CN104418867A - Compound used as PI3K/mTOR inhibitor, preparation method and application - Google Patents

Compound used as PI3K/mTOR inhibitor, preparation method and application Download PDF

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CN104418867A
CN104418867A CN201310376114.1A CN201310376114A CN104418867A CN 104418867 A CN104418867 A CN 104418867A CN 201310376114 A CN201310376114 A CN 201310376114A CN 104418867 A CN104418867 A CN 104418867A
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compound
general formula
cancer
pi3k
compounds
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CN104418867B (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 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

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Abstract

The invention discloses a compound used as a PI3K/mTOR inhibitor, which is a compound with a general formula of (IA) or (IB), wherein R1 is selected from hydrogen, halogen, alkyl, alkyloxy, and amido, or forms a fused ring with R2; R2 is selected from hydrogen, amido, sulfamine, sulfonylurea, alkyl, and alkyloxy, or forms a fused ring with R1; R3 is selected from hydrogen, and C1-C6 alkyl; R4 is selected from hydrogen, amido, acylamino, or sulfamine; R5 is selected from hydrogen, halogen, alkyl or alkyloxy. The invention also discloses a preparation method of the compound used as a PI3K/mTOR inhibitor, and an application of the compound as a drug in treating PI3K/mTOR related diseases, especially PI3K/mTOR related cancers.

Description

As the compound of PI3K/mTOR inhibitor, 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
In the generation evolution of tumour, " PI3K (phosphatidylinositol3-kinase)-Akt (PKB; protein kinase B)-mTOR (mammalian target of rapamycin) " 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 overactivity 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 popular target spot of new type antineoplastic medicine research and development.（Nature Reviews Drug Discovery2009,8,627-644）。
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.Research shows, I type PI3K is process LAN, activation or sudden change in multiple human tumor, with the generation of cancer, develop closely related.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.（Nature Reviews Cancer2008,8,665-669）
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.Sirolimus, Everolimus, Temsirolimus etc. act on the rapamycin compounds of mTOR as medicine listing, and therefore mTOR has been identified is the Effective target site for the treatment of tumour.（Nature Reviews Cancer2006,6,729-734）
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.（Anticancer Research2012,32, 2463-2470）
The PI3K/mTOR inhibitor that the present invention will provide novel structure, biological activity strong, to the further investigation of this compounds, likely obtains the novel antitumor drug being different from existing clinical study compound.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of compound as PI3K/mTOR inhibitor.
Two of technical problem to be solved by this invention is to provide a kind of method preparing compound as PI3K/mTOR inhibitor.
Three of technical problem to be solved by this invention is to provide containing the pharmaceutical composition as the compound of PI3K/mTOR inhibitor.
Four of technical problem to be solved by this invention is to provide containing the application as the pharmaceutical composition of the compound of PI3K/mTOR inhibitor.
As a kind of compound as PI3K/mTOR inhibitor of first aspect present invention, for having the compound of following general formula (IA) or (IB):
Wherein,
R 1be selected from hydrogen, halogen, alkyl, alkoxyl group, amido, or formed and ring with R2;
R 2be selected from hydrogen, amido, sulfoamido, sulfonylurea group, alkyl, alkoxyl group, or formed and ring with R1;
R 3be selected from hydrogen, C 1-C 6alkyl;
R 4be selected from hydrogen, amido, amide group or sulfoamido;
R 5be selected from hydrogen, halogen, alkyl or alkoxyl group.
Further, R 1~ R 5described in alkyl, alkoxyl group, amido, amide group, urea groups, sulfoamido, sulfonylurea group all optionally can be replaced by one or more group, these groups comprise alkyl, thiazolinyl, alkynyl, halogen, alkoxyl group, aryl, heteroaryl, heterocyclic radical, amino, amido, cyano group, nitro, carboxyl, ester group, amine formyl, alkylsulfonyl or sulfoamido.
In some embodiments of the present invention, R 1be selected from chlorine, methoxyl group or and R 2and be phenyl ring.
In some embodiments of the present invention, R 2be selected from sulfoamido, sulfonylurea group or and R 1and be phenyl ring.
In some embodiments of the present invention, R 3be selected from hydrogen, methyl.
