CN103936762B - Morpholine quinolines, Preparation Method And The Use - Google Patents

Morpholine quinolines, Preparation Method And The Use Download PDF

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CN103936762B
CN103936762B CN201310016643.0A CN201310016643A CN103936762B CN 103936762 B CN103936762 B CN 103936762B CN 201310016643 A CN201310016643 A CN 201310016643A CN 103936762 B CN103936762 B CN 103936762B
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cancer
compound
hydrogen
morpholine
acid
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CN103936762A (en
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程建军
秦继红
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Shanghai Huilun Pharmaceutical Co ltd
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Shanghai Huilun Life Science & Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

Morpholine disclosed by the invention quinolines, for having the compound of following general formula (I): wherein, R 1be selected from C1-C6 alkyl, aryl, amido, C3-C10 cycloalkyl, heterocyclic radical, heteroaryl; R 2be selected from hydrogen, halogen ,-OR 10; R 3be selected from hydrogen ,-NHR 10,-NHC (=O) R 10; R 4be selected from hydrogen, C1-C6 alkyl ,-C (=O) R 10,-S (=O) 2r 10; R 5, R 6be selected from hydrogen, C1-C6 alkyl, halogen; R 7, R 8be selected from hydrogen, C1-C6 alkyl, halogen, or R 7, R 8merge into=O; R 9be selected from hydrogen, C1-C6 alkyl ,-OR 10, halogen; Wherein R 10for hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl; Further, R 1 ~ 10described in alkyl, alkoxyl group, aryl, heteroaryl all optionally can be replaced by one or more group, these groups comprise alkyl, thiazolinyl, alkynyl, halogen, alkoxyl group, aryl, heteroaryl, amino, amido, cyano group, nitro, carboxyl, ester group, amine formyl, alkylsulfonyl, sulfoamido etc.Morpholine disclosed by the invention quinolines as medicine in order to the treatment disease relevant to PI3K/mTOR.

Description

Morpholine quinolines, Preparation Method And The Use
Technical field
The present invention relates to a kind of compound as PI3K/mTOR inhibitor, its preparation method, containing they pharmaceutical compositions as activeconstituents, and the purposes of its cancer of being correlated with in order to the treatment disease, particularly PI3K/mTOR relevant to PI3K/mTOR as medicine.
Background technology
Modern study shows, in tumor development process, " PI3K(phosphatidylinositol3-kinase)-Akt(PKB; proteinkinaseB)-mTOR(mammaliantargetofrapamycin) " signal path controls numerous cell biological processes, comprise apoptosis of tumor cells, transcribe, translate, metabolism, angiogenesis and the regulation and control of cell cycle.The activation of this signal path can upset growth and the survival of cell, causes tumor cell proliferation quickening, pernicious transfer and produces common drug resistance.Block the growth of " PI3K-Akt-mTOR " signal path energy inhibition tumor cell and even promote apoptosis of tumor cells, therefore this path is the important target spot of new type antineoplastic medicine research and development.
PI3K is phosphoric acid acyl inositol kinase in a kind of born of the same parents, can the 3-di of catalyze phospholipid acyl inositol and the activation of mediate downstream signal path.PI3K can be divided into I type, II type and type III, and research be the most widely can the I type PI3K that activates by cell surface receptor.I type PI3K mainly comprises PI3K α, PI3K β, PI3K δ and PI3K γ tetra-kinds of hypotypes, and wherein PI3K α, PI3K β, PI3K δ belong to IA type kinase, from transmission of signals such as receptor type tyrosine kinase (RTK), G-protein linked receptors; PI3K γ is IB type kinase, only from G-protein linked receptor (GPCR) transmission of signal.Research shows, I type PI3K is process LAN, activation or sudden change in multiple human tumor, with the generation of cancer, develop closely related.
In " PI3K-Akt-mTOR " signal path, mTOR, as the downstream signaling molecule of PI3K, is one of important substrate of Akt.MTOR is serine/threonine kinases, suppresses this signaling molecule to be proved can to produce the effect of inhibition tumor cell propagation.Act on some forms of rapamycin analogs of mTOR as medicine listing, therefore mTOR is also identified is the target spot for the treatment of tumour.
At present, PI3K inhibitor or PI3K/mTOR double inhibitor have been proved and can have grown by Tumor suppression, and multiple PI3K inhibitor or PI3K/mTOR double inhibitor enter clinical study.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of morpholine as PI3K/mTOR inhibitor and quinolines.
Two of technical problem to be solved by this invention is to provide a kind of preparation as the morpholine of PI3K/mTOR inhibitor and the method for quinolines.
Three of technical problem to be solved by this invention is to provide and contains as the morpholine of PI3K/mTOR inhibitor and the pharmaceutical composition of quinolines.
Four of technical problem to be solved by this invention is to provide and contains as the morpholine of PI3K/mTOR inhibitor and the application of the pharmaceutical composition of quinolines.
As the morpholine of first aspect present invention and quinolines, for having the compound of following general formula (I):
Wherein,
R 1be selected from C1-C6 alkyl, aryl, amido, C3-C10 cycloalkyl, heterocyclic radical, heteroaryl;
R 2be selected from hydrogen, halogen ,-OR 10;
R 3be selected from hydrogen ,-NHR 10,-NHC (=O) R 10;
R 4be selected from hydrogen, C1-C6 alkyl ,-C (=O) R 10,-S (=O) 2r 10;
R 5, R 6be selected from hydrogen, C1-C6 alkyl, halogen;
R 7, R 8be selected from hydrogen, C1-C6 alkyl, halogen, or R 7, R 8merge into=O;
R 9be selected from hydrogen, C1-C6 alkyl ,-OR 10, halogen;
Wherein R 10for hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl;
Further, R 1 ~ 10described in alkyl, alkoxyl group, aryl, heteroaryl all optionally can be replaced by one or more group, these groups comprise alkyl, thiazolinyl, alkynyl, halogen, alkoxyl group, aryl, heteroaryl, amino, amido, cyano group, nitro, carboxyl, ester group, amine formyl, alkylsulfonyl, sulfoamido etc.
In some embodiments of the present invention, R 1be selected from 4-fluorophenyl, 2,4 difluorobenzene base, methyl, cyclopropyl, dimethylin.
In some embodiments of the present invention, R 2be selected from chlorine, methoxyl group.
In some embodiments of the present invention, R 3be selected from hydrogen ,-NH 2,-NHC (=O) CH 3.
In some embodiments of the present invention, R 4be selected from hydrogen, methyl, ethanoyl, methylsulfonyl.
In some embodiments of the present invention, R 5, R 6be selected from hydrogen, methyl.
In some embodiments of the present invention, R 7, R 8be selected from hydrogen, or R 7, R 8merge into=O.
In some embodiments of the present invention, R 9for hydrogen.
The present invention includes but be not limited to do the following compound limited to described substituting group: R in general formula (I) 1for 4-fluorophenyl, 2,4 difluorobenzene base, methyl, cyclopropyl or dimethylin, meanwhile: R 2for chlorine or methoxyl group; R 3for hydrogen ,-NH 2or-NHC (=O) CH 3; R 4for hydrogen, methyl, ethanoyl or methylsulfonyl; R 5, R 6for hydrogen or methyl; R 7, R 8for hydrogen, or R 7, R 8merge into=O; R 9for hydrogen.
Compound of the present invention, can be following structure (I-1) to any one in (I-67):
Described general formula (I) compound is the mixture of any one or arbitrarily both or three in enantiomer, diastereomer, conformer.
Described general formula (I) compound is pharmacy acceptable derivates.
General formula of the present invention (I) compound can exist as a pharmaceutically acceptable salt form, comprise and salt formed by acid, such as hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate; Or acid proton the sodium salt, sylvite, magnesium salts, the calcium salt that replace by metal ion.
As the preparation method of the above-claimed cpd of second aspect present invention, be specially following methods:
(1) R is worked as 3during for hydrogen, the preparation process of compound shown in general formula (I) is: by the 3-amino-4-hydroxy-6-bromoquinoline cyclisation of 3-amino-4-hydroxy-6-bromoquinoline or replacement and to the intermediate A obtaining having quino-morpholine structure after nitrogen atom, then carry out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid replaced or boric acid ester, obtain general formula (I) compound; Or, the bromine of the intermediate A with quino-morpholine structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carries out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
(2) R is worked as 3when not being hydrogen, shown in general formula (I), the preparation process of compound is: the nitrogen-atoms of quino-morpholine class intermediate is carried out oxidized activating, then-2, quinoline-nucleophilic substitution reaction is carried out with nucleophilic reagent, obtain the intermediate A with quino-morpholine structure, then the intermediate A with quino-morpholine structure carries out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid replaced or boric acid ester, obtains general formula (I) compound; Or, the bromine of the intermediate A with quino-morpholine structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carries out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
In above-mentioned reaction formula: R 1, R 2, R 4, R 5, R 6, R 7, R 8, R 9as above, group
As the pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises general formula (I) compound and the acceptable vehicle of pharmacy for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable derivates and the acceptable vehicle of pharmacy of general formula (I) compound for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of general formula (I) compound for the treatment of significant quantity.
Described pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
As the application of fourth aspect present invention, be wherein that general formula (I) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
As the application of fourth aspect present invention, be wherein the application of pharmacy acceptable derivates in preparation adjustment PI3K/mTOR signal path catalytic activity goods of general formula (I) compound.
As the application of fourth aspect present invention, be wherein the application of pharmaceutically useful salt in preparation adjustment PI3K/mTOR signal path catalytic activity goods of general formula (I) compound.
As the application of fourth aspect present invention, be wherein that pharmaceutical composition treats the application in the medicine of the disease relevant with PI3K/mTOR signal path in preparation.
The described disease relevant with PI3K/mTOR signal path is cancer.
Described cancer is incidence cancer, respiratory system cancer, cancer in digestive system, urinary system cancer, Skeletal system cancer, gynecological cancer, hematological cancer or other types cancer.
Described incidence cancer is thyroid carcinoma, nasopharyngeal carcinoma, meninx cancer, acoustic tumor, pituitary tumor, oral carcinoma, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumour or intracranial metastatic tumor.
Described respiratory system cancer is lung cancer.
Described cancer in digestive system is liver cancer, cancer of the stomach, the esophageal carcinoma, large bowel cancer, the rectum cancer, colorectal carcinoma or carcinoma of the pancreas.
Described urinary system cancer is kidney, bladder cancer, prostate cancer or carcinoma of testis.
Described Skeletal system cancer is osteocarcinoma.
Described gynecological cancer is mammary cancer, cervical cancer or ovarian cancer;
Described hematological cancer is leukemia, malignant lymphoma or multiple myeloma.
Described other types cancer is malignant melanoma, neurospongioma or skin carcinoma.
The compound of general formula (I) involved in the present invention also can be used for the biology of PI3K-Akt-mTOR signal path or the research of pharmacology phenomenon and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitor.
Embodiment
The invention provides general formula defined above (I) compound, prepare the method for these compounds, use the pharmaceutical composition of these compounds and use the method for these compounds.
Listed is below definition to the various terms for describing the compounds of this invention.These definition are applied to the term (unless separately having restriction on other occasions) used in each place of specification sheets, and no matter these terms are used alone or as the part of more macoradical.
