CN109942562A - Five-ring heterocycles connection compound in triazine class containing heteroaryl structure and its preparation method and application - Google Patents
Five-ring heterocycles connection compound in triazine class containing heteroaryl structure and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of, and the five-ring heterocycles containing heteroaryl structure join compound in triazine class and preparation method thereof.Five-ring heterocycles of the present invention containing heteroaryl structure join compound in triazine class, and its pharmaceutically acceptable salt, hydrate or solvate are as active ingredient, it is prepared by mixing into composition with pharmaceutically acceptable carrier or excipients, and is prepared into clinically acceptable dosage form.Application of the compounds of this invention in preparation treatment and/or prevention proliferative disease drug, the application in the drug of preparation treatment and/or pre- anti-cancer, is applied in the drug of preparation treatment and/or prevention breast cancer, adenocarcinoma of colon and non-small cell lung cancer.
Description
Technical field
The present invention relates to five-ring heterocycles to join compound in triazine class, joins in particular to a kind of five-ring heterocycles containing heteroaryl structure
Compound in triazine class and its preparation method and application.
Background technique
Tumour is body under the effect of various carcinogenic factors, and the cell of local organization loses at the genetic level gives birth to it
Long normal regulation leads to the neoformation of paraplasm and differentiation and formation.The malignancy of tumour can destroy normal tissue
With organ, and other positions for being transferred to body cause serious organ function impaired, and then form cancer, that is, pernicious
Tumour seriously threatens human health.Malign lung tumor has become the lethal No.1 disease of developed country and development China
No. second lethal disease of family.The most of anti-tumor drug clinically applied at present by directly acting on cell because have
Silk division, synthesis and repair etc. processes and it is generally existing to solid tumor unsatisfactory curative effect, be easy to produce multidrug resistance and toxic side effect
The disadvantages of big.Include cell Proliferation since intracellular signal path is adjusted, adjust and die, survive, grow, shift, angiogenesis
Etc. a variety of vital movements, thus developmental function in the micromolecular inhibitor of critical sites on signal path and effect be antitumor
The new strategy of medicament research and development.These micromolecular inhibitors are compared with traditional tumor therapeutic agent often has better curative effect
With lesser toxic side effect.
PI3K/Akt/mTOR signal path is the important component of intracellular pathways network, it tumour generation,
Extremely important effect is played in development and transfer.PI3K is the molecules upstream of PI3K/Akt/mTOR access, abnormal sharp
Work can cause a series of reaction, control cell growth, proliferation, differentiation, adjust die, shift, being metabolized, transcription and translation etc. it is more
Kind cell biological processes.PI3K is as the critical sites on PI3K/Akt/mTOR signal path, and catalytic subunit is all kinds of
By extensive high expression in tumour cell.Therefore malignant tumour is treated as target spot using PI3K, causes the extensive pass of scientists
Note, so becoming one of the hot spot of neoplasm targeted therapy using PI3K as the research of the anti-tumor drug of target spot.
The cyclopean family that PI3K is made of lipid and serine/threonine kinases, including several phosphinositides kinases and
Protein kinase such as ATM, ATR and DNA-PK etc. that DNA is relied on, it can make the third position di of phosphatidylinositols, generate
Inositol lipid material with second messenger's effect --- phosphatidylinositols -3- phosphate ester (PIP3).Second messenger PIP3 can make
PI3K is combined with the pairing of the effector (especially Akt) in downstream, so as to cause film recruitment and phosphorylation.The study found that wide
PI3K access is generally lacked of proper care in general human tumor, and dysfunction caused by certain gene mutations or missing can cause in the access
Normal cell turnover promotes tumor cell proliferation and survival and the invasion and migration of mediate tumor cell, therefore PI3K is small point
The sub- ideal target site of inhibitor, provides chance for the treatment of cancer.
GDC-0941 is the oral PI3K inhibitor developed by Genentech company, and Phase I clinical trial is completed at present.
IC of the GDC-0941 to p110- α and-δ50Value reaches 3nM, also shows very well to the inhibitory activity of the enzymes such as p110- β and-γ
Inhibitory activity (IC50Respectively 33 nM, 75nM), but it is weaker to the inhibiting effect of mTOR.Preclinical study shows GDC-
0941 pair of a variety of human tumor cell line (including glioblastoma, breast cancer cell, prostate gland cancer cell etc.) shows to show
The Inhibit proliferaton of work acts on, IC50Value reaches 0.009ug/mL.In nude mouse in Anticancer Activities, when oral dose is
75mg/kg reaches 80% or more to the growth inhibition rate of tumour.Later, genentech corp carries out the inhibitor of the type
Deeper into research, filter out multiple selectivity or double inhibitor, such as PI3K/mTOR double inhibitor GNE-477
(Bioorganic&Medicinal Chemistry Letters, 2010,20 (8): 2408-2411), GDC-0980
(Mol.Cancer Ther., 2011,10 (12): 2,426 2436.) etc..GDC-0941, GNE-477, GDC-0980 structure are such as
Shown in lower.
The present inventor carries out the Thienopyrimidine parent nucleus of GDC-0941 on the basis of bibliography and early-stage study
Skeleton transition, and pyrimidine ring is replaced with triazine ring, design has synthesized a series of five-ring heterocycles connection triazines containing heteroaryl structure
Class compound, through in vitro to various tumor cell strains carry out antitumor activity screening, the results showed that its anti-tumor activity quite or
Better than anti-tumor drug GDC-0941, and have to adenocarcinoma of colon highly selective, being expected to develop has better than guide's chemical combination
The targeting anti-tumor inhibitor of object GDC-0941.