In some embodiments of the present invention, R 4be selected from hydrogen, amido.
In some embodiments of the present invention, R 5for hydrogen.
The present invention includes but be not limited to do the following compound limited to described substituting group: general formula (IA) or (IB) middle R 1be selected from chlorine, methoxyl group or and R 2and be phenyl ring, R simultaneously 2be selected from sulfoamido, sulfonylurea group or and R 1and be phenyl ring; R 3be selected from methyl; R 4be selected from hydrogen or amido; R 5for hydrogen.
Compound of the present invention, can be following structure (I-1) to any one in (I-27):
Described general formula (IA) or (IB) compound are the mixture of any one or arbitrarily both or three in enantiomer, diastereomer, conformer.
Described general formula (IA) or (IB) compound are pharmacy acceptable derivates.
General formula of the present invention (IA) or (IB) 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, the compound shown in its formula of (IA) can be prepared from by following methods:
Method one:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepares quinolinoxazole compounds (B), and bromine atoms and boric acid ester (C) will be utilized further to carry out Suzuki linked reaction, and prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
Method two:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), the bromine then Jiang oxazole and in quinolines (B) molecule is converted into boric acid ester (D), carries out Suzuki coupling further with bromide (E), prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
Method three:
Work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as previously mentioned, by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), quinolinoxazole compounds (B) is carried out the activation of-2, quinoline by nitrogen-atoms oxidation, and then introduce quinoline-2-amino (J), compound (K) is prepared by corresponding conversion, further itself and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
As the preparation method of the above-claimed cpd of second aspect present invention, the compound shown in its formula of (IB) can be prepared from by following methods:
Method one:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, quinolinoxazole-2-the ketone compounds (G) of bromo and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
Method two
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then quinolinoxazole-2-the ketone compounds (G) of bromo is converted into corresponding boric acid ester (H), then Suzuki coupling is carried out with bromide (E), prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
Method three
Work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then the quinoline nitrogen-atoms oxidized activating of the quinolinoxazole-2-ketone compounds (G) of bromo, and then introduce quinoline-2-amino (L), compound (M) is prepared by corresponding conversion, then 6 bromine atoms and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
As the pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises the general formula (IA) for the treatment of significant quantity or/and general formula (IB) compound and the acceptable vehicle of pharmacy.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises the general formula (IA) for the treatment of significant quantity or/and the pharmacy acceptable derivates of general formula (IB) compound and the acceptable vehicle of pharmacy.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises the general formula (IA) for the treatment of significant quantity or/and the pharmacy acceptable salt of general formula (IB) compound and the acceptable vehicle of pharmacy.
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 (IA) is or/and general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
As the application of fourth aspect present invention, be wherein that general formula (IA) is or/and the pharmacy acceptable derivates of general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
As the application of fourth aspect present invention, be wherein that general formula (IA) is or/and the pharmaceutically useful salt of general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
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.
General formula (IA) involved in the present invention, the compound of (IB) 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 (IA), (IB) compound, prepare these compounds method, prepare 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, cyclopropyl, normal-butyl, the tertiary butyl, isobutyl-, cyclobutyl, Cvclopropvlmethvl, amyl group, cyclopentyl, hexyl, isohexyl, cyclohexyl, 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 " alkoxyl group " (be used alone or as the part of another group) refers to the alkyl connected by Sauerstoffatom, and such as-OR, wherein R is described alkyl, preferably has the alkyl of 1 to 6 carbon atom.
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, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, carbonyl or carboxyl.In some embodiments, two substituting groups of amido form ring, and such as azetidine, Pyrrolidine, piperidines, piperazine, morpholine, high morpholine etc. are connected on the position of substitution with nitrogen-atoms, are also amido categories of the present invention.
Term " sulfoamido " refers to wherein Ra is described alkyl, aryl or heteroaryl; R ' is hydrogen or described alkyl.
Term " sulfonylurea group " refers to wherein Rb is described amido; R ' is hydrogen or described alkyl.
Term " amide group " refers to wherein Rc is described alkyl, aryl or heteroaryl; R ' is hydrogen or described alkyl.
Term " halogen " refers to independent fluorine, chlorine, the bromine or iodine selected.