Unless otherwise defined, term as used herein " alkyl " (be used alone or as the part of another group) refers to the univalent perssad comprising 1 to 12 carbon atom that alkane derives.Preferred alkyl has 1 to 6 carbon atom.Alkyl is the optional straight chain, side chain or the cyclic saturated hydrocarbon base that replace.Exemplary alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.And described " alkyl " can be selected from following group replaces arbitrarily: alkyl, halogen (as fluorine, chlorine, bromine, iodine), alkoxyl group, amino/amido, haloalkyl (as trichloromethyl, trifluoromethyl), aryl, aryloxy, alkylthio, hydroxyl, cyano group, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, carbamyl, urea or sulfydryl.
Term as used herein " cycloalkyl " (be used alone or as the part of another group) refers to 3 to 10 carbon atoms, is preferably the hydrocarbon ring of the completely saturated or fractional saturation of 3 to 7 carbon atoms.In addition, cycloalkyl can be replace." cycloalkyl of replacement " refer to have once, two or three be selected from following substituent ring: the alkyl of halogen, alkyl, replacement (wherein substituting group as above alkyl substituent define), thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO 2h ,-C (=O) H ,-CO 2-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, five or hexa-atomic ketal (i.e. 1,3-dioxane or 1,3-bis-uh alkane) ,-NR'R " ,-C (=O) NR'R " ,-CO 2nR'R'' ,-C (=O) NR'R " ,-NR'CO 2r " ,-NR'C (=O) R " ,-SO 2nR'R " and-NR'SO 2respective in R ", wherein R' and R " is independently selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl, or R' and R ", form Heterocyclylalkyl or heteroaryl ring together.
Term as used herein " aryl " (be used alone or as the part of another group) refers to monocyclic aromatic ring or polycyclic aromatic ring, the phenyl of such as phenyl, replacement etc. and the group such as naphthyl, the phenanthryl etc. that condense.Thus, aryl comprises the ring that at least one has at least 6 atoms, comprises five such rings (wherein comprising 22 atoms at the most) at the most, and has (conjugation) double bond alternately between adjacent carbon atom or suitable heteroatoms.Preferred aryl comprises 6 to 14 carbon atoms in ring.And described " aryl " can be optionally substituted one or more group, described group has included but not limited to halogen (such as fluorine, chlorine, bromine), alkyl (such as methyl, ethyl, propyl group), substituted alkyl (as trifluoromethyl), cycloalkyl, alkoxyl group (such as methoxy or ethoxy), hydroxyl, carboxyl, amine formyl (-C (=O) NR'R "), alkoxy carbonyl (-CO 2r), amino/amido, nitro, cyano group, thiazolinyl oxygen base, aryl, heteroaryl, alkylsulfonyl (-SO 2r) etc., wherein, R, R', R " is described alkyl.
Term as used herein " heteroaryl " (be used alone or as the part of another group) refers to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 9 or 10 yuan of bicyclic radicals and 11 to 14 yuan of three cyclic group, and these groups have at least one heteroatoms (O, S or N) at least one ring.The each ring comprising heteroatomic heteroaryl can comprise one or two Sauerstoffatoms or sulphur atom and/or one to four nitrogen-atoms, condition is that in each ring, heteroatomic sum is four or less, and each ring has at least one carbon atom, the ring condensed forming above-mentioned bicyclic radicals and three cyclic groups only can comprise carbon atom, and can be saturated or fractional saturation.Nitrogen-atoms and sulphur atom can be oxidations, and nitrogen-atoms can be quaternary ammoniated.The heteroaryl of dicyclo or three rings must comprise the ring of at least one Wholly aromatic, but other ring condensed or multiple ring can be aromatics or non-aromatic.Heteroaryl can connect at any available nitrogen-atoms of any ring or carbon atom place.
Described " heteroaryl " ring system can comprise zero, one, two or three and be selected from following substituting group: the alkyl of halogen, alkyl, replacement, thiazolinyl, block base, aryl, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio ,-CO 2h ,-C (=O) H ,-CO 2the cycloalkyl of-alkyl ,-C (=O) alkyl, phenyl, benzyl, phenylethyl, phenyl oxygen base, thiophenyl, cycloalkyl, replacement, Heterocyclylalkyl, heteroaryl ,-NR'R " ,-C (=O) NR'R " ,-CO 2nR'R " ,-C (=O) NR'R " ,-NR'CO 2r " ,-NR'C (=O) R " ,-SO 2nR'R " and-NR'SO 2r ", wherein R' and R " independently is selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl separately, or R' with R " together with formation Heterocyclylalkyl or heteroaryl ring.
The example of bicyclic heteroaryl comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazoles base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.
The example of bicyclic heteroaryl comprises indyl, benzothiazolyl, benzodioxole base, benzoxazolyl, benzothienyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzofuryl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridyl etc.
The example of tricyclic heteroaryl comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl etc.
The heteroatoms that a carbon atom in term as used herein " heterocycle " (be used alone or as the part of another group) finger ring is selected from O, S or N replaces and 3 extra carbon atoms cycloalkyl (non-aromatic) that can be replaced by described heteroatoms at the most.Term " heterocyclic radical " that the application uses (be used alone or as the part of another group) refers to comprise the stable undersaturated monocyclic ring system of saturated or part of 5 to 7 annular atomses (carbon atom and be selected from other atom of nitrogen, sulphur and/or oxygen).Heterocycle can be 5,6 or 7 yuan of monocycles, and comprises the heteroatoms that, two or three is selected from nitrogen, oxygen and/or sulphur.Heterocycle can be optional replacement; this means that heterocycle can have one or more to be independently selected from following group in one or more commutable ring position replacement: alkyl, Heterocyclylalkyl, heteroaryl, alkoxyl group, nitro, monoalkyl amido, dialkyl amino, cyano group, halogen, haloalkyl, alkyloyl, ammonia/amino-carbonyl, monoalkyl amino-carbonyl, dialkyl amino carbonyl, alkylamidoalkyl, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl oxygen base and aryl, described aryl optionally replaces halogen, alkyl and alkoxyl group.The example of these Heterocyclylalkyls includes but not limited to: piperidines, morpholine, high morpholine, piperazine, parathiazan, tetramethyleneimine and azetidine.
Term as used herein " alkoxyl group " (be used alone or as the part of another group) refers to the alkyl preferably with 1 to 6 carbon atom connected by Sauerstoffatom, and such as-OR, wherein R is described alkyl.
Term as used herein " amino " (be used alone or as the part of another group) refers to-NH 2." amido " can optionally replace one or two substituting groups (-NR'R "); wherein R' and R " can be identical or different, such as alkyl, aryl, arylalkyl, thiazolinyl, alkynyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, alkyl, hetercycloalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, antelope base alkyl, alkoxyalkyl, alkylthio, carbonyl or carboxyl.These substituting groups can replace any one in the alkyl or aryl substituting group had listed by carboxylic acid or the application further.In some embodiments, there are carboxyl or carbonyl amino replacement, forms N-acyl group or N-carbamyl deriveding group.
Term " halogen " refers to independent fluorine, chlorine, the bromine or iodine selected.
Term " anticarcinogen " comprises the medicine known arbitrarily that can be used for Therapeutic cancer, comprising: (1) cytotoxic drug: chlormethine series pharmaceuticals, as melphalan, endoxan; Platinum coordination complex, such as cis-platinum, carboplatin and oxaliplatin; (2) anti-metabolism antitumour drug: 5 FU 5 fluorouracil, capecitabine, methotrexate, Calciumlevofolinate, Raltitrexed, purine antagonist (such as 6-thioguanine and Ismipur); (3) hormones: the female alcohol of 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene; (4) tyrosine kinase inhibitor: EGFR inhibitor, comprises Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cetuximab (Cetuximab), Trastuzumab (Herceptin) etc.; VEGF inhibitor, such as VEGF antibody (Avastin (Avastin)) and micromolecular inhibitor such as Sunitinib, Sorafenib, Vandetanib, Pazopanib, Axitinib etc.; Bcr-Abl inhibitor is as Imatinib, Nilotinib, Dasatinib; Src inhibitor, MEK kinase inhibitor, mapk kinase inhibitor, PI3K kinase inhibitor, c-Met inhibitor, ALK inhibitor etc.; (5) act on the medicine of tubulin, such as vinca medicine, taxanes medicine, epothilones medicine are as ipsapirone (Ixabepilone) etc.; (6) topoisomerase I inhibitor, as topotecan, irinotecan; (7) histon deacetylase (HDAC) (HDAC) inhibitor is as Vorinostat, Romidepsin; (8) proteasome inhibitor is as Velcade (Bortezomib); (9) anticarcinogen of other classifications is as aurora kinase (aurorakinase) inhibitor, biological response modifier, growth inhibitor, glu famine antagonist, angiogenesis inhibitor and anti-vascular medicine, matrix metallo-proteinase inhibitor etc.
" Mammals " comprises the mankind and domestic animal, as cat, dog, pig, ox, sheep, goat, horse, rabbit etc.Preferably, for the purposes of the present invention, described Mammals is the mankind.
When " pharmacy acceptable derivates " represents to recipient's administration, directly or indirectly can provide salt or other derivatives of the salt of any nontoxic salt of the active metabolite of compound of the present invention or its inhibition or resistates, ester, ester, acid amides, acid amides.
" the acceptable vehicle of pharmacy " includes but not limited to be ratified as any assistant agent that can be used for the mankind or domestic animal, carrier, vehicle, glidant, sweeting agent, dispersion agent, thinner, sanitas, suspending agent, stablizer, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, isotonic agent, solvent or emulsifying agent by state food and Drug Administration.
" pharmacologically acceptable salts " comprises acid salt and base addition salt.
" the acceptable acid salt of pharmacy " refers to such salt, and they remain biological effect and the character of free alkali, can not produce adverse consequences in biology or other, and is such as but not limited to hydrochloric acid with mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid is such as but not limited to following acid: formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2,2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, phenylformic acid, paraacetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane-1,2-disulfonic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, glyconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-oxo-pentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, glactaric acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, palm fibre eleostearic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, 4-ASA, sebacic acid, stearic acid, fumaric acid, succsinic acid, tartrate, thiocyanic acid, the formation such as undecylenic acid.
" the acceptable base addition salt of pharmacy " refers to such salt, and they remain biological effect and the character of free acid, can not be improper in biology or other.These salt obtain by mineral alkali or organic bases being added on free acid.The salt being derived from mineral alkali includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Preferred inorganic salt are ammonium, sodium, potassium, calcium and magnesium salts.The salt being derived from organic bases includes but not limited to the salt of following substances: primary amine, secondary amine and tertiary amine, the amine replaced, comprise naturally occurring replacement amine, cyclammonium and deacidite, as ammonia, methylamine, dimethylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, Isopropylamine, diethanolamine, thanomin, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, Benethamine diacetale, quadrol, glycosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperidines, piperazine, N-ethylpiperidine, versamid 900 etc.Preferred organic bases is Isopropylamine, diethylamine, thanomin, triethylamine, dicyclohexyl amine, choline and caffeine.
" pharmaceutical composition " refer to compound of the present invention with biologically active cpds is delivered to Mammals as the medium of the usual acceptance in the mankind the preparation that forms.Such medium comprises all pharmaceutically acceptable carrier, thinner or vehicle to this.