Summary of the invention
It is an object of the invention to provide a kind of, and the five-ring heterocycles containing heteroaryl structure join compound in triazine class and its preparation side
Method and application.
The present invention provides the five-ring heterocycles as shown in general formula I containing heteroaryl structure and joins compound in triazine class, its geometrical isomerism
Body and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, general formula I are as follows:
Wherein:
R1、R2It is identical or different, separately it is selected from (C1~C6) alkyl or (C3~C6) naphthenic base, ethoxy, sulfydryl
Ethyl or R1And R25~10 yuan of saturated heterocyclyls are formed together with the nitrogen-atoms being connect with them, the saturated heterocyclyl removes
And R1And R2Outside the nitrogen-atoms of connection, the hetero atom of O, N and S are optionally selected from containing 1~3；
X is selected from S, O or-NR5；
R3、R4、R5Selected from hydrogen, (C1~C4) alkyl；
Ar is saturated selected from phenyl, naphthalene, 5~10 unit's heteroaryls, 5~10 yuan or the heterocycle of fractional saturation, the benzene
Base, naphthalene, heteroaryl and heterocycle contain 1~3 hetero atom for being selected from O, N or S, and Ar optional 1~4 identical or different
R6Replace；
R6Selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, sulfydryl, C1
~C4Alkyl, C3~C6Naphthenic base, C1~C4Alkenyl, C1~C4Alkynyl, C1~C4Alkoxy, C1~C4Alkylthio group, allyl, (2-
Methyl) allyl, C1~C4Alkoxy methyl, C1~C4Alkyl acyl, C1~C3The substituent group of alkylenedioxy group.
Present invention is preferably related to compound, its geometric isomer and its pharmaceutically acceptable salt of such as above-mentioned general formula I,
Hydrate, solvate or prodrug, in which:
It is selected from:
X is selected from S；
R3、R4、R5Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl；
Ar is selected from
The five-ring heterocycles connection compound in triazine class containing heteroaryl structure of the general formula I is one in following compounds
Kind, but these compounds are not meant to any limitation of the invention:
3- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base)
Phenol,
3- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- three
Piperazine -2- base) phenol,
3- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) phenol,
3- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
5- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2-
Amine,
5- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine,
5- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base)
Pyrimidine -2- amine,
5- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- three
Piperazine -2- base) pyrimidine -2- amine,
5- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2-
Amine,
5- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine,
N1((5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) first
Base)-N1, N2, N2Trimethylethane -1,2- diamines,
5- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -2-
Amine,
4- (4- (1H- indazole -4- base) -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base)
Morpholine,
4- (4- (1H- indazole -4- base) -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base)
Quinoline,
4- (4- (1H- indazole -4- base) -6- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -1,3,5- three
Piperazine -2- base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -
1,3,5- triazine pyridine -2- base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2-
Base) morpholine,
N- ((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N-
Ethyl ethamine,
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N1,
N2, N2Trimethylethane -1,2- diamines,
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) thiophene -2- base)-N, N- diformazan
Base methylamine,
5- (4- (4- methyl-5- ((4- (methyl sulphonyl) piperazine-1- base) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) pyrimidine -2- amine,
N1((5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2-
Base) methyl)-N1, N2, N2Trimethylethane -1,2- diamines,
5- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine,
5- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) pyrimidine -2- amine,
3- (4- (4- methyl-5- ((4- (methyl sulphonyl) piperazine-1- base) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) phenol,
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) -4- methylthiophene -2- base) -6-
Quinoline generation -1,3,5- triazine -2- base) phenol,
3- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
4- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) phenol,
4- (4- (1H- indazole -4- base) -6- (4- methyl -5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -
2- yl) -1,3-, 5- triazine -2- base) morpholine,
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2- base)
Methyl)-N1, N2, N2Trimethylethane -1,2- diamines,
5- (4- (1H- indazole -4- base) -6- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2-
Base) morpholine,
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) -3 methyl thiophene -2- base)-N,
N- dimethyl methylamine,
2,2'- (((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2-
Base) methyl) azane diyl) bis- (ethane -1- alcohol),
(S) -2- (((5- (4- (1H- indazole -4- base) -6- (3- methyl morpholine generation) -1,3,5- triazine -2- base) thiophene -
2- yl) methyl) (methyl) amino) second -1- alcohol,
(R) -3- (4- (5- ((bis- (2- mercaptoethyl) amino) methyl) -4- methylthiophene -2- base) -6- (3- methyl
Quinoline generation) -1,3,5- triazine pyridine -2- base) phenol,
(R) -3- (4- (5- (((2- mercaptoethyl) (methyl) amino) methyl) thiophene -2- base) -6- (3- methyl morpholine
Generation) -1,3,5- triazine -2- base) phenol.
Following synthetic route describes the five-ring heterocycles connection compound in triazine class containing heteroaryl structure of general formula I of the present invention
Preparation, all raw materials be all by mode described in synthetic route, by organic chemistry filed those of ordinary skill it is ripe
It is the method preparation known or commercially available.Finally the five-ring heterocycles containing heteroaryl structure join compound in triazine class to whole of the invention
It is all to be prepared by method described in synthetic route or by similar method, these methods are organic chemistry necks
Domain is well-known to the ordinarily skilled artisan.In the whole variable factors applied in synthetic route definition as follows or such as claim
Definition.
