CN108794478A - Novel purine derivatives class compound, preparation method, pharmaceutical composition and its pharmaceutical applications - Google Patents
Novel purine derivatives class compound, preparation method, pharmaceutical composition and its pharmaceutical applications Download PDFInfo
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- CN108794478A CN108794478A CN201710310770.XA CN201710310770A CN108794478A CN 108794478 A CN108794478 A CN 108794478A CN 201710310770 A CN201710310770 A CN 201710310770A CN 108794478 A CN108794478 A CN 108794478A
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- TUFQWGXSNJMGDE-CALCHBBNSA-N C[C@H](C1)O[C@@H](C)CN1c1c2nc[n](CC3CCOCC3)c2nc(-c(cc2)ccc2NC(NC)=O)n1 Chemical compound C[C@H](C1)O[C@@H](C)CN1c1c2nc[n](CC3CCOCC3)c2nc(-c(cc2)ccc2NC(NC)=O)n1 TUFQWGXSNJMGDE-CALCHBBNSA-N 0.000 description 1
- QJQGALLOOQPOHL-HDICACEKSA-N C[C@H](C1)O[C@@H](C)CN1c1c2nc[n](CC3CCOCC3)c2nc(-c(cc2)ccc2NC(NC2CC2)=O)n1 Chemical compound C[C@H](C1)O[C@@H](C)CN1c1c2nc[n](CC3CCOCC3)c2nc(-c(cc2)ccc2NC(NC2CC2)=O)n1 QJQGALLOOQPOHL-HDICACEKSA-N 0.000 description 1
- RIVWXZXXVOIZDT-UHFFFAOYSA-N O=C(NC1CC1)Nc(cc1)ccc1-c1nc(N2CCOCC2)c2nc[n](CC3CCOCC3)c2n1 Chemical compound O=C(NC1CC1)Nc(cc1)ccc1-c1nc(N2CCOCC2)c2nc[n](CC3CCOCC3)c2n1 RIVWXZXXVOIZDT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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Abstract
The invention belongs to field of medicine and chemical technology, it is related to the compound of Formula I inhibited to mammal mTOR signal paths and its pharmaceutical salt or hydrate, the definition of each substituent group is as used in the description in general formula I；The preparation method of compound of Formula I：Including compound of Formula I or the pharmaceutical composition of its officinal salt or hydrate；The purposes of compound of Formula I or its officinal salt or hydrate in producing drug, the drug are dynamic due to disease caused by mTOR path signal unconventionality expressions for treating lactation.
Description
Technical field
The present invention relates to purine derivative class compound, for field of antineoplastic medicaments and mTOR path signals are not normal leads
The relevant disease of cause.The invention further relates to the preparation method of these compounds, contain their pharmaceutical composition and their works
For the application of drug.
Background technology
MTOR is a kind of protein serine/threonine with high molecular weight (289kDa), it take part in cell growth,
The processes such as proliferation, differentiation, albumen synthesis, transcription, metabolism, autophagy, aging, stem cell homeostasis, tumour formation, lipid synthesis.
When cell is stimulated by the external nourishment factor or growth factor signal, intracellular mTOR can activate some related target eggs of downstream
In vain, and then to the metabolism of entire cell and growth positively or negatively regulated and controled.MTOR can be divided into according to constituent difference
Two hypotypes of mTORC1 and mTORC2：MTORC1 is made of mTOR, PRAS40, mLST8 and Raptor, unlike,
MTORC2 is made of mTOR, mSIN1, PROTOR, mLST8 and Rictor.MTORC1 can activate ribose by phosphorylation
Body protein S6 kinase (Ribosomal protein S6 kinase, p70S6K) and startup factor 4E Binding Protein 1s
(Initiation factor 4E binding protein Isosorbide-5-Nitrae EBP1) influences downstream nutrient, growth factor and cell
The transcription and translation of element, therefore mTORC1 plays the part of vital role in cell growth, apoptosis and metabolism.MTORC2 energy
It includes the regulation process of multiple functions such as cell survival and cell framework to make Akt phosphorylations and also participation.Due to constituent
Difference, mTORC1 and mTORC2 have no biological regulation approach, the common cell cycle regulation process of the two mutual cooperation.
Inhibit mTOR signal paths that can effectively inhibit the activity of downstream S6K1 and 4EBP1, by the growth week of tumor stem cell
Phase is arrested in G1Phase, to slow down the growing multiplication process of tumour cell, therefore, mTOR inhibitor is in resisting tumour stem cells side
There are huge applications potentiality, all kinds of mTOR inhibitors to be widely used in treatment Several Kinds of Malignancy in face.
Invention content
The purpose of the present invention is finding and developing the new compound for having and inhibiting mTOR path signal functions, for treating
With prevent it is various with the relevant disease of mTOR abnormal signals.
The study found that having the function of that following compounds of formula I has inhibits mTOR excessive activations, therefore can be used for
It treats and prevents and the relevant various diseases of mTOR abnormal signals.
Compound described in the invention selects purine formation for female ring, and 2 in purine introduce morpholine ring, and 9 are drawn
Enter 4- methyl oxinane ring structures, increases compound and the binding ability of mTOR.These compound structures are novel, to normal
Cytotoxicity is weaker, and compared with the mTOR pathway inhibitors such as rapamycin reported for work, and has higher to tumour cell
Proliferation Ability ability.
On the one hand, the present invention relates to compounds of formula I, its all possible isomers or its pharmaceutical salt or hydrations
Object.
The present invention relates to compound of formula I
Wherein：
X, Y is each independently selected from C, S, O, N and Se atom；
D, F is independently selected from C and N atoms；
E is C1-C6Alkyl；
A, U, V, W are independently selected from C or N atoms；
R1For C1-C6Alkyl, C3-C10Naphthenic base, C1-C6Alkoxy, C1-C6Alkylthio group, C3-C10Cycloalkyloxy, C1-C6Alkane
Alkenyl, Ene alkynyl base heterocycle, Heterocyclylalkyl, substituted heterocycle alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle, wherein described
C1-C6Alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle it is unsubstituted or by 1,2,3,4 or 5 independently
Replace selected from following substituent group：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano, C1-C6Alkylthio group, C1-C6Alkyl,
C1-C6Alkenyl, C1-C6Alkynyl and C1-C6Alkoxy, aromatic radical；
R2For hydrogen atom, hydroxyl, amino, C1-C6Alkyl, ester group；
R3、R4Respectively stand alone as one or more hydrogen atoms, hydroxyl, amino, C1-C6Alkyl；
In a preferred scheme,
R1For methyl, ethyl, cyclopropyl, ethoxy, pyridin-3-yl, 4- (methylol) phenyl, phenyl, halogenophenyl；
X, Y is each independently selected from O atom；
F is C atoms, D is N atoms；
E is the carbochain for including 1 C atom；
A, U, V, W are C atoms；
R2For hydrogen atom；
R3、R4Respectively stand alone as a hydrogen atom or one or more methyl.