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 includes 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 (-CO2R), amino/amido, nitro, cyano group, thiazolinyl oxygen base, aryl, heteroaryl, alkylsulfonyl (-SO2R) etc.; wherein, R, R', R " are 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, alkynyl, 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'CO2R " ,-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 " 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 (aurora kinase) inhibitor, biological response modifier, growth inhibitor, 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, phenylethylamine, 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 with 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: by will the general formula as defined above (IA) for the treatment of significant quantity or/and general formula (IB) compound and other anticancer agents of at least one give the patient that (or successively) needs this treatment simultaneously, treat proliferative disease (such as cancer) via regulating PI3K/mTOR signal path.In preferred embodiments, proliferative disease is cancer.
Particularly, general formula (IA), or/and general formula (IB) 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 (IA) or/and general formula (IB) 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.
General formula (IA) is or/and the level of the adjustable cell RNA of general formula (IB) 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 (IA) is or/and general formula (IB) 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 (IA) is or/and general formula (IB) 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 (IA) is or/and general formula (IB) compound can be prepared usually as follows.The tautomer of general formula (IA), (IB) 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., Protective Groups in Organic Sy-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.
As the preparation method of the above-claimed cpd of second aspect present invention, the compound shown in its formula of (IA) can be prepared from by following methods:
Method one:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepares quinolinoxazole compounds (B), and bromine atoms and boric acid ester (C) will be utilized further to carry out Suzuki linked reaction, and prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
Method two:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), the bromine then Jiang oxazole and in quinolines (B) molecule is converted into boric acid ester (D), carries out Suzuki coupling further with bromide (E), prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
Method three:
Work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as previously mentioned, by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), quinolinoxazole compounds (B) is carried out the activation of-2, quinoline by nitrogen-atoms oxidation, and then introduce quinoline-2-amino (J), compound (K) is prepared by corresponding conversion, further itself and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
As the preparation method of the above-claimed cpd of second aspect present invention, the compound shown in its formula of (IB) can be prepared from by following methods:
Method one:
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, quinolinoxazole-2-the ketone compounds (G) of bromo and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
Method two
Work as R 4for H, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then quinolinoxazole-2-the ketone compounds (G) of bromo is converted into corresponding boric acid ester (H), then Suzuki coupling is carried out with bromide (E), prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
Method three
Work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as previously mentioned, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then the quinoline nitrogen-atoms oxidized activating of the quinolinoxazole-2-ketone compounds (G) of bromo, and then introduce quinoline-2-amino (L), compound (M) is prepared by corresponding conversion, then 6 bromine atoms and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
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 (IA) defined in summary of the invention above, (IB) be 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 define in summary of the invention above general formula (IA), (IB) compound acid proton with the aqueous solution form of its salt (such as sodium or sylvite) and cyclodextrin blended, then with equivalent acid (such as HCl or H 2sO 4) solution blending, to provide corresponding cyclodextrin inclusion compound.
Now or after the cooling period, corresponding cyclodextrin inclusion compound crystal can crystallization.Or when general formula (IA), (IB) compound be oily and crystallization time, by room temperature stirring (such as 1 is little of 14 days) for a long time, adding 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 Aldrich Chemical Co.), or adopt known method preparation by those skilled in the art.See people such as such as Croft, A.P., " Sythesis of Chemically Modified Cyclodextrins ", Tetrahedron1983,39,9,1417-1474.Suitable cyclodextrin comprises can prepare all kinds of inclusion compound with the compound of institute's column (IA), (IB) 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 (IA), (IB) is 2:1(cyclodextrin: compound).
Comprising general formula (IA) or/and general formula (IB) compound can be suitable for oral form as the pharmaceutical composition of activeconstituents, such as, is 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 ethylene oxide 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 hexitol ether mixture.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's solution), 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 poured 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 (IA) is or/and general formula (IB) 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 general formula (IA) or/and the ointment of general formula (IB) 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 uses the form of the well-known transdermal skin patches of those skilled in the art to be 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 20mg/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 (IA) is or/and (IB) 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 (IA) is or/and general formula (IB) 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 said synthesis route, 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 embodiment (for the preparation of compound of the present invention) provided below 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.