The present invention obtains compound 2 by suzuki coupling reaction by compound 1, and compound 3 occurs necleophilic reaction and obtains
Compound 4, then compound 4 and the generation of compound 2 suzuki coupling reaction obtain compound 5, next proceed through suzuki
Coupling reaction obtains compound 6, and final compound 6 is miscellaneous by five containing heteroaryl structure yuan that reductive amination process obtains general formula I
Ring joins compound in triazine class.
According to some usual methods of the art, the amide structure containing biaryl of above-mentioned general formula I in the present invention
Heterocycle miazines compound can with acid generate pharmaceutically acceptable salt.Pharmaceutically acceptable addition salts include inorganic acid and have
Machine acid-addition salts, the salt with following sour addition is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
P-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, grass
Acid, tartaric acid, benzoic acid etc..
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is above-mentioned general formula I
Derivative, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as
Pass through metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" alkylidene "
Refer to the alkylidene of linear chain or branched chain；" naphthenic base " refers to substituted or unsubstituted naphthenic base；" saturation or fractional saturation it is miscellaneous
Ring group " refers to containing one or more heteroatomic monocycles or polycyclic cyclic annular system for being selected from N, O, S, as pyrrolidinyl,
Quinoline base, piperazinyl, piperidyl, pyrazolidinyl, imidazolidinyl and thiazolinyl etc..
The present invention can contain the five-ring heterocycles connection compound in triazine class and its pharmacy containing heteroaryl structure of above-mentioned general formula I
Upper acceptable salt, hydrate or solvate mix system with pharmaceutically acceptable carrier or excipients as active ingredient
Standby and to be prepared into clinically acceptable dosage form at composition, above-mentioned pharmaceutically acceptable excipients refer to any can be used for
Diluent, adjuvant and/or the carrier of pharmaceutical field.Derivative of the invention can be applied in combination with other active ingredients, only
Them are wanted not generate other unfavorable effects, such as allergic reaction.
The five-ring heterocycles connection compound in triazine class containing heteroaryl structure of the above-mentioned general formula I of the present invention is used for the clinical agent of patient
Amount can basis: active constituent therapeutic efficiency in vivo and bioavilability, their metabolism and discharge rate and patient's
Age, gender, disease phase carry out appropriate adjustment, but adult daily dosage generally should be 10~500mg, preferably
50~300mg.Therefore, when pharmaceutical composition of the invention is made into unit dosage forms, it is contemplated that above-mentioned effective dose, every list
Position preparation should join compound in triazine class containing the five-ring heterocycles containing heteroaryl structure of the above-mentioned general formula I of 10~500mg, preferably
50~300mg.According to the guidance of doctor or pharmacist, these preparations can divide at certain intervals several times administration (preferably one to
Six times).
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common taxes in drug field
Shape agent.Several dosage form as described above can using injection, tablet, capsule, aerosol, suppository, film, pill,
The drug forms such as externally-applied liniment, ointment.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive,
Lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix
Deng.Pharmaceutical preparation can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if certain
Drug is unstable under the conditions of stomach, can be configured to enteric coated tablets.
Reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-proliferate drug list
Solely use, or can with the anti-proliferate Drug combination that has listed, for treating and/or preventing proliferative disease,
Such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
The compounds of this invention has inhibition tumor cell growth activity in vitro, therefore, it may be used as preparation treatment and/
Or the drug of pre- anti-cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone
Marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma etc..
By inhibiting human breast carcinoma MCF-7, human colon adenocarcinoma CaCo-2, non-small cell lung cancer A549 activity test in vitro,
The compounds of this invention significantly inhibits effect to TG, it is especially useful in preparation treatment and/or prevention breast cancer, adenocarcinoma of colon and non-
The drug of Small Cell Lung Cancer.
It is found by testing PI3Ka enzymatic activity, the compounds of this invention has significant inhibition PI3Ka kinase activity, right
The highly expressed human breast carcinoma of PI3Ka, human colon adenocarcinoma, non-small cell lung cancer etc. have stronger inhibiting effect, it is especially useful in preparation
The drug for the treatment of and/or prevention human colon adenocarcinoma.
It is independent that reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-tumor drug
It uses, or can be with the anti-tumor drug (such as the platinum medicine cis-platinum, camptothecine Irinotecan, Changchun that have listed
Flower bases drug Noviburn, deoxidation born of the same parents' former times class drug gemcitabine, etoposide, taxol etc.) it is used in combination.Combination therapy
By by each therapeutic component simultaneously, sequence or separate administration and realize.
Specific embodiment
In order to better explain the present invention, below in conjunction with specific embodiment, the present invention is described in further detail, but
Limiting the invention for they.
Embodiment is intended to illustrate and be not intended to limit the scope of the invention.The nuclear magnetic resonance spectroscopy of derivative is used
BrukerARX-400 measurement, mass spectrum are measured with Agilent 1100LC/MSD；Agents useful for same is that analysis is pure or chemical pure.
The five-ring heterocycles containing heteroaryl structure of general formula I join compound in triazine class:
The structural formula of the embodiment of the present invention 1~40 is as shown in table 1 below.
