CN107556267A

CN107556267A - Novel thiazole derivates class compound, its preparation method, pharmaceutical composition and its pharmaceutical applications

Info

Publication number: CN107556267A
Application number: CN201610494461.8A
Authority: CN
Inventors: 钟武; 李松; 曹爽; 曹瑞源; 杨晶晶
Original assignee: Institute of Pharmacology and Toxicology of AMMS
Current assignee: Institute of Pharmacology and Toxicology of AMMS
Priority date: 2016-06-30
Filing date: 2016-06-30
Publication date: 2018-01-09

Abstract

The invention belongs to field of medicine and chemical technology, it is related to the compound of Formula I inhibited to mammal PI3K/Akt/mTOR signal paths and its pharmaceutically useful salt or hydrate, the definition of each substituted radical is as used in the description in formula I；The preparation method of compound of Formula I：Include 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 medicine is produced, the medicine are dynamic due to disease caused by PI3K/Akt/mTOR path signal unconventionality expressions for treating lactation.

Description

Novel thiazole derivates class compound, its preparation method, pharmaceutical composition and its pharmacy Purposes

Technical field

The present invention relates to thiazolidine derivatives compound, for field of antineoplastic medicaments and PI3K/Akt/mTOR paths The invention further relates to the preparation method of these compounds, the pharmaceutical composition containing them by relevant disease caused by signal is not normal And their applications as medicine.

Background technology

PI3K/Akt/mTOR signal paths mainly comprising PI3K (phosphoinositide-3-kinase, PI3K), Tri- members of Akt, mTOR.PI3K is a kind of esterase, is primarily present under quiescent condition in kytoplasm；PI3K is urged after being fully active Change substrate PIP2 and be changed into PIP3, PIP3 activates the Akt in downstream as second messenger.Akt is PI3K downstreams key protein, is one Kind evolve upper highly conserved serine/threonine protein kitase, it is under quiescent condition to be located in cytoplasm more；The Akt being activated Phosphorylatable suppression TSC1/2 formation, and then Rheb is discharged, it is final to activate downstream mTORC.MTOR belong to serine/ Serineprotein kinase family, possess two hypotypes of mTORC1 and mTORC2, it be cell growth and propagation important regulation because Son；When cell is stimulated by the external nourishment factor or growth factor signal, intracellular mTOR can activate some related targets of downstream Albumen, and then the metabolism to whole cell is positively or negatively regulated and controled with growth.PI3K/Akt/mTOR signal paths participate in adjusting A variety of life processes of ganglion cell, such as：Growth, propagation, albumen synthesis, transcription and the metabolic process of cell.PI3K/Akt/ The abnormal signal of mTOR paths can cause a variety of diseases, including tumour, arterial embolism, early ageing, Alzheimer's disease, excessive immune Deng.

To suppress the expression of the abnormal signal of PI3K/Akt/mTOR paths, people have studied a variety of kinase inhibitors, including： PI3K inhibitor and mTOR inhibitors.Further, since PI3K and mTOR protein three-dimensional structure has height in ATP join domains Homology, so some compounds have two kinds of kinase inhibition abilities, i.e. PI3K/mTOR double inhibitors simultaneously.

It is rapamycin and its derivative that the mono- inhibitor classics of mTOR, which represent medicine, and the mono- inhibitor of mTOR is easily caused medicine and supported Anti-, rapamycin derivative suppresses that Akt feedback activation can be produced during mTOR, causes reactivating for PI3K signal paths, Therefore rapamycin is limited to the rejection ability of tumour cell in inhibiting tumour cells experiment in vitro.

The mono- inhibitor of PI3K can be avoided due to suppression mTOR and the activation of caused Akt feedbacks, but because PI3K is located at MTOR upstream positions, it is limited to the influence power of downstream signal individually to suppress PI3K.PI3K/mTOR double inhibitors have stronger Rejection ability, it is also possible to bringing more obvious side effect.

The content of the invention

The purpose of the present invention is to find and develop the novel compounds with PI3K/Akt/mTOR path signal functions are suppressed Thing, for treating and preventing the various diseases related to PI3K/Akt/mTOR abnormal signals.

Research finds have the function that following compounds of formula I has and suppress PI3K and mTOR transition activations, therefore can For treating and preventing the various disease s related to PI3K and mTOR abnormal signals

Compound selection benzothiazole structure described in the invention is female ring, and in 2 of phenylpropyl alcohol thiazole and 4 introducings Two morpholine ring structures, add the binding ability of compound and mTOR and PI3K.These compound structures are novel, to normal thin Cellular toxicity is weaker, and compared with the PI3K/Akt/mTOR pathway inhibitors such as rapamycin with having reported for work, has higher to swollen Tumor cell proliferation rejection ability.

On the one hand, the present invention relates to compounds of formula I, its all possible isomers or its pharmaceutically useful salt or hydration Thing.

The present invention relates to compound of formula I

Wherein：

X, Y is each independently selected from C, S, O, N and Se atom；

A, U, V, W are independently selected from C or N atoms；

R₁For C₁-C₆Alkyl, C₃-C₁₀Cycloalkyl, 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 Substitute selected from following substituent：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano group, C₁-C₆Alkylthio group, C₁-C₆Alkyl, C₁-C₆Alkenyl, C₁-C₆Alkynyl and C₁-C₆Alkoxy, aromatic radical；

R₂、R₃Each stand alone as hydrogen atom, hydroxyl, amino, C₁-C₆Alkyl, ester group；

R₄、R₅Each stand alone as one or more hydrogen atoms, hydroxyl, amino, C₁-C₆Alkyl；

In a preferred embodiment,

R₁For methyl, ethyl, cyclopropyl, benzyl, pyridin-3-yl, 4- (4- methylpiperazine-1-yls) phenyl, 4- (hydroxyl first Base) phenyl, trifluoromethoxy, halogenophenyl；

X, Y is each independently selected from C, S, O and N atom；

R₂、R₃Each stand alone as hydroxyl, isopropyl, carbethoxyl group；

R₄、R₅Each stand alone as one or more methyl

The present invention is more particularly directed to compound of Formula I or its pharmaceutically useful salt or hydrate preferably below compound：

1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- ethyl carbamides；

1- cyclopropyl -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea；

1- benzyls -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea；

Tolylene urea between 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3-；

1- (2,4- difluorophenyl) -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea；

1- ethyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea；

1- cyclopropyl -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea；

1- benzyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea；

Tolyl urea between 1- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) -3-；

1- (2,4- difluorophenyl) -3- (4- (2 morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea；

1- (4- (4- ((2S, 6R) -2,6- methyl morpholines base) -2- thio-morpholinyls benzothiazol-6-yl) phenyl) -3- second Base urea；

1- (2,4- difluorophenyl) -3- (4- (4- ((2S, 6R) -2,6- dimethylated morpholinyls) -2- morpholinobenzothiazoles - 6- yls) phenyl) urea；

1- ethyls -3- (4- (2- morpholinyls -4- (piperidin-1-yl) benzothiazol-6-yl) phenyl) urea；

1- (2,4- difluorophenyl) -3- (4- (2- morpholinyls -4- (piperidin-1-yl) piperidin-1-yl -6- bases) phenyl) urea；

4- (6- (4- (3- ethyl carbamides) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid second Ester；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- ethyls Urea；

1- (2,4- difluorophenyl) -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazoles - 6- yls) phenyl) urea；

4- (6- (4- (3- ethyl carbamides) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid second Ester；

1- ethyls -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea；

1- (2,4- difluorophenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) benzene Base) urea；

1- ethyls -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea；

1- (2,4- difluoroaniline) -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) benzene Base) urea；

1- ethyls -3- (4- (4- morpholine -2s-(piperidin-1-yl) benzothiazol-6-yl) phenyl) urea；

1- (2,4- difluoroaniline) -3- (4- (4- morpholinyls -2- (piperidin-1-yl) benzothiazol-6-yl) phenyl) urea；

1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- MUs；

1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea；

1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (methylol) phenyl) urea；

1- (4- (2,4- dimethyl-benzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) urea；

4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine Piperazine -1- carboxylic acid, ethyl esters；

1- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methyl Piperazine -1- bases) phenyl) urea；

1- (4- (methylol) phenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) Phenyl) urea；

1- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) Urea；

1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methyl piperazines Piperazine -1- bases) phenyl) urea；

1- (4- (methylol) phenyl) -3- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) benzene Base) urea；

1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) Urea；

4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine Piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- (4- (methylol) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acids Ethyl ester；

4- (4- morpholinyls -6- (4- (3- (pyridin-3-yl) urea) phenyl) benzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl esters；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (methylol) phenyl) urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyrroles Pyridine -3- bases) urea；

4- (6- (4- (3- cyclopropyl urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (2- morpholinyls -6- (4- (3- isophthalic MU) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- benzylureas) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- MUs) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

4- (6- (4- (3- (4- (methylol) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acids Ethyl ester；

4- (2- morpholinyls -6- (4- (3- (pyridin-3-yl) urea) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

1- cyclopropyl -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- isophthalic MU；

1- benzyls -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) Urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- methyl Urea；

4- (2- morpholinyls -6- (4- (3- (4- (trifluoromethoxy) phenyl) urea) phenyl) benzothiazole -4- bases) piperazine -1- Carboxylic acid, ethyl ester；

And its officinal salt or hydrate.

The invention further relates to the suitable pharmaceutically useful salt or hydrate of the compound as shown in formula I, wherein pharmaceutically useful 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 Into salt and with various organic acids, such as maleic acid, malic acid, fumaric acid, butanedioic 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, it is 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 dynamic isomer is present, and the present invention includes the form of its all existence forms, particularly pure isomer.Different Isomeric forms with the isomer separation of various conventional means and other forms or can be split, or certain isomers can 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 percentage by weight).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% The compound or its pharmaceutically useful derivative as shown in formula I.

On the other hand, the present invention relates to the synthetic method 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 can not be bought, it is provided here Preparation method, or they can be prepared by the method for document report.

Specifically, the invention provides compound of Formula I or the method for its officinal salt or hydrate is prepared, it includes Step described in method below：

In the above method,

X, Y is each independently selected from C, S, O, N and Se atom；

Z is selected from F, Cl, Br, I atom；

A, U, V, W are independently selected from C or N atoms；

In a preferred embodiment,

X, Y is each independently selected from C, S, O and N atom；

Z is selected from Cl, Br, I atom；

A, U, V, W are selected from C atoms；

R₂、R₃Each stand alone as hydroxyl, isopropyl, carbethoxyl group；

R₄、R₅Each stand alone as one or more methyl.