The present invention is more particularly directed to compound of Formula I or its pharmaceutical salt or hydrate preferably below compound：
1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) -3- (pyrroles
Pyridine -3- bases) urea；
1- (4- (hydroxymethyl) phenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H-
Purine -2- bases) urea；
1- ethyls -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl)
Urea；
1- methyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl)
Urea；
1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) -3- phenyl
Urea；
1- (2,4- difluorophenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -
2- yls) phenyl) urea；
1- cyclopropyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) benzene
Base) urea；
6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenol；
1- (2- ethoxys) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases)
Phenyl) urea；
((6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- is fast by 4- by 1-
Purine -2- bases) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine
- 2- bases) phenyl)-(4- (methylol) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine
- 2- bases) phenyl) -3- methyl) urea；
3- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenol；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine
- 2- bases) phenyl) -3- ethyls) urea；
1- cyclopropyl -3- (4- (6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine
- 2- bases) phenyl) -3- phenyl) urea；
1- (2,4- difluorophenyl) -3- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4-
Base) methyl) -9H- urea element -2- bases) phenyl) urea.
And its officinal salt or hydrate.
The invention further relates to the suitable pharmaceutical salt or hydrate of the compound as shown in general formula I, wherein pharmaceutical
Salt includes but be not limited to that compound of Formula I and inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid institute
At salt and with various organic acids, such as maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, breast
Salt formed by acid, methanesulfonic acid, p-methyl benzenesulfonic acid, palmitic acid etc..Some compounds in the present invention may use water or various organic
Solvent crystallization or recrystallization, in this case it is possible to form various solvates.The present invention includes the molten of those stoichiometries
Agent compound, including hydrate are also included within the compound for including variable water formed when being prepared with lyophylization.
The invention further relates to the various isomers of compound of Formula I.Part of compounds may be with optical siomerism in the present invention
The form of body or tautomer exists, and the present invention includes the form of its all existence forms, especially pure isomer.Different
Isomeric forms with the isomer separation of various conventional means and other forms or can be split or certain isomers can
It is obtained with various conventional synthetic methods or three-dimensional single-minded or asymmetric syntheses method.Since compound of Formula I is with medicinal
For the purpose of, it is possible to understand that they are preferably provided in a pure form, for example, at least 60% purity, more suitably 75%, more preferably
85%, preferably at least 98% purity (% refers to weight percent).The preparation method of pure compound not can be used to be used for medicine
With form purer in composition.At least contain 1% in these not pure enough products, 5% be more suitable for, preferably at least 10%
Such as general formula I compounds represented or its pharmaceutical derivative.
On the other hand, the present invention relates to the synthetic methods for preparing compound of Formula I.Compounds of formula I can be from known
Or commercially available compound be raw material, prepared by artificial synthesized method.If raw material cannot be bought, it is provided here
Preparation method or they can be prepared by the method for document report.
Specifically, the present invention provides the methods for preparing compound of Formula I or its officinal salt or hydrate comprising
Step described in method below：
X, Y is each independently selected from C, S, O, N and Se atom；
F, D is independently selected from C and N atoms；
E is C1-C6Alkyl；
A, U, V, W are independently selected from C or N atoms；
R1For C1-C6Alkyl, C3-C10Naphthenic base, C1-C6Alkoxy, C1-C6Alkylthio group, C3-C10Cycloalkyloxy, C1-C6Alkane
Alkenyl, Ene alkynyl base heterocycle, Heterocyclylalkyl, substituted heterocycle alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle, wherein described
C1-C6Alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle it is unsubstituted or by 1,2,3,4 or 5 independently
Replace selected from following substituent group：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano, C1-C6Alkylthio group, C1-C6Alkyl,
C1-C6Alkenyl, C1-C6Alkynyl and C1-C6Alkoxy, aromatic radical；
R2For hydrogen atom, hydroxyl, amino, C1-C6Alkyl, ester group；
R3、R4Respectively stand alone as one or more hydrogen atoms, hydroxyl, amino, C1-C6Alkyl；
In a preferred scheme,
R1For methyl, ethyl, cyclopropyl, ethoxy, pyridin-3-yl, 4- (methylol) phenyl, phenyl, halogenophenyl；
X, Y is each independently selected from O atom；
B is C atoms, D is N atoms；
E is the carbochain for including 1 C atom；
A, U, V, W are C atoms；
R2For hydrogen atom；
R3、R4Respectively stand alone as a hydrogen atom or one or more methyl.
Compound of Formula I can individually be synthesized with conventional method, and what also available combination was chemical mix-divides method or parallel projects
Method with library (at least containing two or 5-1000 in each library, preferably 10-100 compounds) be unit synthesis, you can
Solid phase synthesis process can also be used to synthesize in the liquid phase.
See embodiment about the more detailed data of compound of Formula I is prepared.
Another aspect of the present invention relates to described in any one of present invention compound, its officinal salt or its hydrate or
The pharmaceutical composition of the person present invention is preparing antitumor drug, immunosuppressor, PI3K inhibitor, mTOR inhibitors, inhibition
The drug of PI3K-Akt-mTOR path signals inhibits the lymphopoietic drugs of T, antibacterials, antiviral drugs, promotion
The drug of apoptosis of tumor cells makes cell cycle arrest in the drug of G1 phases, the drug for preventing organ rejection response, reduction artery
Purposes in the drug of embolism, antiaging agent, anti-Alzheimer disease drug, anti-inflammatory drug or antibacterials；Specifically, institute
State antitumor drug be treatment and/or prevent and/or auxiliary treatment kidney, lymthoma, lung cancer, liver cancer, breast cancer, nerve in point
Secrete the drug of cancer or gastric cancer.
The present invention is related to a kind of in vivo or extracorporeal anti-tumor, inhibiting immune, inhibit PI3K, inhibiting in another further aspect
MTOR, inhibit PI3K-Akt-mTOR signal paths, inhibit T lymphopoiesis, is antitumor, promote apoptosis of tumor cells, is anti-
Bacterium, it is antiviral, make cell cycle arrest G1, reduce arterial embolism, anti-aging, anti-Alzheimer disease, prevent organ rejection
Reaction, anti-inflammatory or antibacterial method, including the compound described in any one of using a effective amount of present invention, its officinal salt
Or the step of pharmaceutical composition of its hydrate or the present invention.
