with from compound C2-1 To white solid, yield 27.5%.1H NMR (400MHz, DMSO) δ 8.91 (d, J=2.4Hz, 1H), 8.33 (d, J= 2.2Hz, 1H), 8.00 (d, J=8.4Hz, 2H), 7.77-7.70 (m, 1H), 7.64-7.58 (m, 1H), 7.49 (dd, J=8.3, 2.1Hz, 1H), 7.35 (d, J=8.9Hz, 2H), 7.27 (d, J=8.3Hz, 1H), 7.13 (d, J=9.0Hz, 2H), 6.70 (d, J=2.1Hz, 1H), 4.89 (s, 2H), 3.83 (s, 3H) ppm.HRMS (DART-TOF) calculated for C24H18N2O3[M +H]+m/z 382.1317,found 382.1309.
The synthesis of target compound C5-5
The raw material for preparing of compound C5-5 is C5 and 4- hydroxyl phenyl boric acid, other raw materials and operation with from compound C2-1, Obtain white solid, yield 18.4%.1H NMR (400MHz, DMSO) δ 9.59 (s, 1H), 7.30 (d, J=8.9Hz, 2H), 7.20-7.14 (m, 2H), 7.11 (dd, J=9.0,4.8Hz, 4H), 6.75 (d, J=8.6Hz, 2H), 6.43 (d, J=2.0Hz, 1H),4.81(s,2H),3.83(s,3H)ppm.HRMS(DART-TOF)calculated for C21H17NO4[M+H]+m/z 347.1158,found 347.1143.
The synthesis of target compound C6-1
By the bromo- 4- of 6- (4- fluorophenyl) -2H- benzoxazine -3 (4H) -one (C6,50mg, 0.16mmol) and intermediate l (70mg, 0.18mmol) for synthesizing C6-1, the same C2-1 of the operation of other raw materials, PE/EA system is recrystallized to give white solid 40mg, yield 48.7%.1H NMR (400MHz, DMSO) δ 10.03 (s, 1H), 7.93 (d, J=2.3Hz, 1H), 7.75- 7.65 (m, 4H), 7.48 (dd, J=8.7,5.5Hz, 3H), 7.37 (t, J=8.8Hz, 2H), 7.23 (dd, J=8.3,2.0Hz, 1H), 7.18 (d, J=8.3Hz, 1H), 6.40 (s, 1H), 4.86 (s, 2H), 3.65 (s, 3H) ppm.HRMS (DART-TOF) calculated for C26H19F2N3O5S[M+H]+m/z 523.1013,found 523.1011.
The synthesis of target compound C6-2
Compound C6-2 prepare raw material be C6 (50mg, 0.16mmol) and intermediate k (68mg, 0.24mmol), other Raw material and the same C2-1 of operation.Off-white powder 60mg is obtained, yield is about 65.2%.1H NMR(400MHz,DMSO)δ10.43 (s, 1H), 7.73 (dd, J=8.9,5.2Hz, 2H), 7.69 (d, J=8.7Hz, 2H), 7.47 (d, J=8.7Hz, 2H), 7.35 (t, J=8.8Hz, 2H), 7.23 (t, J=7.9Hz, 1H), 7.17 (d, J=1.0Hz, 2H), 7.10-7.03 (m, 2H), 6.99 (d, J=8.1Hz, 1H), 6.37 (s, 1H), 4.85 (s, 2H) ppm.HRMS (DART-TOF) calculated for C26H18F2N2O4S[M+H]+m/z 492.0955,found 492.0949.
The synthesis of target compound C6-3
The raw material for preparing of compound C6-3 is C6 (50mg, 0.16mmol), intermediate h (70mg, 0.19mmol) and connection boron Sour pinacol ester (60mg, 0.24mmol), using " one kettle way ", other raw materials and the same C1-3 of operating method obtain white solid 10mg, yield 12.1%.1H NMR (400MHz, DMSO) δ 10.49 (s, 1H), 8.16 (s, 1H), 8.03 (dd, J=9.0, 5.0Hz, 1H), 7.85-7.79 (m, 1H), 7.73-7.64 (m, 2H), 7.61-7.54 (m, 2H), 7.46 (dd, J=8.5, 3.0Hz, 2H), 7.36 (t, J=8.8Hz, 2H), 7.31-7.26 (m, 1H), 7.22 (dd, J=8.3,2.4Hz, 1H), 6.46 (d, J=12.1Hz, 1H), 4.88 (s, 2H) ppm.HRMS (DART-TOF) calculated for C25H16ClF2N3O4S[M+ H]+m/z 527.0518,found 527.0516.