" treatment significant quantity " refers to when to (the preferred mankind) during Mammals administration, be enough to the relative disease of Mammals (the preferred mankind) or illness realize as hereafter the amount of the compound of the present invention for the treatment of that defines.The amount forming the compound of the present invention of " treatment significant quantity " can according to the activity of such as applied particular compound; The metabolic stability of described compound and effect 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 illness; And experience the individuality for the treatment of and change, but it can be determined according to himself knowledge and the disclosure routinely by those of ordinary skill in the art.
" treat " or " treatment " for containing the Mammals to having relative disease or illness during this paper, the relative disease of the preferred mankind or the treatment of illness, and comprise:
(i) prevent disease or illness to occur in Mammals, especially when such Mammals is ill but when also not diagnosing out ill;
(ii) suppress disease or illness, namely stop it to develop;
(iii) alleviate disease or illness, namely cause disease or illness to disappear;
(iv) stable disease or illness.
During for this paper, term " disease " and " illness " can be exchanged and to be used or can be different, reason is the inducement (thus also not working out the cause of disease) that specified disease or illness may not have oneself to know, therefore also disease is not considered to and only as improper situation or syndrome, wherein clinician have identified concrete syndrome more or less.
The compounds of this invention shown in this article and their structure also represent and comprise all isomer (such as enantiomer, diastereomer, rotamerism or conformational isomerism) form, they can according to amino acid whose absolute stereochemical being defined as to (R)-/(S)-or (D)-/(L)-or (R, R)-/(R, S)-/(S, S)-.The present invention represents and comprises all these possible isomer, and their racemic, enantiomorph enrichment and optional pure form.Optically-active (+) and (-), (R)-and (S)-and (R, R)-/(R, S)-/(S, S)-or (D)-chiral synthesize, chiral separation can be used to prepare with (L)-isomer, or routine techniques can be used to split such as but not limited to using the high performance liquid phase (HPLC) of chiral column.When compound as herein described comprises thiazolinyl double bond or other geometry asymmetric centers, except as otherwise noted, described compound comprises E and Z geometrical isomer.Equally, all tautomeric forms are also comprised.
" steric isomer " refers to be made up of with identical chemical bonding identical atom but to have the compound of different three-dimensional structure, and they are not interchangeable.The present invention is contained various steric isomer and composition thereof and is comprised " enantiomer " and " diastereomer ", and enantiomer refers to two kinds of steric isomers of the mirror image that its molecule each other can not be overlapping; Diastereomer refers to that molecule has two or more chiral centre, and intermolecular be the steric isomer of non-mirror.
" tautomer " refers to that proton moves to another position of same a part from an atom of molecule from original position.The present invention includes the tautomer of any described compound.
In addition, except as otherwise noted, compound of the present invention also comprises the compound that structure difference is only to exist one or more isotopic enrichment atoms.Such as, there is structure of the present invention, except replacing hydrogen with " deuterium " or " tritium ", or using 18f-fluorine mark ( 18f isotropic substance) replace fluorine, or use 11c-, 13c-, or 14the carbon of C-enrichment ( 11c-, 13c-, or 14c-carbon markings; 11c-, 13c-, or 14c-isotropic substance) replace the compound of carbon atom to be in scope of the present invention.Such compound can be used as biological example measure in analysis tool or probe, or can the diagnostic imaging in vivo tracer agent of disease be used as, or as the tracer agent of pharmacodynamics, pharmacokinetics or acceptor research.
The present invention also provides following methods: (simultaneously or successively) needs the patient of this treatment by (I) compound of general formula as defined above and other anticancer agents of at least one for the treatment of significant quantity being given, and treats proliferative disease (such as cancer) via regulating PI3K/mTOR signal path.In preferred embodiments, proliferative disease is cancer.
Particularly, general formula (I) compound can be used for treating kinds cancer, is most specifically those cancers depending on the activation of PI3K/mTOR signal.Usually, compound of the present invention can be used for the treatment of following cancer:
1. incidence cancer, comprises thyroid carcinoma, nasopharyngeal carcinoma, meninx cancer, acoustic tumor, pituitary tumor, oral carcinoma, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumour, intracranial metastatic tumor;
2. respiratory system cancer, comprises lung cancer;
3. cancer in digestive system, comprises liver cancer, cancer of the stomach, the esophageal carcinoma, large bowel cancer, the rectum cancer, colorectal carcinoma, carcinoma of the pancreas;
4. urinary system cancer, comprises kidney, bladder cancer, prostate cancer, carcinoma of testis;
5. Skeletal system cancer, osteocarcinoma;
6. gynecological cancer, comprises mammary cancer, cervical cancer, ovarian cancer;
7. hematological cancer, comprises leukemia, malignant lymphoma, multiple myeloma;
8. other types cancer, comprises malignant melanoma, neurospongioma, skin carcinoma.
General formula (I) compound also can be used for treating any lysis being characterized as abnormal cell proliferation, the restenosis such as, occurred after benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or vascular surgery, inflammatory bowel, graft-rejection, endotoxin shock and fungi infestation.
The level of the adjustable cell RNA of general formula (I) compound and DNA synthesis.Therefore, these materials can be used for the treatment of virus infection (including but not limited to HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, sindbis alphavirus and adenovirus).
General formula (I) compound can be used for the chemoprophylaxis of cancer.Chemoprophylaxis is defined through and blocks initial mutagenesis event or by blocking the progress of pre-malignant cells damaged and carry out the development of anti-invasion cancer or Tumor suppression recurring.General formula (I) compound can be used for Tumor suppression vasculogenesis and transfer.
Compound of the present invention also can combinationally use with known anticarcinogen (include but not limited to mention in above-mentioned " anticarcinogen " those) or anticancer therapy (such as radiotherapy) (together with give or successively give).
Some general formula (I) compound can be prepared according to following route 1 and route 2 usually.The tautomer of general formula (I) compound and solvate (such as hydrate, ethanolates) are also within the scope of the invention.The preparation method of solvate is normally known in the art.Therefore, compound of the present invention can be free form or hydrate forms.
In method hereinafter described, the functional group of midbody compound may need the protecting group by being suitable for protect.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.The protecting group be applicable to for hydroxyl comprise trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl, to methoxy-benzyl etc.Suitable protecting groups for amino comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, trifluoroacetyl group, to methoxy-benzyl etc.Suitable protecting groups for carboxylic acid comprises alkyl, aryl or alkyl aryl.Suitable protecting groups for the heteroaryl such as NH functional group of such as indoles or indazole ring comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, 2-trimethylsilyl-ethoxy methyl, to methoxy-benzyl etc.
Protecting group can be added according to method known to those skilled in the art (Greene, T.W., ProtectiveGroupsinOrganicSy-hesis, the 3rd edition, Wiley in 1999) and standard technique as herein described or remove.Described protecting group also can be that fluoropolymer resin is as Wang resin, Rink resin or 2-chlorine trityl chloride resin.
Meanwhile, although these protected derivatives of the compounds of this invention itself may not have pharmacological activity, they can be administered to Mammals, and then metabolism has the compounds of this invention of pharmacological activity with formation in vivo.Therefore such derivative is described to " prodrug ".All prodrugs of the compounds of this invention include within the scope of the invention.
The compound of general formula of the present invention (I), is prepared by following method:
(1) R is worked as 3during for hydrogen, the preparation process of compound shown in general formula (I) is: by the 3-amino-4-hydroxy-6-bromoquinoline cyclisation of 3-amino-4-hydroxy-6-bromoquinoline or replacement and to the intermediate A obtaining having quino-morpholine structure after nitrogen atom, then carry out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid replaced or boric acid ester, obtain general formula (I) compound; Or, the bromine of the intermediate A with quino-morpholine structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carries out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
(2) R is worked as 3when not being hydrogen, shown in general formula (I), the preparation process of compound is: the nitrogen-atoms of quino-morpholine class intermediate is carried out oxidized activating, then-2, quinoline-nucleophilic substitution reaction is carried out with nucleophilic reagent, obtain the intermediate A with quino-morpholine structure, then the intermediate A with quino-morpholine structure carries out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid replaced or boric acid ester, obtains general formula (I) compound; Or, the bromine of the intermediate A with quino-morpholine structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carries out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
In above-mentioned reaction formula: R 1, R 2, R 4, R 5, R 6, R 7, R 8, R 9as above, group
Wherein, following is abbreviation conventional in statement process of the present invention:
DMF:N, dinethylformamide;
DMSO: dimethyl sulfoxide (DMSO);
THF: tetrahydrofuran (THF)
CDCl 3: deuterochloroform;
LC-MS: LC-MS chromatogram;
TLC: tlc;
1hNMR: proton nmr spectra;
S: unimodal;
D: bimodal;
T: triplet;
Dd: doublet of doublet;
Br: broad peak;
M: multiplet;
H: hour
DEG C: degree Celsius;
Mol: mole;
Mmol: mmole;
ATP: Triphosaden.
Those skilled in the art can use suitable raw material, adopt similar method, prepare in reaction scheme above with no specific disclosure of other compounds of the present invention.
By with suitable inorganic or organic bases or acid treatment, can by according to preparing all the compounds of this invention existed with free alkali or sour form above and change into their pharmacologically acceptable salts.The salt of the compound prepared above can change into their free alkali or sour form by standard technique.
Compound of the present invention comprises its all crystal formations, amorphous forms, dehydrate, hydrate, solvate and salt.In addition, all compounds of the present invention comprising ester group and amide group can oneself knows by those skilled in the art method or change into corresponding acid by method described herein.Equally, the compounds of this invention comprising hydroxy-acid group oneself knows by those skilled in the art method can be converted into corresponding ester and acid amides.Also can oneself knows by those skilled in the art method (such as hydrogenation, alkylation, with acyl chloride reaction etc.) carry out on molecule other replace and replace.
Prepare cyclodextrin inclusion compound of the present invention, can the compound of the general formula (I) defined in summary of the invention be above dissolved in the acceptable solvent of pharmacology such as (but being not limited to) alcohol (preferred alcohol), ketone (such as acetone) or ether (such as ether), and at 20 DEG C to 80 DEG C and alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin, the aqueous solution of preferred beta-cyclodextrin; Or can by the acid of the compound of general formula (I) that defines in summary of the invention above with the aqueous solution form of its salt (such as sodium or sylvite) and cyclodextrin blended, then with the solution blending of equivalent acid (such as HCl or H2SO4), to provide corresponding cyclodextrin inclusion compound.
Now or after the cooling period, corresponding cyclodextrin inclusion compound crystal can crystallization.Or when general formula (I) compound be oily and crystallization time, by room temperature for a long time stir (such as 1 is little of 14 days), add the aqueous solution process of cyclodextrin, also can be converted into corresponding cyclodextrin inclusion compound.Then by filtering and drying, inclusion compound can be separated into solid or crystal.
For cyclodextrin of the present invention commercially available (such as from AldrichChemicalCo.), or adopt known method preparation by those skilled in the art.See people such as such as Croft, A.P., " Sy-hesisofChemicallyModifiedCyclodextrins ", Tetrahedron1983,39,9,1417-1474.Suitable cyclodextrin comprises all kinds preparing inclusion compound with the compound of institute's column (I) above.
By selecting appropriate cyclodextrin and water, the inclusion compound of repeatably active substance content can be obtained according to stoichiometric composition.Inclusion compound can use for dry water suction form or the moisture but form more do not absorbed water.The Typical mole ratios of the compound of cyclodextrin and general formula (I) is 2:1(cyclodextrin: compound).
