CN104557955B

CN104557955B - Tricyclic compound as PI3K/mTOR inhibitor as well as preparation method and application of tricyclic compound

Info

Publication number: CN104557955B
Application number: CN201310504853.4A
Authority: CN
Inventors: 程建军; 秦继红
Original assignee: SHANGHAI HUILUN TECHNOLOGY Co Ltd
Current assignee: Shanghai Huilun Pharmaceutical Co ltd
Priority date: 2013-10-23
Filing date: 2013-10-23
Publication date: 2017-05-03
Anticipated expiration: 2033-10-23
Also published as: CN104557955A

Abstract

The invention discloses a tricyclic compound as a PI3K/mTOR inhibitor. The tricyclic compound is a compound with the general formula (I) in the specification, wherein Ar is selected from aryl or heteroaryl; X, Y and Z are independently selected from O, CR2R3 and NR4 respectively; Q is selected from O, CR2R3 and NR4 or does not exists; R1 represents C1-C6 alkyl; n is selected from integers from 0 to 4; when n is more than or equal to 2, two R1 and a morpholine cycle can be combined into a combined cycle, a bridge cycle or a spiral cycle; R2 and R3 are selected from hydrogen and C1-C6 alkyl; R4 is selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclic radical, acyl and sulfonyl. The invention further discloses a perpetration method of the compound with the general formula (I) as well as a pharmaceutical composition and application of the compound with the general formula (I).

Description

As the tricyclic compoundses of PI3K/mTOR inhibitor, Preparation Method And The Use

Technical field

The present invention relates to a kind of tricyclic compoundses as PI3K/mTOR inhibitor, its preparation method, make containing them For the pharmaceutical composition of active component, and they as medicine to treat the disease related to PI3K/mTOR, particularly The purposes of PI3K/mTOR related cancer.

Background technology

Malignant tumor is the disease for threatening global human health and lives.Modern study shows, in tumor development mistake Cheng Zhong, PI3K（phosphatidylinositol3-kinase）-Akt（PKB, protein kinase B）-mTOR （mammalian target of rapamycin）Signal path controls numerous cell biological processes, including tumor is thin The regulation and control of born of the same parents' apoptosis, transcription, translation, metabolism, angiogenesiss and cell cycle.The activation of the signal path can upset cell Growth and survival, cause tumor cell proliferation quickening, pernicious transfer and produce common drug resistance.Blocking PI3K-Akt- MTOR signal paths can suppress growth of tumour cell or even promote apoptosis of tumor cells, therefore this path is new antitumoral medicine The important target spot of thing research and development（Nature Reviews Drug Discovery2009,8,627-644.）.

In PI3K-Akt-mTOR signal paths, the studied confirmation of PI3K, Akt, mTOR can be used as antineoplastic target Point（Expert Opin.Ther.Targets2012,16(1),121-130.）.PI3K is a kind of intracellular phosphatidyl inositol kinase, Can be catalyzed phosphatidylinositols 3- dis and the activation of mediate downstream signal path.PI3K can be divided into I types, II types and Type III, and it is most widely I types PI3K that can be activated by cell surface receptor to study.I types PI3K mainly include PI3K α, PI3K β, PI3K δ and tetra- kinds of hypotypes of PI3K γ, wherein PI3K α, PI3K β, PI3K δ belong to IA type kinases, from Receptor type tyrosine Kinases（RTK）, the transmission signal such as G- G-protein linked receptors；PI3K γ are IB type kinases, only from G- G-protein linked receptors（GPCR） Transmission signal.Research shows, I types PI3K overexpression, activation or are mutated, the generation, development with cancer in various human tumors It is closely related（Science2004,304,554.）.

In PI3K-Akt-mTOR signal paths, mTOR, as the downstream signaling molecule of PI3K, is the important substrate of Akt One of.MTOR is serine/threonine kinases, suppresses the signaling molecule to have been found to that the effect for suppressing tumor cell proliferation can be produced. Some forms of rapamycin analogs for acting on mTOR are listed as medicine, therefore mTOR is also identified it is the target for treating tumor Point (Cancer Letters2012,319,1-7).

At present, PI3K inhibitor, mTOR inhibitors, PI3K/mTOR double inhibitors have been found to that tumor can be suppressed Growth, tens compounds come into clinical research.The present invention will provide PI3K and/or mTOR with new structure type Inhibitor class compound, these compounds have the potentiality for the treatment of PI3K/mTOR relevant diseases.

The content of the invention

One of the technical problem to be solved is to provide a kind of tricyclic antidepressantss chemical combination as PI3K/mTOR inhibitor Thing.

The two of the technical problem to be solved are provided as the tricyclic compoundses of PI3K/mTOR inhibitor Preparation method.

The three of the technical problem to be solved are to provide containing the tricyclic antidepressantss chemical combination as PI3K/mTOR inhibitor The pharmaceutical composition of thing.

The four of the technical problem to be solved are to provide containing the tricyclic antidepressantss chemical combination as PI3K/mTOR inhibitor The application of the pharmaceutical composition of thing.

It is with below general formula as the tricyclic compoundses of first aspect present invention（I）Compound：

Wherein,

Ar is selected from aryl or heteroaryl, and can be by 1 to 4 optionally from amino, amido, amide groups, sulfoamido, ureine Base, aryl-ureido, heteroaryl urea groups, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl, cyano group, carboxyl, ester group, amine formyl Base, nitro, the substituent group of heterocyclic radical are replaced；

X, Y, Z are respectively and independently selected from O, CR²R³、NR⁴；Q is selected from O, CR²R³、NR⁴Or do not exist；

R¹For C₁To C₆Alkyl；Integers of the n selected from 0-4；When n >=2, can be by two R¹It is combined into morpholine ring group and ring, bridge Ring or volution；R²、R³Selected from hydrogen, C₁To C₆Alkyl；R⁴Selected from hydrogen, C₁To C₆Alkyl, C₃To C₇Cycloalkyl, heterocyclic radical, acyl group, sulphur Acyl group；The alkyl, cycloalkyl, heterocyclic radical, acyl group, sulfonyl can by halogen, hydroxyl, amino, cyano group, ester group, amide groups, Sulfoamido is replaced.

In some embodiments of the present invention, formula（I）Middle Ar is following structural formula（a）~（e）Appointing in compound monomer Meaning is a kind of：

Wherein, R⁵For hydrogen, alkyl, cycloalkyl, aryl, heteroaryl；R⁶For halogen, alkyl, alkoxyl, amido.

In some embodiments of the present invention, formula（I）Middle X, Y are O；Z is CH₂；Q is CH₂Or do not exist.

In some embodiments of the present invention, formula（I）InFor following structural formula（f）~（m）In compound monomer Any one：

Wherein, when the structural formula（f）~（m）When containing chiral carbon atom in compound monomer, be the optics of arbitrary configuration Pure compound monomer or the mixture of enantiomer and diastereomer.

Formula of the present invention（I）Compound, can be following compound（I-1）Extremely（I-12）In any one：

Described formula（I）Compound be enantiomer, diastereomer, conformer in any one or The mixture of both any or three.

The formula（I）Compound is pharmaceutically acceptable derivant.

Formula of the present invention（I）Compound can be present as a pharmaceutically acceptable salt form, including with sour institute into Salt, such as hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, trifluoromethanesulfonic acid Salt, tosilate, tartrate, maleate, fumarate, succinate or malate；Or acid proton is golden Sodium salt, potassium salt, magnesium salt, calcium salt that category ion is replaced.

As the preparation method of the above-claimed cpd of second aspect present invention, specially following synthetic method：Bicyclic adjacent ammonia Base aryl formate class compound A and the common heat fusing of carbamide, obtain tricyclic antidepressantss intermediate B, and the intermediate is in the presence of phosphorus oxychloride Double chloro intermediate C are converted into, nucleophilic displacement of fluorine is carried out with morpholine kind compound, obtain intermediate D, then idol is carried out with aryl compound Connection or nucleophilic substitution, you can obtain formula（I）Compound.As shown in following reaction scheme（Wherein Ar, X, Y, Z, Q, R¹, n is defined as described above）：

As the medicine group containing the aryl morpholine class compound as PI3K/mTOR inhibitor of third aspect present invention The formula of compound, wherein described pharmaceutical composition comprising therapeutically effective amount（I）Compound and pharmaceutically acceptable excipient.

Used as a kind of pharmaceutical composition of third aspect present invention, wherein described pharmaceutical composition includes therapeutically effective amount Formula（I）The pharmaceutically acceptable derivant and pharmaceutically acceptable excipient of compound.

Used as a kind of pharmaceutical composition of third aspect present invention, wherein described pharmaceutical composition includes therapeutically effective amount Formula（I）The pharmaceutically acceptable salt of compound and pharmaceutically acceptable excipient.

Described pharmaceutical composition make tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder, Granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.

As the application of fourth aspect present invention, wherein being formula（I）Compound adjusts PI3K/mTOR signals and leads in preparation Application in the catalysis activity product of road.

As the application of fourth aspect present invention, wherein being formula（I）The pharmaceutically acceptable derivant of compound is in system The standby application adjusted in PI3K/mTOR signal path catalysis activity products.

As the application of fourth aspect present invention, wherein being formula（I）The pharmaceutically useful salt of compound is preparing regulation Application in PI3K/mTOR signal path catalysis activity products.

As the application of fourth aspect present invention, wherein being that pharmaceutical composition leads in preparation treatment and PI3K/mTOR signals Application in the medicine of the relevant disease in road.

The disease relevant with PI3K/mTOR signal paths is cancer, including:

1. incidence cancer, including thyroid carcinoma, nasopharyngeal carcinoma, meninges cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyhgeal canal Tumor, thalamus and brain stem tumor, angiogenic tumor, intracranial metastatic tumor；

2. respiratory system cancer, including pulmonary carcinoma；

3. cancer in digestive system, including hepatocarcinoma, gastric cancer, the esophageal carcinoma, colorectal cancer, rectal cancer, colon cancer, cancer of pancreas；

4. urinary system cancer, including renal carcinoma, bladder cancer, carcinoma of prostate, carcinoma of testis；

5. skeletal system cancer, osteocarcinoma；

6. gynecological cancer, including breast carcinoma, cervical cancer, ovarian cancer；

7. hematological cancer, including leukemia, malignant lymphoma, multiple myeloma；

8. other types cancer, including malignant melanoma, glioma, skin carcinoma.