The synthesis of target compound C6-4
Compound C6-4 prepare raw material be C6 (50mg, 0.16mmol) and 3- quinoline boronic acid (41mg, 0.24mmol), His raw material and operation are recrystallized to give white crystal 36mg, yield 62% with from compound C2-1.1H NMR(400MHz, DMSO) δ 8.95 (d, J=2.4Hz, 1H), 8.36 (d, J=2.2Hz, 1H), 8.00 (d, J=8.3Hz, 2H), 7.78-7.71 (m, 1H), 7.66 (d, J=8.7Hz, 2H), 7.61 (t, J=7.5Hz, 1H), 7.55-7.47 (m, 3H), 7.29 (d, J= 8.3Hz, 1H), 6.73 (d, J=2.1Hz, 1H), 4.87 (s, 2H) ppm.HRMS (DART-TOF) calculated for C23H15FN2O2[M+H]+m/z 370.1118,found 370.1116.
The synthesis of target compound C6-5
Compound C6-5 prepare raw material be C6 (50mg, 0.16mmol) and 4- hydroxyl phenyl boric acid (33mg, 0.24mmol), Other raw materials and operation obtain white solid 13mg, yield 25% with from compound C2-1.1H NMR(400MHz,DMSO)δ 9.74 (s, 1H), 7.65 (d, J=6.6Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 7.24-7.08 (m, 4H), 6.76 (d, J= 8.6Hz, 2H), 6.41 (d, J=2.0Hz, 1H), 4.83 (s, 2H) ppm.HRMS (DART-TOF) calculated for C20H14FNO3[M+H]+m/z 335.0958,found 335.0939.
The synthesis of target compound C7-1
Weigh bromo- 4- cyclohexyl -2H- benzoxazine -3 (4H) -one (C7,60mg, 0.19mmol) of raw material 6-, intermediate l (95mg, 0.23mmol), catalyst PdCl2(dppf) (10.6mg, 0.015mmol) and alkali potassium acetate (60mg, 0.6mmol) add Enter in reaction tube, the dissolution of 4mL dioxane is added.It vacuumizes, is filled with nitrogen, move into 80 DEG C of oil bath pans and react 5h, TCL prison Survey extent of reaction.Processing reaction solution: being cooled to room temperature, add water, extracted with EA, merges organic layer, washes two with saturation NaCl solution Secondary, anhydrous sodium sulfate is dry, and vacuum distillation, dry method loading carries out column chromatography with PE/EA (10:1) eluant, eluent.Collect targeted Object is closed, white crystal 42mg, yield 42.4% are recrystallized to give.1H NMR(400MHz,DMSO)δ10.07(s,1H),8.28 (d, J=2.3Hz, 1H), 7.86-7.77 (m, 3H), 7.45-7.37 (m, 3H), 7.21 (dd, J=8.3,1.9Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 4.54 (s, 2H), 4.26-4.15 (m, 1H), 3.67 (s, 3H), 2.39-2.27 (m, 2H), 1.85- 1.63(m,5H),1.50–1.20(m,3H)ppm.HRMS(DART-TOF)calculated for C26H26FN3O5S[M+H]+m/ z 511.1577,found 511.1559.
The synthesis of target compound C7-2
The raw material for preparing of compound C7-2 is C7 (60mg, 0.19mmol) and intermediate k (68mg, 0.23mmol).Other Raw material and operating method are the same as compound C7-1.It is recrystallized to give white solid 50mg.Yield is 54.6%.1H NMR(400MHz, DMSO) δ 10.47 (s, 1H), 7.85 (dd, J=8.9,5.1Hz, 2H), 7.41 (t, J=8.8Hz, 2H), 7.36-7.30 (m, 4H), 7.15 (dd, J=8.3,1.8Hz, 1H), 7.12-7.08 (m, 2H), 4.55 (s, 2H), 4.25-4.15 (m, 1H), 2.38- 2.24(m,2H),1.89–1.61(m,5H),1.50–1.20(m,3H)ppm.HRMS(DART-TOF)calculated for C26H25FN2O4S[M+H]+m/z 480.1519,found 480.1503.