Comprising general formula (I) compound as the pharmaceutical composition of activeconstituents can be suitable for oral form, such as, be tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis or granule, syrup etc.The composition that can orally use can be prepared according to any means for the preparation of pharmaceutical composition known in the art, and these compositions can comprise the material that one or more is selected from sweeting agent, seasonings, tinting material and sanitas, to provide pharmaceutical elegant and agreeable to the taste preparation.
Tablet comprises activeconstituents, and is mixed with the nontoxic pharmaceutically acceptable vehicle or carrier that are suitable for preparing tablet.These vehicle 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, W-Gum or alginic acid; Tackiness agent, such as starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum powder.Tablet can be non-dressing, or carrys out dressing by known technology, thus covers and make us unhappy drug tastes, or postpones disintegration and absorption in the gastrointestinal tract, provides lasting effect thus within the longer period.Such as, water miscible taste can be used to cover material (such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose) or time lag material (such as ethyl cellulose, cellulose acetate butyrate).
Capsule comprises hard-gelatin capsules, Gelseal.Hard-gelatin capsules is mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin by activeconstituents; Gelseal is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oily medium (such as peanut oil, whiteruss or sweet oil) by activeconstituents.
Aqueous suspension comprises active substance and is suitable for preparing the vehicle of aqueous suspension.These vehicle are suspending agent, such as Xylo-Mucine, methylcellulose gum, hydroxypropyl methyl-cellulose, sodiun alginate, polyvinylpyrrolidone and gum arabic; Dispersion agent or wetting agent, the condensation product (such as polyethylene sorbitan monoleate) of partial ester that can be the condensation product (such as polyoxyethylene stearic acid ester) of naturally occurring phosphatide (such as Yelkin TTS) or oxyalkylene and lipid acid or the condensation product (such as 17 oxygen ethene hexadecanols (heptadecaethylene-oxycetanol)) of ethylene oxide and long chain aliphatic alcohol or ethylene oxide and the condensation product (such as polyoxyethylene 80 sorbitan monooleate) of partial ester derived from lipid acid and hexitol or ethylene oxide and derive from lipid acid and the liquor-saturated mixture of hexitol.Aqueous suspension also can comprise one or more sanitass (such as ethyl p-hydroxybenzoate or n-propyl), one or more tinting material, one or more seasonings and one or more sweeting agent (such as sucrose, asccharin or aspartame).
Oil suspensions is prepared by being suspended in by activeconstituents in vegetables oil (such as peanut oil, sweet oil, sesame oil or cocounut oil) or mineral oil (such as whiteruss).Oil suspensions can comprise thickening material, such as beeswax, paraffinum durum or hexadecanol.Sweeting agent (such as above listed those) and seasonings can be added, thus agreeable to the taste oral preparations is provided.These compositions come anticorrosion by adding antioxidant (such as Butylated Hydroxyanisole or alpha-tocopherol).
Dispersible pulvis and granule comprise activeconstituents, and are mixed with dispersion agent or wetting agent, suspending agent and one or more sanitas.The example of suitable dispersion agent or wetting agent and suspending agent mentioned for above those.Also other vehicle can be comprised, such as sweeting agent, seasonings and tinting material.These compositions come anticorrosion by adding antioxidant (such as xitix).Dispersible pulvis and granule prepare aqueous suspension by adding water.
Syrup can be prepared with sweeting agent (such as glycerine, propylene glycol, sorbyl alcohol or sucrose).These preparations also can comprise negative catalyst, sanitas, seasonings, tinting material and antioxidant.
Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil (such as sweet oil or peanut oil) or mineral oil (such as whiteruss) or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide (such as soybean lecithin), condensation product (such as Polysorbate 80) from the derivative ester of lipid acid and hexitol mixture or partial ester (such as dehydrated sorbitol mono-fatty acid ester) and described partial ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings, sanitas and antioxidant.
Pharmaceutical composition can be the form of the sterile injectable aqueous solution.Spendablely accept carrier and solvent has water, Ringer's solution (Ringer'ssolution), isotonic sodium chloride solution and glucose solution.
Sterile injectable preparation also can be sterile injectable water oil-packaging type micro-emulsion, wherein by solubilize active ingredients in oil phase.Such as, first by solubilize active ingredients in the mixture of soybean oil and Yelkin TTS.Then, obtained oil solution to be imported in the mixture of water and glycerine and to process, thus forming micro emulsion.
Injectable solution or micro emulsion import in the blood flow of patient by local bolus injection, or give described solution or micro emulsion in some way, thus maintain the circulation composition of constant the compounds of this invention.In order to maintain this constant concentration, the continuous intravenous administration set such as infusion pump can be used.
Pharmaceutical composition can be for intramuscular or the sterile injectable water-based of subcutaneous administration or the form of oil-based suspension.This suspension can use above those the suitable dispersion agents that mention or wetting agent and suspending agent to configure according to known technology.Sterile injectable preparation also can be sterile injectable solution or the 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.In order to this object, fixed oil gentle arbitrarily all can use, and comprises direactive glyceride or two glyceryl ester of synthesis.In addition, lipid acid (such as oleic acid) can use preparing in injection.
General formula (I) compound also can give by the form of the suppository for rectal administration.These compositions are prepared by hybrid medicine and suitable nonirritant excipient, and described vehicle is solid at normal temperature but is liquid in rectal temperature, therefore melts in the rectum, thus release medicine.These materials comprise theobroma oil, glycogelatin, hydrogenated vegetable oil, the mixture of polyoxyethylene glycol of different molecular weight and the fatty acid ester of polyoxyethylene glycol.
With regard to local uses, can to prepare and use comprises the ointment of general formula (I) compound, ointment, jelly, solution or suspensoid etc.
Compound of the present invention uses suitable nasal carrier and doser to give with intranasal form by local, or use those skilled in the art the form of well-known transdermal skin patches given by cutaneous routes.Compound of the present invention also can give by the form of the suppository using all matrix as described below: the mixture of the polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight and the fatty vinegar of polyoxyethylene glycol.
When being administered in human subject body by compound of the present invention, every per daily dose is generally determined by the doctor of prescription, and described dosage usually with the symptom of age of patient, body weight, sex and reaction and patient severity and change.Usually, the effective per daily dose of the patient for 70kg is about 0.001mg/kg to 100mg/kg, is preferably 0.01mg/kg to 50mg/kg.
If be mixed with fixed dosage, so these combined prods are used in the compounds of this invention in dosage range described above and other medical active agent treatment in the dosage range of its approval.When combination preparation is improper, general formula (I) compound also successively can give with known anticarcinogen or cytotoxicity medicine.The present invention is not by the restriction of order of administration; General formula (I) compound can give before or after giving known anticarcinogen (multiple anticarcinogen) or cytotoxicity medicine (various kinds of cell toxicity medicine).
Compound of the present invention is the inhibitor of the disease of PI3K/mTOR mediation or the illness of PI3K/mTOR mediation.Term " disease of PI3K/mTOR mediation " and " illness of PI3K/mTOR mediation " represent the effective any morbid state of known PI3K/mTOR tool or other adverse conditions.Term " PI3K/mTOR mediation disease " and " illness that PI3K/mTOR mediates " also represent those diseases by being eased with PI3K/mTOR inhibitor for treating or illness.These diseases and illness include but not limited to cancer and other proliferative disorder.
Therefore, described compound can be used for treating such as Mammals, the following disease especially in the mankind or illness: cancer of the stomach, lung cancer, esophagus cancer, carcinoma of the pancreas, kidney, colorectal carcinoma, thyroid carcinoma, the cancer of the brain, mammary cancer, prostate cancer and other solid tumors; Lymphoma; Leukemia; Adjustment blood vessel occurs; Regulate thrombosis and pulmonary fibrosis.
Compound involved in the present invention also can be used for the biology of PI3K-Akt-mTOR signal path or the research of pharmacology phenomenon and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitor.
Compound is herein including, but not limited to the structure type given by above-mentioned preparation method, and know the personnel of art technology by suitable starting raw material, method like application class obtains the compound specifically do not enumerated.
Embodiment
The following embodiment (for the preparation of compound of the present invention) that provides and bioassay example (for proving the detection of the compounds of this invention purposes) put into practice the present invention to help, and they should not be considered to limit the scope of the invention.
Compounds more of the present invention can by the following corresponding intermediate A of preparation, B, C and D, and then by A and B, or C and D combination is carried out Suzuki coupling and prepares.
The bromo-2H-of intermediate A-1:9-[Isosorbide-5-Nitrae] oxazines is [3,2-c] quinoline-3 (4H)-one also
Step 1: cooled by water (39mL) solution of NaOH (18.6g, 465mmol), drips Nitromethane 99Min. (9.3g, 153mmol), maintains the temperature at 25-30 ° of C.Drip and finish, be heated to 40 ° of C, then cool, then drip Nitromethane 99Min. (9.325g, 152.76mmol), maintain the temperature at 40-45 ° of C.Drip and finish, remain on 40-45 ° of C until solid completely dissolve, occur red clear soln.Then reaction solution is heated to 50-55 ° of C and reacts 2-5 minute, reaction solution is down to 30 ° of C again, pour in 21g ice, with the acidifying of 41.7mL concentrated hydrochloric acid, gained reaction solution adds rapidly 2-amino-5-bromo-benzoic acid (30g, in concentrated hydrochloric acid (13mL) 138.87mmol) and the mixing solutions of water (280mL), gained reaction solution stirred at ambient temperature 18 hours.Filter, filtering thing is through washing, dry, obtains the bromo-2-of 5-((2-nitro-ethyl alkene) is amino) phenylformic acid (39.9g, 100% crude yield).LC-MS(ESI+)：287,289[M+1] +。
Step 2: bromo-for 5-2-((2-nitro-ethyl alkene) is amino) phenylformic acid (19.93g, 69.4mmol) is added in acetic anhydride (360mL), adds anhydrous K 2cO 3(28.79g, 208.276mmol), is heated to 90 ° of C and stirs 1 hour, cooling, filters, and much filtrate is through washing, dry, and gained 3-nitro-4-hydroxyl-6-bromoquinoline (5.936g, 31.7%) crude product is directly used in next step reaction.LC-MS(ESI+):269,271[M+1] +。
Step 3: be dissolved in by 3-nitro-4-hydroxyl-6-bromoquinoline (4.0g, 14.9mmol) in 1NNaOH (148mL, 148mmol), adds inclined sodium sulfite (15.3g, 87.7mmol) in batches.Finish, reaction solution lucifuge stirs 30 minutes.Be cooled to 0 ° of C, with the hcl acidifying of 6N to about pH=7, by the solid filtering produced, use a small amount of washing with acetone, dry, products therefrom 3-amino-4-hydroxy-6-bromoquinoline (3.07g, 86%) crude product is directly used in next step reaction.LC-MS(ESI+):239,241[M+1] +。
Step 4: under ice bath, 3-amino-4-hydroxy-6-bromoquinoline (2.0g, 8.37mmol) is dissolved in THF (10mL), in this solution, add Et 3n (847mg, 8.37mmol), drips the THF(10mL of bromoacetyl bromide (1.69g, 8.37mmol)) solution, stir about 2h adds water cancellation.Filter, merge after filtrate dichloromethane extraction, concentrate to obtain the bromo-N-of 2-(the bromo-4-hydroxyquinoline of 6--3-base) ethanamide (2.1g, 70%) together with filter residue.