Formula involved in the present invention（I）Compound can be additionally used in PI3K-Akt-mTOR signal paths biology or The research of pharmacology's phenomenon and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitors.

Specific embodiment

The present invention provides formula defined above（I）Compound, the method for preparing these compounds, using these chemical combination The pharmaceutical composition of thing and the method using these compounds.

Listed below is the definition to being used for the various terms for describing the compounds of this invention.These definition are applied to In the term that each place of description uses（Unless defined otherwise on other occasions）, no matter these terms be used alone or As the part of more macoradical.

Unless otherwise defined, term as used herein " alkyl "（Alone or as the part of another group）Refer to alkane The derivative univalent perssad comprising 1 to 12 carbon atom of hydrocarbon.Preferred alkyl has 1 to 6 carbon atom.Alkyl is optionally substituted Straight chain, side chain or cyclic saturated hydrocarbon base.Exemplary alkyl includes methyl, ethyl, propyl group, isopropyl, normal-butyl, tertiary fourth Base, isobutyl group, amyl group, hexyl, isohesyl, heptyl, 4,4- dimethyl amyl groups, octyl group, 2,2,4- tri-methyl-amyls, nonyl, the last of the ten Heavenly stems Base, undecyl, dodecyl etc..And " alkyl " can be selected from following group and arbitrarily replace：Alkyl, halogen（As fluorine, Chlorine, bromine, iodine）, alkoxyl, amino/amido, haloalkyl（Such as trichloromethyl, trifluoromethyl）, aryl, aryloxy, alkane sulfur Base, hydroxyl, cyano group, nitro, carboxyl, alkoxy carbonyl, alkyl carbonyl epoxide, carbamyl, urea or sulfydryl.

Term as used herein " cycloalkyl "（Alone or as the part of another group）Refer to 3 to 10 carbon originals Son, fully saturated or fractional saturation the hydrocarbon ring of preferably 3 to 7 carbon atoms.Additionally, cycloalkyl can be replaced." replace Cycloalkyl " refer to one, two or three rings selected from following substituent group：Halogen, alkyl, the alkyl for replacing（Wherein replace Base is defined more than with regard to alkyl substituent）, thiazolinyl, alkynyl, nitro, cyano group, oxo（=O）, hydroxyl, alkoxyl, alkylthio group ,- CO₂H、-C(=O)H、-CO₂- alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O- alkyl, aryl, heteroaryl, five or hexa-atomic contractings Ketone（That is 1,3- dioxanes or 1,3- dioxs）、-NR'R"、-C(=O)NR'R"、-CO₂NR'R''、-C(=O)NR' R"、-NR'CO₂R"、-NR'C(=O)R"、-SO₂NR'R " and-NR'SO₂R ", wherein R' and R " is each independently selected from hydrogen, alkyl, takes The alkyl and cycloalkyl in generation, or R' and R ", forms together Heterocyclylalkyl or heteroaryl ring.

Index number after symbol " C " defines the number of the carbon atom that concrete group can be included.Such as " C₁To C₆Alkane Base ", refers to the straight or branched saturated carbon chains with one to six carbon atom；Example include methyl, ethyl, n-pro-pyl, isopropyl, Normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, sec-amyl, isopentyl and n-hexyl.Based on context, " C₁To C₆Alkane Base " can also refer to the C of two groups of connection₁To C₆Alkylidene.

Term as used herein " aryl "（Alone or as the part of another group）Refer to monocyclic aromatic ring or Polycyclic aromatic ring, such as phenyl, the phenyl for replacing etc. and group such as naphthyl, phenanthryl etc. for condensing.Thus, aryl is comprising at least One ring with least 6 atoms, comprising at most five such rings（Wherein include at most 22 atoms）, and it is adjacent Have between carbon atom or suitable hetero atom alternate（Conjugation）Double bond.Preferred aryl includes 6 to 14 carbon in ring Atom.And " aryl " can be optionally substituted one or more groups, the group includes but is not limited to halogen（Such as fluorine, Chlorine, bromine）, alkyl（Such as methyl, ethyl, propyl group）, replace alkyl（Such as trifluoromethyl）, cycloalkyl, alkoxyl（Such as methoxyl group Or ethyoxyl）, hydroxyl, carboxyl, amine formyl（-C(=O)NR'R"）, alkoxy carbonyl（-CO₂R）, amino/amido, nitro, cyanogen Base, thiazolinyl epoxide, aryl, heteroaryl, sulfonyl（-SO₂R）Deng, wherein, R, R', R " are the alkyl.

Term as used herein " heteroaryl "（Alone or as the part of another group）Refer to and replace and do not take The unit monocycle group of aromatics 5 or 6 in generation, 8 to 10 membered bicyclic groups and 11 to 14 membered tricyclic groups, these groups are at least one ring In have at least one hetero atom（N, O or S）.Each ring comprising heteroatomic heteroaryl can include one to four nitrogen original Son, one or two oxygen atoms and/or sulphur atom, condition is that heteroatomic sum is four or less in each ring, and often Individual ring all has at least one carbon atom, forms the ring for condensing of above-mentioned bicyclic radicals and three cyclic groups and can only include carbon atom, And can be saturation or fractional saturation.Nitrogen-atoms and sulphur atom can be oxidations, and nitrogen-atoms can be quaternary ammoniated 's.Bicyclic or three rings heteroaryl must include at least one complete aromatic ring, but other rings for condensing or multiple rings can Being aromatics or non-aromatic.Heteroaryl can connect at the arbitrarily available nitrogen-atoms of any ring or carbon atom.

" heteroaryl " ring system can be selected from following substituent group comprising zero, one, two or three：Halogen, alkyl, replace Alkyl（Including but not limited to difluoromethyl）, thiazolinyl, alkynyl, aryl, nitro, cyano group, hydroxyl, alkoxyl, alkylthio group ,- CO₂H、-C(=O)H、-CO₂- alkyl ,-C (=O) alkyl, phenyl, benzyl, phenylethyl, phenyl epoxide, thiophenyl, cycloalkyl, take The cycloalkyl in generation, Heterocyclylalkyl, heteroaryl ,-NR'R " ,-C (=O) NR'R " ,-CO₂NR'R"、-C(=O)NR'R"、-NR' CO₂R"、-NR'C(=O)R"、-SO₂NR'R " and-NR'SO₂The alkane that R ", wherein R' and R " is each independently selected from hydrogen, alkyl, replaces Base and cycloalkyl, or R' and R " forms together Heterocyclylalkyl or heteroaryl ring.

The example of bicyclic heteroaryl include pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, pyrrole radicals, pyrazolyl, Pyrazolinyl, imidazole radicals, oxazolyls, di azoly, isoxazolyls, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thiophene Ji, oxadiazolyls etc..

The example of bicyclic heteroaryl includes indyl, indazolyl, benzothiazolyl, benzodioxole base, benzo Oxazolyl, benzothienyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, benzimidazolyl .alpha.-5:6-benzopyran Base, indolizine base, benzofuranyl, chromone base, coumarin base, benzofuranyl, quinoxalinyl, pyrrolopyridinyl, furo Pyridine radicals etc..

The example of tricyclic heteroaryl includes carbazyl, benzindole base, phenanthroline, acridinyl, phenanthridinyl etc..

Term as used herein " heterocycle "（Alone or as the part of another group）A carbon in finger ring Atom is selected from the cycloalkyl that the hetero atom of N, O or S replaces and at most 3 extra carbon atoms can be replaced by the hetero atom（It is non- Aromatics）.Term " heterocyclic radical " used in this application（Alone or as the part of another group）Refer to and include 5 to 7 Annular atom（Carbon atom and other atoms selected from N, O and/or S）The undersaturated monocyclic ring system of stable saturation or part.It is miscellaneous Ring can be 5,6 or 7 unit monocycles, and comprising one, two or three hetero atoms selected from N, O and/or S.Heterocycle can be optional Replace, it means that heterocycle can replace in one or more commutable ring positions there are one or more to be independently selected from following base Group：Alkyl, Heterocyclylalkyl, heteroaryl, alkoxyl, nitro, monoalkyl amido, dialkyl amino, cyano group, halogen, haloalkyl, Alkanoyl, ammonia amine base carbonyl, monoalkyl amino-carbonyl, dialkyl amino carbonyl, alkylamidoalkyl, alkoxyalkyl, alkoxyl Carbonyl, alkyl carbonyl epoxide and aryl, the aryl is optionally substituted with halogen, alkyl and alkoxyl.The reality of these Heterocyclylalkyls Example is included but is not limited to：Piperidines, morpholine, high morpholine, piperazine, tetrahydro-1,4-thiazine, pyrrolidine and azetidine.

Term as used herein " alkoxyl "（Alone or as the part of another group）Refer to and pass through oxygen atom What is connected preferably has the alkyl of 1 to 6 carbon atom, and such as-OR, wherein R are the alkyl.

Term as used herein " amino "（Alone or as the part of another group）Finger-NH₂." amido " can It is optionally substituted with one or two substituent groups（-NR'R"）, wherein R' and R " it is can be identical or different, such as alkyl, aryl, Aryl alkyl, thiazolinyl, alkynyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, cycloalkyl, cycloalkyl-alkyl, haloalkyl, hydroxyl Alkyl, alkoxyalkyl, alkylthio group, carbonyl or carboxyl.These substituent groups can be further substituted with listed by carboxylic acid or the application Alkyl or aryl substituent group in any one.In some embodiments, amino replaces carboxyl or carbonyl, forms N- acyls Base or N- carbamyl deriveding groups.

Term " halogen " refers to fluorine, chlorine, the bromine or iodine of independent selection.