The synthesis of target compound C7-3
Weigh C7 (60mg, 0.19mmol) and intermediate h (83mg, 0.23mmol) and connection boric acid pinacol ester (74mg, 0.29mmol), catalyst PdCl2(dppf) reaction is added in (10.6mg, 0.015mmol) and alkali potassium acetate (60mg, 0.6mmol) In test tube, the dissolution of 4mL dioxane is added.It using " one kettle way ", vacuumizes, is filled with nitrogen, move into 80 DEG C of oil bath pans and react 6h, TCL monitor extent of reaction.Processing reaction solution: being cooled to room temperature, add water, extracted with EA, merges organic layer, with saturation NaCl Solution is washed twice, and anhydrous sodium sulfate is dry, and vacuum distillation, dry method loading carries out column chromatography with PE/EA (8:1) eluant, eluent.It collects Target compound is recrystallized to give faint yellow solid 12mg.Yield is about 12.1%.1H NMR(400MHz,CDCl3)δ10.49 (s, 1H), 8.32 (d, J=2.3Hz, 1H), 8.15 (d, J=2.2Hz, 1H), 7.82 (dd, J=8.9,4.9Hz, 1H), 7.31 (d, J=1.8Hz, 1H), 7.20-7.10 (m, 4H), 7.04 (d, J=6.4Hz, 1H), 4.55 (s, 2H), 4.35-4.21 (m, 1H),2.47–2.31(m,2H),2.01–1.68(m,5H),1.47–1.34(m,3H)ppm.HRMS(DART-TOF) calculated for C25H23ClFN3O4S[M+H]+m/z 515.1082,found 515.1065.
The synthesis of target compound C7-4
The raw material for preparing of compound C7-4 is compound C7 and 3- quinoline boronic acid.Other raw materials and the same C7-1 of operation.It ties again Crystalline substance obtains white solid.Yield is about 68.5%.1H NMR (400MHz, DMSO) δ 9.25 (d, J=2.4Hz, 1H), 8.61 (d, J=2.2Hz, 1H), 8.07 (t, J=8.6Hz, 2H), 7.82-7.75 (m, 1H), 7.69-7.63 (m, 2H), 7.50 (dd, J= 8.3,2.0Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 4.58 (s, 2H), 4.31-4.19 (m, 1H), 2.47-2.35 (m, 2H), 1.86–1.58(m,5H),1.53–1.18(m,3H)ppm.HRMS(DART-TOF)calculated for C23H22N2O2[M+H ]+m/z 358.1681,found 358.1663.
The synthesis of target compound C7-5
The raw material for preparing of compound C7-5 is compound C7 and 4- hydroxyl phenyl boric acid.Other raw materials and the same C7-1 of operation. To white solid.Yield is about 32%.1H NMR (400MHz, DMSO) δ 9.52 (s, 1H), 7.45 (d, J=8.6Hz, 2H), 7.33 (d, J=1.8Hz, 1H), 7.18 (dd, J=8.3,1.9Hz, 1H), 7.05 (d, J=8.3Hz, 1H), 6.85 (d, J= 8.6Hz,2H),4.51(s,2H),4.24–4.12(m,1H),2.41–2.28(m,2H),1.85–1.61(m,5H),1.48– 1.16(m,3H)ppm.HRMS(DART-TOF)calculated for C20H21NO3[M+H]+m/z 323.1521,found 323.1509.
The synthesis of target compound C8-1
The raw material for preparing of compound C8-1 is bromo- 4- cyclopropyl -2H- benzoxazine -3 (4H) -one (C8) of 6- and intermediate L, other raw materials and the same C7-1 of operation.Obtain white solid.Yield is 26.1%.1H NMR(400MHz,DMSO)δ10.06(s, 1H), 8.25 (d, J=2.3Hz, 1H), 7.83 (dd, J=8.9,5.2Hz, 2H), 7.78 (d, J=2.3Hz, 1H), 7.50 (d, J =2.1Hz, 1H), 7.42 (t, J=8.9Hz, 2H), 7.22 (dd, J=8.3,2.1Hz, 1H), 7.07 (d, J=8.3Hz, 1H), 4.62(s,2H),3.68(s,3H),2.91–2.80(m,1H),1.15–1.09(m,2H),0.70–0.62(m,2H)ppm.HRMS (DART-TOF)calculated for C23H20FN3O5S[M+H]+m/z 469.1108,found 469.1105.