Embodiment 1:
Compound I-1:2-methyl-8-(preparation of quinoline-3-base) oxazole also [4,5-c] quinoline, reaction formula is as follows:
Step 1: cooled by water (39mL) solution of NaOH (18.6g, 465mmol), drips Nitromethane 99Min. (9.3g, 153mmol), maintains the temperature at 25-30 DEG C.Drip and finish, be heated to 40 DEG C, then cool, then drip Nitromethane 99Min. (9.325g, 152.76mmol), maintain the temperature at 40-45 DEG C.Drip and finish, remain on 40-45 DEG C until solid completely dissolve, present red clear soln.Then reaction solution is heated to 50-55 DEG C of reaction 2-5 minute, again reaction solution is down to 30 DEG C, pour in ice (21g), with concentrated hydrochloric acid (41.7mL) acidifying, 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 DEG C and stirs 1 hour, cooling, filter, 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 1N NaOH (148mL, 148mmol), adds inclined sodium sulfite (15.3g, 87.7mmol) in batches.Finish, reaction solution lucifuge stirs 30 minutes.Be cooled to 0 DEG 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 hydrochloride (3.07g, 86%) crude product is directly used in next step reaction.LC-MS(ESI+):239,241[M+1] +。
Step 4: be dissolved in by 3-amino-4-hydroxy-6-bromoquinoline hydrochloride (400mg, 1.45mmol) in acetic anhydride (5mL), add sodium acetate, anhydrous (154mg, 1.57mmol), is heated to back flow reaction 4 hours.Be cooled to room temperature, add the vitriol oil (0.1mL), be heated to return stirring 2 hours.Reaction mixture is cooled to room temperature, pours in water (30mL), stirs until homogeneous phase, adds strong caustic, dichloromethane extraction.Dichloromethane extraction liquid merges, and uses saturated common salt water washing, dry, and after concentrated, column chromatography (methylene dichloride: methyl alcohol=100:1) obtains 8-bromo-2-first base oxazole also [4,5-c] quinoline (262mg, 69%).LC-MS(ESI+)：263,265[M+1] +。
Step 5:8-bromo-2-Jia Ji oxazole also [4,5-c] quinoline (132mg, 0.50mmol) is dissolved in 1, in 4-dioxane (10mL) and water (2.0mL), add quinoline-3-boric acid (173mg, 1.0mmol), Pd (dppf) Cl 2(36mg, 0.05mmol) and Cs 2cO 3(489mg, 1.50mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, extraction into ethyl acetate, extraction liquid merges, anhydrous sodium sulfate drying, concentrated, column chromatography purification (ethyl acetate: sherwood oil=4:1) 2-methyl-8-(quinoline-3-base) oxazole also [4,5-c] quinoline (125mg, 80%).LC-MS(ESI+):312[M+1] +。 1H NMR(300MHz,DMSO-d 6)9.01(s,1H),8.62(d,1H,J=3.6Hz),8.32-7.98(m,5H),7.90-7.57(m,3H),2.77(s,3H)。
Embodiment 2:
The preparation of Compound I-2:N-(the chloro-5-of 2-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl)-4-fluorophenyl sulphonamide, reaction formula is as follows:
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 DEG 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 (sherwood oil: ethyl acetate=10:1) obtains (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (861mg, 99%).LC-MS(ESI+):331[M+1] +。
Step 3: by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline (75mg, 0.285mmol) be dissolved in 1, in 4-dioxane (9mL) and water (1.5mL), add (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (141mg, 0.428mmol), Pd (dppf) Cl 2(21mg, 0.029mmol) and Cs 2cO 3(279mg, 0.855mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, dilute with methylene dichloride (30mL), add water extraction, first separate organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, methylene dichloride (3 × 10mL) is used to extract again, methylene dichloride merges, anhydrous sodium sulfate drying, concentrated, column chromatography purification (methylene dichloride: methyl alcohol=80:1) N-(the chloro-5-of 2-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl)-4-fluorophenyl sulphonamide (91mg, 68%).LC-MS(ESI+):469[M+1] +。 1H NMR(300MHz,DMSO-d 6)9.24(s,1H),8.23(d,1H,J=9.0Hz),8.03(d,2H,J=9.9Hz),7.90(d,1H,J=10.8Hz),7.81(t,2H,J=6.9Hz),7.73(s,1H),7.28(t,2H,J=8.7Hz),2.80(s,3H)。