Compound of Formula I can use the single synthesis of conventional method, and what also available combination was chemical mix-divides method or parallel projects Method with storehouse (at least containing two, or 5-1000, preferably 10-100 compound in each storehouse) for unit synthesis, you can Solid phase synthesis process can also be used to synthesize in the liquid phase.

See embodiment on preparing the more detailed data of compound of Formula I.

Another aspect of the present invention be related to compound, its officinal salt or its hydrate any one of the present invention or The pharmaceutical composition of the person present invention is preparing antineoplastic, immunodepressant, PI3K inhibitor, mTOR inhibitors, suppression The medicine of PI3K-Akt-mTOR path signals, suppress the lymphopoietic medicines of T, antibacterials, antiviral drugs, promotion The medicine of apoptosis of tumor cells, make cell cycle arrest in the medicine of G1 phases, the medicine for preventing organ rejection response, reduction artery Purposes in the medicine of embolism, antiaging agent, anti-Alzheimer disease medicine, anti-inflammatory drug or antibacterials；Specifically, institute Antineoplastic is stated as treatment and/or prevention and/or interior point of auxiliary treatment kidney, lymthoma, lung cancer, liver cancer, breast cancer, nerve Secrete the medicine of cancer or stomach cancer.

The present invention is related in another further aspect a kind of in vivo or extracorporeal anti-tumor, to be suppressed immune, suppress PI3K, suppresses MTOR, suppress PI3K-Akt-mTOR signal paths, suppress T lymphopoiesis, be antitumor, promote apoptosis of tumor cells, be anti- Bacterium, it is antiviral, make cell cycle arrest in G1, reduce arterial embolism, anti-aging, anti-Alzheimer disease, prevent organ rejection The method of reaction, anti-inflammatory or antibacterial, including the use of the compound any one of the present invention of effective dose, 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 pharmaceutically useful salt can be used alone, or with it is pharmaceutically useful Carrier or excipient are used in the form of pharmaceutical composition together, when in the form of pharmaceutical composition in use, generally 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 Appropriate administration form or dosage form is made in conjunction, and this program includes mixing component by suitable mode, being granulated, compressing Or dissolving.Therefore, the invention provides pharmaceutical composition, it include compounds of formula I, its all possible isomers or its Pharmaceutically useful salt or hydrate and at least one pharmaceutically useful carrier.

The Pharmaceutical composition of the compounds of this invention, it can be granted with the any-mode of following aspect：Orally, spraying sucks, is straight Enteral administration, nasal-cavity administration, vagina administration, local administration, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, in pin, ventricle In interior, breastbone or intracranial injection or input, or the reservoir medication by a kind of explant, wherein preferably orally, intramuscular injection, intraperitoneal 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 formulation, solid dosage forms.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, warm suspension type.Other Formulation 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..

Conventional carrier can also be contained in the pharmaceutical composition of the present invention, pharmaceutical acceptable carrier described here include but not office It is limited to：Ion-exchanger, aluminum 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 Tie up plain material, polyethylene glycol, CMC, 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, such as filler, lactose, sucrose, cornstarch, calcium phosphate, sorbierite, amion acetic acid, lubricant are such as hard Fatty acid magnesium, talcum, polyethylene glycol, tripoli, such as disintegrant, farina, or acceptable dibutyl phthalate, such as bay sodium alkoxide sulfuric acid Salt.Tablet can be coated with known method in pharmaceutics.

The suspension of water and oil can be made in oral liquid, solution, emulsion, syrup, dry product can also be made, with preceding supplement Water or other suitable mediums.This liquid preparation can include conventional additive, 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 (edible oil may be included), such as almond Pool, grease such as Gan Bo, ethylene glycol, or ethanol；The rotten agent of sun, such as to even yl benzoic acid first vinegar or the third vinegar, sorbic acid.If desired for can add Add flavor enhancement or colouring agent.

Suppository can include conventional suppository base, such as cocoa butter or other glyceride.

To being offerd medicine outside stomach, liquid forms are generally made up of compound and a kind of carrier of sterilization.Carrier first choice water.According to institute The difference of carrier and drug concentration is selected, compound both dissolved in and aaerosol solution is may be made as in carrier, and injection solution is being made When it is first that compound is soluble in water, filtering sterilization after be fitted into sealed bottle or ampoule.

When topical application, the form of appropriate ointment, lotion, or creme can be made in the compounds of this invention, its Middle active component is suspended or dissolved in the carrier of one or more.The carrier that wherein ointment formulation can use includes but not office It is limited to：Mineral oil, Albolene, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water；Lotion Include but is 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.

Weight can be contained according to the difference of administering mode, in component than 0.1%, or more suitably weight compares 10-60% Active component.But when unit dose is included in component, each unit preferably includes 50-500 milligram active components.According to administration The difference of approach and administration frequency, the suitable therapeutic doses for adult are daily 100-3000 milligrams, such as daily 1500 milligrams. 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 optimal dosage of compound of Formula I and interval are administered by compound property and such as What the external condition such as form, path and position and the specific mammal treated determined, and this optimal dosage can Determined with conventional technique.Simultaneously also it should be appreciated that the optimal course for the treatment of, i.e. compound of Formula I are daily within the specified time Dosage, can be determined with method well known in the art.

Term " C₁-C₆Alkyl " refers to the straight or branched alkyl with 1-4 carbon atom, for example, methyl, ethyl, propyl group, Isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, 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 with 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, and difference is to replace oxygen atom For sulphur atom.

Term " C₃-C₁₀Cycloalkyl " refers to the saturated carbon ring group with 3-10 carbon atom.The cycloalkyl 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.This paper ring a heatable brick bed base can be unsubstituted or as described in detail, in one or more commutable positions Substituted by various groups.For example, these cycloalkyl optionally can be substituted 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_}- C₆Haloalkyl, C₁-C₆Halogenated alkoxy.C₃-C₆Cycloalkyl can also do similar understanding.

Term " C₃-C₁₀Cycloalkyloxy " refers to the saturated carbon ring alkoxy base with 3-10 carbon atom.The cycloalkanes oxygen Base can be monocyclic or polycyclic fused system, and can condense on aromatic ring.The example of these groups include ring propoxyl group, Cyclobutoxy group, cyclopentyloxy and cyclohexyloxy.This paper ring a heatable brick bed base can be it is unsubstituted or as describe in detail, at one or Multiple commutable positions are substituted by various groups.For example, these cycloalkyloxies optionally can be substituted 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_}-C₆Haloalkyl, 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 including ethene 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 including 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 there is monocyclic (such as phenyl), polycyclic (such as xenyl) or wherein at least one Ring is the aromatic carbocyclyl groups of multiple fused rings (such as 1,2,3,4- tetralyls, naphthyl) of armaticity, its 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, its Fusion 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 for being selected from nitrogen, oxygen or sulphur.The example of heteroaryl is pyridine radicals, 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 " heterocyclic radical " refer to one or more carbocyclic ring system of five-, six- or seven-membered ring, and it is wrapped The fusion ring system of 4-10 atom is included, the ring system contains at least one and most four hetero atoms for being selected from nitrogen, oxygen or sulphur, bar Part is that the ring of the group is free of two adjacent O or S atom.Fusion ring system can be heterocycle of the fusion on virtue group group.It is excellent The heterocycle of choosing include but is not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, piperidyl, morpholine ring, Hexamethylene ring, piperazine ring etc., they can be substituted 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_}-C₆Haloalkyl, C₁- C₆Halogenated alkoxy.

When for " in vivo ", term " effective dose " refers to can to realize treatment, prevention in subject, 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 treating, preventing, mitigating and/or delaying Solve the animal of disease or illness of the present invention, particularly mammal, such as people, dog, monkey, ox, horse etc..

Term " disease and/or illness " refers to a kind of condition of the subject, the condition and institute of the present invention State disease and/or illness is relevant.

Brief description of the drawings

Fig. 1：The phosphorus in S6K1 Thr389 sites and Akt Ser473 sites in embodiment compound on tumor cell A549 It is acidified suppression situation

Embodiment

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.Unreceipted tool in embodiment Concrete conditions in the establishment of a specific crime person, the condition suggested according to normal condition or manufacturer are carried out.Agents useful for same or the unreceipted production firm person of instrument, For the conventional products of acquisition purchased in market can be passed through.

Melting point compound is determined by SRY-1 types melting point apparatus, and temperature is not calibrated.1H-NMR spectrum are by VARIAN INOVA 600 type nuclear magnetic resonance spectrometers determine；Mass spectrum is determined by API-150EX LC/MS high-resolution mass spectrometers.

Embodiment 1：The preparation of 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- ethyl carbamides

Step 1：The preparation of 2,4,6- tribromo isothiocyanates (intermediate 1)

2,4,6- tribromanilines (20g, 60.6mmol) are added in dichloromethane (100ml) at room temperature, after dissolved clarification Thiophosgene (20.9g, 181.8mmol) is disposably added into dichloromethane.By DMAP (DMAP) (37.01g, Dichloromethane (100ml) 303mmol) is dissolved in, is slowly dropped in 1h in reaction solution, stirring reaction stops reaction after 5 hours.Post Chromatograph to obtain 2,4,6- tribromo isothiocyanates (21.41g, 57.6mmol, yield 95%).

Step 2：The preparation of the bromo- benzothiazole (intermediate 2) of 2- morpholinyls -4,6- bis-

2,4,6- tribromo isothiocyanates (21.41g, 57.6mmol) are dissolved in dioxane (250ml) at room temperature, added Enter morpholine (5.27g, 60.48mmol), stirring reaction 30min.After raw material total overall reaction, addition cesium carbonate (28.15g, 86.4mmol) and 105 DEG C are warming up to, stirring reaction 3h.Solvent under reduced pressure is evaporated rear column chromatography, obtains white 2- morpholines -4,6- bis- Bromo- benzothiazole (20.04g, 52.99mmol, yield 92%).