Term " anticarcinogen " includes can be used for any known medicine for the treatment of cancer, including：（1）Cytotoxic drug： Chlormethine series pharmaceuticals, such as melphalan, cyclophosphamide；Platinum coordination complex, such as cisplatin, carboplatin and oxaliplatin；（2）Anti-metabolism Antineoplastic agent：5-fluorouracil, Capecitabine, methotrexate, calcium folinate, Raltitrexed, purine antagonist（For example 6- is thio Guanine and Ismipur）；（3）Hormoness：The female alcohol of 17 alpha-acetylenes, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, propanoic acid are bent His androsterone, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyl are pregnant Ketone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene；（4）Tyrosine kinase inhibitor：EGFR inhibitor, bag Include gefitinib（Gefitinib）, Erlotinib（Erlotinib）, Cetuximab（Cetuximab）, Trastuzumab （Herceptin）Deng；VEGF inhibitor, such as VEGF antibody（Avastin（Avastin））With micromolecular inhibitor such as Sunitinib, Sorafenib, Vandetanib, Pazopanib, Axitinib etc.；Bcr-Abl inhibitor such as Imatinib, Nilotinib、Dasatinib；B-Raf inhibitor such as Sorafenib, Vemurafenib, Dabrafenib etc.；MEK kinases presses down Preparation such as Trametinib, Selumetinib etc.；And mapk kinase inhibitor, PI3K kinase inhibitors, c-Met inhibitor, ALK inhibitor, Src inhibitor etc.；（5）Act on the medicine of tubulin, such as vinca medicine, taxanes medicine, Epothilones medicine such as ipsapirone（Ixabepilone）Deng；（6）Topoisomerase I inhibitor, such as topotecan, Yi Li For health；（7）Histon deacetylase (HDAC)（HDAC）Inhibitor such as Vorinostat, Romidepsin；（8）Proteasome inhibitor Such as bortezomib（Bortezomib）；（9）The anticarcinogen of other classifications such as aurora kinase（aurora kinase）Inhibitor, life Thing answer-reply regulator, growth inhibitor, glu famine antagonist, angiogenesis inhibitor and anti-vascular medicine, matrix metalloproteinase Inhibitor etc..

" mammal " includes the mankind and domestic animal, such as cat, Canis familiaris L., pig, cattle, sheep, goat, horse, rabbit.Preferably, in order to The purpose of the present invention, the mammal is the mankind.

" pharmaceutically acceptable derivant " represent to receiver be administered when, can directly or indirectly provide the present invention chemical combination Any nontoxic salt of the active metabolite or residue of thing or its inhibition, ester, the salt of ester, amide, the salt of amide or other Derivant.

" pharmaceutically acceptable excipient " is included but is not limited to by state food and Drug Administration's approval conduct Can be used for any adjuvant of the mankind or domestic animal, carrier, excipient, fluidizer, sweeting agent, dispersant, diluent, preservative, help Suspension, stabilizer, dyestuff/coloring agent, flavour enhancer, surfactant, wetting agent, isotonic agent, solvent or emulsifying agent.

" pharmaceutically acceptable salt " includes acid-addition salts and base addition salts.

" pharmaceutically acceptable acid-addition salts " refer to such salt, and they remain the biological effect and property of free alkali, Adverse consequencess will not be produced in terms of biology or other, and is to be such as, but not limited to hydrochloric acid, hydrobromic acid, sulfur with mineral acid Acid, nitric acid, phosphoric acid etc., and the such as, but not limited to, following acid of organic acids：Formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, fluoroform Sulfonic acid, ethyl sulfonic acid, 2- ethylenehydrinsulfonic acids, benzenesulfonic acid, p-methyl benzenesulfonic acid, 2,2- dichloroacetic acid, adipic acid, alginic acid, Vitamin C Acid, aspartic acid, benzoic acid, paraacetaminobenzoic acid, dextrocamphoric acid., Camphora -10- sulfonic acid, capric acid, caproic acid, octanoic acid, carbonic acid, Cinnamic acid, citric acid, cyclohexane sulfamic acid, lauryl sulphate acid, ethane -1,2- disulfonic acid, Fumaric acid, galactose two Acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, 1,3-propanedicarboxylic acid, 2- oxos -1,3-propanedicarboxylic acid, phosphoglycerol, ethanol Acid, hippuric acid, isopropylformic acid., lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, glactaric acid, naphthalene -2- sulphurs Acid, naphthalene -1,5- disulfonic acid, 1- hydroxy-2-naphthoic acids, nicotinic acid, Oleic acid, orotic acid, oxalic acid, brown eleostearic acid, pamoic acid, propanoic acid, Pyroglutamic acid, acetone acid, salicylic acid, 4-ASA, decanedioic acid, stearic acid, fumaric acid, succinic acid, tartaric acid, sulfur cyanogen Acid, undecylenic acid etc. are formed.

" pharmaceutically acceptable base addition salts " refer to such salt, and they remain the biological effect and property of free acid, Will not be improper in terms of biology or other.These salt are obtained by inorganic base or organic base are added on free acid.Source Sodium, potassium, lithium, ammonium, calcium, magnesium, ferrum, zinc, copper, manganese, aluminium salt etc. are included but is not limited to from the salt of inorganic base.Preferred inorganic salt is Ammonium, sodium, potassium, calcium and magnesium salt.The salt of following substances is included but is not limited to from the salt of organic base：Primary amine, secondary amine and tertiary amine, replacement Amine, including naturally occurring replacement amine, such as cyclammonium and deacidite, ammonia, methylamine, dimethylamine, trimethylamine, diethyl Amine, triethylamine, tripropyl amine (TPA), 2-aminopropane., diethanolamine, ethanolamine, DMAE, 2-diethylaminoethanol, two hexamethylenes Amine, lysine, arginine, histidine, caffeine, procaine, Hai Baming（hydrabamine）, choline, glycine betaine, benzene second Benzylamine, ethylenediamine, glycosamine, methylglucosamine, theobromine, triethanolamine, trometamol, purine, piperidines, piperazine, N- ethyls Piperidines, polyamino resin etc..Preferred organic base is 2-aminopropane., diethylamine, ethanolamine, triethylamine, hexanamine, choline and coffee Cause.

" pharmaceutical composition " refers to the compound of the present invention and biologically active cpds is delivered to into the mammal such as mankind In usual acceptance the preparation that constituted of medium.Such medium includes all of pharmaceutically acceptable carrier to this, dilute Release agent or excipient.

" therapeutically effective amount " refers to when being administered to mammal（It is preferred that the mankind）, it is sufficient to mammal（It is preferred that the mankind）'s Relevant disease or disease realize the amount of the compound of the invention for the treatment of as defined below.Constitute the sheet of " therapeutically effective amount " The amount of the compound of invention can be according to the activity of the particular compound for example applied；The metabolic stability and work of the compound Use duration；Age of patient, body weight, holistic health, sex and diet；Mode of administration and time；Discharge rate；Drug combination； The seriousness of specific illness or disease；And experience the individual for the treatment of and change, but it can be by those of ordinary skill in the art Routinely determined according to its own knowledge and the disclosure.

" treatment " or " treatment " is used to cover to the mammal with relevant disease or disease, preferred people during this paper The relevant disease of class or the treatment of disease, and including：

（1）There is disease or disease in prevention mammal, especially when such mammal it is ill but without When being diagnosed to be illness；

（2）Suppress disease or disease, that is, prevent it from developing；

（3）Alleviate disease or disease, that is, cause disease or disease to disappear；

（4）Stable disease or disease.

During for this paper, term " disease " and " disease " can be with used interchangeablies or can be with difference, and reason is specified disease Or the inducement that disease may be known without oneself（So as to also not work out the cause of disease）, therefore be not also considered as disease and be only used as Improper situation or syndrome, wherein clinician more or less have identified specific syndrome.

The compounds of this invention shown in this article and their structure are also represented by including all isomers（Such as enantiomerism Body, diastereomer, geometrical isomerism or conformational isomerism）Form, they can be according to for the absolute stereochemical of aminoacid Be defined as (R) -/(S)-either (D) -/(L)-or (R, R) -/(R, S) -/(S, S)-.The present invention represent include it is all these can Can isomer, and their enrichment of racemic, enantiomer and optional pure form.Optically-active (+) and (-), (R)- (S)-and (R, R) -/(R, S) -/(S, S)-or (D)-can be using chiral synthesis, chiral separation system with (L)-isomer It is standby, or routine techniquess can be used such as but not limited to using the efficient liquid phase of chiral column（HPLC）Split.When described herein Compound comprising thiazolinyl double bond or during other geometry asymmetric centers, unless otherwise stated, the compound includes that E and Z is several Both what isomers.Equally, also including all tautomeric forms.

" stereoisomer " is referred to and is made up of with identical chemical bonding identical atom but with different three dimensional structures Compound, they are non-interchangeable.The present invention covers various stereoisomers and its mixture and including " enantiomer " and " non- Enantiomer ", enantiomer refers to two kinds of stereoisomers of the mirror image that its molecule can not be overlapped each other；Diastereomer Refer to that molecule has two or more chiral centres, and the intermolecular stereoisomer for non-mirror image relationship.

" tautomer " refers to that proton moves to another position of same molecule from an atom of molecule from original position On.Tautomer of the present invention including any compound.

In addition, unless otherwise stated, the compound of the present invention is also different only in that one or more of presence is same including structure The compound of the plain enriched atoms in position.For example, with the structure of the present invention, except replacing hydrogen, Huo Zheyong with " deuterium " or " tritium "¹⁸F- fluorine Labelling（¹⁸F isotopes）Replace fluorine, Huo Zheyong¹¹C-,¹³C-, or¹⁴The carbon of C- enrichments（¹¹C-,¹³C-, or¹⁴C- carbon markingses；¹¹C-,¹³C-, or¹⁴C- isotopes）The compound for replacing carbon atom is within the scope of the invention.Such compound can use Analytical tool or probe in work such as biological characteristis, or the diagnostic imaging in vivo tracer of disease is can serve as, or As the tracer of pharmacodynamicss, pharmacokineticss or receptor research.

The present invention also provides following methods：By by the formula as defined above of therapeutically effective amount（I）Compound with At least one other anticancer agents give（Simultaneously or successively）The patient of this treatment is needed, is believed via PI3K/mTOR is adjusted Number path is treating proliferative disease（Such as cancer）.In preferred embodiments, proliferative disease is cancer.

Specifically, formula（I）Compound can be used to treat kinds cancer, is most specifically and depends on PI3K/mTOR signals to live Those cancers changed.Generally, the compound of the present invention can be used to treat following cancer：

2. respiratory system cancer, including pulmonary carcinoma；

5. skeletal system cancer, osteocarcinoma；

8. other types cancer, including malignant melanoma, glioma, skin carcinoma.