Embodiment 3:
The preparation of the fluoro-N-of Compound I-3:4-(2-methoxyl group-5-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) benzsulfamide, reaction formula is as follows:
Step 1: by 2-methoxyl group-3-amino-5-bromopyridine (500mg, 2.5mmol) be dissolved in tetrahydrofuran (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) dilute reaction solution, wash with saturated sodium bicarbonate, anhydrous sodium sulfate drying, concentrated, resistates column chromatography (sherwood oil: ethyl acetate=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 DEG 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 (sherwood oil: ethyl acetate=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] +。
Step 3: by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline (75mg, 0.285mmol) 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 (177mg, 0.428mmol), Pd (dppf) Cl 2(21mg, 0.029mmol) and Cs 2cO 3(279mg, 0.855mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, dilute with methylene dichloride (30mL), add water extraction, first separate organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, methylene dichloride (3 × 10mL) is used to extract again, this dichloromethane solution is dry, concentrated, resistates column chromatography (methylene dichloride: methyl alcohol=80:1) obtains the fluoro-N-of 4-(2-methoxyl group-5-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) benzsulfamide (45mg, 34%).LC-MS(ESI+):465[M+1] +； 1H NMR(300MHz,DMSO-d 6)10.12(br,1H),9.26(s,1H),8.51(s,1H),8.27(t,2H,J=11.0Hz),8.04(d,2H,J=15.3Hz),7.83(t,2H,J=6.6Hz),7.42(t,2H,J=8.7Hz),3.68(s,3H),2.79(s,3H)。
Copy the method for embodiment 2,3, with 2,4 difluorobenzene SULPHURYL CHLORIDE replacement 4-fluorophenylsulfonyl chloride wherein, following I-4 compound and I-5 compound can be prepared respectively:
Embodiment 6:
The preparation of Compound I-6:N-(the chloro-5-of 2-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) Toluidrin, reaction formula is as follows:
Step 1: chloro-for 2-3-amino-5-bromopyridine (2.5g, 12.05mmol) is dissolved in pyridine (30mL), adds methane sulfonyl chloride (4.66mL, 60.25mmol), stirring at room temperature 48 hours.By reaction solution concentrating under reduced pressure, add methyl alcohol (50mL) and Isosorbide-5-Nitrae-dioxane (50mL) in resistates, then add Anhydrous potassium carbonate (16.65g, 120.5mmol), be heated to 60 DEG C and stir 5 hours.Be cooled to room temperature, reaction solution be poured into water (500mL), be adjusted to pH5 with concentrated hydrochloric acid.Be extracted with ethyl acetate, merge organic phase, use water respectively, saturated common salt water washing, dry, concentrated, resistates column chromatography (sherwood oil: ethyl acetate=10:1) obtains N-(the bromo-2-chloropyridine of 5--3-base) Toluidrin (2.70g, 79%).LC-MS(ESI+):285[M+1]。
Step 2: nitrogen protection by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline (2.63g, 10mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (100mL), add connection boric acid pinacol ester (5.08g, 20mmol), Pd (dppf) Cl 2(732mg, 1mmol), KOAc(1.47g, 15mmol), be heated to 100 DEG C and stir 5 hours, concentrated, obtain (2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) boric acid (2.12g, 93%) through silica gel column chromatography.