Step 3：The preparation of the 2- morpholinyl bromo- benzothiazoles of -4- morpholinyls -6- (intermediate 3)

By the 2- morpholine bromo- benzothiazoles of -4- morpholines -6- (20.04g, 52.99mmol), morpholine (5.54g, 63.59mmol), three (dibenzalacetone) two palladium (3.4g, 3.71mmol), R-BINAP (2.31g, 3.71mmol), cesium carbonate In (25.89g, 79.49mmol) input DMF (200ml), 90 DEG C are heated to, reacts 8h under nitrogen protection.After reaction terminates, Extracted with water/dichloromethane, then column chromatography obtains the mixture of 4 substitutions and 6 substitutions.6 times are dissolved in after mixture is heated The ethyl acetate of amount, 0-5 DEG C of crystallization obtain white 2- morpholines -4- morpholines -6- bromo- benzothiazole (9.16g, 23.85mmol, yield 45%).Step 4：The preparation of 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- ethyl carbamides

By intermediate 13 (9.16g, 23.85mmol), 4- ethyl carbamides-phenyl boric acid pinacol ester side chain (10.38g, 35.78mmol), tetra-triphenylphosphine palladium (1.93g, 1.67mmol), potassium carbonate (9.89g, 71.55) are dissolved in glycol dimethyl ether (200ml) and distilled water (40ml) composition in the mixed solvent, react 3h in 80 DEG C under nitrogen protection.Solvent under reduced pressure is evaporated Column chromatography afterwards, obtain white powder 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- ethyl carbamide sterlings (8.59g, 18.36mmol, yield 77%).m.p.256-260℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.51 (s, 1H), 7.64 (s, 1H) 7.56 (d, 2H, J=8.0Hz), 7.46 (d, 2H, J=8.0Hz), 6.96 (s, 1H), 6.12 (t, 1H, J =4.0Hz, J=4.0Hz), 3.81 (s, 4H), 3.75 (s, 4H), 3.53 (s, 4H), 3.37 (s, 4H), 3.12 (m, 2H), 1.06 (m, 3H)；EI-MS：468.2[M+1]⁺。

Embodiment 2：The preparation of 1- cyclopropyl -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are changed to 4- isopropyls urea-phenyl boric acid pinacol Ester, obtain white powder 1- cyclopropyl -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea sterling (total recovery： 27.2%).m.p.238-240℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.39 (s, 1H), 7.64 (s, 1H) 7.56 (d, 2H, J=8.0Hz), 7.47 (d, 2H, J=8.0Hz), 6.96 (s, 1H), 6.41 (s, 1H), 3.80 (s, 4H), 3.75 (s, 4H), 3.53 (s, 4H), 3.38 (s, 4H), 3.12 (m, 2H), 1.99 (s, 1H), 1.17 (t, 1H, J=8.0Hz), 0.65 (d, 2H, J= 8.0Hz), 0.41 (s, 2H)；EI-MS：480.1[M+1]⁺。

Embodiment 3：The preparation of 1- benzyls -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are changed to 4- benzyls urea-phenyl boric acid pinacol Ester, it is (total to receive to obtain white powder 1- benzyls -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea mTOR-20 sterlings Rate：24.5%).m.p.252-255℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.68 (s, 1H), 7.64 (s, 1H) 7.58 (d, 2H, J=8.0Hz), 7.48 (d, 2H, J=8.0Hz), 7.33 (m, 4H), 7.25 (m, 1H), 6.96 (s, 1H), 6.66 (t, 1H, J=4.0Hz), 4.32 (s, 2H, J=4.0Hz), 3.80 (s, 4H), 3.75 (s, 4H), 3.54 (s, 8H)；EI-MS：530.2 [M+1]⁺。

Embodiment 4：The preparation of tolylene urea between 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3-

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are changed to aminomethyl phenyl urea-phenyl boric acid frequency between 4- That alcohol ester, tolylene urea sterling is (total to receive between obtaining white powder 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- Rate：30.1%).m.p.240-244℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.68 (s, 1H), 7.64 (s, 1H) 7.58 (d, 2H, J=8.0Hz), 7.48 (d, 2H, J=8.0Hz), 7.33 (m, 4H), 7.25 (m, 1H), 6.96 (s, 1H), 6.66 (t, 1H, J=4.0Hz), 4.32 (s, 2H, J=4.0Hz), 3.80 (s, 4H), 3.75 (s, 4H), 3.54 (s, 8H)；EI-MS：530.4 [M+1]⁺。

Embodiment 5：The system of 1- (2,4- difluorophenyl) -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea It is standby

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are changed to 4- (2,4- difluoro-benzene base) urea-benzene Boric acid pinacol ester, obtain white powder 1- (2,4- difluorophenyl) -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) benzene Base) urea sterling (total recovery：31.5%).m.p.244-247℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.22 (s, 1H), 8.61 (s, 1H) 8.09 (m, 1H), 7.67 (s, 1H), 7.63 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.33 (m, 1H), 6.97 (s, 1H), 3.81 (s, 4H), 3.74 (s, 4H), 3.53 (s, 4H), 3.37 (s, 4H)；EI-MS：552.2[M+ 1]⁺。

Embodiment 6：The preparation of 1- ethyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are changed to thiomorpholine, obtain pale yellow powder 1- ethyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea sterling (total recovery：24.5%). m.p.240-243℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.51 (s, 1H), 7.62 (s, 1H) 7.55 (d, 2H, J= 8.0Hz), 7.46 (d, 2H, J=8.0Hz), 6.98 (s, 1H), 6.11 (t, 1H, J=8.0Hz), 3.75 (s, 4H), 3.60 (s, 4H), 3.52 (s, 4H), 3.11 (m, 2H), 2.79 (d, 4H, J=8.0Hz), 1.06 (t, 3H, J=8.0Hz)；EI-MS：484.5 [M+1]⁺。

Embodiment 7：The system of 1- cyclopropyl -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea It is standby

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are changed to thiomorpholine, and 6 side chains are changed to 4- Isopropyl urea-phenyl boric acid pinacol ester, obtain white powder 1- cyclopropyl -3- (4- (2- morpholinyl -4- thio-morpholinyl benzos Thiazole -6- bases) phenyl) urea sterling (total recovery：26.7%).m.p.244-246℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.39 (s, 1H), 7.63 (s, 1H) 7.56 (d, 2H, J=8.0Hz), 7.47 (d, 2H, J=8.0Hz), 6.99 (s, 1H), 6.41 (t, 1H, J=8.0Hz), 3.75 (s, 4H), 3.60 (s, 4H), 3.55 (s, 4H), 2.79 (d, 4H), 0.63 (m, 2H), 0.41 (m, 2H)；EI-MS：496.4[M+1]⁺。

Embodiment 8：The preparation of 1- benzyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are changed to thiomorpholine, and 6 side chains are changed to 4- Benzylurea-phenyl boric acid pinacol ester, obtain white powder 1- benzyls -3- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazole - 6- yls) phenyl) urea sterling (total recovery：30.7%).m.p.250-252℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.93 (s, 1H), 7.63 (s, 1H) 7.53 (d, 2H, J=12.0Hz), 7.50 (d, 2H, J=8.0Hz), 7.32 (m, 4H), 7.26 (m, 1H), 6.98 (s, 1H), 4.31 (d, 2H, J=4.0Hz), 3.75 (d, 4H, J=8.0Hz), 3.60 (s, 4H), 3.55 (s, 4H), 2.79 (d, 3H), 0.63 (m, 2H), 0.41 (m, 2H)；EI-MS：546.4[M+1]⁺。

Embodiment 9：Tolyl urea between 1- (4- (2- morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) phenyl) -3- Prepare

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are changed to thiomorpholine, and 6 side chains are changed to 4- Isophthalic MU-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- morpholinyl -4- thio-morpholinyl benzothiazoles -6- Base) phenyl) tolyl urea sterling (total recovery between -3-：24.7%).m.p.241-242℃；¹H-NMR (400MHz, DMSO-d₆δ Ppm), 8.75 (s, 1H), 8.62 (s, 1H), 7.65 (s, 1H) 7.62 (d, 2H, J=12.0Hz), 7.53 (d, 2H, J= 8.0Hz), 7.31 (s, 1H), 7.23 (d, 1H, J=12.0Hz), 7.18 (d, 1H, J=8.0Hz), 7.00 (s, 1H), 6.81 (s, 1H), 3.76 (s, 4H), 3.61 (s, 4H), 3.54 (s, 4H), 2.80 (s, 4H), 2.28 (s, 3H)；EI-MS：546.4[M+1]⁺。

Embodiment 10：1- (2,4- difluorophenyl) -3- (4- (2 morpholinyl -4- thio-morpholinyls benzothiazol-6-yl) benzene Base) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with thiomorpholine, 6 side chain 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester is replaced, and obtains white powder 1- (2,4- difluorophenyl) -3- (4- (2- Quinoline base -4- thio-morpholinyls benzothiazol-6-yl) phenyl) urea sterling (total recovery：22.8%).m.p.224-226℃；¹H- NMR (400MHz, DMSO-d₆δ ppm), 8.53 (s, 1H), 8.10 (m, 1H), 7.66 (s, 1H), 7.63 (dd, 4H, J= 8.0Hz), 7.33 (m, 1H), 7.06 (t, 1H), 7.01 (s, 1H), 3.76 (s, 4H), 3.62 (s, 4H), 3.54 (s, 4H), 2.80 (s, 4H)；EI-MS：568.3[M+1]⁺。

Embodiment 11：1- (4- (4- ((2S, 6R) -2,6- methyl morpholines base) -2- thio-morpholinyls benzothiazol-6-yl) Phenyl) -3- ethyl carbamides preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, obtain white powder 1- (4- (4- ((2S, 6R) -2,6- methyl morpholines base) -2- thio-morpholinyls benzothiazol-6-yl) Phenyl) -3- ethyl carbamide sterling (total recoverys：21.9%).m.p.266-268℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.50 (s, 1H), 7.60 (m, 1H), 7.53 (d, 2H, J=8.0Hz), 7.46 (d, 2H, J=8.0Hz), 6.92 (s, 1H), 6.10 (t, 1H, J=4.0Hz), 3.99 (d, 2H), 3.76 (m, 6H), 3.52 (m, 4H), 3.11 (m, 2H), 2.35 (t, 2H)；EI-MS： 496.4[M+1]⁺。