The structural formula of 1 Examples 1 to 40 of table
Embodiment 1
5- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2-
Amine；
The synthesis of step A 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) thiophene -2-formaldehyde
By 1.68g 5- bromothiophene -2- formaldehyde, 3.4g duplex pinacol base diborane, bis- (triphenylphosphine) dichloros of 756mg
Change palladium and 2.587g potassium acetate is added in Isosorbide-5-Nitrae-dioxane solution, in N2Lower protection is stirred 6 hours at 80 DEG C.By adding
Water quenching reaction, and extracted by methylene chloride.By organic phase Na2SO 4It is dry, and be concentrated under reduced pressure.Pass through silica gel chromatograph
Method (petroleum/methylene chloride=1/3) purification of crude product, obtains target compound, is yellow solid, yield 88.7%.
The synthesis of step B 4- (the chloro- 1,3,5- triazine -2- base of 4,6- bis-) morpholine
Under condition of ice bath, 1.7g morpholine is slowly added dropwise into acetone (50ml) solution of the 5.0g Cyanuric Chloride of stirring
With acetone (50ml) solution of 1.9g triethylamine, react 30 minutes.Gained mixture is quenched with water, is filtered, with water and Leng Jia
Alcohol is washed and is dried, and obtains target target compound, is white solid, yield: 98%.
The synthesis of step C 5- (the chloro- 6- morpholino -1,3,5- triazine -2- base of 4-) thiophene -2-formaldehyde
By 5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolane -2- base) thiophene -2-formaldehyde, 24- (4,6- bis-
Chloro-1,3,5-triazines -2- base) morpholine (825mg), bis- (triphenylphosphine) palladium chlorides of 226mg and potassium carbonate are added to water
In Isosorbide-5-Nitrae-dioxane (60mL) solution of (8mL), in N2Under protection, stirred 2 hours at 70 DEG C.Then reaction is mixed
Object is cooled to room temperature and distributes between EtOAc and water.Concentration of organic layers obtains target by column chromatography eluting residue
Compound is yellow solid, yield: 70%.
Step D 5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- formaldehyde
Synthesis
By 5- (the chloro- 6- morpholino of 4- -1,3,5-triazines -2- base) thiophene -2-formaldehyde (250mg), 5- (4,4,5,5- tetra-
Methyl-[1,3,2] dioxaborolan alkane -2- base)-pyrimidine -2-base amine (76mg), bis- (triphenylphosphine) dichlorides of 350mg
Palladium and potassium carbonate are added in Isosorbide-5-Nitrae-dioxane (60mL) solution of water (8mL), in N2Under protection, 8 are stirred at 140 DEG C
Hour.Reaction mixture is cooled to room temperature and is distributed between EtOAc and water.Concentration of organic layers, by column chromatography eluting
Residue obtains target compound, is yellow solid, yield: 46%.
Step E 5- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base)
The synthesis of pyrimidine -2- amine
By 100mg 5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5-triazines -2- base) thiophene -2-formaldehyde,
90mg pyrrolidines is added to 50ml 1, in 2- dichloroethane solution, acetic acid is then added dropwise into solution to pH=6, stirring 12 is small
When, sodium triacetoxy borohydride is then added, stirs 48 hours.By adding sodium bicarbonate aqueous solution quenching reaction, and pass through
Methylene chloride extraction.Concentration of organic layers obtains target compound by column chromatography eluting residue, is yellow solid, receives
Rate: 60%
ESI-MS[M+H](m/z):424.18
1H NMR(400MHz,CDCl3)δ9.29(s,2H),7.97(s,1H),6.97(s,1H),5.57 (s,2H),3.98
(s, 4H), 3.83 (d, J=5.8Hz, 6H), 2.60 (s, 4H), 1.25 (s, 4H)
According to the method for embodiment 1, first with different substituted phenylboric acid pinacol esters and 5- (the chloro- 6- morpholine of 4-
Generation -1,3,5- triazine -2- base) thiophene -2-formaldehyde and 5- (the chloro- 6- morpholino -1,3,5- triazine -2- base of 4-) -3- methyl thiazolium
Different substituted intermediates are made in the reaction of pheno -2- formaldehyde；Later again with formulaIt is reacted according to the method for step E,
2~40 compound of embodiment is made respectively
Embodiment 2
5- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2- amine
ESI-MS[M+H](m/z):440.17
Embodiment 3
5- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base)
Pyrimidine -2- amine
ESI-MS[M+H](m/z):453.21
Embodiment 4
5- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- three
Piperazine -2- base) pyrimidine -2- amine
ESI-MS[M+H](m/z):517.17
1H NMR(400MHz,DMSO-d6) δ 9.30 (s, 2H), 7.97 (d, J=3.6Hz, 1H), 6.97 (d, J=
3.7Hz, 1H), 5.62 (s, 2H), 4.00 (s, 4H), 3.81 (d, J=4.6Hz, 4H), 3.76 (s, 2H), 2.59 (s, 8H),
2.35(s,3H).
Embodiment 5
5- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2- amine
ESI-MS[M+H](m/z):438.20
Embodiment 6
5- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine
ESI-MS[M+H](m/z):426.20
Embodiment 7
N1((5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) first
Base)-N1, N2, N2Trimethylethane -1,2- diamines
ESI-MS[M+H](m/z):455.22
1H NMR(400MHz,DMSO-d6) δ 9.30 (s, 2H), 7.97 (d, J=3.6Hz, 1H), 6.97 (d, J=
3.7Hz, 1H), 5.62 (s, 2H), 4.00 (s, 4H), 3.81 (d, J=4.6Hz, 4H), 3.76 (s, 2H), 2.59 (s, 8H),
2.35(s,3H).