Step 3: will (2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) boric acid (114mg, 0.50mmol) be dissolved in 1, in 4-dioxane (10mL) and water (1.5mL), add N-(the bromo-2-chloropyridine of 5--3-base) Toluidrin (157mg, 0.55mmol), Pd (dppf) Cl 2(37mg, 0.05mmol) and Cs 2cO 3(245mg, 0.75mmol), nitrogen fully replaces post-heating to 100 DEG C, stirs 1 hour.Be cooled to room temperature, regulate pH5-6 with the hydrochloric acid of 1N, concentrated, through silica gel column chromatography, obtain N-(the chloro-5-of 2-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) Toluidrin (141mg, 73%).MS(ESI+):389[M+H]; 1HNMR(300MHz,DMSO-d 6)10.03(br,1H),9.43(s,1H),9.05(s,1H),8.50-8.51(m,1H),7.93-8.21(m,3H),3.52(s,3H),2.85(s,3H)。
Embodiment 7:
The preparation of Compound I-7:N-(2-methoxyl group-5-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) Toluidrin, reaction formula is as follows:
Step 1: 2-methoxyl group-3-amino-5-bromopyridine (1g, 4.925mmol) is dissolved in pyridine (15mL), adds MsCl (1.9mL, 24.626mmol), stirred at ambient temperature 48 hours.By concentrated for reaction solution dry, add methyl alcohol (20mL) and Isosorbide-5-Nitrae-dioxane (20mL) in resistates, then add Anhydrous potassium carbonate (16.81g, 49.25mmol), be heated to 60 DEG C of reactions 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 (sherwood oil: ethyl acetate=10:1) obtains N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin (994mg, 72%).LC-MS(ESI+):281,283[M+1] +。
Step 2: will (2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) boric acid (114mg, 0.50mmol) be dissolved in 1, in 4-dioxane (10mL) and water (1.5mL), add N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin (154mg, 0.55mmol), Pd (dppf) Cl 2(37mg, 0.05mmol) and Cs 2cO 3(245mg, 0.75mmol), nitrogen fully replaces post-heating to 100 DEG C, stirs 1 hour.Be cooled to room temperature, regulate pH5-6 with the hydrochloric acid of 1N, concentrated, through silica gel column chromatography, obtain N-(2-methoxyl group-5-(2-Jia Ji oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) Toluidrin (117mg, 61%).MS(ESI+):385[M+H]; 1HNMR(300MHz,DMSO-d 6)9.46(s,1H),9.01(s,1H),8.52(m,1H),7.91-8.07(m,3H),3.91(s,3H),3.52(s,3H),2.86(s,3H)。
Copy the method for embodiment 6 and embodiment 7, respectively with the Methanesulfonyl chloride that cyclopropyl sulfonyl chloride (CAS:139631-62-2) and dimethylin SULPHURYL CHLORIDE (CAS:13360-57-1) replace wherein, can prepare respectively following Compound I-8, Compound I-9, Compound I-10 and, Compound I-11:
Embodiment 12:
The preparation of Compound I-12:N-(5-(4-amino-2-Jia Ji oxazole also [4,5-c] quinoline-8-yl)-2-chloropyridine-3-base)-4-fluorophenyl sulphonamide, reaction formula is as follows:
Step 1: by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline (980mg, 3.725mmol) be dissolved in N, in the mixing solutions of N-N,N-DIMETHYLACETAMIDE (15mL) and sherwood oil (30mL), add mCPBA (1.021g, 5.066mmol) in batches.Finish, stirred at ambient temperature 2 hours.Add mCPBA (481mg, 0.64mmol), continue stirring 1.5 hours.Filter, filtering thing is through N, N-N,N-DIMETHYLACETAMIDE/sherwood oil=1/2(20mL) washing, methylene dichloride (40mL) is dissolved in after drying, in the mixing solutions of methyl alcohol (20mL) and water (20mL), add salt of wormwood (612mg, 4.428mmol), stirring reaction 30 minutes, separate organic phase, aqueous phase dichloromethane extraction three times, merge organic phase, wash with saturated common salt, dry, concentrated, resistates column chromatography (methylene dichloride: methyl alcohol=80:1), obtain 8-bromo-2-Jia Ji oxazole [4, 5-c] quinoline-5-N oxide compound (702mg, 56%).LC-MS(ESI+):279,281[M+1] +。