Step 5: bromo-for 2-N-(the bromo-4-hydroxyquinoline of 6--3-base) ethanamide (2.1g, 5.8mmol) is dissolved in DMF(20mL) in, add K 2cO 3(403mg, 2.92mmol), is heated to 50 degree and stirs 4h.Concentrating under reduced pressure, resistates purification by silica gel column chromatography obtains the bromo-2H-of light yellow solid 9-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one (900mg, 55%).
The bromo-2-methyl of intermediate A-2:9--[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one
By bromo-for 9-2H-[1,4] oxazines also [3,2-c] quinoline-3 (4H)-one (1.05g, 3.76mmol) be dissolved in THF (25mL) and DMF (25mL), be cooled to 0 ° of C, add NaH (300mg, 7.5mmol), react and add methyl iodide (1.07g, 7.5mmol) after 15 minutes, rise to room temperature reaction 3 hours.Add methylene dichloride (100mL) dilute reaction solution, organic phase is through washing, saturated common salt is washed, dry, concentrated, resistates column chromatography (DCM:MeOH=100:1) the bromo-2-methyl of 9--[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one (397mg, 36%).LC-MS(ESI+):293,295[M+1] +。
Bromo-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines of intermediate A-3:9-also [3,2-c] quinoline
By 3-amino-4-hydroxy-6-bromoquinoline (2.0g, 8.37mmol) be dissolved in acetone (50mL), in DMF (12mL) and water (12mL), add salt of wormwood (3.47g, 25.1mmol), then drip glycol dibromide (7.86g, 41.83mmol), reflux stirs and spends the night.Reaction solution is chilled to room temperature, concentrating under reduced pressure, in resistates, adds methylene dichloride (100mL) and water (20mL).1N hydrochloric acid adjusts about pH to 8, dichloromethane extraction, and with saturated common salt washing after organic phase merges, anhydrous sodium sulfate drying, concentrated, resistates column chromatography (DCM:MeOH=150:1) obtains intermediate A-3 (1.15g, 52%).LC-MS(ESI+):265,267[M+1] +。
The bromo-4-of intermediate A-4:9-(methylsulfonyl)-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline
Aforementioned intermediate A-3 (1.25g, 4.73mmol) is dissolved in THF (50mL), adds Et 3n (1.44g, 14.2mmol), then drip MsCl (1.63g, 14.2mmol), drip and finish, stirred at ambient temperature 3 hours.Reaction solution concentrating under reduced pressure, resistates column chromatography (DCM:MeOH=100:1) intermediate A-4 (1.24g, 76%).LC-MS(ESI+):343,345[M+1] +。
The bromo-4-of intermediate A-5:9-(ethanoyl)-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline
Aforementioned intermediate A-3 (400mg, 1.51mmol) is dissolved in THF (25mL), adds triethylamine (611mg; 6.03mmol); be cooled to 0 ° of C, add Acetyl Chloride 98Min. (474mg, 6.03mmol) under nitrogen protection.Finish, rise to room temperature reaction and spend the night.Reaction solution concentrating under reduced pressure, resistates column chromatography (DCM:MeOH=100:1) obtains intermediate A-5 (456mg, 98%).LC-MS(ESI+):307,309[M+1] +。
Intermediate A-6:9-bromo-4-methyl-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline
Nitrogen protection, by aforementioned intermediate A-2(500mg, 1.71mmol) be dissolved in THF(15mL) in, carefully drip borane dimethylsulfide complex (2NinTHF, 3.5mL, 7mmol), be heated to 50 degree of stirrings and spend the night.Be chilled to room temperature, drip 1N hydrochloric acid (7mL), be heated to return stirring 1 hour, be cooled to room temperature, be adjusted to alkalescence with saturated sodium bicarbonate solution, be extracted with ethyl acetate, dry, concentrated, obtain intermediate A-6(120mg through silica gel column chromatography, 25%).
Bromo-2,2-dimethyl-2H-[Isosorbide-5-Nitrae] oxazines [3,2-c] quinoline-3 (4H)-one of intermediate A-7:9-
Step 1: under ice bath, adds Et in THF (3mL) solution of 3-amino-4-hydroxy-6-bromoquinoline (500mg, 2.1mmol) 3n (212mg, 2.1mmol), drips the THF(3mL of 2-bromine isobutyl acylbromide (481mg, 2.1mmol)) solution, stirring at room temperature 2 hours.In reaction solution, add a small amount of methyl alcohol, concentrating under reduced pressure, obtain crude product 612mg, be directly used in next step reaction.(DCM:MeOH=20:1,Rf=0.5)。
Step 2: gained crude product (612mg) in step 1 is dissolved in DMF(10mL), add salt of wormwood (218mg, 1.58mmol), be heated to 50 degree, stir 5 hours.Be cooled to room temperature, concentrating under reduced pressure, residue by silicagel column chromatography obtains light yellow solid intermediate A-7(190mg, and 40%).
Bromo-2,2,4-trimethylammonium-2H-[Isosorbide-5-Nitrae] oxazines [3,2-c] quinoline-3 (4H)-one of intermediate A-8:9-
Nitrogen protection, aforementioned intermediate A-7(2.0g, 6.51mmol) be dissolved in DMF(30mL) and mixed solvent THF(30mL) in, ice bath is lowered the temperature; add NaH(60%, 520mg, 13mmol), stir 15 minutes; drip methyl iodide (1.85g, 13mmol), rise to room temperature, stirring is spent the night.Reaction solution concentrating under reduced pressure, residue by silicagel column chromatography obtains light yellow solid intermediate A-8(1.1g, and 53%).
Bromo-2,2,4-trimethylammonium-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines of intermediate A-9:9-also [3,2-c] quinoline
Nitrogen protection, by intermediate A-8(500mg, 1.56mmol) be dissolved in THF(10mL) in; add borane dimethylsulfide complex (2N, THF solution, 3.1mL; 6.2mmol), be heated to 50 degree of stirrings and spend the night, TLC shows raw material and disappears; add the hydrochloric acid (5mL) of 1N, be heated to the 1h that refluxes, cooling; be adjusted to alkalescence with saturated sodium bicarbonate solution, be extracted with ethyl acetate, dry; concentrated, obtain light yellow gum thing A-9(130mg through silica gel column chromatography, 27%).
The chloro-5-of intermediate B-1:(6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid
Step 1: by chloro-for 2-3-amino-5-bromopyridine (500mg, 2.46mmol) be dissolved in THF (10mL), add LiHMDS (7.4mL, 7.4mmol), stir ten minutes, add 4-fluorophenylsulfonyl chloride (1.44g, 7.4mmol) again, room temperature for overnight.Add methylene dichloride (20mL) dilution, wash with saturated sodium bicarbonate, extract with methylene dichloride (4 × 30mL), merge organic phase, dry, concentrated, resistates column chromatography (sherwood oil: ethyl acetate=20:1) obtains N-(the bromo-2-chloropyridine of 5--3-base)-4-fluorobenzenesulfonamide (770mg, 87%).LC-MS(ESI+):361,363[M+1] +。
Step 2: by N-(the bromo-2-chloropyridine of 5--3-base)-4-fluorobenzenesulfonamide (770mg, 2.1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (25mL), add connection boric acid pinacol ester (704mg, 2.8mmol), Pd (dppf) Cl 2(156mg, 0.213mmol) and KOAc (628mg, 6.396mmol), nitrogen replacement three post-heating to 100 ° C stir 3 hours.Be cooled to room temperature, dilute by ethyl acetate (30mL), with water and saturated common salt water washing, dry, concentrated, resistates column chromatography (PE:EA=10:1) obtains (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (861mg, 99%).LC-MS(ESI+):331[M+1] +。
The fluoro-N-of intermediate B-2:4-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-base) pyridin-3-yl) benzsulfamide
Step 1: by 2-methoxyl group-3-amino-5-bromopyridine (500mg, 2.5mmol) be dissolved in THF (10mL), add LiHMDS (7.4mL, 7.4mmol), react ten minutes, add 4-fluorophenylsulfonyl chloride (1.44g, 7.4mmol) again, room temperature for overnight.Add methylene dichloride (20mL) dilute reaction solution, wash with saturated sodium bicarbonate, anhydrous sodium sulfate drying, concentrated, resistates column chromatography (PE:EA=20:1) obtains N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide (770mg, 87%).LC-MS(ESI+):361,363[M+1] +。
Step 2: by N-(the bromo-2-methoxypyridine of 5--3-base)-4-fluorobenzenesulfonamide (770mg, 2.1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (25mL), add connection boric acid pinacol ester (704mg, 2.8mmol), Pd (dppf) Cl 2(156mg, 0.21mmol) and KOAc (628mg, 6.4mmol).Nitrogen replacement three post-heating to 100 ° C stir 3 hours, be cooled to room temperature, dilute by ethyl acetate (30mL), with water and saturated common salt water washing, dry, concentrated, resistates column chromatography (PE:EA=10:1) obtains the fluoro-N-of 4-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide (861mg, 99%).LC-MS(ESI+):409[M+1] +。
The chloro-5-of intermediate B-3:(6-(2,4 difluorobenzene sulfoamido) pyridin-3-yl) boric acid
Replace the 4-fluorophenylsulfonyl chloride in intermediate B-1 preparation process with 2,4 difluorobenzene SULPHURYL CHLORIDE, copy step 1 and the step 2 of intermediate B-1 preparation process, can intermediate B-3 be obtained.LC-MS:349[M+1]。
The fluoro-N-of intermediate B-4:2,4-bis-(2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-base) pyridin-3-yl) benzsulfamide
Replace the 4-fluorophenylsulfonyl chloride in intermediate B-2 preparation process with 2,4 difluorobenzene SULPHURYL CHLORIDE, copy step 1 and the step 2 of intermediate B-2 preparation process, can intermediate B-4 be obtained.LC-MS:427[M+1]。
Embodiment 1:N-(the chloro-5-of 2-(3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines is [3,2-c] quinoline-9-base also) pyridin-3-yl)-4-fluorobenzenesulfonamide (I-1)
Nitrogen protection, by bromo-for 9-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one (100mg, 0.360mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (9mL) and H 2o(1.5mL) (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (178mg, 0.540mmol) in, is added, Pd (dppf) Cl 2(27mg, 0.036mmol) and Cs 2cO 3(105mg, 0.323mmol), is heated to 100 degree, stirs 3h, and concentrated, residue by silicagel column chromatography obtains white solid, is target compound I-1(70mg, 40%).LC-MS(ESI+):485(M+1); 1HNMR(300MHz,DMSO-d 6)11.13(s,1H),8.71(s,1H),8.53(s,1H),7.91-8.09(m,4H),7.79-7.84(m,2H),7.42-7.48(m,2H),4.95-4.96(m,2H)。
Embodiment 2:N-(2-methoxyl group-5-(3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines is [3,2-c] quinoline-9-base also) pyridin-3-yl)-4-fluorobenzenesulfonamide (I-2)