Formula（I）Compound can also be used to treat any lysis for being characterized as abnormal cell proliferation, such as it is benign before Row gland hypertrophy, neurofibromatosiss, atherosclerosiss, pulmonary fibrosiss, arthritis, psoriasiss, glomerulonephritiies, angiopoiesises Restenosiss, inflammatory bowel, graft-rejection, endotoxin shock and the fungal infection occurred after art or vascular surgery.

Formula（I）Compound scalable cell RNA and the level of DNA synthesis.Therefore, these materials can be used to treat disease Poison infection（Including but not limited to HIV, human papillomavirus, herpesviruss, poxvirus, Epstein-Barr virus, sindbis alphaviruses and adenopathy Poison）.

Formula（I）Compound can be used for the chemoprophylaxiss of cancer.Chemoprophylaxiss are defined as to dash forward by blocking initial cause The progress of change event or the pre-malignant cells for suffering from damaging by blocking is come the development of anti-invasion cancer or suppresses tumor Recurrence.

Formula（I）Compound can be used to suppress tumor-blood-vessel growth and transfer.

The compound of the present invention also can be with known anticarcinogen（Mention in including but not limited to above-mentioned " anticarcinogen " that A bit）Or anticancer therapy（Such as radiotherapy）It is applied in combination（Give together or successively give）.

Some formulas（I）Compound generally can be prepared according to following route.Formula（I）The tautomer of compound and Solvate（Such as hydrate, ethanolates）It is also within the scope of the invention.The preparation method of solvate is in the art Commonly known.Therefore, compound of the invention can be free form or hydrate forms.

In method discussed below, the functional group of midbody compound may need to be protected by suitable protection group.This The functional group of sample includes hydroxyl, amino, sulfydryl and carboxylic acid.For hydroxyl suitable protection group include trialkylsilkl or Diarylalkyl-silyl（Such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl first silicon Alkyl）, THP trtrahydropyranyl, benzyl, to methoxy-benzyl etc..Suitable protecting groups for amino include tertbutyloxycarbonyl, benzyloxy Carbonyl, acetyl group, benzoyl, trifluoroacetyl group, to methoxy-benzyl etc..For carboxylic acid Suitable protecting groups include alkyl, Aryl or alkyl aryl.Suitable protecting groups for the heteroaryl such as NH functional groups of such as indole or indazole ring include tertiary fourth Oxygen carbonyl, benzyloxycarbonyl group, acetyl group, benzoyl, 2- trimethylsilyl-ethoxy methyl, to methoxy-benzyl etc..

Protection group can be according to method known to those skilled in the art（Greene, T.W., Protective Groups In Organic Sythesis, 1999, the 3rd edition, Wiley）Add with standard technique as herein described or remove.The guarantor Shield base can also be fluoropolymer resin such as Wang resin, Rink resins or 2- chlorine trityl chloride resins.

Meanwhile, although these protected derivants of the compounds of this invention itself may not have pharmacological activity, it Can be administered to mammal, then in vivo metabolism forming the compounds of this invention with pharmacological activity.So Derivant therefore be described as " prodrug ".All prodrugs of the compounds of this invention are included within the scope of the present invention.

Formula of the present invention（I）Compound, can be prepared by the following method：Bicyclic adjacent aminoaryl formic acid class chemical combination Thing A and the common heat fusing of carbamide, obtain tricyclic antidepressantss intermediate B, and the intermediate is converted in the middle of double chloros in the presence of phosphorus oxychloride Body C, with morpholine kind compound nucleophilic displacement of fluorine is carried out, and obtains intermediate D, then carries out coupling reaction with aryl compound or nucleophilic takes Generation, you can obtain formula（I）Compound.As shown in following reaction scheme（Wherein Ar, X, Y, Z, Q, R¹, n institutes as defined above State）：

Wherein, following is the abbreviation commonly used during present invention statement：

DMF：N,N-dimethylformamide；

DMSO：Dimethyl sulfoxide；

THF:Tetrahydrofuran

CDCl₃：Deuterochloroform；

LC-MS:LC-MS chromatograph；

TLC：Thin layer chromatography；

1H NMR：Proton nmr spectra；

s：It is unimodal；

d：It is bimodal；

t：Triplet；

dd：Doublet of doublet；

br：Broad peak；

m：Multiplet；

℃：Degree Celsius；

mol：Mole；

mmol：MM.

Those skilled in the art can use appropriate raw material, the method using being similar to, and prepare and do not have in reaction scheme above There are other compounds of the specifically disclosed present invention.

By with suitable inorganic or organic base or acid treatment, will can be deposited with free alkali or sour form according to being prepared as above All the compounds of this invention change into their pharmaceutically acceptable salt.The salt of the compound being prepared as above can be by mark Free alkali or sour form of the quasi- technical transform into them.

The compound of the present invention includes its all crystal formations, amorphous forms, dehydrate, hydrate, solvate and salt.This Outward, all compounds of the invention comprising ester group and amide group can pass through oneself method for knowing of those skilled in the art Or corresponding acid is changed into by method described herein.Equally, the compounds of this invention comprising hydroxy-acid group can pass through Those skilled in the art oneself the method known be converted into corresponding ester and amide.Oneself side for knowing of those skilled in the art can also be passed through Method（Such as hydrogenation, alkylation and acyl chloride reaction etc.）Other carried out on molecule replace and replace.

The cyclodextrin clathrate of the present invention is prepared, can be by the formula defined in summary of the invention above（I）Compound It is dissolved in the acceptable solvent of pharmacology for example（But it is not limited to）Alcohol（Preferred alcohol）, ketone（Such as acetone）Or ether（Such as ether） In, and in 20 DEG C to 80 DEG C and alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin, the aqueous solution of preferred beta-schardinger dextrin-；Or Can be by the formula defined in summary of the invention above（I）Compound acid with its salt（Such as sodium or potassium salt）Aqueous solution form It is blended with cyclodextrin, then with equivalent acid（Such as hydrochloric acid or sulphuric acid）Solution blending, to provide corresponding cyclodextrin inclusion compound Thing.

Now or after the cooling period, corresponding cyclodextrin clathrate crystal can crystallize precipitation.Or work as formula（I）Chemical combination When thing is oily and crystallization, by stirring for a long time at room temperature（Such as 1 hour to 14 days）, add the aqueous solution of cyclodextrin Process, it is also possible to be converted into corresponding cyclodextrin clathrate.Then by filtering and being dried, clathrate can be separated into solid Or crystal.

Cyclodextrin for the present invention is commercially available（For example from Aldrich Chemical Co.）, or by this area skill Art personnel are prepared using known method.Croft, A.P. et al. are see, for example, " Sy-hesis of Chemically Modified Cyclodextrins",Tetrahedron1983,39,9,1417-1474.Suitable cyclodextrin include with above Institute's column（I）Compound prepare all kinds of clathrate.

By selecting appropriate cyclodextrin and water, repeatable active substance content can be obtained according to stoichiometric composition Clathrate.Clathrate can be to be dried water suction form or form that is aqueous but less absorbing water is used.Cyclodextrin and formula （I）Compound Typical mole ratios be 2：1（Cyclodextrin：Compound）.

Comprising formula（I）Compound can be adapted for oral form as the pharmaceutical composition of active component, for example, Tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder or granule, syrup etc..It is orally available to use Compositionss can be prepared according to known in the art for preparing any means of pharmaceutical composition, and these compositionss can be wrapped The material of sweeting agent, flavoring agent, coloring agent and preservative is selected from containing one or more, to provide pharmaceutical elegant and agreeable to the taste system Agent.

Tablet includes active component, and is mixed with and is suitable to the nontoxic pharmaceutically acceptable excipient for preparing tablet or carrier.These figurations Agent or carrier can be inert diluent, such as Calcium Carbonate, sodium carbonate, Lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, Such as Celluloasun Microcrystallisatum, carmethose, corn starch or alginic acid；Binding agent, such as starch, gelatin, polyvinylpyrrolidine Ketone or arabic gum；And lubricant, such as magnesium stearate, stearic acid or Pulvis Talci.Tablet can be uncoated, or can pass through Known technology carrys out coating, so as to cover unpleasant drug tastes, or postpones disintegrate and absorption in the gastrointestinal tract, thus exists Lasting effect is provided in the longer period.For example, material can be covered using water miscible taste（Such as hydroxypropyl-methyl is fine Dimension element or hydroxypropyl-cellulose）Or time delay material（Such as ethyl cellulose, cellulose acetate-butyrate）.

Capsule includes hard-gelatin capsules, Gelseal.Hard-gelatin capsules are by active component and inert solid Diluent such as Calcium Carbonate, calcium phosphate or Kaolin mix；Gelseal is by active component and water-solubility carrier（Such as gather Ethylene glycol）Or oil medium（Such as Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil）Mixing.

Aqueous suspension is comprising active substance and is suitable to prepare the excipient of aqueous suspension.These excipient are suspending Agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl-cellulose, sodium alginate, polyvinylpyrrolidone and Ah Draw primary glue；Dispersant or wetting agent, can be naturally occurring phospholipid（Such as lecithin）Or the condensation of oxyalkylene and fatty acid Product（Such as Myrj 45）Or the condensation product of ethylene oxide and long-chain fatty alcohol（Such as 17 oxygen ethylene spermaceti Alcohol（heptadecaethylene-oxycetanol））Or ethylene oxide and the condensation from partial ester derived from fatty acid and hexitol Product（Such as polyoxyethylene 80 sorbitan monooleate）Or ethylene oxide with from derived from fatty acid and hexose alcohol-ether mixture The condensation product of partial ester（Such as polyethylene sorbitan monoleate）.Aqueous suspension also can be anti-comprising one or more Rotten agent（Such as ethylparaben or n-propyl）, one or more coloring agent, one or more flavoring agents and one or more are sweet Taste agent（Such as sucrose, saccharin or aspartame）.