Step 2:8-bromo-2-Jia Ji oxazole [4,5-c] quinoline-5-N oxide compound (600mg, 2.15mmol) be dissolved in the mixed solvent of methylene dichloride (40mL) and methyl alcohol (20mL), be cooled to 0 DEG C, add ammoniacal liquor (5mL), drip methylene dichloride (10mL) solution of p-methyl benzene sulfonic chloride (1.23g, 6.45mmol) again.Drip Bi Shengzhi stirring at room temperature 2 hours.By concentrated for reaction solution dry, resistates column chromatography (methylene dichloride: methyl alcohol=20:1) obtains 8-bromo-2-Jia Ji oxazole also [4,5-c] quinoline-4-amino (255mg, 42%).LC-MS(ESI+):278,280[M+1] +。
Step 3: by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline-4-amino (100mg, 0.36mmol) be dissolved in 1, in 4-dioxane (9mL) and water (1.5mL), add (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid (178mg, 0.539mmol), Pd (dppf) Cl 2(26mg, 0.036mmol) and Cs 2cO 3(176mg, 0.539mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, dilute with methylene dichloride (30mL), add water extraction, first separate organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, methylene dichloride (3 × 10mL) is used to extract again, this dichloromethane solution is dry, concentrated, resistates obtains N-(5-(4-amino-2-Jia Ji oxazole also [4,5-c] quinoline-8-yl)-2-chloropyridine-3-base)-4-fluorophenyl sulphonamide (54mg, 31%) through column chromatography for separation (methylene dichloride: methyl alcohol=40:1).LC-MS(ESI+):484[M+1]+； 1H NMR(300MHz,DMSO-d 6)δ8.66(s,1H),8.06(s,1H),7.98(s,1H),7.79-7.83(m,3H),7.68-7.72(m,1H),7.45(t,2H,J=6.0Hz),7.26(br,2H),2.73(s,3H)。
Embodiment 13:
The preparation of Compound I-13:N-(5-(4-amino-2-Jia Ji oxazole also [4,5-c] quinoline-8-yl)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide, reaction formula is as follows:
Step: by bromo-for 8-2-Jia Ji oxazole also [4,5-c] quinoline-4-amino (100mg, 0.36mmol) 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 boric acid ester group) pyridin-3-yl) benzsulfamide (220mg, 0.539mmol), Pd (dppf) Cl 2(26mg, 0.036mmol) and Cs 2cO 3(176mg, 0.539mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, dilute with methylene dichloride (30mL), add water extraction, first separate organic phase, aqueous phase 1N hydrochloric acid adjusts pH to 7-8, methylene dichloride (3 × 10mL) is used to extract again, this dichloromethane solution is dry, concentrated, resistates obtains N-(5-(4-amino-2-Jia Ji oxazole also [4,5-c] quinoline-8-yl)-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide (92mg, 53%) through column chromatography for separation (methylene dichloride: methyl alcohol=40:1).LC-MS(ESI+):480[M+1] +； 1H NMR(300MHz,DMSO-d 6)δ10.06(br,1H),8.37(s,1H),7.65-7.95(m,6H),7.42(t,2H,J=8.9Hz),7.05(br,2H),3.66(s,3H),2.72(s,3H)。
Embodiment 14:
Compound I-14:3-methyl-8-(preparation of quinoline-3-base) oxazole also [4,5-c] quinoline-2 (3H)-one, reaction formula is as follows:
Step 1: nitrogen protection, is dissolved in THF(100mL by 3-amino-4-hydroxy-6-bromoquinoline (3.0g, 12.5mmol)) in, be heated to backflow.At reflux, add carbonyl dimidazoles (2.64g, 16.29mmol) in batches, finish and continue return stirring 3 hours.Be cooled to room temperature, filter, solid with methylene chloride (50mL) is washed, dry, obtains 8-bromine-oxazole also [4,5-c] quinoline-2 (3H)-one crude product.
Step 2: by 8-bromine-oxazole also [4,5-c] quinoline-2 (3H)-one (2.3g, 4.35mmol) be dissolved in DMF (60mL), ice-water bath lower the temperature, add NaH(60%, 699mg, 8.69mmol), stir 20 minutes.Drip methyl iodide (1.23g, 4.35mmol), finish and rise to stirring at room temperature 1 hour.Frozen water cools, and with the hydrochloric acid of 1N, and regulation system is to pH5-6, and add water (300mL), and be extracted with ethyl acetate (3 × 100mL), ethyl acetate merges mutually, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrated.Residue by silicagel column chromatography purification obtains 8-bromo-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (600mg, two step yields 17%).