Nitrogen protection, by bromo-for 9-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one (intermediate) (60mg, 0.21mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (9mL) and H 2o(1.5mL), in, the fluoro-N-of 4-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide (132mg, 0.32mmol) is added, Pd (dppf) Cl 2(17mg, 0.021mmol) and Cs 2cO 3(105mg, 0.32mmol), is heated to 100 degree and stirs 3h.Be chilled to room temperature, concentrating under reduced pressure, residue by silicagel column chromatography obtains light yellow solid (65mg, 63%).LC-MS(ESI+):485(M+1); 1HNMR(300MHz,DMSO-d 6)11.10(s,1H),10.10(s,1H),8.50(s,1H),8.40(s,1H),7.98-8.00(m,2H),7.79-7.89(m,4H),7.39-7.44(m,2H),4.96(s,2H),3.67(s,1H)。
Embodiment 3:N-(the chloro-5-of 2-(4-methyl-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (I-3)
By bromo-for 9-2-methyl-[1,4] oxazines also [3,2-c] quinoline-3 (4H)-one (180mg, 0.614mmol) be dissolved in 1, in 4-dioxane (12mL) and water (2mL), add (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (254mg, 0.768mmol), Pd (dppf) Cl 2(45mg, 0.061mmol) and Cs 2cO 3(600mg, 1.842mmol).Nitrogen replacement three post-heating to 100 ° C react 3 hours, be cooled to room temperature, with methylene dichloride (50mL) dilution, add water extraction, first separates organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, use methylene dichloride (3 × 20mL) to extract again, this dichloromethane solution is dry, concentrated, resistates column chromatography (DCM:MeOH=80:1) obtains target product (I-3) (27mg, 9%).LC-MS(ESI+):499[M+1] +； 1HNMR(300MHz,DMSO-d6)10.59(br,1H),8.93(s,1H),8.73(s,1H),8.00-8.18(m,4H),7.79-7.84(m,2H),7.45(t,2H,J=8.7Hz),5.10(s,2H),3.46(s,3H)。
Embodiment 4:N-(2-methoxyl group-5-(4-methyl-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) pyridin-3-yl)-4-fluorobenzenesulfonamide (I-4)
By bromo-for 9-2-methyl-[1,4] oxazines also [3,2-c] quinoline-3 (4H)-one (44mg, 0.15mmol) be dissolved in 1, in 4-dioxane (9mL) and water (1.5mL), add the fluoro-N-of 4-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide (188mg, 0.46mmol), Pd (dppf) Cl 2(11mg, 0.015mmol) and Cs 2cO 3(147mg, 0.45mmol).Nitrogen replacement three post-heating to 100 ° C react 3 hours, be cooled to room temperature, with methylene dichloride (20mL) dilution, add water extraction, first separates organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, use methylene dichloride (3 × 10mL) to extract again, this dichloromethane solution is dry, concentrated, resistates column chromatography (DCM:MeOH=80:1) obtains target product (I-4) (20mg, 27%).LC-MS(ESI+):495[M+1] +； 1HNMR(300MHz,DMSO-d6)8.83(s,1H),8.40(s,1H),8.02-8.04(m,2H),7.78-7.94(m,4H),7.39-7.47(m,2H),5.04(s,2H),3.68(s,3H),3.45(s,3H)。
Adopt method similar to the above embodiments, compound listed in following table can be prepared respectively:
Intermediate C-1:(3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) boric acid
The bromo-2H-[1 of 9-, 4] oxazines also [3,2-c] quinoline-3 (4H)-one (500mg, 1.792mmol) be dissolved in 1, in 4-dioxane (40mL), add connection boric acid pinacol ester (682mg, 2.687mmol), Pd (dppf) Cl 2(131mg, 0.179mmol) and KOAc (264mg, 2.687mmol).Be heated to 100 ° of C under nitrogen protection and react 3 hours.LC-MS display reacts completely, and by concentrated for reaction solution dry, resistates column chromatography (DCM:MeOH=50:1) obtains intermediate C-1 (247mg, 56%).LC-MS(ESI+):245[M+1] +。
Intermediate C-2:(4-methyl-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) boric acid
The bromo-2-methyl-[1 of 9-, 4] oxazines also [3,2-c] quinoline-3 (4H)-one (100mg, 0.341mmol) be dissolved in 1, in 4-dioxane (10mL), add connection boric acid pinacol ester (130mg, 0.512mmol), Pd (dppf) Cl 2(25mg, 0.034mmol) and KOAc (100mg, 1.023mmol).Be heated to 100 ° of C under nitrogen protection and react 3 hours.LC-MS display reacts completely, and reaction solution is concentrated dry, adds methylene dichloride (10mL), filtering insolubles, and filtrate is concentrated dry, resistates column chromatography (DCM:MeOH=100:1) intermediate C-2 (83mg, 94%).LC-MS(ESI+):259[M+1] +。
Intermediate C-3:(2,2-dimethyl-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) boric acid
9-bromo-2,2-dimethyl-2H-[1,4] oxazines [3,2-c] quinoline-3 (4H)-one (600mg, 1.954mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (50mL), add connection boric acid pinacol ester (744mg, 2.93mmol), Pd (dppf) Cl 2(143mg, 0.195mmol) and KOAc (288mg, 2.93mmol).Be heated to 100 ° of C under nitrogen protection and react 3 hours.LC-MS display reacts completely, and by concentrated for reaction solution dry, resistates column chromatography (DCM:MeOH=50:1) obtains compound 2 (491mg, 92.4%).LC-MS(ESI+):273[M+1] +。
Intermediate C-4:(2,2,4-trimethylammonium-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) boric acid
9-bromo-2,2,4-trimethylammonium-2H-[1,4] oxazines [3,2-c] quinoline-3 (4H)-one (800mg, 2.491mmol) is dissolved in 1, in 4-dioxane (80mL), add connection boric acid pinacol ester (1.265g, 4.982mmol), Pd (dppf) Cl 2(182mg, 0.249mmol) and KOAc (367mg, 3.737mmol).Be heated to 100 ° of C under nitrogen protection and react 3 hours.LC-MS display reacts completely, and by concentrated for reaction solution dry, resistates column chromatography (DCM:MeOH=100:1) obtains compound 2 (445mg, 62.4%).LC-MS(ESI+):287[M+1] +。
Intermediate D-1:N-(the bromo-2-chloropyridine of 5--3-base) Toluidrin
Chloro-for 2-3-amino-5-bromopyridine (2.5g, 12.05mmol) is dissolved in pyridine (30mL), adds MsCl (4.66mL, 60.25mmol), stirring at room temperature 48 hours.By reaction solution concentrating under reduced pressure, methyl alcohol (50mL) and 1 is added in resistates, 4-dioxane (50mL), add Anhydrous potassium carbonate (16.65g again, 120.5mmol), be heated to 60 ° of C and stir 5 hours. be chilled to room temperature, reaction solution is poured into water (500mL), is adjusted to pH5. with concentrated hydrochloric acid and is extracted with ethyl acetate, merge organic phase, use water respectively, saturated common salt water washing, dry, concentrated, resistates column chromatography (PE:EA=10:1) obtains N-(the bromo-2-chloropyridine of 5--3-base) Toluidrin (2.70g, 79%).LC-MS(ESI+):285[M+1]。
Intermediate D-2:N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin
2-methoxyl group-3-amino-5-bromopyridine (1g, 4.925mmol) is dissolved in pyridine (15mL), adds MsCl (1.9mL, 24.626mmol), react 48 hours under room temperature.By concentrated for reaction solution dry, methyl alcohol (20mL) and 1 is added in resistates, 4-dioxane (20mL), add Anhydrous potassium carbonate (16.81g again, 49.25mmol), be heated to 60 ° of C and react 5 hours. reaction solution is poured into water (100mL), pH=5. is regulated to be extracted with ethyl acetate with concentrated hydrochloric acid, merge organic phase, use water respectively, saturated common salt water washing, dry, concentrated, resistates column chromatography (PE:EA=10:1) obtains N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin (994mg, 71.8%).LC-MS(ESI+):281,283[M+1] +。
Intermediate D-3:N-(the bromo-2-chloropyridine of 5--3-base) cyclopropylsulfonamide
By chloro-for 2-3-amino-5-bromopyridine (2.0g, 9.64mmol) be dissolved in THF (30mL), be cooled to-5 DEG C, toward wherein adding LiHMDS (14.5mL, 1M), stir after 15 minutes, in solution, add cyclopropyl sulfonyl chloride (2.03g, 14.46mmol), stirred overnight at room temperature is risen to gradually.In reaction solution, add methyl alcohol (5mL), column chromatography purification after solvent evaporated, obtain intermediate D-3(1.0g, 33%).LC-MS(ESI+)：311，313[M+1] +。
Intermediate D-4:N-(the bromo-2-methoxypyridine of 5--3-base) cyclopropylsulfonamide
Copy the preparation method of intermediate D-3, replace the chloro-3-amino of 2--5-bromopyridine wherein with 2-methoxyl group-3-amino-5-bromopyridine, this intermediate D-4.LC-MS(ESI+)：306，308[M+1] +。
Intermediate D-5:N-(the bromo-2-chloropyridine of 5--3-base) dimethylamino sulfonylurea
Dimethylin SULPHURYL CHLORIDE (2.08g, 14.5mmol) and DMAP (29mg, 0.24mmol) is added in pyridine (8mL) solution of 2-chloro-3-amino-5-bromopyridine (500mg, 2.41mmol).Reaction solution is heated to 100 ° of C, reacts 20 hours under nitrogen protection.By concentrated for reaction solution dry, add ethyl acetate and water, separate organic phase, aqueous phase is extracted with ethyl acetate three times, merges organic phase, wash with water respectively, saturated common salt is washed, dry, concentrated, resistates obtains sulfonylurea intermediate (273mg, 36%) through column chromatography purification (PE:EA=20:1).LC-MS(ESI+):314,316[M+1] +。
Intermediate D-6:N-(the bromo-2-methoxypyridine of 5--3-base) dimethylamino sulfonylurea
Dimethylin SULPHURYL CHLORIDE (2.12g, 14.8mmol) and DMAP (29mg, 0.25mmol) is added in pyridine (8mL) solution of 2-methoxyl group-3-amino-5-bromopyridine (500mg, 2.463mmol).Reaction solution is heated to 100 ° of C, reacts 20 hours under nitrogen protection.By concentrated for reaction solution dry, add ethyl acetate and water, separate organic phase, aqueous phase is extracted with ethyl acetate three times, merges organic phase, wash with water respectively, saturated common salt is washed, dry, concentrated, resistates obtains intermediate D-6 (310mg, 41%) through column chromatography purification (PE:EA=20:1).LC-MS(ESI+):310,312[M+1] +。
Embodiment 27:
Intermediate C-1 (104mg, 0.426mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (18mL) and water (3mL), adds intermediate D-1 (243mg, 0.852mmol), Pd (dppf) Cl 2(31mg, 0.043mmol) and Cs 2cO 3(208mg, 0.639mmol).Nitrogen replacement post-heating to a 100 ° C reacts 1 hour, and LC-MS display reacts completely, and by concentrated for reaction solution dry, resistates column chromatography (DCM:MeOH=40:1) obtains target compound (62mg, 36%).LC-MS(ESI+):405[M+1] +； 1HNMR(300MHz,DMSO-d6)δ11.12(br,1H),9.88(br,1H),8.71(s,1H),8.53(s,1H),8.19-8.26(m,2H),7.96-8.05(m,2H),4.95(s,2H),3.18(s,3H)。