Oil suspensions can be by being suspended in vegetable oil by active component（Such as Oleum Arachidis hypogaeae semen, olive oil, Oleum Sesami or cocos nucifera oil） Or mineral oil（Such as liquid paraffin）In preparing.Oil suspensions can include thickening agent, such as Cera Flava, hard paraffin or spermaceti Alcohol.Sweeting agent can be added（Such as those listed above）And flavoring agent, so as to provide agreeable to the taste oral formulations.These combinations Thing can be by adding antioxidant（Such as butylated hydroxyanisole or alpha-tocopherol）Carry out anti-corrosion.

Dispersible powder and granule include active component, and are mixed with dispersant or wetting agent, suspending agent and one or more Plant preservative.The example of suitable dispersant or wetting agent and suspending agent is those already mentioned by the above.Also other can be included Excipient, such as sweeting agent, flavoring agent and coloring agent.These compositionss can be by adding antioxidant（Such as ascorbic acid）Come Anti-corrosion.Dispersible powder and granule can prepare aqueous suspension by adding water.

Syrup can use sweeting agent（Such as glycerol, Propylene Glycol, Sorbitol or sucrose）To prepare.These preparations also can be included Demulcent, preservative, flavoring agent, coloring agent and antioxidant.

The pharmaceutical composition of the present invention can also be the form of oil-in-water emulsion.Oil phase can be vegetable oil（Such as olive Olive oil or Oleum Arachidis hypogaeae semen）Or mineral oil（Such as liquid paraffin）Or their mixture.Suitable emulsifying agent can be naturally occurring Phospholipid（Such as soybean lecithin）, from fatty acid and ester or partial ester derived from hexose alcohol mixture（Such as sorbitan Monoleate）With the partial ester and the condensation product of ethylene oxide（Such as Polysorbate 80）.Breast Agent can also include sweeting agent, flavoring agent, preservative and antioxidant.

Pharmaceutical composition can be the form of sterile injectable aqueous solution.The acceptable carriers and solvent that can be used have water, Ringer's solution（Ringer's solution）, isotonic sodium chloride solution and glucose solution.

Sterile injectable preparation can also be sterile injectable water oil-packaging type micro-emulsion, wherein active component is dissolved in into oil phase In.For example, active component is dissolved in the mixture of soybean oil and lecithin first.Then, resulting oil solution is fallen Enter in the mixture of water and glycerol and process, so as to form microemulsion.

Injectable solution or microemulsion can be imported in the blood flow of patient by local bolus injection, or give institute in some way Solution or microemulsion are stated, so as to maintain the circulation composition of constant the compounds of this invention.In order to maintain this constant concentration, can make With the continuous intravenous administration set such as infusion pump.

Pharmaceutical composition could be for the sterile injectable aqueouss or the form of oil-based suspension of intramuscular or subcutaneous administration. This suspension can be according to more than known technology the use suitable dispersant of those already mentioned or wetting agent and suspending agent To configure.Sterile injectable preparation can also be the sterile injectable solution or suspension of nontoxic pharmaceutically acceptable diluent or solvent, The solution of such as 1,3 butylene glycol.In addition, sterile, fixed oils can be easily used as solvent or suspension medium.For this mesh , arbitrarily gentle fixed oil all can be used, including the monoglyceride or two glyceride of synthesis.In addition, fatty acid（Such as oil Acid）Can be used in injection be prepared.

Formula（I）Compound also can be given by the form of the suppository for rectally.These compositionss can be by mixed Composite medicine is prepared with suitable nonirritant excipient, the excipient room temperature be solid but rectal temperature be liquid, Therefore melt in the rectum, so as to discharge medicine.These materials include cocoa butter, glycerin gelatine, hydrogenated vegetable oil, different molecular The mixture of the Polyethylene Glycol of amount and the fatty acid ester of Polyethylene Glycol.

For the use of local, can prepare and use comprising formula（I）It is the ointment of compound, ointment, jelly, molten Liquor or suspensoid etc..

The compound of the present invention can in intranasal form be given by local using suitable nasal carrier and doser, Or given by cutaneous routes using the form of the transdermal skin patches well-known to those skilled in the art.This Bright compound also can be given by the form of the suppository of substrate using such as following：Cocoa butter, glycerin gelatine, hydrogenation The fatty acid ester of vegetable oil, the mixture of the Polyethylene Glycol of different molecular weight and Polyethylene Glycol.

When the compound of the present invention is administered in human subject body, daily dosage is typically by the doctor of prescription It is raw to determine, and age of the dosage generally with patient, body weight, the order of severity of the symptom of sex and reaction and patient become Change.It is about 0.001mg/kg to 100mg/kg, preferably 0.01mg/kg extremely typically for the effective daily dose of patient of 70kg 50mg/kg。

If being configured to fixed dosage, then these combination products use this in dosage range described above Bright compound and other the pharmaceutically active agent treatments in the dosage range that it is ratified.When combination preparation is improper, formula（I） Compound also can successively give with known anticarcinogen or cytotoxicity medicine.The present invention is not limited by order of administration；Formula（I） Compound can give known anticarcinogen（Various anticarcinogens）Or cytotoxicity medicine（Various kinds of cell toxicity medicine）Before or after To give.

The compound of the present invention is the inhibitor of the disease of the disease of PI3K/mTOR mediations or PI3K/mTOR mediations.Term " disease of PI3K/mTOR mediations " and " disease of PI3K/mTOR mediations " represents that known PI3K/mTOR has effective any disease Diseased state or other adverse conditions.Term " disease of PI3K/mTOR mediations " and " disease of PI3K/mTOR mediations " are also represented by leading to Cross those diseases or disease being eased with PI3K/mTOR inhibitor for treating.These diseases and disease include but is not limited to cancer Disease and other proliferative disorders.

Therefore, the compound can be used to treat the following disease or illness in such as mammal, the especially mankind：Stomach Cancer, pulmonary carcinoma, esophageal carcinoma, cancer of pancreas, renal carcinoma, colon cancer, thyroid carcinoma, the brain cancer, breast carcinoma, carcinoma of prostate and other entities Tumor；Lymphoma；Leukemia；Adjust blood vessel generation；Adjust thrombosiss and pulmonary fibrosiss.

Compound involved in the present invention can be additionally used in the biology of PI3K-Akt-mTOR signal paths or pharmacology's phenomenon Research and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitors.

Compound involved by herein includes but is not limited to the structure type given by said synthesis route, knows ability The personnel of field technique can obtain the compound specifically do not enumerated using similar method by appropriate initiation material.

Embodiment

Examples provided below（For preparing the compound of the present invention）With biological test example（For proving of the present inventionization The detection of compound purposes）The practice present invention is to aid in, they are not considered as limiting the scope of the present invention.

Embodiment 1：Structural formula（I-1）5- (8- morpholines-[1,3] dioxs [4,5-g] quinazoline -6- bases) pyrimidine - The preparation of 2- ammonia, concrete reaction equation is as follows：

Step 1：By piperic acid（20g, 0.12mmol）It is dissolved in methanol（160mL）In, Deca concentrated sulphuric acid（16mL）, it is heated to 70 DEG C are stirred 5 hours.TLC shows that raw material disappears, and is cooled to room temperature, and concentrating under reduced pressure adjusts pH with 5% sodium hydrate aqueous solution To alkalescence, it is extracted with ethyl acetate, is dried, is concentrated to give methyl piperate（White needles 21.0g, 97%）.

Step 2：Methyl piperate（21.0g, 0.117mmol）It is dissolved in glacial acetic acid（130mL）In, the lower Deca smoke of stirring Nitric acid（44.8mL）, finish, it is warming up to 70 DEG C and stirs 1 hour.It is cooled to room temperature, concentrates, is neutralized with 5% sodium hydrate aqueous solution, Solid is separated out, and is filtered, filter cake distillation washing, is dried, and obtains 6- nitro benzo [d] [1,3] diox -5- methyl formates （19.6g, 75%）.

Step 3：6- nitro benzo [d] [1,3] diox -5- methyl formates（18.0g, 79.9mmol）Add ethanol （200mL）And water（40mL）In, heating makes dissolving, and take a policy powder（48.0g, 276mmol）, it is warming up to 80 DEG C and stirs 2 hours. Cooling, filters, and filter cake dichloromethane/ethanol is washed, and collects filtrate, and concentration adds dichloromethane/ethanol and is sufficiently stirred for, mistake Filter, filter cake dichloromethane/ethanol is washed, and collects filtrate, and concentration obtains 6- amino benzo [d] [1,3] diox -5- carboxylate methyl esters （12.3g, 79%）.

Step 4：By NaOH（2.95g, 73.8mmol）Add water（75mL）In, 6- amino benzos are added after stirring and dissolving [d] [1,3] diox -5- carboxylate methyl esters（12.0g, 61.5mmol）, it is warming up to 90 DEG C and stirs 2 hours.Frozen water is cooled down, and uses dense salt Acid for adjusting pH has solid to separate out to 2, is sufficiently stirred for, and filters, and filter cake is washed with water, dries to obtain 6- amino benzo [d] [1,3] two Evil Alkane -5- formic acid（7.2g, 65%）.

Step 5：Nitrogen is protected, by carbamide（4.97g, 82.8mmol）In being placed in single port bottle, it is heated to 160 DEG C and is allowed to molten Melt, add 6- amino benzo [d] [1,3] diox -5- formic acid（1.0g, 5.52mmol）, stir 3 hours.100 DEG C are cooled to, Carefully add water（5mL）, stir 10 minutes, filter, filter cake is washed with water, collects solid, in adding to 5% sodium hydrate aqueous solution, plus Heat is stirred to clarify to 100 DEG C, is cooled down, and pH is adjusted to 2 with concentrated hydrochloric acid, is sufficiently stirred for, and is filtered, and filter cake is washed with water, dry [1,3] dioxs [4,5-g] quinazolines -6,8 (5H, 7H)-diketone（600mg, 53%）.

Step 6：Nitrogen is protected, by [1,3] dioxs [4,5-g] quinazoline -6,8 (5H, 7H)-diketone（1.2g, 5.82mmol）Add phosphorus oxychloride（20mL）In, add DIPEA（752mg, 5.82mmol）, backflow is heated to, stir 5 hours. TLC shows that raw material disappears, and is cooled to room temperature, and concentrating under reduced pressure, the careful water quenching on the rocks of residue is gone out, is extracted with ethyl acetate, is dried, Solvent is evaporated off, chloro- [1,3] diox [4, the 5-g] quinazolines of 6,8- bis- are obtained（900mg, 64%）.