The synthesis of target compound C8-2
The raw material for preparing of compound C8-2 is compound C8 and intermediate k, other raw materials and the same C7-1 of operation.Obtain yellow Grease.Yield is about 43.1%.1H NMR (400MHz, DMSO) δ 10.46 (s, 1H), 7.86 (dd, J=8.9,5.1Hz, 2H), 7.47-7.38 (m, 3H), 7.35-7.30 (m, 3H), 7.14 (dd, J=8.3,2.1Hz, 1H), 7.10-7.04 (m, 2H), 4.62(s,2H),2.86–2.78(m,1H),1.15–1.09(m,2H),0.70–0.63(m,2H)ppm.HRMS(DART-TOF) calculated for C23H19FN2O4S[M+H]+m/z 438.1050,found 438.1039.
The synthesis of target compound C8-3
The raw material for preparing of compound C8-3 is compound C8, intermediate h and connection boric acid pinacol ester, other raw materials and operation Same C7-3.It is recrystallized to give Off-white solid, yield 17.3%.1H NMR(400MHz,DMSO)δ10.51(s,1H),8.52 (s, 1H), 7.88 (d, J=2.2Hz, 1H), 7.82 (dd, J=8.8,5.2Hz, 2H), 7.56 (d, J=1.8Hz, 1H), 7.43 (t, J=8.8Hz, 2H), 7.30 (dd, J=8.3,1.9Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 4.65 (s, 2H), 2.90- 2.78(m,1H),1.15–1.07(m,2H),0.71–0.64(m,2H)ppm.HRMS(DART-TOF)calculated for C22H17ClFN3O4S[M+H]+m/z 473.0612,found 473.0601.
The synthesis of target compound C8-4
The raw material for preparing of compound C8-4 is compound C8 and 3- quinoline boronic acid.Other raw materials and operation are the same as compound C7- 1.Obtain white crystal.Yield is 33.5%.1H NMR (400MHz, DMSO) δ 9.25 (d, J=2.3Hz, 1H), 8.62 (d, J =2.2Hz, 1H), 8.07 (dd, J=7.6,5.6Hz, 2H), 7.84 (d, J=2.0Hz, 1H), 7.78 (t, J=8.2Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.53 (dd, J=8.3,2.0Hz, 1H), 7.16 (d, J=8.3Hz, 1H), 4.67 (s, 2H), 2.93–2.86(m,1H),1.26–1.18(m,2H),0.74–0.67(m,2H)ppm.HRMS(DART-TOF)calculated for C20H16N2O2[M+H]+m/z 316.1212,found 316.1206.
The synthesis of target compound C8-5
The raw material for preparing of compound C8-5 is compound C8 and 4- hydroxyl phenyl boric acid.Other raw materials and the same C7-1 of operation. To white solid.Yield is about 22.4%.1H NMR (400MHz, DMSO) δ 9.52 (s, 1H), 7.51 (d, J=2.1Hz, 1H), 7.45 (d, J=8.6Hz, 2H), 7.18 (dd, J=8.3,2.1Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 6.85 (d, J= 8.6Hz,2H),4.59(s,2H),2.86–2.80(m,1H),1.17–1.10(m,2H),0.69–0.62(m,2H)ppm.HRMS (DART-TOF)calculated for C17H15NO3[M+H]+m/z 281.1052,found 281.1041.
Inhibitory activity of 2 target compound of embodiment to tumour cell
The target compound used when carrying out experiment in vitro is stored with the concentration that DMSO is configured to 20mg/mL, chemical combination Object is placed in 4 DEG C of refrigerators and is kept in dark place, and when experiment is diluted according to required concentration with complete medium.Tumour used is thin Born of the same parents strain include: human colon cancer cell strain (HCT-116), human lung adenocarcinoma cell line (A549), Breast cancer lines (MCF-7), Human liver tumor cell's strain (HepG2), people's malignant melanoma cell (A375), human cervical carcinoma cell lines (Hela) etc. are above thin Born of the same parents' strain is purchased from ATCC company, the U.S..Steps are as follows for specific test method:
Bed board: collecting the tumour cell in logarithmic growth phase first and the concentration of cell suspension is adjusted with culture medium.So Afterwards with 2~4 × 104The cell density in/hole is inoculated in 96 orifice plates, and every hole is added 100 μ L cell suspensions and is placed in 37 DEG C, and 5% CO2Continue to be incubated for for 24 hours in incubator.