Copy the method for embodiment, intermediate C-1 to C-4 combined respectively at D-1 to D-6, carry out Suzuki linked reaction, compound as shown in the table can be prepared respectively:
The bromo-4-methyl of intermediate A-10:5-amino-9--2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-3 (4H)-one
Step 1: intermediate A-2 (1g, 3.41mmol) is dissolved in the mixed solution of DME (25mL) and PE (50mL), adds mCPBA (1.38g, 6.82mmol) in batches.Finish, react 2 hours under room temperature, TLC (DCM:MeOH=20:1) display reacts completely.Filter, filter residue is with DME/PE=1/2 (20mL) washing, dry, and gained crude product (1.583g, 100% thick yield) is directly used in next step reaction.LC-MS(ESI+):309,311[M+1] +。
Step 2: in step 1, gained crude product (1.58g) is dissolved in DCM (40mL), in the mixing solutions of MeOH (20mL) and water (10mL), adds salt of wormwood (471mg, 3.41mmol), stirring reaction 30 minutes, separates organic phase, and aqueous phase DCM extracts three times, merge organic phase, with saturated common salt washing, dry, concentrated, resistates column chromatography (DCM:MeOH=40:1) obtains (0.69g, 66%).LC-MS(ESI+):309,311[M+1] +。
Step 3: by gained (0.69g in step 2,2.24mmol) be dissolved in DCM (40mL) and MeOH (25mL), be cooled to 0 ° of C, add ammoniacal liquor (9mL), drip p-methyl benzene sulfonic chloride (1.28g again, DCM (10mL) solution 6.72mmol), drips and finishes, rise to room temperature reaction 6 hours.By concentrated for reaction solution dry, resistates column chromatography (DCM/MeOH=60/1) obtains intermediate A-10 (491mg, 71%).LC-MS(ESI+):308,310[M+1] +。
Intermediate A-11:9-bromo-4-methyl-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-5-is amino
Above-mentioned intermediate A-10 (276mg, 0.896mmol) is dissolved in anhydrous THF (20mL), drips 2M borane dimethylsulfide ethereal solution (1.79mL, 3.582mol).Drip and finish, be heated to 50 ° of C reaction overnight.Add 1N hydrochloric acid (10mL), be heated to back flow reaction 1 hour.Be cooled to room temperature, adjust pH to alkalescence with saturated sodium bicarbonate solution, with dichloromethane extraction, anhydrous sodium sulfate drying, concentration residue obtains intermediate A-11 (188mg, 71%) through column chromatography purification (DCM:MeOH=100:1).LC-MS(ESI+):294,296[M+1] +。
Intermediate A-12:N-(9-bromo-4-methyl-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-5-base) ethanamide
By Acetyl Chloride 98Min. (85mg, 1.1mmol) add intermediate A-11 (160mg, 0.54mmol) with triethylamine (110mg, in DMF (5mL) solution 1.1mmol), react 2 hours under being heated to 45 ° of C, add diacetyl oxide (0.39mL, 4.1mmol) again, continue reaction 1 hour.LC-MS display reacts completely, and by concentrated for reaction solution dry, resistates column chromatography obtains intermediate A-12 (158mg, 86%).LC-MS(ESI+):336,338[M+1] +。
Bromo-2,2,4-trimethylammonium-2H-[Isosorbide-5-Nitrae] oxazines of intermediate A-13:5-amino-9-also [3,2-c] quinoline-3 (4H)-one
Copy the preparation method of intermediate A-10, with intermediate A-8 replacement intermediate A-2 wherein, can intermediate A-13 be prepared.LC-MS(ESI+):336,338[M+1] +。
Embodiment 51:
By the bromo-4-methyl of intermediate A-10(5-amino-9--2H-[1,4] oxazines also [3,2-c] quinoline-3 (4H)-one) (100mg, 0.33mmol) be dissolved in 1, in 4-dioxane (9mL) and water (1.5mL), add the chloro-5-of intermediate B-1((6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid) (161mg, 0.49mmol), Pd (dppf) Cl 2(22mg, 0.033mmol) and Cs 2cO 3(159mg, 0.49mmol).Nitrogen replacement three post-heating to 100 ° C react 3 hours, be cooled to room temperature, with methylene dichloride (30mL) dilution, add water extraction, first separates organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, use methylene dichloride (3 × 10mL) to extract again, this dichloromethane solution is dry, concentrated, resistates obtains Compound I-51 (90mg, 54%) through column chromatography for separation.LC-MS(ESI+):514[M+1] +； 1HNMR(300MHz,DMSO-d 6)δ8.62(s,1H),7.78-7.88(m,5H),7.41-7.58(m,3H),6.63(br,2H),4.84(s,2H),3.32(s,3H)。
Copy the method for embodiment 51, intermediate A-10 combined to B-4 to A-13 and intermediate B-1, carries out Suzuki linked reaction, following compound can be prepared:
Intermediate C-5:(5-amino-4-methyl-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines also [3,2-c] quinoline-9-base) boric acid
Copy the preparation method of intermediate C-1 to C-4, with intermediate A-10 for raw material, this intermediate can be prepared.LC-MS(ESI+):274[M+1] +。
Amino-2,2,4-trimethylammonium-3-oxygen-3,4-dihydro-2H-[Isosorbide-5-Nitrae] oxazines of intermediate C-6:(5-also [3,2-c] quinoline-9-base) boric acid
Copy the preparation method of intermediate C-1 to C-4, with intermediate A-13 for raw material, this intermediate can be prepared.LC-MS(ESI+):302[M+1] +。
Intermediate C-5, C-6 and intermediate D-1 to D-6 are combined and carry out Suzuki linked reaction, can prepare with the compound shown in following table:
Above-mentioned intermediate can be carried out various combination according to general knowledge known in the art and prepare the compounds of this invention by those skilled in the art, or passes through to prepare the apparent analogue of above-mentioned intermediate and the preparation carrying out general formula (I) compound described in our face.
Biological examples 1: the compounds of this invention measures the half-inhibition concentration (IC50) of PI3K α, PI3K β, PI3K δ, PI3K γ and mTOR
1. raw material
1) p110 α/p85a, purchased from Invitrogen, catNo.PV4788;
2) p110 δ/p85a, purchased from Millipore, catNo.14-604-K;
3) p110 β, purchased from Millipore, catNo.14-603-K;
4) p110 γ, purchased from Invitrogen, catNo.PR8641C;
5) mTOR, purchased from Millipore, catNo.14-770;
6) Kinase-GloPlusL μM of inesce-KinaseAssay, purchased from Promege, catNo.V3771;
7) ADP-GloKinaseAssay, purchased from Promege, catNo.v9102/3;
2. experimental technique
2.1 diluted chemical compound
1) compound test final concentration is 1 μM, is first configured to 100 times of concentration, namely 100 μMs.In the first perform hole of 96 orifice plates, add the 10mM compound of 10 μ L respectively, add the 100%DMSO of 90 μ L, be made into the 1mM compound of 100 μ L.In the second perform hole of 96 orifice plates, add the 1mM compound of 10 μ L respectively, add the 100%DMSO of 90 μ L, be made into 100 μMs of compounds of 100 μ L.
2) in the secondary series hole of another 96 orifice plate, add the above-mentioned 100 μMs of compounds of 100 μ L, other holes add the 100%DMSO of 60 μ L.From the 2nd hole, get 30 μ L compounds adds in the 3rd hole, down does 3 times of dilutions successively, dilutes 8 concentration altogether.
3) 100 μ L100%DMSO are added respectively in the first hole and the 12 hole.
2.2 compound intermediate dilute
1) 4 μ L compounds are shifted in new 96 orifice plates
2) the kinase buffer liquid of the 1x of 96 μ L is added
3) to vibrate on vibration plate machine mixing 10 minutes.
2.3 transfer compounds are to Sptting plate
From above-mentioned 96 orifice plates, take out 2.5 μ L in one piece of 384 hole Sptting plate, such as, the A1 hole of 96 orifice plates is transferred in A1 and the A2 hole of 384 orifice plates, and the A2 hole of 96 orifice plates is transferred in A3 and the A4 hole of 384 orifice plates, by that analogy.
3. prepare 1x kinase buffer liquid
1) 1xmTOR kinase buffer liquid
50mMHEPES,pH7.5
10mMMgCl2
1mMEGTA
3mMMnCl
0.01%Tween-20
2mMDTT
2) 1xPI3K α, PI3K δ kinase buffer liquid
50mMHEPES,pH7.5
3mMMgCl2
1mMEGTA
100mMNaCl
0.03%CHAPS
2mMDTT
3) 1xPI3K β, PI3K γ kinase buffer liquid
50mMHEPES,pH7.5
3mMMgCl2
1mMEGTA
100mMNaCl
0.03%CHAPS
2mMDTT
4. prepare 4x kinase solution
1) 1 times of kinase buffer liquid is used to configure 4 times of mTOR solution, PI3K α solution, PI3K β solution, PI3K γ solution and PI3K δ solution.Kinase solution final concentration is respectively mTOR2.5nM; PI3K α 1.65nM; PI3K β 4.8nM; PI3K γ 7.6nM; PI3K δ 5.7nM.
2) transferase 12 .5mL4 times of enzyme solution is in 384 orifice plate reacting holes, and negative control hole adds 1 times of kinase buffer liquid.
3) vibrate, mixing, left at room temperature
5. prepare 2x substrate solution
1) 1 times of kinase buffer liquid is used to configure 2 times of substrate solutions.The substrate solution final concentration of mTOR, PI3K α, PI3K β, PI3K γ and PI3K δ five enzyme reaction systems is respectively
mTOR：ULight-4E-BP150nM；ATP10.8μM。
PI3Kα：PIP250μM；ATP25μM。
PI3Kβ：PIP250μM；ATP25μM。
PI3Kγ：PIP250μM；ATP25μM。
PI3Kδ：PIP250μM；ATP25μM。
2) initial action in transferase 45 μ L2 times substrate solution to 384 orifice plate reacting holes
3) vibrate, mixing.
6. kinase reaction
By 384 orifice plate cover lids, in incubated at room temperature, mTOR, PI3K α, PI3K β and PI3K γ 1 hour, PI3K δ 2 hours.
7. the detection of reaction result
7.1mTOR result detects
1) detection reagent is equilibrated to room temperature.
2) termination reaction in 10 μ L detection reagent to 384 orifice plate reacting holes is shifted.
3) vibrate gently on vibration plate machine 15 minutes.Equilibrate at room temperature 1 hour.
7.2PI3K α and PI3K δ result detect
1) Kinase-Glo detection reagent is equilibrated to room temperature.
2) termination reaction in 10 μ LKinase-Glo detection reagent to 384 orifice plate reacting holes is shifted.
3) vibrate gently on vibration plate machine 15 minutes.
7.3PI3K β and PI3K γ result detect
1) ADP-Glo reagent is equilibrated to room temperature.
2) transferase 45 μ L reaction solution is in one piece of new 384 orifice plate reacting hole.
3) termination reaction in transferase 45 μ LADP-Glo reagent to 384 orifice plate reacting holes.
4) vibrate gently on vibration plate machine 40 minutes.
5) shift 10 μ L kinase assay reagent in each reacting hole, vibrate 1 minute, room temperature leaves standstill 1 hour.