On the other hand, compounds of formula I of the invention or its pharmaceutical salt can be used alone, or with it is pharmaceutical
Carrier or excipient are used in the form of pharmaceutical composition together, when in the form of pharmaceutical composition in use, usually will be effective
The compound of Formula I of the present invention of dosage or its officinal salt or hydrate and one or more pharmaceutical acceptable carrier or diluent knot
Administration form or dosage form appropriate is made in conjunction, this program includes mixing component by suitable mode, granulation, compressing
Or dissolving.Therefore, the present invention provides pharmaceutical composition, it include compounds of formula I, 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 sucks, is straight
Enteral administration, nasal-cavity administration, vagina administration, local administration, parenterai administration be such as subcutaneous, in vein, intramuscular, peritonaeum, in pin, 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 the pharmaceutical composition of the present 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,
Glycerine, 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
The plain substance of dimension, 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.
Oral tablet and capsule can contain excipient such as adhesive, such as syrup, Arabic gum, sorbierite, tragacanth, or
Polyvinylpyrrolidone, filler, such as lactose, sucrose, cornstarch, calcium phosphate, sorbierite, amion acetic acid, lubricant are such as hard
Fatty acid magnesium, talcum, polyethylene glycol, tripoli, disintegrant, such as potato starch or acceptable dibutyl phthalate, such as bay sodium alkoxide sulfuric acid
Salt.Tablet can be coated with well known method in pharmaceutics.
The suspension of water and oil can be made in oral solution, and solution, emulsion, dry product can also be made in syrup, with preceding supplement
Water or other suitable mediums.This liquid preparation can include the additive of routine, such as suspending agent, sorbierite, cellulose first
Enzyme, dextrose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, the edible oil and fat of hydrogenation, emulsification
Agent, such as lecithin, sorbitan esters list oleate, gum arabic；Or nonaqueous carrier (may include edible oil), such as almond
Pool, grease such as Gan Bo, ethylene glycol or ethyl alcohol；Positive corruption agent, such as to even yl benzoic acid first vinegar or the third vinegar, sorbic acid.As needed can to add
Add flavoring agent or colorant.
Suppository may include conventional suppository base, such as cocoa butter or other glyceride.
To offeing medicine outside stomach, liquid forms are usually made of compound and a kind of carrier of disinfection.Carrier first choice water.According to institute
It selects the difference of carrier and drug concentration, compound both to dissolve in and may be made as aaerosol solution in carrier, injection solution is being made
When it is first that compound is soluble in water, filtering disinfection after be fitted into sealed bottle or ampoule.
When topical application, the form of ointment appropriate, lotion or creme can be made in the compounds of this invention,
Middle active constituent is suspended or dissolved in one or more carriers.The carrier that wherein ointment formulation can use includes but not office
It is limited to：Mineral oil, Albolene, albolene, propylene glycol, polyethylene glycol oxide, polypropylene oxide, emulsifying wax and water；Lotion
Include but not limited to carrier workable for creme：Mineral oil, sorbitan monostearate vinegar, polysorbate60, hexadecane ester
Wax, hexadecene is fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
According to the difference of administering mode, weight ratio 0.1%, or more suitably weight ratio 10-60% can be contained in component
Active component.But when in component including unit dose, each unit preferably includes 50-500 milligrams of active constituents.Foundation is given
The difference of medicine approach and administration frequency, the suitable therapeutic doses for adult are daily 100-3000 milligrams, such as daily 1500 milli
Gram.This dose corresponds to 1.5-50 mg kg days, and suitable dosage is 5-20 mg kg days.
It should be appreciated that the best dosage of compound of Formula I and interval are administered by compound property and such as
What the external conditions such as form, path and position and the specific mammal treated determined, and this best dosage can
It is determined with conventional technique.Simultaneously also it should be appreciated that the best course for the treatment of, i.e. compound of Formula I every mesh within the specified time
Dosage, can be determined with method well known in the art.
Term " C1-C6Alkyl " refers to the linear or branched alkyl group for having 1-6 carbon atom, for example, methyl, ethyl, propyl,
Isopropyl, normal-butyl, sec-butyl, tertiary butyl, amyl, 2- amyls, isopentyl, neopentyl, hexyl, 2- hexyls, 3- hexyls etc.；
C1-C4Alkyl, C1-C3Alkyl or C1-C2Alkyl can also do similar understanding.Specific alkyl is C1-C4Alkyl, C1-C3Alkyl or C1-
C2Alkyl.
Term " C1-C6Alkoxy " refers to the straight or branched alkoxyl for having 1-6 carbon atom, such as methoxyl group, ethoxy
Base, propoxyl group, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, amoxy, 2- amoxys, isoamoxy, new penta oxygen
Base, hexyloxy, 2- hexyloxies, 3- hexyloxies etc.； C1-C4Alkoxy, C1-C3Alkoxy or C1-C2Alkoxy can also do similar reason
Solution.Specific alkoxy is C1-C4Alkoxy, C1-C3Alkoxy or C1-C2Alkoxy.
Term " C1-C6Alkylthio group " can be with " C1-C6Alkoxy " does similar understanding, the difference is that oxygen atom is replaced
For sulphur atom.
Term " C3-C10Naphthenic base " refers to the saturated carbon ring group for having 3-10 carbon atom.The naphthenic base can be single
Ring or polycyclic fused system, and can condense on aromatic ring.The example of these groups includes cyclopropyl, cyclobutyl, ring penta
Base and cyclohexyl.The ring a heatable brick bed base of this paper can be unsubstituted or as being described in detail, in one or more commutable positions
Replaced by various groups.For example, these naphthenic base can optionally be replaced by following group：C1-C6Alkyl, C1-C6Alkoxy, itrile group,
Halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Alkenyl, C2-C6Alkynyl, C}-
C6Halogenated alkyl, C1-C6Halogenated alkoxy.C3-C6Naphthenic base can also do similar understanding.
Term " C3-C10Cycloalkyloxy " refers to the saturated carbon ring alkoxy base for having 3-10 carbon atom.The cycloalkanes oxygen
Base can be monocycle or polycyclic fused system, and can condense on aromatic ring.The example of these groups include ring propoxyl group,
Cyclobutoxy group, cyclopentyloxy and cyclohexyloxy.The naphthenic base of this paper can be it is unsubstituted or as be described in detail, at one or
Multiple commutable positions are replaced by various groups.For example, these cycloalkyloxies can optionally be replaced by following group：C1-C6Alkane
Base, C1-C6Alkoxy, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-
C6Alkenyl, C2-C6Alkynyl, C}-C6Halogenated alkyl, C1-C6Halogenated alkoxy.C3-C6Cycloalkyloxy can also do similar understanding.
Term " C2-C6Alkenyl " refers to the alkenyl with 2-6 carbon atom and at least one double bond, and includes ethylene
Base, acrylic, 1- butyl- 3- alkenyls, the amyl- 3- alkenyls of 1-, 1- hex- 5- alkenyls etc.；C3-C5Alkenyl can also do similar understanding.Preferably
It is C3-C5Alkenyl.