Dosing: using coubling dilution, the target compound of 20mg/mL be diluted to various concentration with complete medium, Wherein the concentration of primary dcreening operation is set as 40,20,10 μM, and the concentration of fine screen is designed as 20,10,5,2.5,1.25,0.625 μM.It will not Solution title compound with concentration is added in 96 orifice plates with the amount in 100 holes μ L/.In addition, the BEZ235 of setting 2mg/mL is positive Medicine is the blank control group of control group and only culture solution.To reduce error, each concentration is three multiple holes.Continue to cultivate 48h。
Processing: taking out 96 orifice plates, and MTT is configured to the solution of 5mg/mL and is added in 96 orifice plates with the amount in 20 holes μ L/, is continued It is incubated for 2~4h, liquid is discarded supernatant, then 150 μ L DMSO are added into each hole, sufficiently rocks 10~15min.
Detection: after every hole concussion even dyeing, the absorbance value in every hole is measured at wavelength 570nm with microplate reader, takes it Average value.According to formula: Relative cell proliferation inhibiting rate (%)=(blank control group-experimental group)/blank control group × 100%, to calculate the corresponding tumour cell of each target compound with respect to proliferation inhibition rate, reuse IC50Software for calculation Acquire half-inhibitory concentration (IC50, μm ol/L).Its test result is shown in Table 1.
Table 1 (unit μm ol/L)
By the above IC50Data are it is found that target compound has certain proliferation inhibition activity to different tumor cell lines mostly. Wherein, the activity of C2-1, C3-1, C5-1 and C8-1 are preferably.
3 target compound of embodiment studies the kinase activity of PI3K α
It takes above-mentioned molecule, after carrying out purity testing, then weighs and be sent to Shanghai sagacity chemical company and carry out kinases to PI3K α Active measurement.These molecules are measured to the IC50 of PI3K α.Its measurement result is shown in Table 2.
Table 2
Shown according to enzyme activity test result, we obtained it is a collection of can efficient targeting in the molecule of PI3K α, wherein compound C5-1 is substantially better than the IC50 (9.57nM) in this experiment as the PI-103 of positive control drug to the IC50 of PI3K alpha kinase, Better than control molecule BEZ235 (80.5nM).
C5-1 and PI-103 is shown in Table 3 to the IC50 calculating of PI3K α.C5-1, PI-103 and BEZ235 are to PI3K/mTOR target spot Inhibitory activity be shown in Table 4.Numerical value is IC50, unit nM in table 4.
Table 3
Calculate C5-1 is 0.627nM to the IC50 of PI3K α, PI-103 is 9.57nM to the IC50 of PI3K α.
Table 4 (IC50:nM)
Target spot PI3Kα PI3Kβ PI3Kγ PI3Kδ mTOR
C5-1 0.63 94.54 22 9.2 13.85
PI-103 9.6 11.98 64.03 11 5.3
BEZ235 80.5 703.9 104.2 85.3 1.43
As it can be seen that C5-1 not only targets PI3K α, also there is preferable inhibitory activity to PI3K β, PI3K γ, PI3K δ and mTOR.
4 target compound of embodiment and control compounds compare the kinase activity of PI3K α
Part of compounds is taken, the control compounds (US2010/0311736A1) of simultaneously synthesizing report measure the dense of 100nM To the inhibiting rate of PI3K α under degree, the result is shown in tables 5.Wherein, the nuclear-magnetism of control compounds is characterized as below:
C3-6-1:1H NMR(400MHz,CDCl3) δ=8.13 (d, J=2.3,1H), 8.05 (d, J=2.3,1H), 7.72 (dd, J=8.4,1.1,2H), 7.63-7.56 (m, 1H), 7.44 (dd, J=10.8,4.9,2H), 7.37-7.27 (m, 4H), 7.16 (dd, J=8.3,2.0,1H), 7.10 (d, J=8.3,1H), 7.04 (d, J=2.0,1H), 5.21 (s, 2H), 4.79 (s, 2H)
C3-6:1H NMR(400MHz,CDCl3) δ=8.05 (d, J=2.3,1H), 7.96 (d, J=2.2,1H), 7.75- 7.68 (m, 2H), 7.61-7.54 (m, 3H), 7.48-7.41 (m, 2H), 7.34-7.28 (m, 2H), 7.17 (d, J=1.1,2H), 6.53 (t, J=1.1,1H), 4.83 (s, 2H)
C2-1-1:1H NMR(400MHz,CDCl3) δ=8.20 (d, J=2.2,1H), 7.99-7.91 (m, 4H), 7.40 (d, J=2.2,1H), 7.35-7.29 (m, 4H), 7.25-7.17 (m, 5H), 7.08-6.99 (m, 3H), 5.21 (s, 2H), 4.78 (s,2H),3.61(s,3H).