Step 7：Nitrogen is protected, by chloro- [1,3] diox [4, the 5-g] quinazolines of 6,8- bis-（900mg, 3.7mmol）Add Dichloromethane（25mL）In, add morpholine（387mg, 4.44mmol）, triethylamine（450mg, 4.44mmol）, it was stirred at room temperature Night.TLC shows that raw material disappears, and concentration, residue by silicagel column chromatographs to obtain the chloro- 8- morpholines of 6--[1,3] bis- Evil [4,5-g] quinolines Oxazoline（560mg, 52%）.

Step 8：Nitrogen is protected, the chloro- 8- morpholines of 6--[1,3] dioxs [4,5-g] quinazoline（100mg, 0.34mmol）, 2- aminopyrimidine-5-boric acid pinacol esters（113mg, 0.51mmol）、Cs₂CO₃（150mg, 0.51mmol）、Pd (dppf)Cl₂（23mg, 0.034mmol）It is mixed in 1,4- dioxane（9mL）And water（1.5mL）Mixed solvent in, heating To 100 DEG C, stir 1 hour.Room temperature is cooled to, concentrating under reduced pressure, Jing silica gel column chromatography purification obtains 5- (8- morpholines-[1,3] two Oxane [4,5-g] quinazoline -6- bases) pyrimidine -2- ammonia（56mg, 47%）.MS(ESI)m/z=353[M+H]；¹H NMR(300MHz, DMSO-d₆)9.14(s,2H),7.32(s,1H),7.23(s,1H),7.15(s,2H),6.23(s,2H),3.82(m,4H), 3.59(m,4H)。

Embodiment 2：Structural formula（I-2）5- (8- morpholines-[1,3] dioxs [4,5-g] quinazoline -6- bases) -4- (three Methyl fluoride) pyridine -2- ammonia preparation, concrete reaction equation is as follows：

Nitrogen is protected, the chloro- 8- morpholines of 6--[1,3] dioxs [4,5-g] quinazoline（100mg,0.34mmol）, 4- tri- Methyl fluoride-PA -5- pinacol borates（【Reference literature is prepared ACS Med.Chem.Lett.2011,2, 774–779.】, 198mg, 0.68mmol）, aqueous sodium carbonate（2N,0.74mL）、Pd(dppf)Cl₂（36mg）, ethylene glycol bisthioglycolate Methyl ether（2mL）Mixing, tube sealing is heated to 90 DEG C, is stirred overnight, and TLC shows that raw material disappears substantially, adds diluted ethyl acetate, uses Saturation Na₂CO₃Solution/water/strong aqua ammonia=5/4/1（10mL）Washing, then use saturated aqueous ammonium chloride（20mL）Washing, then with satisfy And saline solution（20mL）Wash, be dried, concentration.Residue by silicagel column chromatography purification, obtains 5- (8- morpholines-[1,3] dioxs [4,5-g] quinazoline -6- bases) -4- (trifluoromethyl) pyridine -2- ammonia（31mg, 55%）.MS(ESI)m/z=420[M+H]；¹H NMR(500MHz,DMSO-d₆)8.58(s,1H),7.34(s,1H),7.23(s,1H),6.84(s,1H),6.81(br,2H), 6.24 (s, 2H), 3.77 (m, 4H), 3.56 (m, 4H).

Embodiment 3：Structural formula（I-3）6- (1H- indazole -4- bases) -8- morpholines-[1,3] dioxs [4,5-g] quinoline azoles The preparation of quinoline, concrete reaction equation is as follows：

Under nitrogen protection, the chloro- 8- morpholines of 6--[1,3] dioxs [4,5-g] quinazoline（100mg,0.34mmol）、1H- Indazole -4- pinacol borates（209mg, 0.51mmol）、Cs₂CO₃（167mg, 0.52mmol）、Pd(dppf)Cl₂（23mg, 0.034mmol）It is mixed in 1,4- dioxane（9mL）And water（1.5mL）Mixed solvent in, be heated to 100 DEG C, stirring 1 is little When.TLC show raw material disappear, concentration, residue by silicagel column chromatography purification, obtain 6- (1H- indazole -4- bases) -8- morpholines - [1,3] dioxs [4,5-g] quinazolines（54mg, 43%）.MS(ESI)m/z=376[M+H]；¹H NMR(300MHz,DMSO-d₆) 13.18 (s, 1H), 9.00 (s, 1H), 8.27 (d, 1H, J=6.6Hz), 7.65 (d, 1H, J=7.8Hz), 7.42-7.48 (m, 2H), 7.33(s,1H),6.23(s,2H),3.84(m,4H),3.59(m,4H)。

Embodiment 4：Structural formula（I-4）1- ethyl -3- (4- (8- morpholines-[1,3] dioxs [4,5-g] quinazolines - 6- yls) phenyl) urea preparation, concrete reaction equation is as follows：

Step 1：4- bromanilines（10.0g, 58mmol）It is dissolved in DMF（100mL）In, sequentially add 4-DMAP（7.1g, 58mmol）, DIPEA（15.0g, 116mmol）, add ethyl isocyanate（8.25g, 116mmol）, it is stirred at room temperature 3 hours.Subtract Pressure concentration, residue adds water beating, and filtration takes solid, with ethyl acetate/methanol=100:1（50mL）, beating, filtration.It is dried, Obtain 1- (4- bromophenyls) -3- ethyl carbamides（8.8g, 62%）.

Step 2：Under nitrogen protection, 1- (4- bromophenyls) -3- ethyl carbamides（2.0g, 8.22mmol）, connection boric acid pinacol ester （4.18g, 16.5mmol）、Pd(dppf)Cl₂（600mg, 0.82mmol）, potassium acetate（1.21g, 12.3mmol）With 1,4- dioxies Six rings（50mL）Mixing, is heated to 100 DEG C and stirs 2 hours.It is cooled to room temperature, concentrating under reduced pressure.Add water in residue, use acetic acid second Ester is extracted, and is dried, and concentration, silica gel column chromatography obtains 1- ethyl -3- (4- pinacol borate -2- bases) phenyl) urea（2.0g, 84%）.

Step 3：Nitrogen is protected, the chloro- 8- morpholines of 6--[1,3] dioxs [4,5-g] quinazoline（100mg, 0.34mmol）, 1- ethyl -3- (4- pinacol borate -2- bases) phenyl) urea（58mg, 0.34mmol）、Cs₂CO₃（166mg, 0.51mmol）、Pd(dppf)Cl₂（25mg）It is mixed in 1,4- dioxane（9mL）And water（1.5mL）Mixed solvent in, plus Heat is stirred 2 hours to 100 DEG C.TLC shows that raw material disappears substantially, concentrates, and adds water and is quenched, and is extracted with dichloromethane, is dried, dense Contracting, Jing silica gel column chromatographies obtain 1- ethyl -3- (4- (8- morpholines-[1,3] dioxs [4,5-g] quinazoline -6- bases) phenyl) urea （79mg, 55%）.MS(ESI)m/z=422[M+H]；¹H NMR(500MHz,DMSO-d₆)8.65(brs,1H),8.29(d,2H,J= 8.5Hz),7.50(d,2H,J=8.5Hz),7.31(s,1H),7.24(s,1H),6.21(s,2H),6.16(br,1H),3.83 (t,4H,J=5.5Hz),3.59(t,4H,J=5.0Hz),3.12-3.17(q,2H),1.05-1.08(t,3H)。

Embodiment 5：Structural formula（I-5）6- (2- (difluoromethyl) -1H- benzos [d] imidazoles -1- bases) -8- morpholines - [preparation of 1,3] bis- Evil [4,5-g] quinazolines, concrete reaction equation is as follows：

Nitrogen is protected, the chloro- 8- morpholines of 6--[1,3] bis- Evil [4,5-g] quinazolines（100mg, 0.34mmol）, 2- (difluoros Methyl) -1H- benzos [d] imidazoles（【It is prepared by list of references：J.Med.Chem.2011,54,7105–7126】113mg, 0.68mmol）、K₂CO₃（188mg, 1.36mmol）In being mixed in DMSO, 130 DEG C are heated to, are stirred 4 hours.It is cooled to room temperature, Add water and be quenched, be extracted with ethyl acetate, be dried, concentration, residue by silicagel column chromatography purification, obtain 6- (2- (difluoromethyl)- 1H- benzos [d] imidazoles -1- bases) -8- morpholines-[1,3] bis- Evil [4,5-g] quinazolines（62mg, 43%）.MS(ESI)m/z=426 [M+H]；¹H NMR(300MHz,CDCl₃),8.54(m,1H),7.94(d,1H),7.45(m,3H),7.29(s,1H),7.19(s, 1H),6.18(s,2H),3.97(m,4H),3.75(m,4H)。

Embodiment 6：Structural formula（I-6）5- (4- morpholine -7,8- dihydros-[1,4] bioxin [2,3-g] quinazoline -2- Base) pyrimidine -2- ammonia preparation, concrete reaction equation is as follows：

Step 1：Isosorbide-5-Nitrae-benzodioxane -6- formic acid（25.0g, 139mmol）It is dissolved in methanol（180mL）In, Deca is dense Sulphuric acid（17.5mL）, it is heated to 70 DEG C and stirs 5 hours.It is cooled to room temperature, concentrating under reduced pressure adjusts pH with 5% sodium hydrate aqueous solution To alkalescence, it is extracted with ethyl acetate, is dried, is concentrated to give Isosorbide-5-Nitrae-benzodioxane -6- methyl formates（White solid 26.8g, 99%）.

Step 2：By Isosorbide-5-Nitrae-benzodioxane -6- methyl formates（26.0g, 133.9mmol）Add acetic acid（150mL） In, it is stirred to dissolve, Deca fuming nitric aicd（51mL）, finish, it is warming up to 70 DEG C and stirs 1 hour.Room temperature is cooled to, is reduced pressure dense Contracting, with 5% sodium hydrate aqueous solution pH to 7 is adjusted, and adds ethyl acetate extraction, the washing of organic faciess Jing to be dried, and concentration obtains 7- Nitro -2,3- dihydrobenzos [b] [1,4] bioxin -6- carboxylate methyl esters（31.1g, 97%）.