Term " C2-C6Alkynyl " refers to the alkyl with 2-6 carbon atom and at least one three key, and includes acetylene
Base, propinyl, butynyl, pentyne -2- bases etc.；C3-C5Alkynyl can also do similar understanding.Preferably C3-C5Alkynyl.
Term " halogen " refers to fluorine, chlorine, bromine and iodine atom.
Term " aromatic rings " or " aryl " refer to monocycle (such as phenyl), polycyclic (such as xenyl) or in which at least one
Ring is the aromatic carbocyclyl groups of multiple fused rings (such as 1,2,3,4- tetralyls, naphthalene) of armaticity, optionally by such as halogen,
Low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl mono-, di- or three substitutions.
Term " aryl alkyl " refers to by the alkyl (as defined above) of one or more aryl substitution (as defined above).
Preferred aryl alkyl is aryl-C1-C3Alkyl.Example includes benzyl, phenylethyl etc..
Term " aromatic heterocycle " or " heteroaryl " refer to one or more aromatics ring systems of five-, six- or seven-membered ring,
Condensed ring system (wherein at least one ring is armaticity) including 5-10 atom, the ring system contains at least one and most
Four hetero atoms selected from nitrogen, oxygen or sulphur.The example of heteroaryl is pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl, triazolyl, pyrrole
Piperazine base, tetrazole radical, furyl, thienyl, isoxazolyls, thiazolyl, oxazolyls, isothiazolyl, pyrrole ring, quinoline ring, isoquinoline
Quinoline ring, indole ring, benzimidazole, benzofuran ring, benzothiophene ring, benzothiazole ring, pyridazine ring etc..It is optionally by such as halogen
Element, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl mono-, di- or three substitutions.
Term " heterocycle " or " heterocycle " refer to one or more carbocyclic ring system of five-, six- or seven-membered ring, packet
The condensed ring system of 4-10 atom is included, the ring system contains at least one and most four hetero atoms selected from nitrogen, oxygen or sulphur, item
Part is that the ring of the group is free of two adjacent O or S atom.Condensed ring system can be the heterocycle condensed on virtue group group.It is excellent
The heterocycle of choosing include but not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, piperidyl, morpholine ring,
Hexamethylene ring, piperazine ring etc., they can be replaced by following group：C1-C6Alkyl, C1-C6Alkoxy, itrile group, halogen, hydroxyl, ammonia
Base, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Alkenyl, C2-C6Alkynyl, C}-C6Halogenated alkyl, C1-
C6Halogenated alkoxy.
When for " in vivo ", term " effective quantity " refer to can be realized in subject treatment, prevention, mitigate and/or
Alleviate the dosage of disease or illness of the present invention.
Term " subject " can refer to patient or other receive the present composition to treat, prevent, mitigate and/or delay
Solve the animal of disease or illness of the present invention, especially mammal, such as people, dog, monkey, ox, horse etc..
Term " disease and/or illness " refers to a kind of physical condition of the subject, the physical condition and institute of the present invention
It states disease and/or illness is related.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following examples are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Tool is not specified in embodiment
Concrete conditions in the establishment of a specific crime person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer,
For can be with conventional products that are commercially available.
Melting point compound is measured by RY-1 type melting point apparatus, and temperature is not calibrated.1H-NMR is composed by JNM-ECA-400 superconductions
NMR instrument measures, working frequency1H NMR 400MHz；Mass spectrum is measured by API3000 mass spectrographs.
Embodiment 1：1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) benzene
Base) -3- (pyridin-3-yl) urea
Step 1：The preparation of the chloro- 6- morpholines -9H- purine (intermediate 1) of 2-
2,6- dichloropurines (10g, 0.05mol) are added in ethyl alcohol (120ml) at room temperature, after dissolved clarification, then to anti-
It answers and morpholine (6.91g, 0.08mol) is added dropwise in liquid, about 3h is stirred at room temperature.After stopping reaction, filtering, filter cake washs three with ether
It is secondary, obtain shallow milk yellow powder (12.02g, yield 95%).
Step 2：4- (the chloro- 9- of 2- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -6- bases) morpholine (intermediate 2)
Preparation
Triphenylphosphine (7.65g, 0.03mol) is added in the anhydrous THF solution of 100ml at room temperature, stirring to dissolved clarification,
Add 4- methylols oxinane (2.90g, 0.02mol) dissolved clarification.It is anhydrous that DEAD (4.72g, 0.03mol) is dissolved in 5ml
THF solution is slowly added dropwise into reaction solution under ice bath, stirs 30min.Reaction is finished, and intermediate 1 (5g, 0.02mol) is taken to be dissolved in nothing
Water THF solution, is slowly added dropwise into reaction solution, at room temperature, reaction overnight.Reaction is finished, and the extraction of EA/ water is added three times, is associated with
Machine layer, solvent evaporated, column chromatography obtain white solid (4.93g, yield 70%).
Step 3：1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) -
The preparation of 3- (pyridin-3-yl) urea
By intermediate 2 (2g, 5.93mmol), 4- (3- pyridines) urea-phenyl boric acid pinacol ester side chain (3.01g,
8.90mmol), tetra-triphenylphosphine palladium (3.43g, 2.97mmol) is added in microwave reaction pipe, and the DMF of 70mL is added to stir dissolved clarification,
Again plus potassium carbonate (1.64g, 11.87mmol) is just dissolved in the aqueous solution to reaction solution of water, 120 DEG C of microwave, reacts 1h.Reaction
Finish, three times with ethyl acetate/water extraction, solvent evaporated column chromatography obtains white powder (0.46g, yield 15%).m.p.252-256
℃；1H-NMR (400 MHz, DMSO-d6)δ(ppm)：9.05 (s, 1H), 8.90 (s, 1H), 8.62 (d, J=7.8Hz, 1H),
8.33 (d, J=8.8Hz, 2H), 8.20 (dd, J=4.6,1.3Hz, 1H), 8.18 (s, 1H), 7.97 (ddd, J=8.3,2.5,
1.5Hz, 1H), 7.57 (d, J=8.8Hz, 2H), 7.33 (dd, J=8.3,4.7Hz, 1H), 4.30 (s, 4H), 4.15 (d, J=
7.1Hz, 2H), 3.87-3.81 (m, 2H), 3.80-3.74 (m, 4H), 3.28-3.21 (m, 2H), 2.20-2.14 (m, 1H),
1.45 (d, J=12.1Hz, 2H), 1.30 (dd, J=12.7,4.1Hz, 2H) .MS m/z (M+H)+：515.6.