C2-6-1:1H NMR(400MHz,CDCl3) δ=8.05 (dd, J=17.3,2.3,1H), 7.97 (dd, J=8.5, 1.1,1H), 7.75-7.67 (m, 2H), 7.60-7.53 (m, 2H), 7.43 (t, J=7.8,1H), 7.35 (t, J=4.7,2H), 7.29 (d, J=5.0,1H), 7.12-7.05 (m, 2H), 5.22 (d, J=14.0,2H), 4.80 (s, 2H)
C2-6:1H NMR(400MHz,CDCl3) δ=8.04 (s, 1H), 7.96-7.90 (m, 1H), 7.68 (dd, J= ), 11.2,3.8,2H 7.60 (t, J=7.6,2H), 7.53 (dd, J=14.8,7.2,2H), 7.41 (t, J=7.6,2H), 7.35 (dd, J=10.5,3.3,2H), 7.16 (s, 2H), 6.56 (d, J=5.8,1H), 4.85 (d, J=5.6,2H)
Table 5
The above Structure Comparison absolutely proves, benzylidene is introduced in structure in activity completely not as good as directly even with phenyl ring It is associated with benefit.
Inhibitory activity of the 5 compound C5-1 of embodiment to DNA-PK
DNA dependent protein kinase (DNA-dependent protein kinase, DNA-PK) is genomic DNA damage Key protein kinase in repair process participates in and decides the entire process of non-homologous end joining DNA damage repair pathways Furthermore DNA-PK also takes part in the apoptotic signal Signal Transduction Pathways of ionization radiation induction, immunocyte V (D) J recombination, immunocyte point The processes such as the cell response under change, insulin stimulating have the function of maintaining the active raising of Telomere Stability .DNA-PK that can drop Sensibility of the low tumour to radiation.
The inhibiting rate under the concentration of 100nM to DNA-PK is measured, the results show that the inhibiting rate of C5-1 molecule pair is in 100nM Reach 75%, has been a potent DNA-PK inhibitor.
The plate clone of 6 compound C5-1 of embodiment
Plate clone is also known as plate clone and forms experiment, and this method is suitable for the experiment of attached cell.Mainly pass through inoculation After tumour cell, adherent survive of cell is formed by clone's quantity, i.e. Cell colonies assay (cell inoculation survival rate) is examined Examine the proliferative capacity of reflection tumour cell.Clone cell refers to by individual cells after the more than generation culture of sustainable growth 6, with it The set that progeny cell is formed.It comprising size is 0.3~1.0 in the set, quantity is 50 or more cells.By tumour cell After treated with medicaments, proliferative capacity will receive the influence of drug, so that clone generates quantity and modal variation. By clone cell after the nucleic acid in cell is dyed bluish violet by coloring agent (usually with crystal violet), can intuitively it sentence from color The case where disconnected tumor cell clone formation, and reflect with this effect of Drug inhibition cell Proliferation.
Bed board: the human cervical carcinoma cell Hela of logarithmic growth phase is digested with pancreatin, and cell be suspended in containing It is spare in the DMEM complete medium of 10% fetal calf serum.It is inoculated in 24 orifice plates with the density that cell quantity is 100/hole, Orifice plate is placed in 37 DEG C, cultivates 12h in the incubator of 5%CO2.
Dosing: taking out orifice plate, after observation cell is adherent, removes supernatant culture medium and experimental group and control group is arranged.By medicine Target compound C5-1 equimultiple is diluted to six of 20,10,5,2.5,1.25,0.625,0.375 μM with complete medium by object 1.5mL medical fluid is added in concentration, every hole.Isometric culture medium without medical fluid is added in control group.Orifice plate is placed in 37 DEG C, 5% Continue incubation in the incubator of CO2 2~3 weeks.
Processing: cell culture is terminated when forming macroscopic cell colony in observation orifice plate, then removes supernatant And washed twice repeatedly with PBS buffer solution, then fix 15min with 4% paraformaldehyde fixer, fixer is discarded, is finally used 0.5% violet staining liquid dyes 20~30min, then removes dyeing liquor and wash away extra dyeing with PBS buffer solution.Under room temperature It is dry, it is taken pictures with camera, and for statistical analysis to Colony forming quantity, is detailed in Fig. 1 and Fig. 2.