Embodiment 8
5- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine
ESI-MS[M+H](m/z):398.16
Embodiment 9
3- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):437.19
1H NMR(400MHz,CDCl3) δ 8.01 (d, J=7.6Hz, 1H), 7.93 (d, J=3.4Hz, 2H), 7.35 (t, J
=7.7Hz, 1H), 7.05 (d, J=7.1Hz, 1H), 6.97 (s, 1H), 3.97 (d, J=20.2Hz, 6H), 3.82 (s, 4H),
2.66(s,4H),1.70(s,4H),1.45(s,2H).
Embodiment 10
3- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):439.17
1H NMR(400MHz,CDCl3) δ 8.16 (d, J=7.8Hz, 1H), 8.08 (d, J=3.5Hz, 2H), 7.50-
7.41(m,1H),7.20–7.07(m,2H),4.12(s,4H),3.90(s,12H).
Embodiment 11
3- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base)
Phenol
ESI-MS[M+H](m/z):452.20
Embodiment 12
3- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- three
Piperazine -2- base) phenol
ESI-MS[M+H](m/z):516.16
Embodiment 13
3- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):423.17
1H NMR(400MHz,CDCl3) δ 8.02 (d, J=7.7Hz, 1H), 7.91 (d, J=10.9Hz, 2H), 7.33 (d,
J=7.4Hz, 1H), 7.02 (d, J=13.6Hz, 2H), 3.98 (s, 6H), 3.80 (s,
4H),2.76(s,4H),1.87(s,4H).
Embodiment 14
3- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):425.19
1H NMR(400MHz,DMSO-d6) δ 9.68 (s, 1H), 7.96 (d, J=3.6Hz, 1H), 7.87 (d, J=
8.3Hz, 2H), 7.31 (t, J=7.8Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=7.5 Hz, 1H), 3.91 (d, J=
15.0Hz, 4H), 3.78 (s, 2H), 3.70 (s, 4H), 3.33 (s, 4H), 0.99 (t, J=7.0Hz, 6H)
Embodiment 15
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):454.22
Embodiment 16
3- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):397.16
Embodiment 17
4- (4- (1H- indazole -4- base) -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base)
Morpholine
ESI-MS[M+H](m/z):461.20
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.44(s,1H),8.06(s,1H),7.71 (s,1H),7.52
(s,1H),7.10(s,1H),4.08(s,4H),3.85(s,6H),2.61(s,4H),1.71(s, 6H).
Embodiment 18
4- (4- (1H- indazole -4- base) -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) morpholine
ESI-MS[M+H](m/z):463.18
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.45(s,1H),8.05(s,1H),7.71 (s,1H),7.54
(s, 1H), 7.05 (s, 1H), 4.08 (s, 4H), 3.82 (d, J=20.0Hz, 12H)
Embodiment 19
4- (4- (1H- indazole -4- base) -6- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -1,3,5- three
Piperazine -2- base) morpholine
ESI-MS[M+H](m/z):476.21
Embodiment 20
4- (4- (1H- indazole -4- base) -6- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -
1,3,5- triazine pyridine -2- base) morpholine
ESI-MS[M+H](m/z):540.17
1H NMR(400MHz,DMSO-d6) δ 9.09 (s, 1H), 8.44 (d, J=7.1Hz, 1H), 8.04 (s, 1H), 7.70
(d, J=8.5Hz, 1H), 7.53 (d, J=7.2Hz, 1H), 7.01 (s, 1H), 4.08 (s, 4H), 3.87 (d, J=19.7Hz,
6H),3.30(s,3H),2.80(s,4H),2.66(s,4H).