Embodiment 2：1- (4- (hydroxymethyl) phenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (4- cresyls) urea-phenyl boric acid frequency
That alcohol ester is replaced, and white powdery solids, yield 16% are obtained.m.p.213-217℃；1H-NMR (400MHz, DMSO-d6)δ
(ppm)：8.88 (s, 1H), 8.68 (s, 1H), 8.32 (d, J=8.7Hz, 2H), 8.18 (s, 1H), 7.74 (dt, J=7.0,
3.6Hz, 1H), 7.68 (dd, J=5.7,3.3Hz, 1H), 7.56 (d, J=8.8Hz, 2H), 7.42 (d, J=8.4Hz, 2H),
7.24 (d, J=8.4Hz, 2H), 5.10 (t, J=5.7Hz, 1H), 4.43 (d, J=5.6Hz, 2H), 4.36-4.22 (m, 2H),
4.15 (d, J=6.8Hz, 2H), 3.89-3.79 (m, 2H), 3.80-3.75 (m, 4H), 3.29-3.21 (m, 4H), 1.48-
1.41 (m, 2H), 1.31-1.22 (m, 2H), 1.17 (t, J=7.1Hz, 1H) .MS m/z (M+H)+：544.6.
Embodiment 3：1- ethyls -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- ethyl carbamides-phenyl boric acid pinacol ester
It changes, obtains white powdery solids, yield 15.8%.m.p.207-210℃；1H-NMR (400 MHz, DMSO-d6)δ(ppm)：
8.79 (s, 1H), 8.26 (d, J=8.9Hz, 2H), 8.16 (s, 1H), 7.49 (d, J=8.9Hz, 2H), 6.28 (t, J=
5.6Hz, 1H), 4.35-4.23 (m, 4H), 4.14 (d, J=7.1 Hz, 2H), 3.83 (ddd, J=10.9,3.7,1.9Hz,
2H), 3.78-3.73 (m, 4H), 3.24 (td, J=11.9,2.0Hz, 2H), 3.16-3.08 (m, 2H), 2.19-2.12 (m,
1H), 1.48-1.41 (m, 2H), 1.36-1.25 (m, 2H), 1.06 (t, J=7.2Hz, 3H) .MS m/z (M+H)+：466.5.
Embodiment 4：1- methyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- methylurea-phenyl boric acid pinacol ester
It changes, obtains white powdery solids, yield 16.8%.m.p.229-232℃；1H-NMR (400 MHz, DMSO-d6)δ(ppm)：
8.72 (s, 1H), 8.26 (d, J=8.8Hz, 2H), 8.16 (s, 1H), 7.49 (d, J=8.8Hz, 2H), 7.47-7.44 (m,
1H) 4.34-4.23 (m, 4H), 4.14 (d, J=7.1Hz, 2H), 3.87-3.79 (m, 2H), 3.79-3.72 (m, 4H), 3.24
(td, J=11.9,1.9Hz, 2H), 2.66 (d, J=4.6Hz, 3H), 1.45 (dd, J=13.7,2.4Hz, 2H), 1.36-
1.26 (m, 2H) .MS m/z (M+H)+：452.5.
Embodiment 5：1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) benzene
Base) -3- phenylureas preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- phenylureas-phenyl boric acid pinacol ester
It changes, obtains white powdery solids, yield 16.2%.m.p.259-262℃；1H NMR (400 MHz, DMSO-d6)δ(ppm)：
8.90 (s, 1H), 8.72 (s, 1H), 8.33 (d, J=8.7Hz, 2H), 8.18 (s, 1H), 7.56 (d, J=8.8Hz, 2H),
7.47 (d, J=7.8Hz, 2H), 7.30 (t, J=7.9Hz, 2H), 6.99 (t, 1H), 4.30 (s, 4H), 4.15 (d, J=
7.2Hz, 2H), 3.84 (dd, J=10.8,3.8 Hz, 2H), 3.77 (t, 4H), 3.25 (t, J=11.4Hz, 2H), 2.22-
2.13 (m, 1H), 1.45 (d, J=10.8Hz, 2H), 1.36-1.24 (m, 2H) .MS m/z (M+H)+：512.6.
Embodiment 6：1- (2,4- difluorophenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -
9H- purine -2- bases) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (2,4- difluorophenyl) urea-phenyl boric acid
Pinacol ester is replaced, and white powdery solids, yield 17.5% are obtained.m.p.259-262℃；1H NMR (400MHz, DMSO-d6)δ
(ppm)：9.64 (s, 1H), 8.81 (s, 1H), 8.33 (d, J=8.7 Hz, 2H), 8.19 (s, 1H), 8.16-8.05 (m, 1H),
7.58 (d, J=8.7Hz, 2H), 7.35-7.28 (m, 1H), 7.09-7.02 (m, 1H), 4.29 (s, 4H), 3.84 (d, J=
14.5Hz, 2H), 3.80-3.74 (m, 4H), 3.25 (t, J=11.4Hz, 4H), 2.23-2.12 (m, 1H), 1.48-1.40 (m,
2H), 1.39-1.31 (m, 2H) .MS m/z (M+H)+：550.6.
Embodiment 7：1- cyclopropyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -
2- yls) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- cyclopropyl urea-phenyl boric acid pinacol ester
It replaces, obtains white powdery solids, yield 17.3%.m.p.201-204℃；1H NMR (400 MHz, DMSO-d6)δ(ppm)：
8.54 (s, 1H), 8.27 (d, J=8.8Hz, 2H), 8.16 (s, 1H), 7.50 (d, J=8.8Hz, 2H), 6.44 (d, J=
2.4Hz, 1H), 4.28 (s, 4H), 4.14 (d, J=7.1 Hz, 2H), 3.83 (dd, 2H), 3.76 (t, J=4.6Hz, 4H),
3.24 (t, J=10.8Hz, 2H), 2.58-2.52 (m, 1H), 2.18-2.11 (m, 1H), 1.46-1.38 (m, 2H), 1.34-
1.25 (m, 2H), 0.67-0.62 (m, 2H), 0.46-0.36 (m, 2H) .MS m/z (M+H)+：478.6.
Embodiment 8：6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenol preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (3- phenol) urea-boric acid pinacol ester
It replaces, obtains white powdery solids, yield 16.6%.m.p.208-212℃；1H NMR (400 MHz, DMSO-d6)δ(ppm)：
9.49 (s, 1H), 8.21 (s, 1H), 7.86-7.82 (m, 2H), 7.26 (t, J=8.1Hz, 1H), 6.85-6.81 (m, 1H),
4.29 (s, 4H), 4.15 (d, J=7.2Hz, 2H), 3.86-3.81 (m, 2H), 3.77 (t, 4H), 3.24 (td, J=11.7,
2.0Hz, 2H), 1.47-1.40 (m, 2H), 1.32-1.28 (m, 2H), 1.26-1.22 (m, 1H) .MS m/z (M+H)+：
496.5.