Embodiment 12：1- (2,4- difluorophenyl) -3- (4- (4- ((2S, 6R) -2,6- dimethylated morpholinyls) -2- morpholinyls Benzothiazol-6-yl) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester, obtain white powder 1- (2,4- difluoros Phenyl) -3- (4- (4- ((2S, 6R) -2,6- dimethylated morpholinyls) -2- morpholinobenzothiazole -6- bases) phenyl) urea sterling is (always Yield：23.4%).m.p.268-270℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.52 (s, 1H), 8.10 (m, 1H), 7.64 (m, 3H), 7.53 (m, 2H), 7.33 (m, 1H), 7.06 (m, 1H), 6.95 (s, 1H), 4.01 (d, 2H, J =4.0Hz), 3.77 (m, 8H), 3.53 (m, 4H), 2.36 (m, 2H), 1.15 (d, 6H)；EI-MS：579.6[M+1]⁺。

Embodiment 13：The system of 1- ethyls -3- (4- (2- morpholinyls -4- (piperidin-1-yl) benzothiazol-6-yl) phenyl) urea It is standby

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with piperidines, obtain white powder 1- Ethyl -3- (4- (2- morpholinyls -4- (piperidin-1-yl) benzothiazol-6-yl) phenyl) urea sterling (total recovery：22.6%). m.p.236-238℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.49 (s, 1H), 7.57 (s, 1H), 7.51 (dd, 4H, J= 12.0Hz), 7.46 (s, 1H), 6.94 (s, 1H), 6.11 (m, 1H), 3.76 (s, 4H), 3.53 (s, 4H), 3.30 (s, 4H), 3.11 (m, 2H), 1.70 (s, 4H), 1.58 (s, 2H), 1.06 (t, 2H, J=8.0Hz)；EI-MS：466.3[M+1]⁺。

Embodiment 14：1- (2,4- difluorophenyl) -3- (4- (2- morpholinyls -4- (piperidin-1-yl) piperidin-1-yl -6- bases) Phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with piperidines, 6 side chains with 4- (2, 4- difluoro-benzenes base) urea-phenyl boric acid pinacol ester replacement, obtain white powder 1- (2,4- difluorophenyl) -3- (4- (2- morpholines Base -4- (piperidin-1-yl) piperidin-1-yl -6- bases) phenyl) urea sterling (total recovery：20.6%).m.p.224-226℃；¹H- NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.53 (s, 1H), 8.10 (m, 1H), 7.61 (m, 3H), 7.52 (m, 2H), 7.32 (m, 1H), 6.97 (s, 1H), 3.76 (m, 4H), 3.55 (s, 4H), 3.34 (m, 8H), 1.70 (s, 4H), 1.58 (s, 2H)；EI-MS：550.2[M+1]⁺。

Embodiment 15：4- (6- (4- (3- ethyl carbamides) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid second The preparation of ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, are obtained white The powdered 4- of color (6- (4- (3- ethyl carbamides) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters sterling is (total Yield：25.9%).m.p.252-254℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.50 (s, 1H), 7.64 (s, 1H), 7.53 (dd, 4H, J=12.0Hz), 6.97 (s, 1H), 6.11 (t, 1H), 4.08 (m, 2H), 3.75 (s, 4H), 3.57 (m, 8H), 3.34 (s, 4H), 3.12 (m, 2H), 1.21 (t, 3H, J=8.0Hz), 1.06 (t, 3H, J=8.0Hz)；EI-MS：539.4[M+ 1]⁺。

Embodiment 16：4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine The preparation of piperazine -1- carboxylic acid, ethyl esters

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (2,4- difluoros Phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：20.5%). m.p.235-237℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.54 (s, 1H), 8.11 (m, 1H), 7.67 (s, 1H), 7.63 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.33 (m, 1H), 7.06 (t, 1H), 6.99 (s, 1H), 4.08 (m, 2H), 3.76 (m, 4H), 3.56 (s, 8H), 3.35 (s, 4H), 1.21 (m, 3H)；EI-MS：623.4[M+1]⁺。

Embodiment 17：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- ethyl carbamides preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, obtain white powder 1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- ethyl carbamide sterling (total recoverys：24.7%).m.p.264-265℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.51 (s, 1H), 7.63 (s, 1H), 7.54 (dd, 4H, J=12.0Hz), 6.95 (s, 1H), 6.11 (t, 1H), 3.82 (m, 4H), 3.71 (m, 4H), 3.35 (s, 4H), 3.12 (m, 2H), 2.80 (m, 2H), 1.17 (m, 6H), 1.06 (t, 3H)；EI-MS：496.5[M+ 1]⁺。

Embodiment 18：1- (2,4- difluorophenyl) -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinyls Benzothiazol-6-yl) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester, obtain white powder 1- (2,4- difluoros Phenyl) -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling is (always Yield：30.0%).m.p.242-244℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.12 (s, 1H), 8.54 (s, 1H), 8.10 (m, 1H), 7.66 (s, 1H), 7.64 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.06 (t, 1H), 6.97 (s, 1H), 3.82 (m, 8H), 2.81 (t, 2H, J=8.0Hz), 1.19 (d, 6H, J=8.0Hz)；EI-MS：580.2[M+1]⁺。

Embodiment 19：4- (6- (4- (3- ethyl carbamides) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid second Ester

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with ethyl oxygen carbonyl piperazine, are obtained white The powdered 4- of color (6- (4- (3- ethyl carbamides) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl esters sterling is (total Yield：27.4%).m.p.248-251℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.51 (s, 1H), 7.63 (s, 1H), 7.53 (d, 2H, J=8.0Hz), 7.46 (d, 2H, J=8.0Hz), 6.95 (s, 1H), 6.11 (t, 1H, J=8.0Hz), 4.07 (m, 2H), 3.80 (s, 4H), 3.56 (s, 8H), 3.35 (s, 4H), 3.10 (m, 2H), 1.21 (m, 3H), 1.06 (m, 3H)；EI- MS：539.4[M+1]⁺。

Embodiment 20：4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine The preparation of piperazine -1- carboxylic acid, ethyl esters

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (2,4- difluoros Phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：29.9%). m.p.224-226℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 9.12 (s, 1H), 8.54 (s, 1H), 8.10 (m, 1H), 7.67 (s, 1H), 7.64 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.07 (m, 1H), 6.98 (s, 2H), 4.08 (m, 2H), 3.81 (s, 4H), 3.56 (s, 8H), 3.37 (s, 4H), 1.23 (m, 3H)；EI-MS：623.3[M+1]⁺。

Embodiment 21：1- ethyls -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) benzene Base) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with N- isopropyls piperazine, are obtained white Powdered 1- ethyls -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling is (total Yield：24.5%).m.p.200-202℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.51 (s, 1H), 7.61 (s, 1H), 7.55 (d, 2H), 7.46 (d, 2H), 6.94 (s, 1H), 6.11 (t, 1H, J=4.0Hz), 3.80 (s, 4H), 3.56 (s, 4H), 3.11 (m, 2H), 2.58 (s, 4H), 1.06 (m, 3H), 1.01 (d, 6H, J=12.0Hz)；EI-MS：509.5[M+1]⁺。

Embodiment 22：1- (2,4- difluorophenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinyl benzo thiophenes Azoles -6- bases) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with N- isopropyls piperazine, 6 side chains Replaced with 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester, obtain white powder 1- (2,4- difluorophenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling (total recovery：17.2%). m.p.232-236℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.53 (s, 1H), 8.10 (m, 1H), 7.63 (m, 3H), 7.53 (m, 2H), 7.35 (m, 1H), 7.06 (m, 1H), 6.96 (s, 1H), 3.81 (s, 4H), 3.54 (s, 4H), 3.37 (s, 4H), 2.73 (s, 1H), 2.58 (s, 4H), 0.99 (d, 6H)；EI-MS：593.5[M+1]⁺。

Embodiment 23：1- ethyls -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) The preparation of urea

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with 4- hydroxy piperidines, obtain white powder Last shape 1- ethyls -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling is (total to receive Rate：26.1%).m.p.204-206℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.50 (s, 1H), 7.59 (s, 1H), 7.52 (d, 2H), 7.46 (d, 2H), 6.93 (s, 1H), 6.11 (t, 1H, J=4.0Hz), 3.84 (s, 8H), 3.35 (s, 8H), 3.11 (m, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.06 (t, 3H, J=8.0Hz)；EI-MS：482.4[M+1]⁺。

Embodiment 24：1- (2,4- difluoroaniline) -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazoles - 6- yls) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with 4- hydroxy piperidines, and 6 side chains are used 4- (2,4- difluoro-benzene base) urea-phenyl boric acid pinacol ester is replaced, and obtains white powder 1- (2,4- difluoroaniline) -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling (total recovery：22.4%).m.p.198- 200℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.53 (s, 1H), 8.12 (m, 1H), 7.62 (m, 3H), 7.52 (d, 2H, J=4.0Hz), 7.06 (m, 1H), 6.96 (s, 1H), 4.87 (s, 1H), 3.81 (s, 8H), 3.36 (s, 8H), (1.86 m, 2H), 1.49 (m, 2H)；EI-MS：566.3[M+1]⁺。

Embodiment 25：The preparation of 1- ethyls -3- (4- (4- morpholine -2s-(piperidin-1-yl) benzothiazol-6-yl) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with piperidines, obtain white powder 1- Ethyl -3- (4- (4- morpholine -2s-(piperidin-1-yl) benzothiazol-6-yl) phenyl) urea sterling (total recovery：17.2%). m.p.228-231℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.50 (s, 1H), 7.59 (s, 1H), 7.52 (d, 2H), 7.46 (d, 2H), 6.93 (s, 1H), 6.11 (t, 1H, J=4.0Hz), 3.81 (s, 8H), 3.54 (s, 8H), 3.36 (s, 4H), 3.11 (m, 2H), 1.63 (m, 6H), 1.06 (t, 3H, J=8.0Hz)；EI-MS：466.3[M+1]⁺。