Step 3：7- nitros -2,3- dihydrobenzos [b] [1,4] bioxin -6- carboxylate methyl esters（32g, 134mmol）Add second Alcohol（350mL）And water（70mL）In, heating for dissolving, take a policy powder（80.4g, 462mmol）, it is warming up to 80 DEG C and stirs 2 hours. Cooling, filters, and filter cake dichloromethane/ethanol is washed, and collects filtrate, and concentration adds dichloromethane dissolving, organic faciess Jing water Wash, saturated common salt washing is dried, and concentration obtains 7- amino -2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] bioxin -6- carboxylate methyl esters （10.9g, 39%）.

Step 4：By NaOH（2.43g, 61mmol）Add water（70mL）In, add 7- amino -2,3- dihydrobenzos [b] [1,4] bioxin -6- carboxylate methyl esters（10.6g, 51mmol）, it is warming up to 90 DEG C and stirs 2 hours.TLC shows that raw material disappears, cold But, pH to 2 is adjusted with concentrated hydrochloric acid, solid is separated out, is sufficiently stirred for, and is filtered, and filter cake is washed with water, dries to obtain 7- amino -2,3- dihydros Benzo [b] [1,4] bioxin -6- formic acid（8.66g, 88%）.

Step 5：Nitrogen is protected, by 7- amino -2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] bioxin -6- formic acid（9.17g, 47mmol）, carbamide（22.57g, 376mmol）And phenol（35.4g, 376mmol）In being placed in single port bottle, it is heated to 150 DEG C and is allowed to Melting, stirs 2 hours at this temperature.100 DEG C are cooled to, ethanol is added（100mL）And water（100mL）, stir 10 minutes, mistake Filter, filter cake is washed with water, then is washed with a small amount of ethanol, collects solid, is dried, and obtains 7,8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinoline azoles Quinoline -2,4 (1H, 3H)-diketone（4.1g, 40%）.

Step 6：Nitrogen is protected, by 7,8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline -2,4 (1H, 3H)-diketone （4.0g, 18.2mmol）Add phosphorus oxychloride（30mL）In, add DIPEA（2.35g, 18.2mmol）, it is refluxed 5 hours. Room temperature is cooled to, concentrating under reduced pressure, the careful water quenching on the rocks of residue is gone out, is extracted with ethyl acetate, and extract merges, and is dried, concentration, Obtain the chloro- 7,8- dihydros of 2,4- bis--[1,4] bioxin [2,3-g] quinazoline（4.47g, 96%）.

Step 7：Nitrogen is protected, by chloro- 7, the 8- dihydros of 2,4- bis--[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline（4.5g, 17.5mmol）Add dichloromethane（30mL）And methanol（50mL）In, add morpholine（1.83g, 21mmol）, triethylamine （2.12g, 21mmol）, room temperature reaction 2 hours, TLC display raw material disappearances, concentration, addition dichloromethane and water, have in residue Machine is mutually washed with water respectively, saturated common salt washing, is dried, and concentration obtains chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2, 3-g] quinazoline（4.9g, 92%）.

Step 8：Nitrogen is protected, chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline（150mg, 0.487mmol）, 2- aminopyrimidine-5-boric acid pinacol esters（161mg, 0.73mmol）、Cs₂CO₃（238mg, 0.73mmol）、Pd (dppf)Cl₂（36mg, 0.049mmol）It is mixed in 1,4- dioxane（15mL）And water（2.5mL）Mixed solvent in, heating To 100 DEG C, stir 1 hour.Room temperature is cooled to, concentrating under reduced pressure, Jing silica gel column chromatography purification obtains 5- (4- morpholine -7,8- bis- Hydrogen-[1,4] bioxin [2,3-g] quinazoline -2- bases) pyrimidine -2- ammonia（106mg, 59%）.MS(ESI+)m/z=367[M+1]；¹H NMR(400MHz,DMSO-d₆)δ9.13(s,2H),7.34(s,1H),7.22(s,1H),7.09(br,2H),4.35-4.40(m, 4H),3.86(t,4H,J=2.8Hz),3.67(t,4H,J=4.0Hz)。

Embodiment 7：Structural formula（I-7）5- (4- morpholine -7,8- dihydros-[1,4] bioxin [2,3-g] quinazoline -2- Base) -4- (trifluoromethyl) pyridine -2- ammonia preparation, concrete reaction equation is as follows：

Nitrogen is protected, chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline（194mg, 0.632mmol）, 4- trifluoromethyls-PA -5- pinacol borates（140mg, 0.486mmol）、Cs₂CO₃（238mg, 0.73mmol）、Pd(dppf)Cl₂（36mg, 0.049mmol）It is mixed in 1,4- dioxane（18mL）And water（3mL）Mixing In solvent, 100 DEG C are heated to, are stirred 1 hour.Room temperature is cooled to, concentrating under reduced pressure, Jing silica gel column chromatography purification obtains 5- (4- morphines Quinoline -7,8- dihydros-[1,4] bioxin [2,3-g] quinazoline -2- bases) -4- (trifluoromethyl) pyridine -2- ammonia（71mg, 26%）.MS (ESI+)m/z=434[M+1]；¹H NMR(300MHz,DMSO-d₆)δ8.54(s,1H),7.35(s,1H),7.20(s,1H), 6.81(s,1H),6.75(br,2H),4.38(t,4H,J=6.9Hz),3.75(t,4H,J=4.1Hz),3.60(t,4H,J= 2.9Hz)。

Embodiment 8：Structural formula（I-8）2- (1H- indazole -4- bases) -4- morpholine -7,8- dihydros-[1,4] bioxin The preparation of [2,3-g] quinazoline, concrete reaction equation is as follows：

The method for copying embodiment 3, with chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline, 1H- indazole -4- pinacol borates are raw material, can prepare 2- (1H- indazole -4- bases) -4- morpholine -7,8- dihydros-[Isosorbide-5-Nitrae] two Evil English [2,3-g] quinazoline.MS(ESI+)m/z=390[M+1]；¹H NMR(400MHz,DMSO-d₆)δ13.2(br,1H),9.01 (s,1H),8.29(d,1H,J=8.0Hz),7.67(d,1H,J=8.0Hz),7.48(t,1H,J=5.9Hz),7.44(s,1H), 7.39(s,1H),4.39-4.43(m,4H),3.86(t,4H,J=3.2Hz),3.70(d,4H,J=4.4Hz)。

Embodiment 9：Structural formula（I-9）1- ethyl -3- (4- (4- morpholine -7,8- dihydros-[1,4] bioxin [2,3- G] quinazoline -2- bases) phenyl) and urea preparation, concrete reaction equation is as follows：

The method for copying embodiment 4, with chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline, 1- ethyl -3- (4- pinacol borate -2- bases) phenyl) urea be raw material, 1- ethyl -3- (4- (4- morpholine -7,8- can be prepared Dihydro-[1,4] bioxin [2,3-g] quinazoline -2- bases) phenyl) urea.MS(ESI+)m/z=436[M+1]；¹H NMR (400MHz,DMSO-d₆)δ8.67(br,1H),8.3(d,2H,J=8.8Hz),7.51(d,2H,J=8.8Hz),7.33(s,1H), 7.23(s,1H),6.18(br,1H),4.36-4.40(m,4H),3.81(t,4H,J=3.2Hz),3.66(d,4H,J=4.4Hz), 3.11-3.14(m,2H),1.06(t,3H,J=5.3Hz)。

Embodiment 10：Structural formula（I-10）2- (2- (difluoromethyl) -1H- benzos [d] imidazoles -1- bases) -4- morpholines - 7,8- dihydros-[preparation of Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline, concrete reaction equation is as follows：

The method for copying embodiment 5, with chloro- 4- morpholine -7 of 2-, 8- dihydros-[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline, 2- (difluoromethyl) -1H- benzos [d] imidazoles be raw material, can prepare 2- (2- (difluoromethyl) -1H- benzos [d] imidazoles -1- bases) - 4- morpholine -7,8- dihydros-[1,4] bioxin [2,3-g] quinazolines.MS(ESI+)m/z=440[M+1]；¹H NMR (400MHz,DMSO-d₆)δ8.49(d,1H,J=8.0Hz),7.91(t,1H,J=39.8Hz),7.84(d,1H,J=8.0Hz), 7.49(t,1H,J=5.7Hz),7.41(t,2H,J=5.7Hz),7.33(s,1H),4.37-4.43(m,4H),3.79(d,8H,J= 8.0Hz)。

Embodiment 11：Structural formula（I-11）(S) -1- ethyl -3- (4- (8- (3- methylmorpholines)-[1,3] dioxs [4,5-g] quinazoline -6- bases) phenyl) urea preparation, concrete reaction equation is as follows：

Step 1：Nitrogen is protected, by chloro- [1,3] two Evil [4, the 5-g] quinazolines of 6,8- bis-（589mg, 2.42mmol）Add Dichloromethane（15mL）And methanol（15mL）In, add (S) -3- methyl morpholines（491mg, 4.85mmol）, triethylamine（491mg, 4.85mmol）, room temperature reaction 5 hours, TLC display raw material disappearances, concentration, addition dichloromethane and water, organic faciess in residue Wash with water respectively, saturated common salt washing, be dried, concentration, obtain (S) -6- chloro- 8- (3- methylmorpholines)-[1,3] dioxs [4, 5-g] quinazoline（168mg, 22%）.