Embodiment 9：((6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- is fast by 4- by 1- (2- ethoxys) -3-
Purine -2- bases) phenyl) urea preparation
Synthesized by the synthetic method of 1 compound of embodiment, 2 side chains with 4- (2- ethoxys) urea-phenyl boric acid frequency that
Alcohol ester is replaced, and white powdery solids, yield 15% are obtained.m.p.190-195℃；1H NMR (400MHz, DMSO-d6)δ8.80
(s, 1H), 8.26 (d, J=8.9Hz, 2H), 8.17 (s, 1H), 7.52-7.46 (m, 3H), 4.81-4.77 (m, 1H), 4.33-
4.24 (m, 4H), 4.22 (t, J=6.6Hz, 2H), 4.16-4.10 (m, 4H), 3.87-3.78 (m, 2H), 3.76 (t, J=
4.7Hz, 4H), 3.49- 3.41 (m, 2H), 1.71-1.66 (m, 2H), 1.65-1.59 (m, 1H), 1.45-1.40 (m, 2H) .MS
m/z(M+H)+：482.5.
Embodiment 10：1- (4- (6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) and urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (3- pyridines) urea-phenyl boric acid pinacol
Ester is replaced, and 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 16.4%.m.p.150-155
℃；1H NMR (400MHz, DMSO-d6)δ(ppm)：9.05 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.34 (d, J=
8.8Hz, 2H), 8.21 (d, J=3.8Hz, 1H), 8.17 (s, 1H), 7.97 (d, J=8.7Hz, 1H), 7.58 (d, J=
8.8Hz, 2H), 7.36-7.29 (m, 1H), 4.15 (d, J=7.1Hz, 2H), 3.87-3.79 (m, 2H), 3.72-3.64 (m,
2H), 3.25 (td, J=11.7,1.9Hz, 2H), 2.77 (s, 2H), 2.54-2.46 (m, 2H), 2.20-2.12 (m, 1H),
1.45 (d, J=15.8Hz, 2H), 1.32 (td, J=13.1,12.7,4.7Hz, 2H), 1.21 (d, J=6.2Hz, 6H) .MS
m/z(M+H)+：543.6.
Embodiment 11：1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) and-(4- (methylol) phenyl) urea synthesis
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (4- cresyls) urea-phenyl boric acid frequency
That alcohol ester is replaced, and 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 16.5%.m.p.158-
163℃；1H NMR (400MHz, DMSO-d6)δ(ppm)：8.88 (s, 1H), 8.69 (s, 1H), 8.33 (d, J=8.8Hz, 2H),
8.18 (s, 1H), 7.56 (d, J=8.9Hz, 2H), 7.42 (d, J=8.5Hz, 2H), 7.24 (d, J=8.6Hz, 2H), 5.16-
5.00 (m, 1H), 4.43 (s, 2H), 4.15 (d, J=7.4Hz, 2H), 3.87-3.80 (m, 2H), 3.72-3.65 (m, 2H),
3.25 (t, 2H), 2.83-2.71 (m, 2H), 2.53-2.47 (m, 2H), 2.20-2.12 (m, 1H), 1.49-1.39 (m, 2H),
1.35-1.27 (m, 2H), 1.25-1.17 (m, 6H) .MS m/z (M+H)+：572.7.
Embodiment 12：1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) -3- methyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- methylurea-phenyl boric acid pinacol ester
It changes, 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 16.8%.m.p.242-247℃；1H NMR (400MHz, DMSO-d6)δ(ppm)：8.74 (s, 1H), 8.27 (d, J=8.6Hz, 2H), 8.16 (s, 1H), 7.51
(d, J=8.7Hz, 2H), 6.08 (d, J=4.7 Hz, 1H), 4.13 (d, J=7.1Hz, 2H), 3.83 (d, J=13.6Hz,
2H), 3.73-3.64 (m, 2H), 3.24 (t, J=11.7Hz, 2H), 2.83-2.71 (m, 2H), 2.66 (d, J=4.4Hz,
3H), 2.51 (s, 2H), 2.19-2.09 (m, 1H), 1.44 (d, J=16.2Hz, 2H), 1.36-1.25 (m, 2H), 1.26-
1.16 (m, 6H) .MS m/z (M+H)+：480.6.
Embodiment 13：3- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -
9H- purine -2- bases) phenol preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (3- phenol) urea-boric acid pinacol ester
It replaces, 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 17.5%.m.p.172-177℃
；1H NMR (400MHz, DMSO-d6)δ(ppm)：9.49 (s, 1H), 8.20 (s, 1H), 7.86-7.81 (m, 2H), 7.27 (t, J
=7.9Hz, 1H), 6.86-6.82 (m, 1H), 4.14 (d, J=7.1Hz, 2H), 3.87-3.79 (m, 2H), 3.73-3.65 (m,
2H), 3.24 (t, J=11.4Hz, 2H), 2.78 (s, 2H), 2.22-2.10 (m, 1H), 1.49-1.38 (m, 2H), 1.36-
1.24 (m, 2H), 1.23-1.16 (m, 6H), 0.96-0.80 (m, 2H) .MS m/z (M+H)+：424.5.
Embodiment 14：1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) -3 ethyls) urea preparation
It being synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- ethyl carbamides-boric acid pinacol ester,
6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 17.5%. m.p.216-220℃；1H
NMR (400MHz, DMSO-d6)δ(ppm)：8.64 (s, 1H), 8.27 (d, J=8.8Hz, 2H), 8.16 (s, 1H), 7.49 (d, J
=8.8Hz, 2H), 6.16 (t, J=5.6Hz, 1H), 4.13 (d, J=7.1Hz, 2H), 3.86-3.80 (m, 2H), 3.72-
3.63 (m, 2H), 3.24 (t, J=11.4Hz, 2H), 3.17-3.08 (m, 2H), 2.77 (s, 2H), 2.53-2.47 (m, 2H),
2.20-2.09 (m, 1H), 1.44 (d, J=14.4Hz, 2H), 1.34-1.26 (m, 2H), 1.20 (d, J=6.1Hz, 6H),
1.07 (t, J=7.2Hz, 3H) .MS m/z (M+H)+：494.6.
Embodiment 15：1- cyclopropyl -3- (4- (6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrroles
Mutter -4- bases) methyl) -9H- purine -2- bases) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- cyclopropyl urea-phenyl boric acid pinacol ester
It replaces, 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 17.4%.m.p.77-80℃；1H
NMR (400MHz, DMSO-d6)δ(ppm)：8.53 (s, 1H), 8.27 (d, J=8.6Hz, 2H), 8.16 (s, 1H), 7.51 (d, J
=8.6Hz, 2H), 6.44 (d, J=2.4 Hz, 1H), 4.14 (d, J=7.1Hz, 2H), 3.83 (d, J=11.1Hz, 2H),
3.72-3.63 (m, 2H), 3.24 (t, J=11.7Hz, 2H), 2.82-2.70 (m, 2H), 2.59-2.53 (m, 1H), 2.20-
2.12 (m, 1H), 1.48-1.38 (m, 2H), 1.33-1.26 (m, 2H), 1.21 (d, J=6.1Hz, 6H), 0.88-0.81 (m,
2H), 0.70-0.62 (m, 2H), 0.44-0.40 (m, 2H) .MS m/z (M+H)+：506.6.