Embodiment 21
4- (4- (1H- indazole -4- base) -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2-
Base) morpholine
ESI-MS[M+H](m/z):447.18
Embodiment 22
N- ((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N-
Ethyl ethamine
ESI-MS[M+H](m/z):449.20
Embodiment 23
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N1,
N2, N2Trimethylethane -1,2- diamines
ESI-MS[M+H](m/z):478.23
Embodiment 24
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) thiophene -2- base)-N, N- diformazan
Base methylamine
ESI-MS[M+H](m/z):421.17
Embodiment 25
5- (4- (4- methyl-5- ((4- (methyl sulphonyl) piperazine-1- base) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) pyrimidine -2- amine
ESI-MS[M+H](m/z):531.18
Embodiment 26
N- (5- (4- morpholino -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) pyridine -2- base) -5- (4- tri-
Trifluoromethylphenyl) picolinamide
ESI-MS[M+H](m/z):469.24
Embodiment 27
5- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine
ESI-MS[M+H](m/z):454.19
Embodiment 28
5- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) pyrimidine -2- amine
ESI-MS[M+H](m/z):412.18
Embodiment 29
3- (4- (4- methyl-5- ((4- (methyl sulphonyl) piperazine-1- base) methyl) thiophene-2- base) morpholino-1-6-,
3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):530.18
Embodiment 30
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) -4- methylthiophene -2- base) -6-
Quinoline generation -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):468.23
Embodiment 31
3- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):453.18
Embodiment 32
5- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) phenol
ESI-MS[M+H](m/z):411.17
Embodiment 33
4- (4- (1H- indazole -4- base) -6- (4- methyl -5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -
2- yl) -1,3-, 5- triazine -2- base) morpholine
ESI-MS[M+H](m/z):554.19
Embodiment 34
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2- base)
Methyl)-N1, N2, N2Trimethylethane -1,2- diamines
ESI-MS[M+H](m/z):492.24
Embodiment 35
4- (4- (1H- indazole -4- base) -6- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2-
Base) morpholine
ESI-MS[M+H](m/z):477.19
Embodiment 36
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) -3 methyl thiophene -2- base)-N,
N- dimethyl methylamine
ESI-MS[M+H](m/z):435.18
Embodiment 37
2,2'- (((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2-
Base) methyl) azane diyl) bis- (ethane -1- alcohol)
ESI-MS[M+H](m/z):495.21
Embodiment 38
(S) -2- (((5- (4- (1H- indazole -4- base) -6- (3- methyl morpholine generation) -1,3,5- triazine -2- base) thiophene -
2- yl) methyl) (methyl) amino) second -1- alcohol
ESI-MS[M+H](m/z):465.19
Embodiment 39
(R) -3- (4- (5- ((bis- (2- mercaptoethyl) amino) methyl) -4- methylthiophene -2- base) -6- (3- methyl
Quinoline generation) -1,3,5- triazine pyridine -2- base) phenol
ESI-MS[M+H](m/z):517.16
Embodiment 40
(R) -3- (4- (5- (((2- mercaptoethyl) (methyl) amino) methyl) thiophene -2- base) -6- (3- methyl morpholine
Generation) -1,3,5- triazine -2- base) phenol
ESI-MS[M+H](m/z):457.16
The pharmacological research of product of the present invention
In vitro cytotoxic effect
External suppression has been carried out to the five-ring heterocycles connection compound in triazine class containing heteroaryl structure of general formula I according to the invention
Non-small cell lung cancer A549 processed, breast cancer MCF-7, adenocarcinoma of colon CaCo-2 screening active ingredients, reference substance GDC-0941 is according to document
(J.Med.Chem., 2008,51 (18), pp 5522-5532) the method is prepared.
1) after 2~3 stabilizations of cell recovery and passage, make it from culture bottle bottom with trypsin solution (0.25%)
Digestion is got off.After cell dissociation buffer is poured into centrifuge tube, culture solution is added later to terminate digestion.By centrifuge tube in 800r/
It is centrifuged 10min under min, 5mL culture solution is added after discarding supernatant liquid, piping and druming mixes cell, draws 10 μ L cell suspensions and is added
It is counted in cell counting board, adjustment cell concentration is 104A/hole.Except the hole A1 is that blank well is not added extracellularly in 96 orifice plates,
It is remaining that 100 μ L cell suspensions are all added.96 orifice plates are put into incubator and are cultivated for 24 hours；
2) with 50 μ L dmso solution given the test agent, appropriate culture solution is then added, sample is made to be dissolved into 2mg/mL
Then sample is diluted to 20,4,0.8,0.16,0.032 μ g/mL in 24 orifice plates by medical fluid；
3 holes are added in each concentration, wherein surrounding two rows, two column cell growing way is affected by environment larger, it is only and thin for blank
Hilum uses.96 orifice plates are put into incubator and cultivate 72h；
3) band medicine culture solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole
Middle 100 μ L of addition MTT (tetrazole) (0.5mg/mL) is put into incubator after 4h, discards MTT solution, and dimethyl sulfoxide is added
100μL.Oscillation dissolves survivaling cell sufficiently with MTT reaction product formazan on magnetic force oscillator, is put into microplate reader and measures
As a result.Drug IC can be found out by Bliss method50Value.
The non-small cell lung cancer A549 of compound, breast cancer MCF-7, adenocarcinoma of colon CaCo-2 Activity Results such as 2 institute of table
Show.
The experiment of PI3K α enzymatic activity
1, solution is prepared
1) untested compound adds 1mL DMSO, is made into 10mM storage solutions.Positive compound GDC-0941 storing liquid concentration
For 10mM (being dissolved in DMSO), the storing liquid concentration of positive compound cis-platinum is 2mM (being dissolved in DMSO).
2) DMSO diluted compounds storing liquid is used, 2mM solution (100X) is made into.
3) the 2mM solution of 2 μ L is taken, 18 μ L reaction solution diluted compounds are added to 200 μM of (10X) solution.
4) the above-mentioned solution of 2 μ L and 18 μ L reaction solutions are added in working plate, are made into 10X solution.
5) it takes with 1 μ L of solution in upper plate to detection plate.
6) 1 μ L kinase reaction liquid is added in the full inhibition control and null suppression control wells of detection plate, so that
The concentration of DMSO is 10%.
2, experimental procedure
1) layout of orifice plate
384 orifice plates is needed to arrange according to experiment, in which:
A) HPE (complete to inhibit control): kinases and compound is not added, adds ATP, substrate and 1%DMSO.
B) ZPE (null suppression control): compound is not added, adds kinases, ATP, substrate and 1%DMSO.
C) positive reference compound hole: add kinases, ATP, substrate and various concentration positive compound.
D) untested compound hole: add kinases, ATP, substrate and untested compound.