Step 2：(S) the chloro- 8- of -6- (3- methylmorpholines)-[1,3] dioxs [4,5-g] quinazolines（168mg, 0.546mmol）, 1- ethyl -3- (4- pinacol borate -2- bases) phenyl) urea（174mg, 0.60mmol）、Cs₂CO₃（267mg, 0.819mmol）、Pd(dppf)Cl₂（40mg, 0.055mmol）It is dissolved in 1,4- dioxane（18mL）With water（3mL）Mixing In solvent, 100 DEG C are heated to, are stirred 2 hours.TLC shows that raw material disappears, and concentration, residue by silicagel column chromatography purification must be marked Topic compound（111mg, 47%）.LC-MS(ESI+)m/z=436[M+1]；¹H NMR(300MHz,CDCl₃)δ8.39(d,2H,J= 8.4Hz),7.41(d,2H,J=8.4Hz),7.20(s,1H),7.11(s,1H),6.09(s,2H),5.31(br,1H),4.23 (s,1H),3.85-3.98(m,3H),3.64(s,3H),3.28(t,2H,J=6.5Hz),2.14(br,1H),1.34(d,3H,J= 6.6Hz),1.13(t,3H,J=6.8Hz)。

Embodiment 12：Structural formula（I-11）(S) -1- ethyl -3- (5- (4- (3- methylmorpholines) -7,8- dihydros-[1, 4] bioxin [2,3-g] quinazoline -2- bases) pyrimidine -2-base) urea preparation, concrete reaction equation is as follows：

The method for copying embodiment 11, with chloro- 7, the 8- dihydros of 2,4- bis--[Isosorbide-5-Nitrae] bioxin [2,3-g] quinazoline it is replaced In chloro- [1,3] two Evil [4, the 5-g] quinazolines of 6,8- bis-, (S) -1- ethyl -3- (5- (4- (3- methylmorphines can be prepared Quinoline) -7,8- dihydros-[1,4] bioxin [2,3-g] quinazoline -2- bases) pyrimidine -2-base) urea.MS(ESI+)m/z:450[M+1] ；¹H NMR(300MHz,CDCl₃)δ8.38(d,2H,J=8.1Hz),7.37-7.42(m,4H),5.33(br,1H),4.37(m, 5H),3.68-3.98(m,6H),3.24-3.33(m,2H),2.06(br,1H),1.40(d,3H,J=5.7Hz),1.11(t,3H, J=6.9Hz)。

Biology test case 1：Using the method test compound of Kinase-Glo Luminescent Kinase Assay Inhibitory activity to PI3K α

1. the kinase buffer liquid of 1 times of PI3K α is prepared：50mM HEPES, pH7.5；3mM MgCl₂；1mM EGTA；100mM NaCl；0.03%CHAPS；2mM DTT.

2. compound is prepared

1）Compound test final concentration of 100nM and 10nM, is configured to first 100 times of concentration, i.e., 10 μM.In 96 orifice plates The 10mM compounds of 10 μ L are separately added in the first row hole, the 100%DMSO of 90 μ L is added, the 1mM compounds of 100 μ L are made into. The 1mM compounds of 10 μ L are separately added in second row hole of 96 orifice plates, the 100%DMSO of 90 μ L is added, the 100uM of 100 μ L is made into Compound, is separately added into 100 μM of compounds of 10 μ L in the third line hole of 96 orifice plates, adds the 100%DMSO of 90 μ L, is made into 10 μM of compounds of 100 μ L, then dilute 10 times, it is made into 1 μM of compound solution.

2）100 μ L100%DMSO are separately added in first hole and the 12nd hole.

3）Compound intermediate dilute.In shifting 96 new orifice plates of 4 μ L compounds to, 1 times of 96 μ L of kinases is added Buffer, the vibration on vibration plate machine is mixed 10 minutes.

3. 4 times of kinase solutions are prepared

1）4 times of PI3K α solution are configured using 1 times of kinase buffer liquid.The final concentration of 1.65nM of kinase solution；

2）To in 384 orifice plate reacting holes, negative control hole adds 1 times of kinase buffer liquid to transferase 12 .5 μ L4 times enzymatic solution；

3）Vibration, mixes, and stands under room temperature.

4. 2 times of substrate solutions are prepared

1）2 times of substrate solutions are configured using 1 times of kinase buffer liquid.The final concentration of PIP2 of substrate solution (50 μM)；ATP(25μ M)；

2）Transferase 45 μ L2 times substrate solutions are to initial action in 384 orifice plate reacting holes；

3）Vibration, mixes.

5. kinase reaction

96 orifice plates are closed the lid, is incubated 1 hour at room temperature.

6. the detection of reaction result

1）Kinase-Glo detectable is equilibrated to into room temperature；

2）Shift terminating reaction in 10 μ L Kinase-Glo detectable to 384 orifice plate reacting holes；

3）Gently vibrate on vibration plate machine 15 minutes.

7. digital independent

Sample luminous numerical value is read in Flexstation.

8. curve matching

1）The data of luminous reading are replicated from Flexstation programs；

2）The value of luminous reading is converted to into inhibition percentage by formula.

Percent inhibition=(max-conversion)/(max-min)*100

" max " is the not enzyme-added control sample fluorescence reading for being reacted；" min " is to add DMSO glimmering as the sample of control Photoreading；

3）Import data to MS Excel and carried out curve fitting using Graphpad5.0.

Biology test case 2：Lived using suppression of the method test compound of Lance Ultra Assay to mTOR kinases Property

1. 1 times of kinase buffer liquid is prepared：50mM HEPES,pH7.5；10mM MgCl₂；1mM EGTA；3mMMnCl₂； 0.01%Tween-20；2mM DTT.

2. compound is prepared

1）Compound test final concentration of 100nM and 10nM, is configured to first 100 times of concentration, i.e. 10uM and 1uM.96 The 10mM compounds of 10 μ L are separately added in the first row hole of orifice plate, the 100%DMSO of 90 μ L is added, the 1mMization of 100 μ L is made into Compound.The 1mM compounds of 10 μ L are separately added in the second row hole of 96 orifice plates, the 100%DMSO of 90 μ L is added, 100 μ L are made into 100 μM of compounds, be separately added into 100 μM of compounds of 10 μ L in the third line hole of 96 orifice plates, add the 100% of 90 μ L DMSO, is made into 10 μM of compounds of 100 μ L, then dilutes 10 times, is made into 1 μM of compound.

2）100 μ L100%DMSO are separately added in first hole and the 12nd hole.

3）Compound intermediate dilute.In shifting 96 new orifice plates of 4 μ L compounds to, 1 times of kinases for adding 96 μ L delays Liquid is rushed, the vibration on vibration plate machine is mixed 10 minutes.

3. 4 times of kinase solutions are prepared

1）4 times of mTOR solution are configured using 1 times of kinase buffer liquid.The final concentration of 2.5nM of kinase solution；

3）Vibration, mixes, and stands under room temperature.

4. 2 times of substrate solutions are prepared

1）2 times of substrate solutions are configured using 1 times of kinase buffer liquid.The final concentration of ULight-4E-BP150nM of substrate solution； ATP10.8μM；

3）Vibration, mixes.

5. kinase reaction

96 orifice plates are closed the lid, is incubated 1 hour at room temperature.

6. the detection of reaction result

1）Detectable is equilibrated to into room temperature；

2）Shift terminating reaction in 10 μ L detectable to 384 orifice plate reacting holes；

3）Gently vibrate on vibration plate machine 15 minutes.Balance 1 hour under room temperature.

7. digital independent

Sample luminous numerical value is read in Envision.

8. curve matching

1）The data of luminous reading are replicated from Envision programs；

2）The value of luminous reading is converted to into inhibition percentage by formula；

Percent inhibition=(Lance signal-min)/(max-min)*100

" max " is the not enzyme-added control sample fluorescence reading for being reacted；" min " is to add DMSO glimmering as the sample of control Photoreading.

3）Import data to MS Excel and carried out curve fitting using Graphpad5.0.

Suppression ratio such as following table of the part of compounds of the present invention to PI3K α and mTOR under two concentration of 100nM and 10nM It is shown：

Claims

1. one kind has the compound or its pharmaceutically acceptable salt of below general formula (I)：

Wherein,

Logical formula (I) compound, is any one in following compound (I-1) to (I-12)：

2. formula (I) compound is led to as claimed in claim 1, it is characterised in that the logical formula (I) chemical combination

The form of the pharmaceutically acceptable salt of thing is the formed salt of logical formula (I) compound and acid or acid proton by metal ion Sodium salt, potassium salt, magnesium salt, the calcium salt for being replaced.

3. formula (I) compound is led to as claimed in claim 1, it is characterised in that the logical formula (I) compound and the formed salt of acid For hydrochlorate, hydrobromate, mesylate, sulfate, phosphate, acetate, trifluoroacetate, fluoroform sulphonate, to first Benzene sulfonate, tartrate, maleate, fumarate, succinate or malate.

4. the claims 1 to 3 any one claim of pharmaceutical composition, wherein described pharmaceutical composition comprising therapeutically effective amount Described logical formula (I) compound or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

5. pharmaceutical composition as claimed in claim 4, wherein described pharmaceutical composition makes tablet, capsule, aqueouss mixing Suspension, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection Agent.

6. prepared by the logical formula (I) compound or its pharmaceutically acceptable salt described in any one of claims 1 to 3 claim Adjust the application in PI3K/mTOR signal path catalysis activity products.

7. the pharmaceutical composition described in any one of claim 4 to 5 claim is preparing treatment and PI3K/mTOR signal paths Application in the medicine of relevant disease.

8. application as claimed in claim 7, wherein the disease relevant with PI3K/mTOR signal paths is cancer.

9. application as claimed in claim 8, wherein the cancer is incidence cancer, respiratory system cancer, digestive system cancer Disease, urinary system cancer, skeletal system cancer, gynecological cancer, hematological cancer, malignant melanoma, glioma or Skin carcinoma.

10. the application described in claim 9, wherein the incidence cancer disease is thyroid carcinoma, nasopharyngeal carcinoma, meninges cancer, acoustic nerve Tumor, pituitary tumor, oral cancer, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumor or intracranial metastatic tumor.

Application described in 11. claim 9, wherein the respiratory system carcinoma disease is pulmonary carcinoma.

Application described in 12. claim 9, wherein the cancer in digestive system is hepatocarcinoma, gastric cancer, the esophageal carcinoma, colorectal cancer, rectum Cancer, colon cancer or cancer of pancreas.

Application described in 13. claim 9, wherein the urinary system cancer is renal carcinoma, bladder cancer, carcinoma of prostate or testis Cancer.

Application described in 14. claim 9, wherein the skeletal system cancer is osteocarcinoma.

Application described in 15. claim 9, wherein the gynecological cancer is breast carcinoma, cervical cancer or ovarian cancer.

Application described in 16. claim 9, wherein the hematological cancer is leukemia, malignant lymphoma or multiple bone Myeloma.