Embodiment 16：1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) first
Base) -9H- purine -2- bases) phenyl) -3- phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains are replaced with 4- phenylureas-phenyl boric acid pinacol ester
It changes, 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 17.3%.m.p.217-221℃；1H NMR (400MHz, DMSO-d6)δ(ppm)：8.89 (s, 1H), 8.72 (s, 1H), 8.39-8.30 (m, 2H), 8.18 (s,
1H), 7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=7.6Hz, 2H), 7.30 (t, J=7.9Hz, 2H), 6.99 (t, J=
7.3Hz, 1H), 4.15 (d, J=7.0 Hz, 2H), 3.86-3.79 (m, 2H), 3.73-3.64 (m, 2H), 3.25 (t, J=
12.0Hz, 2H), 2.88-2.69 (m, 2H), 2.54-2.45 (m, 2H), 2.21-2.12 (m, 1H), 1.45 (d, J=16.3Hz,
2H), 1.36-1.25 (m, 2H), 1.21 (d, 6H) .MS m/z (M+H)+：542.6.
Embodiment 17：1- (2,4- difluorophenyl) -3- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysenes -
2H- pyrans -4- bases) methyl) -9H- urea element -2- bases) phenyl) urea preparation
It is synthesized by the synthetic method of 1 compound of embodiment, 2 side chains 4- (2,4-- difluorophenyl) urea-benzene boron
Sour pinacol ester is replaced, and 6 use (2R, 6S) -2,4,6- trimethyl morpholines obtain white powdery solids, yield 17.7%.
m.p.233-238℃；1H NMR (400MHz, DMSO-d6)δ(ppm)：9.24 (s, 1H), 8.57 (d, J=2.1Hz, 1H),
8.34 (d, J=8.8Hz, 2H), 8.18 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.33 (ddd, J=11.6,8.9,
2.9Hz, 1H), 7.10-7.04 (m, 1H), 5.76 (s, 1H), 4.15 (d, J=7.1Hz, 2H), 3.83 (dd, J=11.3,
2.4Hz, 2H), 3.69 (ddd, J=8.8,7.2,2.5Hz, 2H), 3.25 (t, J=11.5Hz, 2H), 2.85-2.71 (m,
2H), 2.55- 2.49 (m, 2H), 2.21-2.12 (m, 1H), 1.45 (d, J=12.0Hz, 2H), 1.32 (td, J=12.3,
11.8,3.9Hz, 2H), 1.21 (d, J=6.2Hz, 6H) .MS m/z (M+H)+：578.6.
Embodiment 18：MTOR inhibition of enzyme activity is tested
Evaluate inhibitory activity of the embodiment compound to mTOR enzymes.
Experiment material：HEPES (Sigma companies), EGTA (Sigma companies), MnCl2(Sigma companies), Tween-20
(Sigma companies), DTT (Sigma companies), ATP (Sigma companies), antibody LanthaScreen Tb-anti-p4E-BP1
(Thr46) Invitrogen companies are purchased from, mTOR enzymes, substrate GFP-4E-BP1 and TR-FRET buffer solution are purchased from Invitrogen
Company.Positive reference compound selects PKI-587.
Test reagent prepares：
(1) 99.9 μ l substrates GFP-4E-BPI (20.02 μM, stock), 1.5 μ lATP (10nM) are dissolved in 1898.6 μ l
Buffer solution in, obtain the substrate solution that final concentration is 0.4 μM of GFP-4E-BPI, 3 μM of ATP；
(2) 11.9 μ l mTOR (0.21mg/mL) are dissolved in the buffer solution of 1988.1 μ l, and it is 0.5 μ to obtain final concentration
The mTOR enzyme working solutions of g/mL；
(3) 5.16 μ l antibody Tb-anti-p4E-BP1,180 μ lEDTA are dissolved in 4314.8 μ l TR-FRET buffer solutions, are obtained
The detection solution of a concentration of 2nM antibody Tb-anti-p4E-BP1,10mM EDTA to the end.
Experiment process：
(1) it takes 5mM, 100 μM of positive drug to be dissolved in DMSO untested compound and is configured to solution to be measured, be added to taking 10 μ l
In 384 orifice plates；
(2) 3 times of DMSO serial dilutions are used, 11 points are diluted；
(3) take dilution in 1 μ l (2) and 19 μ l enzyme buffer liquids to another 384 orifice plate (black ProxiPlate)
In；
(4) solution in 4 μ l mTOR enzymes working solutions, 2 μ l (3) is added to be added to (black in 384 orifice plates again
ProxiPlate)；
(5) incubated at room temperature 15min；
(6) add 4 μ l substrate solution activating reactions again, continue to be incubated at room temperature 60min；
(7) 10 μ l detection buffer solutions is finally added to continue to be incubated 30min.
TR-FRET values are read on instrument,
IC50Calculation formula is：Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X)*HillSlope))；
X：Cpd concentration；Y：TR-FRET values；Top and Bottom：With Y commensurates；LogIC50：With X commensurates；
HillSlope：Slope.
The mTOR enzyme inhibition activities of 1 part of compounds of table
The experimental results showed that the IC of multiple embodiment compounds50Value has apparent mTOR enzymatic activitys all in nanomole grade.
Although the specific implementation mode of the present invention has obtained detailed description, it will be understood to those of skill in the art that：Root
According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change the guarantor in the present invention
Within the scope of shield.The full scope of the present invention is given by the appended claims and any equivalents thereof.