As seen from the figure, colony-forming efficiency is decreased obviously the experimental group of Hela cell compared with the control group, and is showed brighter Aobvious concentration dependent.Its Colony forming and drug concentration are in inverse ratio, i.e. drug concentration is higher, and cloning efficiency is lower.5 μM or more drug concentration orifice plate in, tumour cell almost without formed clone also formed without apparent cell colony, and When 1.25 μM of concentration, compared with the cell of negative control group, more than half Clone formations has been inhibited.
The pharmacokinetic of 7 compound C5-1 molecule of embodiment
Experimental animal: healthy adult male SD rat, 6,180~250g of weight.Administration route: tail vein (i.v.)； Stomach-filling (p.o.) dosage: 1mg/kg (i.v.), 10mg/kg (p.o.), administered volume 5ml/kg.Form of administration is vein Administration: 15/ physiological saline of DMA/Solutol HS (5:10:85, v/v/v)；Oral administration: 0.5%CMC-Na.
Medicine ordinance: i.v. administration group: precision weighs appropriate amount of drug (being equivalent to original shape drug 1.0mg), and DMA is added 0.25ml, Solutol HS15 0.5ml, ultrasound make to dissolve, after be slowly added to physiological saline to final volume 5ml, ultrasound, vortex It mixes.
P.o. administration group: precision weighs appropriate amount of drug (being equivalent to original shape drug 10.0mg), 0.5%CMC-Na 5ml, surpasses Sound, vortex mix.
Experimental program: healthy adult SD rat 6, it is divided to two groups (each 3 of every group of i.v. and p.o.)；Overnight fasting is (freely Drinking-water) after, difference tail vein and gastric infusion, administered volume 5ml/kg；Administration group is injected intravenously before administration and is administered 5min, 15min, 0.5 afterwards, 1,2,4,8,12, for 24 hours by retroorbital venous clump take a blood sample 0.2ml, 4 DEG C of centrifugation 5min separated plasmas, It is to be measured in -20 DEG C of preservations.Gastric infusion group respectively at administration before and administration after 0.5,1,2,4,6,8,12,24h by eye socket after it is quiet Arteries and veins clump blood sampling 0.2ml, processing method is same to be injected intravenously administration group.
Sample analysis: using the drug concentration in LC/MS/MS method measurement blood plasma, the result is shown in tables 6.
Table 6
The internal antitumor activity of 8 compound C5-1 molecule of embodiment
In order to study the anti-tumor activity of C5-1 in animal body, cell strain Hela and A549 is selected to construct xenogenesis shifting Tumor model is planted, experimental animal is Balb/c nude mouse.
Experimental animal
Mouse used in this project is purchased from Beijing HFK Bio-Technology Co., Ltd., and raising is controlled in Sichuan University's biology It treats National Key Laboratory's animal house (SPF grades).Mouse is SPF grades, according to NationalInstitutes of Health Guide for the Care and Use of Laboratory Animals feeding standard.The use of experimental animal is by Sichuan The University Ethics committee (Institutional Ethics Committee of Sichuan University) examines and approves. Experimental animal feeding condition: 16-26 DEG C of temperature, relative humidity 40%-70%, using artificial lighting system, 12h light and shade replaces, Co60 sterilizing feed (Beijing Australia, section pull together feed corporation,Ltd), free water.
The specific method is as follows:
1) after Hela the and A549 tumour cell of pancreatin digestion logarithmic growth phase, cell is collected by centrifugation；With double nothings (no antibiosis Plain serum-free) culture medium cleaning cell 3 times；It is added appropriate pair and tumour cell is resuspended without culture medium, and tumour cell is carried out close Degree measurement；Cell density is adjusted to 1 × 10 according to requirement of experiment7A/mL.
2) by the cell being resuspended according to every mouse 1 × 106A cell (0.1mL) seeds cells into mouse (6-8 weeks Age, weight 18-22g) right axillary portion it is subcutaneous.
3) 10 days or so after being inoculated with, mouse inoculation region tumors tumor formation, 150~200mm of volume3When, by all tumour bodies The similar mouse of product is grouped at random.5 groups of (control group, positive drug group BEZ235 20mg/kg, C5-1 are arranged in Hela model experiment 10mg/kg, C5-1 20mg/kg, C5-1 40mg/kg, C5-1 50mg/kg), 4 groups of (control group, sun are arranged in A549 model experiment Property medicine group BEZ235 20mg/kg, C5-1 20mg/kg, C5-1 40mg/kg) every group 6.Medicine solvent uses PEG300:NMP =9 mixed solvent, by medicine ordinance at corresponding concentration
Experiment Data Records: an every 3 days gross tumor volumes of measurement and mouse weight, including tumour major diameter and perpendicular to major diameter Minor axis, unit: millimeter (mm)；Mouse weight, unit: gram (g).It should be noted that observing mouse health status, such as during experiment Animal activity situation, water inlet meal situation, mouse hair glossiness and color, whether there is or not diarrhea and tumor locus no inflammation etc..