2) agents useful for same is prepared
4XATP: ATP is diluted to 4X with reaction solution.
4X substrate solution: substrate is diluted to 4X with reaction solution.
2.5X kinase solution: with reaction solution by kinase dilution to 2.5X.
3) kinase reaction
A) molten according to arrangement 1 μ L10X compound (positive control of untested compound or various kinases) of every hole addition
Liquid is complete to inhibit control and null suppression control wells that 1 μ L reaction solution is added.
B) 4 μ L2.5X kinase solutions are added according to the every hole of arrangement.It is complete to inhibit control wells that 4 μ L reaction solutions are added.
C) it will test plate 1000rpm centrifugation to mix.
D) 4XATP solution is mixed in equal volume with 4X substrate solution, obtains 2XATP- substrate solution.
E) the above-mentioned 2XATP- substrate solution of 5 μ L is added according to the every hole of arrangement.
F) it will test plate 1000rpm centrifugation to mix.
G) it will test plate and be placed in 30 DEG C of reactions 1 hour.
H) 10 μ LKinase glo plus or ADP-Glo reaction reagents are added in every hole, and 27 DEG C are placed 20 minutes.
I) 20 μ LKinase Detection reagents are added in every hole, and 27 DEG C are placed 30 minutes.
J) Envision reads fluorescence values.
Note: needing preset room temperature before the use of Kinase glo plus, ADP-Glo and Kinase Detection reagent
Half an hour.
4) primary data analysis
Prism5.0 analyzes initial data.
The IC of compound is calculated according to Bliss method50
Experimental result is as shown in table 2.Inhibiting rate in table 2 >=80%, it is indicated with " +++ ", 80% > inhibiting rate >=60%,
It is indicated with " ++ ", 60% > inhibiting rate >=40%, it is indicated with "+", inhibiting rate≤40% is indicated with "-", and " ND " expression is not surveyed
Examination.
2 target compound anti tumor activity in vitro of table and enzymatic activity
From above-mentioned test result it can be clearly seen that the compound of the claimed general formula I of the present invention, has good
Anti tumor activity in vitro, quite or be better than anti-tumor drug GDC-0941.
The compound of formula of I of the present invention can be administered alone, but usually give with pharmaceutical carrier mixture, the medicine
It will be according to required route of administration and standard pharmaceutical practice, separately below with the various drugs of such compound with the selection of carrier
Dosage form, such as the preparation side of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment
Method illustrates its new opplication in pharmaceutical field.
Application examples 1: tablet
100 are pressed into after adding auxiliary material 20g to mix according to the general pressed disc method of pharmacy with 1 compound 10g of embodiment,
Every slice weight 300mg.
Application examples 2: injection
Activated carbon adsorption is carried out, through 0.65 μm of miillpore filter according to pharmacy conventional method with 6 compound 10g of embodiment
After filtering, hydro-acupuncture preparation is made in filling nitrogen gas tank, and every dress 2mL is filling 100 bottles total.
Application examples 3: pill
It is instilled in cryogenic liquid paraffin after being mixed with matrix 50g heating fusings such as gelatin with 7 compound 10g of embodiment,
1000 ball of dripping pill is made altogether.
Application examples 4: film
With 10 compound 10g of embodiment, will be dissolved by heating after the stirrings such as polyvinyl alcohol, medicinal glycerin, water expansion, 80 mesh
The screen to filtrate, then 18 compound of embodiment is added to stirring and dissolving in filtrate, film applicator is film-made 100.
Application examples 5: aerosol
It after distilled water and other spoke material are added, is made after the dissolution of appropriate propylene glycol with 16 compound 10g of embodiment
The clear solution of 500mL to obtain the final product.
Application examples 6: suppository
With 18 compound 10g of embodiment, by finely ground addition glycerol it is appropriate, the glycerin gelatine melted is added after grinding well,
Grinding uniformly, is poured into the model for having applied lubricant, and suppository 50 is made.
Application examples 7: externally-applied liniment
With 21 compound 10g of embodiment, according to the auxiliary materials 2.5g mixed grinding such as conventional dose method and emulsifier, then
Add distilled water obtained to 200mL.
Application examples 8: ointment
With 25 compound 10g of embodiment, ground well after finely ground with oleaginous bases 500g such as vaseline obtained.
Application examples 9: capsule
With 27 compound 10g of embodiment be packed into hollow glue after auxiliary material 20g being mixed according to the requirement of pharmacy capsule
Capsule, each capsule weight 300mg.
Although describing the present invention by specific embodiment, modification and equivalent variations are for being proficient in this field
Technical staff for will be apparent from, and they are included within the scope of the invention.