Claims (11)
1. compounds of formula I
Wherein：
X, Y is each independently selected from C, S, O, N and Se atom；
F, D is independently selected from C and N atoms；
E is C1-C6Alkyl；
A, U, V, W are independently selected from C or N atoms；
R1For C1-C6Alkyl, C3-C10Naphthenic base, C1-C6Alkoxy, C1-C6Alkylthio group, C3-C10Cycloalkyloxy, C1-C6Alkane alkenyl,
Ene alkynyl base heterocycle, Heterocyclylalkyl, substituted heterocycle alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle, wherein the C1-C6
Alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle it is unsubstituted or by 1,2,3,4 or 5 independently selected from
Following substituent group substitution：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano, C1-C6Alkylthio group, C1-C6Alkyl, C1-C6
Alkenyl, C1-C6Alkynyl and C1-C6Alkoxy, aromatic radical；
R2For hydrogen atom, hydroxyl, amino, C1-C6Alkyl, ester group；
R3、R4Respectively stand alone as one or more hydrogen atoms, hydroxyl, amino, C1-C6Alkyl；
2. compound according to claim 1, wherein
X, Y is each independently selected from C, S, O and N atom；
F, D is independently selected from C and N atoms；
E is C1-C6Alkyl；
A, U, V, W are C atoms；
R1For C1-C6Alkyl, C3-C10Naphthenic base, C1-C6Alkoxy, aromatic rings, aromatic heterocycle, the wherein described C1-C6Alkyl,
Aromatic rings, aromatic heterocycle are unsubstituted or are replaced independently selected from following substituent group by 1,2,3：-F,-Cl,-
Br ,-I, hydroxyl, C1-C6Alkyl and C1-C6Alkoxy；
R2For hydrogen atom, hydroxyl, C1-C6Alkyl, ester group；
R3、R4Respectively stand alone as one or more hydrogen atoms, C1-C6Alkyl；
3. compound according to claim 1 or 2, wherein
R1For methyl, ethyl, cyclopropyl, ethoxy, pyridin-3-yl, 4- (methylol) phenyl, phenyl, halogenophenyl；
X, Y is each independently selected from O atom；
F is C atoms, D is N atoms；
E is the carbochain for including 1 C atom；
A, U, V, W are C atoms；
R2For hydrogen atom；
R3、R4Respectively stand alone as a hydrogen atom or one or more methyl.
4. according to claim 1-3 any one of them compounds, selected from as follows：
1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) -3- (pyridine -3-
Base) urea；
1- (4- (hydroxymethyl) phenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -
2- yls) urea；
1- ethyls -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) urea；
1- methyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) urea；
1- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) -3- phenylureas；
1- (2,4- difluorophenyl) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases)
Phenyl) urea；
1- cyclopropyl -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenyl) urea；
6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) phenol；
1- (2- ethoxys) -3- (4- (6- morpholinoes -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) benzene
Base) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl)-(4- (methylol) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) -3- methyl) urea；
3- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2- bases) benzene
Phenol；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) -3- ethyls) urea；
1- cyclopropyl -3- (4- (6- ((2S, 6R) -2,6- thebaine generations) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -
9H- purine -2- bases) phenyl) urea；
1- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases) methyl) -9H- purine -2-
Base) phenyl) -3- phenyl) urea；
1- (2,4- difluorophenyl) -3- (4- (6- ((2S, 6R) -2,6- thebaines) -9- ((tetrahydrochysene -2H- pyrans -4- bases)
Methyl) -9H- urea element -2- bases) phenyl) urea.
5. the isomers of compound, pharmaceutical salt and hydrate described in claim 1-4.
6. the method for preparing the compound described in claim 1-4 comprising：
In the above method,
X, Y is each independently selected from C, S, O, N and Se atom；
F, D is independently selected from C and N atoms；
E is C1-C6Alkyl；
A, U, V, W are independently selected from C or N atoms；
R1For C1-C6Alkyl, C3-C10Naphthenic base, C1-C6Alkoxy, C1-C6Alkylthio group, C3-C10Cycloalkyloxy, C1-C6Alkane alkenyl,
Ene alkynyl base heterocycle, Heterocyclylalkyl, substituted heterocycle alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle, wherein the C1-C6
Alkyl, aromatic rings, aromatic heterocycle, benzo aromatic heterocycle it is unsubstituted or by 1,2,3,4 or 5 independently selected from
Following substituent group substitution：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano, C1-C6Alkylthio group, C1-C6Alkyl, C1-C6
Alkenyl, C1-C6Alkynyl and C1-C6Alkoxy, aromatic radical；
R2For hydrogen atom, hydroxyl, amino, C1-C6Alkyl, ester group；
R3、R4Respectively stand alone as one or more hydrogen atoms, hydroxyl, amino, C1-C6Alkyl；
7. according to claim 1-4 any one of them compound, its officinal salt or its hydrate or the drug of the present invention
Composition is preparing anticancer drug, immunosuppressor, mTOR inhibitors, the drug for inhibiting PI3K-Akt-mTOR path signals, suppression
T processed lymphopoietic drug, antiviral drugs, the drug for promoting apoptosis of tumor cells, makes the cell cycle stop at antibacterials
Stagnant drug in the G1 phases, the drug for preventing organ rejection response, drug, antiaging agent, the anti-A Erci for reducing arterial embolism
Purposes in sea silent medicine, anti-inflammatory drug or antibacterials.
8. the cancer types in claim 7 are including but not limited to liver cancer, lung tumor, breast cancer, leukaemia, colorectal cancer, ovary
The drug of cancer, glioma, prostate cancer or neuroendocrine carcinoma.
9. can inhibit mammalian body for producing according to claim 1-4 any one of them compound or its pharmaceutical salt
The purposes of the drug of interior mTOR enzymatic activitys.
10. can inhibit mammal for producing according to claim 1-4 any one of them compound or its pharmaceutical salt
The purposes of the drug of internal PI3K/Akt/mTOR signal path related enzyme activities.
11. pharmaceutical composition, it includes according to claim 1-4 any one of them compound or its pharmaceutical salt, isomery
Body, hydrate and at least one pharmaceutical carrier.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824701A (en) * | 2019-03-26 | 2019-05-31 | 武汉工程大学 | A kind of pyridothiazole compound and its preparation method and application |
| CN111875606A (en) * | 2020-07-20 | 2020-11-03 | 武汉工程大学 | Purine compound obtained based on virtual docking and preparation method and application thereof |
| CN112707907A (en) * | 2019-10-24 | 2021-04-27 | 张飞 | Novel purine derivative and intermediate thereof and application of purine derivative in preparation of anti-cancer drugs |
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2017
- 2017-05-05 CN CN201710310770.XA patent/CN108794478A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109824701A (en) * | 2019-03-26 | 2019-05-31 | 武汉工程大学 | A kind of pyridothiazole compound and its preparation method and application |
| CN109824701B (en) * | 2019-03-26 | 2021-08-13 | 武汉工程大学 | A kind of pyridothiazole compound and its preparation method and application |
| CN112707907A (en) * | 2019-10-24 | 2021-04-27 | 张飞 | Novel purine derivative and intermediate thereof and application of purine derivative in preparation of anti-cancer drugs |
| WO2021078141A1 (en) * | 2019-10-24 | 2021-04-29 | 苏州锐明新药研发有限公司 | Novel purine derivative, intermediate and application thereof in preparing anticancer medicine |
| CN112707907B (en) * | 2019-10-24 | 2023-05-23 | 张飞 | Purine derivative and intermediate thereof, and application of purine derivative and intermediate thereof in preparation of anti-cancer drugs |
| CN111875606A (en) * | 2020-07-20 | 2020-11-03 | 武汉工程大学 | Purine compound obtained based on virtual docking and preparation method and application thereof |
| CN111875606B (en) * | 2020-07-20 | 2023-04-07 | 武汉工程大学 | Purine compound obtained based on virtual docking and preparation method and application thereof |
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