Embodiment 26：1- (2,4- difluoroaniline) -3- (4- (4- morpholinyls -2- (piperidin-1-yl) benzothiazol-6-yl) Phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with piperidines, 6 side chains with 4- (2, 4- difluoro-benzenes base) urea-phenyl boric acid pinacol ester replacement, obtain white powder 1- (2,4- difluoroaniline) -3- (4- (4- morpholines Base -2- (piperidin-1-yl) benzothiazol-6-yl) phenyl) urea sterling (total recovery：18.3%).m.p.260-262℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.11 (s, 1H), 8.50 (s, 1H), 8.06 (m, 1H), 7.58 (m, 3H), 7.48 (d, 2H, J =4.0Hz), 7.29 (t, 1H, J=8.0Hz), 7.02 (m, 1H), 6.91 (s, 1H), 3.77 (s, 4H), 3.51 (s, 4H), 3.33 (s, 4H), 1.60 (s, 6H)；EI-MS：550.4[M+1]⁺。、

Embodiment 27：The preparation of 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- MUs

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are replaced with 4- MUs-phenyl boric acid pinacol ester Change, obtain white powder 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- MU sterling (total recoverys： 20.3%).m.p.274-278℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.59 (s, 1H), 7.63 (s, 1H), 7.53 (d, 2H), 7.47 (d, 2H), 6.95 (s, 1H), 6.01 (m, 1H), 7.02 (m, 1H), 3.80 (s, 4H), 3.75 (s, 4H), 3.54 (s, 4H), 3.36 (s, 4H), 2.64 (d, 3H, J=8.0Hz)；EI-MS：454.3[M+1]⁺。

Embodiment 28：1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (4- methylpiperazine-1-yls) Phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains 4- (4- methyl piperazines benzene) urea-phenyl boric acid Pinacol ester is replaced, and obtains white powder 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (4- methyl piperazines Piperazine -1- bases) phenyl) urea sterling (total recovery：17.6%).m.p.214-216℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 7.95 (s, 1H), 7.65 (s, 1H), 7.56 (m, 4H), 7.36 (d, 2H), 6.97 (s, 1H), 6.87 (d, 2H), 3.81 (d, 1H, J =48.0Hz), 3.54 (s, 4H), 3.04 (s, 4H), 2.89 (s, 10H), 2.73 (s, 9H), 2.46 (s, 2H), 2.21 (s, 2H), 1.07 (s, 1H)；EI-MS：614.5[M+1]⁺。

Embodiment 29：1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (methylol) phenyl) urea Prepare

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains are with 4- to phenmethylol urea-phenyl boric acid pinacol Ester is replaced, and obtains white powder 1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- (4- (methylol) phenyl) urea Sterling (total recovery：22.7%).m.p.223-224℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.94 (s, 1H), 8.84 (s, 1H), 7.66 (s, 1H), 7.59 (d, 2H, J=8.0Hz), 7.52 (d, 2H, J=8.0Hz), 7.43 (d, 2H, J= 8.0Hz), 7.23 (d, 2H, J=8.0Hz), 6.97 (s, 1H), 5.08 (s, 1H), 4.42 (s, 2H), 3.81 (d, 8H, J= 48.0Hz), 3.53 (s, 4H)；EI-MS：546.4[M+1]⁺。

Embodiment 30：The preparation of 1- (4- (2,4- dimethyl-benzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) urea

Synthesized by the synthetic method of the compound of embodiment 1,6 side chains 4- (3- pyridines) urea-phenyl boric acid pinacol Ester is replaced, and it is (total to obtain white powder 1- (4- (2,4- dimethyl-benzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) ureas sterling Yield：16.2%).m.p.209-211℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.92 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.97 (d, 2H, J=8.0Hz), 7.66 (s, 1H), 7.64 (d, 2H, J=12.0Hz), 7.55 (d, 2H), 7.33 (s, 1H), 6.98 (s, 1H), 3.81 (s, 4H), 3.75 (s, 4H), 3.55 (s, 4H)；EI-MS：517.5 [M+1]⁺。

Embodiment 31：4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -2- morpholinyl benzo thiophenes Azoles -4- bases) piperazine -1- carboxylic acid, ethyl esters preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (4- methyl piperazines benzene) urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (4- (4- methyl piperazines Piperazine -1- bases) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys： 21.2%).m.p.267-268℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 9.30 (s, 1H), 9.10 (s, 1H), 7.65 (s, 1H), 7.65 (m, 4H), 7.35 (d, 2H, J=8.0Hz), 6.98 (s, 1H), 6.87 (d, 2H, J=8.0Hz), 4.08 (m, 2H), 3.77 (s, 4H), 3.56 (s, 8H), 3.04 (s, 4H), 2.46 (m, 5H), 2.21 (s, 3H), 1.21 (m, 3H)；EI-MS：685.7 [M+1]⁺。

Embodiment 32：1- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- The preparation of (4- (4- methylpiperazine-1-yls) phenyl) urea

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with N- isopropyls piperazine, 6 side chains Replaced with 4- (4- methyl piperazines benzene) urea-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- (4- isopropyl piperazines -1- Base) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea sterling (total recovery： 23.5%).m.p.256-257℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.69 (s, 1H), 8.45 (s, 1H), 7.62 (s, 1H), 7.57 (m, 2H), 7.51 (d, 2H), 7.31 (d, 2H), 6.95 (s, 1H), 6.88 (d, 2H), 3.80 (s, 4H), 3.52 (s, 4H), 3.04 (s, 4H), 2.57 (s, 4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.00 (d, 6H, J=4.0Hz)；EI-MS： 655.7[M+1]⁺。

Embodiment 33：1- (4- (hydroxyl oxygen methyl) phenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinyl benzene And thiazole -6- bases) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with N- isopropyls piperazine, 6 side chains Phenmethylol urea-phenyl boric acid pinacol ester is replaced with 4-, obtains white powder 1- (4- (hydroxyl oxygen methyl) phenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling (total recovery：15.4%).m.p.274- 278℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.74 (s, 1H), 8.65 (s, 1H), 7.63 (s, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.43 (m, 2H), 7.24 (m, 2H), 6.96 (s, 1H), 5.09 (t, 1H, J=8.0Hz), 3.80 (s, 4H), 3.53 (s, 4H), 2.73 (m, 1H), 2.58 (s, 4H), 1.01 (s, 6H)；EI-MS：587.5[M+1]⁺。

Embodiment 34：1- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- The preparation of (pyridin-3-yl) urea

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with N- isopropyls piperazine, 6 side chains Replaced with 4- (3- pyridines) urea-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- (4- isopropyl piperazine -1- bases) -4- Morpholinobenzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) urea sterling (total recovery：15.4%).m.p.245-247℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.74 (s, 1H), 8.65 (s, 1H), 7.63 (s, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.43 (m, 2H), 7.24 (m, 2H), 6.96 (s, 1H), 5.09 (t, 1H, J=8.0Hz), 3.80 (s, 4H), 3.53 (s, 4H), 2.73 (m, 1H), 2.58 (s, 4H), 1.01 (s, 6H)；EI-MS：587.5[M+1]⁺。

Embodiment 35：1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with 4- hydroxy piperidines, and 6 side chains are used 4- (4- methyl piperazines benzene) urea-phenyl boric acid pinacol ester is replaced, obtain white powder 1- (4- (2- (4- hydroxy piperidine -1- bases) - 4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea sterling (total recovery：16.9%). m.p.277-279℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.65 (s, 1H), 8.41 (s, 1H), 7.61 (s, 1H), 7.57 (d, 2H), 7.51 (d, 2H), 7.32 (d, 2H, J=8.0Hz), 6.95 (s, 1H), 6.89 (d, 1H, J=8.0Hz), 4.84 (s, 1H), 3.81 (s, 8H), 3.05 (s, 4H), 2.47 (s, 4H), 2.22 (s, 3H), 1.89 (s, 2H), 1.51 (s, 2H)；EI-MS： 628.7[M+1]⁺。

Embodiment 36：1- (4- (hydroxyl oxygen methyl) phenyl) -3- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinyl benzos Thiazole -6- bases) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with 4- hydroxy piperidines, and 6 side chains are used 4- (4- hydroxy piperidines) urea-phenyl boric acid pinacol ester is replaced, and obtains white powder 1- (4- (hydroxyl oxygen methyl) phenyl) -3- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea mTOR-53 sterling (total recoverys：18.3%). m.p.243-246℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.73 (s, 1H), 8.64 (s, 1H), 7.61 (m, 3H), 7.53 (d, 2H, J=8.0Hz), 7.41 (d, 2H, J=8.0Hz), 7.24 (t, 2H, J=4.0Hz), 6.96 (s, 1H), 5.07 (t, 1H, J=4.0Hz), 4.42 (t, 1H, J=8.0Hz), 3.81 (s, 8H), 3.37 (s, 4H), 1.87 (m, 2H), 1.49 (m, 2H)；EI-MS：560.3[M+1]+.

Embodiment 37：1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyrroles Pyridine -3- bases) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with 4- hydroxy piperidines, and 6 side chains are used 4- (3- pyridines) urea-phenyl boric acid pinacol ester is replaced, and obtains white powder 1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholines Base benzothiazol-6-yl) phenyl) -3- (pyridin-3-yl) urea sterling (total recovery：16.7%).m.p.211-212℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.90 (d, 2H, J=12.0Hz), 8.62 (s, 1H), 8.19 (s, 1H), 7.95 (m, 1H), 7.62 (m, 3H), 7.60 (d, 2H), 7.32 (m, 1H), 6.96 (s, 1H), 4.84 (s, 1H), 3.81 (s, 8H), 3.33 (s, 4H), 1.86 (m, 2H), 1.49 (m, 2H)；EI-MS：531.2[M+1]⁺。

Embodiment 38：4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -4- morpholinyl benzo thiophenes Azoles -2- bases) piperazine -1- carboxylic acid, ethyl esters preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (4- methyl piperazines benzene) urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (4- (4- methyl piperazines Piperazine -1- bases) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys： 22.2%).m.p.274-278℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.66 (s, 1H), 8.42 (s, 1H), 7.65 (s, 1H), 7.58 (d, 2H), 7.52 (d, 2H), 7.32 (d, 2H, J=12.0Hz), 6.97 (s, 1H), 6.89 (d, 2H, J= 8.0Hz), 4.09 (m, 2H), 3.81 (s, 4H), 3.56 (s, 6H), 3.05 (s, 4H), 2.45 (s, 4H), 2.22 (s, 4H), 1.21 (m, 3H)；EI-MS：685.4[M+1]⁺。

Embodiment 39：4- (6- (4- (3- (4- (hydroxyl oxygen methyl) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) The preparation of piperazine -1- carboxylic acid, ethyl esters