Knurl accumulates (mm3)=tumour major diameter × minor axis × minor axis/2
Tumour inhibiting rate (%)=(control group tumor average volume-experimental group tumor average volume)/control group tumour is averaged body Product × 100%.
Experiment carries out 30 days, and test result is shown in Fig. 3~6.
According to experimental result, under 50,40,20mg/kg administration concentrations, the tumour inhibiting rate to Hela Transplanted tumor model is C5-1 87.7%, 79%, 66.6%, positive drug tumour inhibiting rate under 20mg/kg administration concentration is 66.5%.C5-1 gives in 40,20mg/kg Under concentration, the tumour inhibiting rate to A549 Transplanted tumor model is 70.16% and 66.6%, and positive drug is under 20mg/kg administration concentration Tumour inhibiting rate is 56.08%.Under comparable sodium, the internal anti-tumor activity of C5-1 approaches or slightly above positive drug BEZ235.However During the administration, it is observed that the mouse weight of C5-1 administration group is steady, it is shown that the hypotoxicity of the molecule.Positive drug The mouse weight of group is always below C5-1 administration group, illustrates that this molecule has the advantages that high-efficiency low-toxicity compared with positive drug.

Claims (14)

1. benzoxazine ketones derivant, which is characterized in that its structural formula is as shown in formula I:
Wherein, R1For C3-C6 naphthenic base, heterocycle orR6For monosubstituted or multi-substituent, R6Selected from hydrogen, halogen Element, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or the C1-C4 alkyl replaced by hydroxyl, amino, nitro；
R2ForOrR3For hydrogen, C1-C4 alkoxy, halogen or hydroxyl, R4For hydrogen orR5For hydrogen or halogen, X1For C or N, X2For C or N.
2. benzoxazine ketones derivant according to claim 1, it is characterised in that: R1For C3-C6 naphthenic base orR6For monosubstituted base；It is preferred that R1For cyclopropyl, cyclohexyl, phenyl ring or by halogen, methyl or methoxy list Substituted phenyl.
3. benzoxazine ketones derivant according to claim 1, which is characterized in that its structural formula is as shown in formula II:
Wherein, R6For monosubstituted base, R6Selected from hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, hydroxyl, amino, nitro or by hydroxyl The C1-C4 alkyl that base, amino, nitro replace；It is preferred that R6For chlorine, bromine, methyl or methoxy.
4. benzoxazine ketones derivant according to claim 3, which is characterized in that its structural formula is as shown in formula III:
5. benzoxazine ketones derivant according to claim 1, it is characterised in that: R1For C3-C6 naphthenic base；It is preferred that R1 For cyclopropyl or cyclohexyl.
6. described in any item benzoxazine ketones derivants according to claim 1~5, it is characterised in that: R2ForIt is preferred that X1For N；More preferable R4ForMore preferable R4For Further preferred R3For chlorine or methoxyl group.
7. described in any item benzoxazine ketones derivants according to claim 1~5, it is characterised in that: R2ForIt is preferred that X2For N.
8. benzoxazine ketones derivant according to claim 1, which is characterized in that its structural formula is as follows:
9. the isomers of benzoxazine ketones derivant according to any one of claims 1 to 8, pharmaceutical salt and hydration Object.
10. benzoxazine ketones derivant according to any one of claims 1 to 8 inhibits in the mammalian body for producing The purposes of the drug of PI3K/Akt/mTOR signal path.
11. the purposes of benzoxazine ketones derivant according to any one of claims 1 to 8 in the preparation of antitumor drugs.
12. a kind of pharmaceutical composition, it is characterised in that: it is made of effective component and pharmaceutically acceptable auxiliary material, it is described effective According to any one of claims 1 to 8 benzoxazine ketones derivant or its isomers of the ingredient comprising therapeutically effective amount can Medicinal salt or hydrate.
13. the purposes that benzoxazine ketones derivant according to any one of claims 1 to 8 is used to prepare DNA-PK inhibitor.
14. purposes according to claim 13, which is characterized in that the benzoxazine ketones derivant is compound C5-1.
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