Claims (6)
1. a kind of five-ring heterocycles containing heteroaryl structure join compound in triazine class, which is characterized in that structure is as shown in the following general formula I:
Wherein:
R1、R2It is identical or different, separately it is selected from (C1~C6) alkyl or (C3~C6) naphthenic base, ethoxy, mercaptoethyl,
Or R1And R2Be formed together 5~10 yuan of saturated heterocyclyls with the nitrogen-atoms being connect with them, the saturated heterocyclyl in addition to R1
And R2Outside the nitrogen-atoms of connection, the hetero atom of O, N and S are optionally selected from containing 1~3；
X is selected from S, O or-NR5；
R3、R4、R5Selected from hydrogen, (C1~C4) alkyl；
Ar is saturated selected from phenyl, naphthalene, 5~10 unit's heteroaryls, 5~10 yuan or the heterocycle of fractional saturation, the phenyl, naphthalene
Base, heteroaryl and heterocycle contain 1~3 hetero atom for being selected from O, N or S, and optional 1~4 identical or different R of Ar6It takes
Generation；
R6Selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, sulfydryl, C1~C4Alkane
Base, C3~C6Naphthenic base, C1~C4Alkenyl, C1~C4Alkynyl, C1~C4Alkoxy, C1~C4Alkylthio group, allyl, (2- methyl)
Allyl, C1~C4Alkoxy methyl, C1~C4Alkyl acyl, C1~C3The substituent group of alkylenedioxy group.
2. the five-ring heterocycles according to claim 1 containing heteroaryl structure join compound in triazine class, it is characterised in that:
It is selected from:
X is selected from S；
R3、R4、R5Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl；
Ar is selected from
3. the five-ring heterocycles according to claim 1 containing heteroaryl structure join compound in triazine class, it is characterised in that: described logical
The compound of Formulas I is selected from one of following compounds:
3- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) phenol,
3- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) thiophene -2- base) -6- morpholino -1,3,5-
Triazine -2- base) phenol,
3- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
5- (4- morpholino -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2- amine,
5- (4- morpholino -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine,
5- (4- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -
2- amine,
5- (4- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2-
Base) pyrimidine -2- amine,
5- (4- morpholino -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) pyrimidine -2- amine,
5- (4- (5- ((diethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -2- amine,
N1((5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N1,
N2, N2Trimethylethane -1,2- diamines,
5- (4- (5- ((dimethylamino) methyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -2- amine,
4- (4- (1H- indazole -4- base) -6- (5- (piperidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- ((4- methylpiperazine-1-yl) methyl) thiophene -2- base) -1,3,5- triazine -2-
Base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -1,3,5-
Triazine pyridine -2- base) morpholine,
4- (4- (1H- indazole -4- base) -6- (5- (pyrrolidin-1-yl methyl) thiophene -2- base) -1,3,5- triazine -2- base)
Quinoline,
N- ((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N- ethyl second
Amine,
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) thiophene -2- base) methyl)-N1, N2, N2-
Trimethylethane -1,2- diamines,
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) thiophene -2- base)-N, N- dimethyl methyl
Amine,
5- (4- (4- methyl -5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5-
Triazine -2- base) pyrimidine -2- amine,
N1((5- (4- (2- aminopyrimidine -5- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2- base) first
Base)-N1, N2, N2Trimethylethane -1,2- diamines,
5- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) pyrimidine -2- amine,
5- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) is phonetic
Pyridine -2- amine,
3- (4- (4- methyl -5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2- base) -6- morpholino -1,3,5-
Triazine -2- base) phenol,
3- (4- (5- (((2- (dimethylamino) ethyl) (methyl) amino) methyl) -4- methylthiophene -2- base) -6- morpholino -
1,3,5- triazine -2- base) phenol,
3- (4- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) phenol,
3- (4- (5- ((dimethylamino) methyl) -4- methylthiophene -2- base) -6- morpholino -1,3,5- triazine -2- base) benzene
Phenol,
4- (4- (1H- indazole -4- base) -6- (4- methyl -5- ((4- (methyl sulphonyl) piperazine -1- base) methyl) thiophene -2-
Base) -1,3-, 5- triazine -2- base) morpholine,
N1((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2- base) methyl) -
N1, N2, N2Trimethylethane -1,2- diamines,
4- (4- (1H- indazole -4- base) -6- (4- methyl -5- (morpholinomethyl) thiophene -2- base) -1,3,5- triazine -2- base)
Quinoline,
1- (5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5-triazines -2- base) -3 methyl thiophene -2- base)-N, N- bis-
Methyl methylamine,
2,2'- (((5- (4- (1H- indazole -4- base) -6- morpholino -1,3,5- triazine -2- base) -3 methyl thiophene -2- base) first
Base) azane diyl) bis- (ethane -1- alcohol),
(S) -2- (((5- (4- (1H- indazole -4- base) -6- (3- methyl morpholine generation) -1,3,5- triazine -2- base) thiophene -2- base)
Methyl) (methyl) amino) second -1- alcohol,
(R) -3- (4- (5- ((bis- (2- mercaptoethyl) amino) methyl) -4- methylthiophene -2- base) -6- (3- methyl morpholine generation) -
1,3,5- triazine pyridine -2- base) phenol, (R) -3- (4- (5- (((2- mercaptoethyl) (methyl) amino) methyl) thiophene -2-
Base) -6- (3- methyl morpholine generation) -1,3,5- triazine -2- base) phenol.
4. a kind of five-ring heterocycles containing heteroaryl structure as described in any one of claim 1-3 join compound in triazine class,
Application in preparation treatment and/or prevention proliferative disease drug.
5. a kind of five-ring heterocycles containing heteroaryl structure as described in any one of claim 1-3 join compound in triazine class,
Application in the drug of preparation treatment and/or pre- anti-cancer.
6. a kind of five-ring heterocycles containing heteroaryl structure as described in any one of claim 1-3 join compound in triazine class,
Application in the drug of preparation treatment and/or prevention breast cancer, adenocarcinoma of colon and non-small cell lung cancer.
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