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- to phenmethylol urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (4- (hydroxyl oxygen methyl) phenyl) Urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：17.3%).m.p.276-277 ℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.75 (s, 1H), 8.66 (s, 1H), 7.60 (d, 2H), 7.53 (d, 2H), 7.43 (d, 2H, JJ=8.0Hz), 7.24 (d, 2H, J=8.0Hz), 6.97 (s, 1H), 5.09 (s, 1H), 4.43 (m, 2H), 4.08 (m, 2H), 3.81 (s, 4H), 3.56 (s, 8H), 1.21 (m, 3H)；EI-MS：617.6[M+1]⁺。

Embodiment 40：4- (4- morpholinyls -6- (4- (3- (pyridin-3-yl) urea) phenyl) benzothiazole -2- bases) piperazine -1- The preparation of carboxylic acid, ethyl ester

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (3- pyridines) urea-phenyl boric acid pinacol ester, obtains white powder 4- (4- morpholinyls -6- (4- (3- (pyridine -3- Base) urea) phenyl) benzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：27.9%).m.p.274-278℃；¹H- NMR (400MHz, DMSO-d₆δ ppm), 8.92 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.97 (d, 2H, J=8.0Hz), 7.68 (s, 1H), 7.61 (d, 2H, J=8.0Hz), 7.55 (d, 2H, J=12.0Hz), 7.33 (m, 1H), 6.98 (s, 1H), 4.09 (m, 2H), 3.81 (s, 4H), 3.56 (s, 8H), 1.21 (m, 3H)；EI-MS：588.4[M+1]⁺。

Embodiment 41：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- (4- (4- methylpiperazine-1-yls) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- (4- methyl piperazines benzene) urea-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methylpiperazine-1-yls) phenyl) Urea sterling (total recovery：22.1%).m.p.234-236℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.66 (s, 1H), 8.42 (s, 1H), 7.65 (s, 1H), 7.58 (d, 2H), 7.52 (d, 2H), 7.32 (d, 2H), 6.97 (s, 1H), 6.89 (d, 2H, J= 8.0Hz), 3.85 (m, 6H), 3.71 (m, 2H), 3.05 (t, 4H, J=4.0Hz), 2.81 (t, 2H, J=12.0Hz), 2.46 (s, 5H), 2.22 (s, 3H), 1.17 (t, 6H, J=8.0Hz)；EI-MS：642.6[M+1]⁺。

Embodiment 42：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- (4- (hydroxyl oxygen methyl) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- to phenmethylol urea-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- ((2S, 6R) -2, 6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (hydroxyl oxygen methyl) phenyl) urea sterling (total receipts Rate：25.2%).m.p.265-266℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.74 (s, 1H), 8.65 (s, 1H), 7.66 (s, 1H), 7.60 (d, 2H), 7.53 (d, 2H), 7.43 (d, 2H, J=8.0Hz), 7.24 (d, 1H, J=8.0Hz), 6.97 (s, 1H), 5.09 (t, 1H, J=4.0Hz), 4.42 (d, 2H, J=8.0Hz), 3.85 (m, 6H), 3.71 (m, 2H), 2.81 (m, 2H), 1.19 (m, 6H)；EI-MS：574.5[M+1]⁺。

Embodiment 43：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- (pyridin-3-yl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- (3- pyridines) urea-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- ((2S, 6R) -2, 6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyridin-3-yl) urea sterling (total recovery： 23.9%).m.p.274-278℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.92 (s, 1H), 8.88 (s, 1H), 8.62 (s, 1H), 8.19 (m, 1H), 7.95 (m, 1H), 7.66 (s, 1H), 7.61 (d, 2H), 7.54 (d, 2H), 7.34 (s, 1H), 6.98 (s, 1H), 3.83 (m, 6H), 3.73 (m, 2H), 2.81 (m, 2H), 1.17 (m, 6H)；EI-MS：545.3[M+1]⁺。

Embodiment 44：4- (6- (4- (3- cyclopropyl urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acids The preparation of ethyl ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- isopropyls urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- cyclopropyl urea) phenyl) -2- Quinoline base benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：17.3%) .m.p.276-277 DEG C；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.39 (s, 1H), 7.70 (s, 1H), 7.54 (d, 2H, J=8.0Hz), 7.46 (d, 2H, J= 8.0Hz), 6.97 (s, 1H), 6.42 (s, 1H), 4.08 (m, 2H), 3.75 (s, 4H), 3.54 (m, 8H), 2.50 (s, 1H), 1.21 (m, 3H), 0.64 (m, 2H), 0.42 (m, 2H)；EI-MS：551.3[M+1]⁺。

Embodiment 45：4- (2- morpholinyls -6- (4- (3- isophthalic MU) phenyl) benzothiazole -4- bases) piperazine -1- carboxylics The preparation of acetoacetic ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with aminomethyl phenyl urea between 4--phenyl boric acid pinacol ester, obtains white powder 4- (2- morpholinyls -6- (4- (3- isophthalic first Base urea) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：28.8%).m.p.233-235℃；¹H- NMR (400MHz, DMSO-d₆δ ppm), 8.75 (s, 1H), 8.62 (s, 1H), 7.67 (s, 1H), 7.62 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.31 (s, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 6.99 (s, 1H), 6.80 (s, 1H), 4.10 (m, 2H), 3.75 (s, 4H), 3.56 (t, 8H, J=4.0Hz), 2.28 (s, 3H), 1.21 (t, 3H, J=8.0Hz)；EI- MS：601.4[M+1]⁺。

Embodiment 46：4- (6- (4- (3- benzylureas) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid second The preparation of ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- benzylureas-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- benzylureas) phenyl) -2- morpholinyls Benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：23.3%).m.p.278-279℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.67 (s, 1H), 7.65 (s, 1H), 7.55 (d, 2H), 7.49 (d, 2H), 7.33 (m, 4H), 7.24 (m, 1H), 6.97 (s, 1H), 6.65 (t, 1H, J=8.0Hz), 6.99 (s, 1H), 6.80 (s, 1H), 4.10 (m, 2H), 3.75 (s, 4H), 3.56 (t, 8H, J=4.0Hz), 4.32 (s, 2H), 4.06 (m, 2H), 3.55 (s, 8H), 1.19 (m, 3H)；EI-MS： 601.4[M+1]⁺。

Embodiment 47：4- (6- (4- (3- MUs) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid second The preparation of ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- MUs-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- MUs) phenyl) -2- morpholinyls Benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：14.9%).m.p.219-220℃；¹H-NMR (400MHz, DMSO-d₆δ ppm), 8.59 (s, 1H), 7.63 (s, 1H), 7.53 (d, 2H), 7.47 (d, 2H), 6.97 (s, 1H), 6.04 (m, 1H), 4.08 (m, 2H), 3.75 (s, 4H), 3.57 (s, 8H), 3.33 (s, 4H), 2.66 (s, 3H), 1.21 (s, 3H)；EI-MS： 525.4[M+1]⁺。

Embodiment 48：4- (6- (4- (3- (4- (hydroxyl oxygen methyl) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) The preparation of piperazine -1- carboxylic acid, ethyl esters

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (4- phenmethylols) urea-phenyl boric acid pinacol ester, obtains white powder 4- (6- (4- (3- (4- (hydroxyl oxygen methyl) benzene Base) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：19.4%).m.p.244- 248℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.74 (s, 1H), 8.66 (s, 1H), 7.67 (s, 21H), 7.62 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.43 (d, 2H, J=8.0Hz), 7.24 (d, 2H, J=8.0Hz), 6.99 (s, 1H), 5.09 (s, 1H), 4.44 (d, 2H, J=8.0Hz), 4.06 (m, 2H), 3.75 (s, 4H), 3.58 (s, 8H), 3.36 (s, 3H), 1.21 (m, 3H)；EI-MS：617.4[M+1]⁺。

Embodiment 49：4- (2- morpholinyls -6- (4- (3- (pyridin-3-yl) urea) phenyl) benzothiazole -4- bases) piperazine -1- The preparation of carboxylic acid, ethyl ester

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- (3- pyridines) urea-phenyl boric acid pinacol ester, obtains white powder 4- (2- morpholinyls -6- (4- (3- (pyridine -3- Base) urea) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：16.3%).m.p.284-288℃；1H- NMR (400MHz, DMSO-d₆δ ppm), 8.92 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 8.19 (s, 1H), 7.96 (d, 2H, J=8.0Hz), 7.67 (s, 1H), 7.63 (d, 2H, J=8.0Hz), 7.55 (d, 2H), 7.33 (m, 1H), 6.99 (s, 1H), 4.08 (m, 2H), 3.76 (s, 4H), 3.58 (s, 8H), 3.35 (s, 4H), 1.21 (t, 3H, J=8.0Hz)；EI-MS：588.3[M +1]⁺。

Embodiment 50：1- cyclopropyl -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinyl benzo thiophenes Azoles -6- bases) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- isopropyls urea-phenyl boric acid pinacol ester, obtain white powder 1- cyclopropyl -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling (total recovery：22.1%). m.p.274-278℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.38 (s, 1H), 7.63 (s, 1H), 7.54 (d, 2H), 7.48 (d, 2H), 6.95 (s, 1H), 6.41 (m, 1H), 3.82 (m, 6H), 3.71 (m, 2H), 2.80 (t, 2H, J=12.0Hz), 2.55 (m, 1H), 1.17 (d, 6H, J=8.0Hz), 0.63 (m, 2H), 0.41 (m, 2H)；EI-MS：508.3[M+1]⁺。

Embodiment 51：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- isophthalic MUs preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with aminomethyl phenyl urea between 4--phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- ((2S, 6R)- 2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- isophthalic MU sterling (total recoverys： 24.0%).m.p.277-278℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.75 (s, 1H), 8.61 (s, 1H), 7.65 (s, H), 7.62 (d, 2H, J=8.0Hz), 7.53 (d, 2H, J=8.0Hz), 7.32 (s, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 6.80 (s, 1H), 3.83 (m, 6H), 3.71 (m, 2H), 2.80 (t, 2H, J=8.0Hz), 2.29 (s, 3H), 1.19 (d, 2H, J=8.0Hz)；EI-MS：558.2[M+1]⁺。