8. digital independent
The luminous numerical value of sample is read at Envision.
9. fitting of a curve
1) data of luminous reading are copied from Envision program
2) value of luminous reading is converted to inhibition percentage by formula.
MTOR conversion formula:
Percentinhibition=(Lancesignal-min)/(max-min)*100
PI3K α, PI3K β, PI3K γ and PI3K δ conversion formula:
Percentinhibition=(max-conversion)/(max-min)*100
" max " is the not enzyme-added control sample fluorescence reading carrying out reacting; " min " is for adding DMSO fluorescent reading in contrast.
3) Graphpad5.0 is used to carry out curve fitting data importing MSExcel.
The IC50 test result of part of compounds of the present invention to PI3K α, PI3K β, PI3K γ, PI3K δ and mTOR five enzymes is as shown in the table:
Biological examples 2: adopt CellTiter-Glo luciferase kit to measure the compounds of this invention to tumor cell proliferation half-inhibition concentration (IC50)
1. raw material
1) U-87MG cell strain, purchased from ATCC, Cat.No.HTB-14, LotNo.5018014;
2) A549 cell strain, purchased from ATCC, Cat.No.CCL-185, LotNo.7502546;
3) PC-3 cell strain, purchased from ATCC, Cat.No.CRL-1435, LotNo.7348670;
4) BT474 cell strain, purchased from ATCC, Cat.No.HTB-20, LotNo.5188737;
5) F-12K nutrient solution, purchased from Invitrogen, Cat.No.21127-022;
6) EMEM nutrient solution, purchased from Invitrogen, Cat.No.11095;
7) 96 orifice plates, purchased from Corning, Cat.No.CLS3903;
8) CellTiterGloassaykit, purchased from Promega, Cat.No.G7571, Lot.No.256984;
9) foetal calf serum, purchased from Invitrogen, Cat.No.10099-141, Lot.No.8153379.
2. experimental technique
2.1 plating cells
1) perfect medium is prepared:, fully mix.
2) cell strain that growth selection is in good condition.
3) Tissue Culture Flask is taken out from incubator, check the Cell Name that bottle marks, type of culture medium and cell algebraically.
4) discard substratum, with trysinization, after having digested, neutralize with the substratum containing serum, piping and druming cell, makes cell detachment.With transfer pipet, cell suspension is moved in centrifuge tube, the centrifugal 3-5 minute of rotating speed of 800-1000.
5) the cell conditioned medium liquid abandoned in centrifuge tube is inhaled.
6) in centrifuge tube, add the substratum of proper volume, soft piping and druming makes cell evenly resuspended.
7) Vi-CellXR cell counter counting is used.
8) cell suspension is adjusted to suitable concn.
9) cell suspension is added in 96 white orifice plates of the saturating wall in the end, 100 microlitres/hole.Labeled cell title, plant plate density, the details such as date, are positioned over CO by culture plate 2spend the night in incubator.
2.2 cell experiment conditions:
Cell strain Every number of perforations Incubation time Medium
U-87MG 3000 72h EMEM+10%FBS+1%PS+1x NEAA
A549 2000 72h F12K+10%FBS+1%PS
PC-3 3000 72h F12K+10%FBS+1%PS
BT474 4000 96h Hybri-care+10%FBS+1%PS
The preparation of 2.3 compounds and interpolation:
1) compound powder is first mixed with 10mM concentration storage liquid with DMSO, then with DMSO, compound 3 times of gradient dilutions is diluted to 9 concentration point (these 9 points are intermediate concentration).
2) get the compound solution of 0.5uL from above-mentioned intermediate concentration, add in 500uL nutrient solution, piping and druming mixing, DMSO final concentration is 0.1%, and what be made into ultimate density contains compound substratum.
3) substratum containing different compound is added when cell changes liquid.
4) in 37 ° of C incubators, the specified time is hatched.
2.4 detect and analyze
1) observation of cell form under inverted microscope.
2) Tissue Culture Plate is placed in room temperature and balance 30 minutes.
3) cytoactive detection reagent 100 μ l/ hole is added in culture plate.
4) on vibration plate machine, 2 minutes are mixed, inducing cell lysis.
5) 96 orifice plates are placed 10 minutes at room temperature, its luminous signal is stablized.
6) paste the counterdie of white bottom culture plate, use Flexstation3 drafting board. (be correlated with and be set to: be luminous, integrating time 500ms).
7) experimental result of record analysis gained.
According to software analysis result, the cell inhibitory effect Activity Results of part of compounds of the present invention is as following table:

Claims (31)

1. morpholine quinolines, for having the compound of following general formula (I):
Wherein,
R 1be selected from 4-fluorophenyl, 2,4 difluorobenzene base, methyl, cyclopropyl, dimethylin;
R 2be selected from hydrogen, halogen ,-OR 10;
R 3be selected from hydrogen ,-NHR 10,-NHC (=O) R 10;
R 4be selected from hydrogen, C 1-C 6alkyl ,-C (=O) R 10,-S (=O) 2r 10;
R 5, R 6be selected from hydrogen, C 1-C 6alkyl;
R 7, R 8be selected from hydrogen, C 1-C 6alkyl, or R 7, R 8merge into=O;
R 9be selected from hydrogen;
Wherein R 10for hydrogen, C 1-C 6alkyl.
2. morpholine as claimed in claim 1 quinolines, wherein R 2be selected from chlorine, methoxyl group.
3. morpholine as claimed in claim 1 quinolines, wherein R 3be selected from hydrogen ,-NH 2,-NHC (=O) CH 3.
4. morpholine as claimed in claim 1 quinolines, wherein R 4be selected from hydrogen, methyl, ethanoyl, methylsulfonyl.
5. morpholine as claimed in claim 1 quinolines, wherein R 5, R 6be selected from hydrogen, methyl.
6. morpholine as claimed in claim 1 quinolines, wherein R 7, R 8be selected from hydrogen, or R 7, R 8merge into=O.
7. morpholine as claimed in claim 1 quinolines, R in its formula of (I) 1for 4-fluorophenyl, 2,4 difluorobenzene base, methyl, cyclopropyl or dimethylin, meanwhile: R 2for chlorine or methoxyl group; R 3for hydrogen ,-NH 2or-NHC (=O) CH 3; R 4for hydrogen, methyl, ethanoyl or methylsulfonyl; R 5, R 6for hydrogen or methyl; R 7, R 8for hydrogen, or R 7, R 8merge into=O; R 9for hydrogen.
8. morpholine as claimed in claim 1 quinolines, the compound of its formula of (I) be following structure (I-1) to any one in (I-67):
9. morpholine as claimed in claim 1 quinolines, described general formula (I) compound is the mixture of any one or both or three arbitrarily in enantiomer, diastereomer, conformer.
10. morpholine as claimed in claim 1 quinolines, wherein said general formula (I) compound exists as a pharmaceutically acceptable salt form.
11. morpholines as claimed in claim 10 quinolines, wherein said pharmacy acceptable salt for salt formed by acid or acid proton the salt that replaces by metal ion.
12. morpholines as claimed in claim 11 quinolines, wherein said is hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
13. morpholines as claimed in claim 11 quinolines, wherein said acid proton the salt that replaces by metal ion be sodium salt, sylvite, magnesium salts or calcium salt.
Morpholine described in 14. claim 1-8 the preparation method of quinolines, be specially following methods:
(1) R is worked as 3during for hydrogen, the preparation process of compound shown in general formula (I) is: by the 3-amino-4-hydroxy-6-bromoquinoline cyclisation of 3-amino-4-hydroxy-6-bromoquinoline or replacement and to obtaining after nitrogen atom having morpholine and the intermediate A of quinoline structure, then carry out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid replaced or boric acid ester, obtain general formula (I) compound; Or, will there is morpholine and the bromine of the intermediate A of quinoline structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carry out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
(2) R is worked as 3when not being hydrogen, the preparation process of compound shown in general formula (I) is: by morpholine and the nitrogen-atoms of quinoline intermediate carries out oxidized activating, then-2, quinoline-nucleophilic substitution reaction is carried out with nucleophilic reagent, obtain there is morpholine and the intermediate A of quinoline structure, there is morpholine and then the intermediate A of quinoline structure carries out Suzuki linked reaction with the intermediate B containing the pyridine boronic acid that replaces or boric acid ester, obtain general formula (I) compound; Or, will there is morpholine and the bromine of the intermediate A of quinoline structure is converted into containing boric acid or borate ester intermediate C, then with containing the pyridine bromide intermediate D replaced carry out Suzuki linked reaction, obtain general formula (I) compound; Concrete reaction formula is as follows:
In above-mentioned reaction formula: R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9respectively as claim 1-8 define, group
15. pharmaceutical compositions, wherein said pharmaceutical composition comprises general formula according to claim 1 (I) compound and the acceptable vehicle of pharmacy for the treatment of significant quantity.
16. pharmaceutical compositions as claimed in claim 15, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
17. pharmaceutical compositions, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of general formula according to claim 1 (I) compound for the treatment of significant quantity.
18. pharmaceutical compositions as claimed in claim 17, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
Morpholine described in 19. claim 1-9 the application of quinolines are wherein that general formula (I) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
Morpholine described in 20. claim 1-9 the application of quinolines are wherein the pharmaceutically useful salt of general formula (I) compound regulates in PI3K/mTOR signal path catalytic activity goods application in preparation.
The application of the pharmaceutical composition described in 21. claim 15-18 is wherein that pharmaceutical composition treats the application in the medicine of the disease relevant with PI3K/mTOR signal path in preparation.
22. apply as claimed in claim 21, and the wherein said disease relevant with PI3K/mTOR signal path is cancer.
23. apply as claimed in claim 22, and wherein said cancer is incidence cancer, respiratory system cancer, cancer in digestive system, urinary system cancer, Skeletal system cancer, gynecological cancer, hematological cancer or other types cancer.
24. apply as claimed in claim 23, and wherein said incidence cancer is thyroid carcinoma, nasopharyngeal carcinoma, meninx cancer, acoustic tumor, pituitary tumor, oral carcinoma, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumour or intracranial metastatic tumor.
25. apply as claimed in claim 23, and wherein said respiratory system cancer is lung cancer.
26. apply as claimed in claim 23, and wherein said cancer in digestive system is liver cancer, cancer of the stomach, the esophageal carcinoma, large bowel cancer, the rectum cancer, colorectal carcinoma or carcinoma of the pancreas.
27. apply as claimed in claim 23, and wherein said urinary system cancer is kidney, bladder cancer, prostate cancer or carcinoma of testis.
28. apply as claimed in claim 23, and wherein said Skeletal system cancer is osteocarcinoma.
29. apply as claimed in claim 23, and wherein said gynecological cancer is mammary cancer, cervical cancer or ovarian cancer.
30. apply as claimed in claim 23, and wherein said hematological cancer is leukemia, malignant lymphoma or multiple myeloma.
31. apply as claimed in claim 23, and wherein said other types cancer is malignant melanoma, neurospongioma or skin carcinoma.
CN201310016643.0A 2013-01-17 2013-01-17 Morpholine quinolines, Preparation Method And The Use Active CN103936762B (en)

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WO2019201283A1 (en) * 2018-04-20 2019-10-24 Xrad Therapeutics, Inc. Dual atm and dna-pk inhibitors for use in anti-tumor therapy

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