Embodiment 52：1- benzyls -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazoles - 6- yls) phenyl) urea preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- benzylureas-phenyl boric acid pinacol ester, obtain white powder 1- benzyls -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) urea sterling (total recovery：19.2%). m.p.214-218℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.66 (s, 1H), 7.63 (s, 1H), 7.55 (d, 2H, J= 8.0Hz), 7.49 (d, 2H, J=8.0Hz), 7.33 (m, 4H), 7.23 (m, 1H), 6.95 (s, 1H), 6.64 (t, 1H, J= 4.0Hz), 4.32 (d, 2H, J=4.0Hz), 3.71 (m, 2H), 3.82 (m, 6H), 3.71 (m, 2H), 2.80 (t, 2H, J= 12.0Hz), 1.17 (t, 6H)；EI-MS：558.2[M+1]⁺。

Embodiment 53：1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) benzene Base) -3- MUs preparation

Synthesized by the synthetic method of the compound of embodiment 1,2 bit substituents ((2S, 6R) -2,6- dimethyl) morpholine Replace, 6 side chains are replaced with 4- MUs-phenyl boric acid pinacol ester, obtain white powder 1- (4- (2- ((2S, 6R) -2,6- bis- Methyl morpholine base) -4- morpholinobenzothiazole -6- bases) phenyl) -3- MU sterling (total recoverys：18.9%).m.p.224- 228℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.59 (s, 1H), 7.62 (s, 1H), 7.53 (d, 2H, J=8.0Hz), 7.47 (d, 2H, J=8.0Hz), 6.95 (s, 1H), 6.01 (t, 1H, J=8.0Hz), 3.84 (m, 6H), 3.71 (m, 2H), 2.80 (t, 2H), 2.65 (s, 3H), 1.17 (d, 6H, J=4.0Hz)；EI-MS：482.5[M+1]⁺。

Embodiment 54：4- (2- morpholinyls -6- (4- (3- (4- (trifluoromethoxy) phenyl) urea) phenyl) benzothiazole -4- Base) piperazine -1- carboxylic acid, ethyl esters preparation

Synthesized by the synthetic method of the compound of embodiment 1,4 bit substituents are replaced with ethyl oxygen carbonyl piperazine, 6 sides Chain is replaced with 4- to Trifluoromethoxyphen-l urea-phenyl boric acid pinacol ester, obtains white powder 4- (2- morpholinyls -6- (4- (3- (4- (trifluoromethoxy) phenyl) urea) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl ester sterling (total recoverys：20.7%). m.p.254-258℃；1H-NMR (400MHz, DMSO-d₆δ ppm), 8.92 (s, 1H), 8.83 (s, 1H), 7.57 (m, 8H), 7.29 (d, 2H, J=8.0Hz), 6.99 (s, 1H), 4.07 (m, 3H), 3.75 (s, 4H), 3.58 (s, 8H), 1.99 (s, 1H), 1.21 (m, 8H)；EI-MS：671.2[M+1]⁺。

Embodiment 55：Inhibiting tumour cells are tested

Evaluate activity of the embodiment compound to kinds of tumor cells.

Experiment material：The high sugared cell culture mediums (Hyelone companies) of DMEM, hyclone (FBS) (Gibco companies) are blue or green Mycin, streptomysin are purchased from Huabei Pharmaceutic Co., Ltd, and phosphoric acid normal saline buffer solution (PBS) is purchased from Gibco companies, CellCell viability detection reagent is purchased from Promega companies, and pancreatin and dimethyl sulfoxide (DMSO) are Sigma companies Product.Liver cancer cells (HepG2 cells), Lu-csf-1's (A549 cells), human breast cancer cell (MCF7), human leukemia Cell (K562), cervical cancer cell (Hela), ovarian cancer cell (SKOV3), gastric adenocarcinoma cells (AGS), people's sarcoma of uterus are thin Born of the same parents (MES-SA), breast cancer cell (MDA-MB-231), colon cancer cell (SW-620) and prostatic cell (PC-3, DU145) are equal Purchased from ATCC companies.Positive reference compound selects rapamycin.

Experimental method：

White saturating 96 orifice plate (Costar) in wall bottom, 37 DEG C of 5%CO are inoculated with the quantity of every 5000 cells in hole₂Under the conditions of cultivate 24h.Testing compound is dissolved to 100mM using DMSO, as compound stock solutions.

Using the DMEM nutrient solution diluted compounds containing 2%FBS, concentration gradient 3, concentration range is 100 μM~ 3nM.Each dilution factor compound is added in cultured 96 orifice plate cell, per the μ l of hole 100.37℃CO₂Under the conditions of cultivate 72h, After abandoning supernatant, cell viability test experience is carried out.

By CellReaction buffer and substrate carry out etc. than after mixing, adding in 96 orifice plates, per hole 100μl.4min is with inducing cell lysis for level concussion.Equilibrium at room temperature 15min, to stablize reaction signal.Examined using chemiluminescence Survey the chemiluminescence unit that instrument detects every hole in 96 orifice plates.

According to the chemiluminescence detection value in every hole, the inhibiting rate of each dilution factor of each compound is calculated, utilizes Origin 8.0 softwares carry out S type curve matchings to the different gradients of each compound, calculate IC₅₀Value.It the results are shown in Table 1 and table 2.

External increment rejection ability of the embodiment compound of table 1 to kinds of tumor cells

The external increment rejection ability of the section Example compound on prostate tumour cell of table 2

As a result (Tables 1 and 2) proves, compound of the invention can effectively suppress liver cancer cells (HepG2 cells), people Lung adenocarcinoma cell system (A549 cells), human breast cancer cell (MCF7), human leukemia cell (K562), cervical cancer cell (Hela), ovarian cancer cell (SKOV3), gastric adenocarcinoma cells (AGS), people's sarcoma of uterus cell (MES-SA), breast cancer cell (MDA- MB-231), the propagation of a variety of cancer cells such as colon cancer cell (SW-620) and prostatic cell (PC-3, DU145), part chemical combination Thing effect of (such as prostate tumor cells) on specific cancer cell is even better than rapamycin, therefore the present invention relates to compound With the potentiality for preparing antineoplastic.

Embodiment 56：Normal cell Inhibition test

Evaluate inhibitory activity of the embodiment compound to human embryonic lung fibroblasts (MRC5).

Experiment material：The high sugared cell culture mediums (Hyclone companies) of DMEM, hyclone (FBS) (Gibco companies) are blue or green Mycin, streptomysin are purchased from Huabei Pharmaceutic Co., Ltd, and phosphoric acid normal saline buffer solution (PBS) is purchased from Gibco companies, CellCell viability detection reagent is purchased from Promega companies, and pancreatin and dimethyl sulfoxide (DMSO) are Sigma companies Product.Human embryonic lung fibroblasts (MRC5) are purchased from ATCC companies.Positive reference compound selects rapamycin.

Experimental method：

Using the DMEM nutrient solution diluted compounds containing 2%FBS, concentration gradient 3, concentration range is 100 μM~ 3nM.Each dilution factor compound is added in cultured 96 orifice plate cell, per the μ l of hole 100.37℃CO₂Under the conditions of cultivate 72h, After supernatant discarding, cell viability test experience is carried out.

According to the chemiluminescence detection value in every hole, the inhibiting rate of each dilution factor of each compound is calculated, utilizes Origin 8.0 softwares carry out S type curve matchings to the different gradients of each compound, calculate IC₅₀Value.It the results are shown in Table 3.

Inhibitory activity of the embodiment compound of table 3 to human embryonic lung fibroblasts (MRC5)

As a result show, compound of the present invention is weaker to human normal cell line rejection ability, and part of compounds is to people The inhibitory activity of normal cell is weaker than rapamycin；Also indicate that toxicity of the compound of the present invention to human normal cell line simultaneously It is relatively low.

Embodiment 57：Compound is tested to mTORC1 and mTORC2 inhibitory activity

Evaluate molecular mechanism of action of the embodiment compound in tumour cell A549.

Experiment material：The high sugared cell culture mediums (Hyclone companies) of DMEM, hyclone (FBS) (Gibco companies) are blue or green Mycin, streptomysin are purchased from Huabei Pharmaceutic Co., Ltd, and phosphoric acid normal saline buffer solution (PBS) is purchased from Gibco companies, pancreatin And dimethyl sulfoxide (DMSO) is Sigma Products.A549 cell lines (Lu-csf-1) are purchased from ATCC.The anti-human p- of mouse P70S6K (T389) monoclonal antibody is purchased from Cell Signaling Technology companies, and the anti-human p70S6K monoclonals of mouse resist Body is purchased from Cell Signaling Technology companies, and mouse anti-human p-AKT (S473) monoclonal antibody is purchased from Cell Signaling Technology companies, the anti-human AKT monoclonal antibodies of mouse are public purchased from Cell Signaling Technology Department.Sheep anti mouse, the goat-anti mouse monoclonal antibody of HRPO mark are public purchased from Cell Signaling Technology Department.Cell pyrolysis liquid is purchased from Beijing Suo Laibao Science and Technology Ltd, and sample-loading buffer is purchased from green skies company, SDS running buffers Liquid is purchased from green skies company, and transferring film buffer solution is purchased from green skies company, and TBS is purchased from green skies company, and TBST is public purchased from the green skies Department.ECL chemical luminescence for liquid is purchased from Beijing Puli's lema gene Technology Co., Ltd., and developer solution, fixing solution are purchased from Shijiazhuang City chemical industry Ten factories, NC films are purchased from Whatman companies, and film is purchased from sharp jade-like stone (Xiamen) medical equipment Co., Ltd, and skimmed milk power is purchased from Beijing Xi Kai Creative Technology Ltd..

Experimental method：

A549 cells are spread to 96 orifice plates, the non-serum starved training overnight when cell growth reaches 80%-90% to density Support, be incubated 2 hours altogether with 167nM insulin and compound within second day, then cell lysis is examined respectively using western blot method Phosphorylation level of the embodiment compound to S6K1 Thr389 sites and Akt Ser473 sites is surveyed, sxemiquantitative is come with this Reflect suppression level of the compound to mTORC1 and mTORC2.Positive reference compound selects rapamycin.Evaluation result is shown in figure 1.Comprise the following steps that：

1. handle cell：

1) cell is seeded in six orifice plates by, and cell is paved with 80%-90% after 24h；

2) after .PBS washs cell once, 2mL serum free mediums, starved overnight are changed；

3) adds the cell training that 2 μ L contain testing compound (20 μM) and insulin (167nM) in cell after treatment Nutrient solution is incubated 2h altogether.

2. cell lysis：

1) is blown down the cell in 6 orifice plates come 1500rpm centrifugations 5min with 10ml PBS；

2) adds 60 μ l cell lysis buffer solutions (containing protease inhibitors) after abandoning supernatant, cracks 20-30min on ice, 2-3s is shaken with oscillator after 10min, is put back on ice；

3) 3s is shaken again before centrifugations, then with 4 DEG C, 13000rpm, centrifuge 10min；

4) adds the μ l of 2 × loading buffer 60, boiling water bath 5min, -20 DEG C or -80 DEG C freeze it is standby；

3. protein blot experiment：

1) .SDS-PAGE, first run with 80V volt voltages to concentration glue, then run through separation gel with 120V voltages；

2) transferring films, wet turn, in ice bath, 250mA, 150min；

3) .5% milk room temperature closing 1-2h (can 4 DEG C overnight)；

4) adds primary antibody (being diluted with TBS), and 4 DEG C overnight；

5) .TBST washs 3 × 10min.

6) adds the secondary antibody (using 3% skimmed milk power, TBS configurations dilute) of 1: 2000 dilution, and room temperature on sealed membrane in being incubated 2h；

7) .TBST washs 3 × 10min.

8) each 500 μ l of .ECL chemiluminescences nitrite ion A, B liquid are mixed in plate, rinse 5min；

9) film is placed in exposure holder by, and certain time is exposed in darkroom, is subsequently placed in 2min in developer solution, fixing solution Middle 5min, running water develop photographic film, drying；

10) takes pictures preservation.

As a result show (see accompanying drawing 1), compound of the embodiment of the present invention 6,7,11,12,13,16,17,19,20,21,22, 26th, 27,28,30,33,35,36,37,40,41,42,43,44,45,49,50,51,52,53 can effectively suppress mTORC1, And inhibition is not weaker than rapamycin.

Embodiment 58：The PI3K enzyme inhibition activities of section Example compound

With the PI3K β enzyme inhibition activities of ADP-Glo kinase assay method test compounds, (PI3K β enzymes are purchased from Promega companies).

Test reagent prepares：10 μ l (1 μ g, promega, #V1691) PI3K enzymes are dissolved in 310 μ l 2.5x enzyme reactions buffering Liquid (Promega, #V1691), obtain 320 μ l 2.5x enzyme reaction solution.50μl PIP2：3PS substrates are dissolved in 100 μ l 10x Lipid buffer solution, 400 μ l are added water to, obtain 2.5x PIP2：3PS lipid substrates working solutions.25 μ l ultrapure ATP (10mM) quilt 975 μ l water are dissolved in, obtain 250 μM of ATP aqueous solution.

On-test, test compound is dissolved in the prepare liquid that DMSO is configured to 10 μM, takes 1 μ l to add 384 orifice plates.Then 4 μ l 2.5x PIP2 are added into compound：3PS lipid substrates working solutions.Then, then thereto add 4 μ l 2.5x enzyme works Make solution.Wherein, no enzyme control group only adds 4 μ l 1x enzyme reaction buffer solutions, and DMSO groups only add DMSO.Add into reaction solution Enzyme reaction formally starts after entering 1 μ l, 250 μM of ATP, plank is mixed on shaking table 60 seconds, is then incubated 1 hour at 23 DEG C.It is incubated After, 10 μ l ADP-Glo are added thereto^TMReagent (Promega, #V1691) consumes not anti-to terminate enzyme reaction The ATP answered.After 40 minutes, 20 μ L enzymes detection reagents (Promega, #V1691) are added, are shaken one minute, incubation 40 minutes, so Afterwards fluorescent value is read with ELIASA.According to the chemiluminescence detection value in every hole, the inhibiting rate of compound is calculated.Inhibiting rate calculates public Formula is：(max-sample RLU)/(max-min) × 100%；max：DMSO is compareed；min：Compareed without enzyme；sample RLU： Sample luminous value.

The PI3K β enzyme inhibition activities of the part of compounds of table 4

Experimental result (table 4) prove multiple embodiment compounds under 1 μM of concentration can obvious PI3K β enzymes activity.

Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that：Root According to disclosed all teachings, those details can be carried out with various modifications and replacement, these change in the guarantor of the present invention Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.

Claims

1. compounds of formula I

Wherein：

X, Y is each independently selected from C, S, O, N and Se atom；

A, U, V, W are independently selected from C or N atoms；

R₁For C₁-C₆Alkyl, C₃-C₁₀Cycloalkyl, 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-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 substitution：- F ,-Cl ,-Br ,-I, nitro, hydroxyl, amino, cyano group, C₁-C₆Alkylthio group, C₁-C₆Alkyl, C₁-C₆ Alkenyl, C₁-C₆Alkynyl and C₁-C₆Alkoxy, aromatic radical；

2. compound according to claim 1, wherein,

X, Y is each independently selected from C, S, O and N atom；

A, U, V, W are C atoms；

R₁For C₁-C₆Alkyl, C₃-C₁₀Cycloalkyl, C₁-C₆Alkoxy, aromatic rings, aromatic heterocycle, wherein described C₁-C₆Alkyl, Aromatic rings, aromatic heterocycle are unsubstituted or are substituted by 1,2,3 independently selected from following substituent：-F、-Cl、- Br ,-I, hydroxyl, C₁-C₆Alkyl and C₁-C₆Alkoxy；

R₂、R₃Each stand alone as hydrogen atom, hydroxyl, C₁-C₆Alkyl, ester group；

R₄、R₅Each stand alone as one or more hydrogen atoms, C₁-C₆Alkyl；

3. compound according to claim 1 or 2, wherein,

R₁For methyl, ethyl, cyclopropyl, benzyl, pyridin-3-yl, 4- (4- methylpiperazine-1-yls) phenyl, 4- (methylol) benzene Base, trifluoromethoxy, halogenophenyl；

X, Y is each independently selected from C, S, O and N atom；

A, U, V, W are C atoms；

R₂、R₃Each stand alone as hydroxyl, isopropyl, carbethoxyl group；

R₄、R₅Each stand alone as one or more methyl.

4. according to the compound described in claim any one of 1-3, it is selected from as follows：

1- benzyls -3- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) urea；

1- (4- (4- ((2S, 6R) -2,6- methyl morpholines base) -2- thio-morpholinyls benzothiazol-6-yl) phenyl) -3- ethyls Urea；

1- (2,4- difluorophenyl) -3- (4- (4- ((2S, 6R) -2,6- dimethylated morpholinyls) -2- morpholinobenzothiazoles -6- Base) phenyl) urea；

4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid, ethyl esters；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- ethyl carbamides；

1- (2,4- difluorophenyl) -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazoles -6- Base) phenyl) urea；

4- (6- (4- (3- (2,4- difluorophenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid, ethyl esters；

1- (2,4- difluorophenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) Urea；

1- (2,4- difluoroaniline) -3- (4- (2- (4- hydroxyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) urea；

1- (4- (2,4- dimorpholine base benzothiazol-6-yl) phenyl) -3- MUs；

4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine - 1- carboxylic acid, ethyl esters；

1- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methyl piperazines - 1- yls) phenyl) urea；

1- (4- (methylol) phenyl) -3- (4- (2- (4- isopropyl piperazine -1- bases) -4- morpholinobenzothiazole -6- bases) benzene Base) urea；

1- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- methyl piperazines -1- Base) phenyl) urea；

1- (4- (methylol) phenyl) -3- (4- (2- (4- hydroxy piperidine -1- bases) -4- morpholinobenzothiazole -6- bases) phenyl) Urea；

4- (6- (4- (3- (4- (4- methylpiperazine-1-yls) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine - 1- carboxylic acid, ethyl esters；

4- (6- (4- (3- (4- (methylol) phenyl) urea) phenyl) -4- morpholinobenzothiazole -2- bases) piperazine -1- carboxylic acid second Ester；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (4- first Base piperazine -1- bases) phenyl) urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (4- (hydroxyl first Base) phenyl) urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- (pyridine -3- Base) urea；

4- (6- (4- (3- (4- (methylol) phenyl) urea) phenyl) -2- morpholinobenzothiazole -4- bases) piperazine -1- carboxylic acid second Ester；

1- cyclopropyl -3- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) Urea；

Benzyl between 1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- Urea；

1- (4- (2- ((2S, 6R) -2,6- dimethylated morpholinyls) -4- morpholinobenzothiazole -6- bases) phenyl) -3- MUs；

4- (2- morpholinyls -6- (4- (3- (4- (trifluoromethoxy) phenyl) urea) phenyl) benzothiazole -4- bases) piperazine -1- carboxylic acids Ethyl ester.

5. the isomers of compound, pharmaceutically useful salt and hydrate described in claim 1-4.

6. preparing the method for the compound described in claim 1-4, it includes：

In the above method,

X, Y is each independently selected from C, S, O, N and Se atom；

Z is selected from F, Cl, Br, I atom；

A, U, V, W are independently selected from C or N atoms；

R₄、R₅Each stand alone as one or more hydrogen atoms, hydroxyl, amino, C₁-C₆Alkyl.

7. the medicine of the compound, its officinal salt or its hydrate or the present invention according to claim any one of 1-4 Composition is preparing cancer therapy drug, immunodepressant, PI3K inhibitor, mTOR inhibitors, suppression PI3K-Akt-mTOR path letters Number medicine, suppress the lymphopoietic medicines of T, antibacterials, antiviral drugs, the medicine for promoting apoptosis of tumor cells, Make cell cycle arrest the G1 phases medicine, prevent organ rejection response medicine, reduce arterial embolism medicine, Kangshuaining mixture Purposes in thing, anti-Alzheimer disease medicine, anti-inflammatory drug or antibacterials.

8. cancer types in claim 7 including but not limited to liver cancer, lung knurl, breast cancer, leukaemia, cervical carcinoma, oophoroma, The medicine of stomach cancer, prostate cancer or neuroendocrine carcinoma.

9. the compound or its pharmaceutically useful salt according to claim any one of 1-4 are used to produce that mammalian body can be suppressed The purposes of the medicine of interior PI3K/Akt/mTOR signals.

10. pharmaceutical composition, it includes the compound or its pharmaceutically useful salt, isomery according to claim any one of 1-4 Body, hydrate and at least one pharmaceutically useful carrier.