Step 3:8-bromo-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (140mg, 0.50mmol) be dissolved in 1, in 4-dioxane (10mL) and water (2.0mL), add quinoline-3-boric acid (173mg, 1.0mmol), Pd (dppf) Cl 2(36mg, 0.05mmol) and Cs 2cO 3(489mg, 1.50mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, extraction into ethyl acetate, extraction liquid merges, anhydrous sodium sulfate drying, concentrated, column chromatography purification (ethyl acetate: sherwood oil=3:1) 3-methyl-8-(quinoline-3-base) oxazole also [4,5-c] quinoline-2 (3H)-one (116mg, 71%).MS(ESI+):328[M+1] +。 1H NMR(300MHz,DMSO-d 6)9.07(s,1H),8.65(d,1H,J=3.6Hz),8.33-8.01(m,5H),7.90-7.61(m,3H),3.50(s,3H)。
Copy the method for embodiment 14, by bromo-for 8-3-Jia Ji oxazole also [4, 5-c] quinoline-2 (3H)-one fluoro-N-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide with 4-respectively, (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid, 2, the fluoro-N-of 4-bis-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide, (the chloro-5-(2 of 6-, 4-difluorobenzenesulfonamide base) pyridin-3-yl) boric acid carries out Suzuki linked reaction, the Compound I-15 in following table can be prepared respectively, Compound I-16, Compound I-17 and Compound I-18:
Embodiment 19:
The preparation of Compound I-19:N-(2-methoxyl group-5-(3-methyl-2-oxo-2,3-dihydro-oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) methylsulfonamides, reaction formula is as follows:
Step 1: nitrogen protection by bromo-for 8-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (1.08g, 3.87mmol) be dissolved in 1; in 4-dioxane (100mL); add connection boric acid pinacol ester (1.97g, 7.74mmol), Pd(dppf) Cl 2(281mg, 0.389mmol), KOAc(725mg, 5.80mmol), be heated to 100 DEG C and stir 5 hours, concentrated, 3-methyl-8-tetramethyl ethylene ketone boric acid ester group-oxazole also [4,5-c] quinoline-2 (3H)-one (1.2g, 95%) is obtained through silica gel column chromatography.
Step 2: nitrogen protection; by 3-methyl-8-tetramethyl ethylene ketone boric acid ester group-oxazole also [4; 5-c] quinoline-2 (3H)-one (100mg; 0.306mmol) be dissolved in 1; in 4-dioxane (9mL) and water (1.5mL); add N-(the bromo-2-methoxypyridine of 5--3-base) Toluidrin (95mg, 0.337mmol), Pd (dppf) Cl 2(23mg, 0.031mmol) and Cs 2cO 3(150mg, 0.460mmol), is heated to 100 DEG C, stirs 1 hour.Be cooled to room temperature, regulate pH5-6 with the hydrochloric acid of 1N, concentrated, through silica gel column chromatography, obtain N-(2-methoxyl group-5-(3-methyl-2-oxo-2,3-dihydro-oxazole also [4,5-c] quinoline-8-yl) pyridin-3-yl) methylsulfonamides (86mg, 70%).MS(ESI +):401[M+H]; 1HNMR(300MHz,DMSO-d 6)9.42(s,1H),9.00(s,1H),8.50-8.51(m,1H),7.98-8.22(m,3H),3.98(s,3H),3.51(s,3H),3.11(s,3H)。
Copy the method for embodiment 19, by 3-methyl-8-tetramethyl ethylene ketone boric acid ester group-oxazole also [4,5-c] quinoline-2 (3H)-one carries out Suzuki coupling with corresponding pyridine bromide base sulphonamide respectively, can prepare Compound I-20, Compound I-21, Compound I-22, Compound I-23, Compound I-24 in following table respectively:
Embodiment 25:
Compound I-25:4-amino-3-methyl-8-(preparation of quinoline-3-base) oxazole also [4,5-c] quinoline-2 (3H)-one, reaction formula is as follows:
Step 1: by bromo-for 8-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (2.80g, 10mmol) be dissolved in N, in the mixing solutions of N-N,N-DIMETHYLACETAMIDE (28mL) and sherwood oil (56mL), add mCPBA (4.03g, 20mmol) in batches.Finish, stirred at ambient temperature 2 hours.Filter, filtering thing is through N, N-N,N-DIMETHYLACETAMIDE/sherwood oil=1/2(50mL) washing, be dissolved in the mixing solutions of methylene dichloride (80mL), methyl alcohol (40mL) and water (40mL) after drying, add salt of wormwood (2.07g, 15mmol), stirring at room temperature 30 minutes.Leave standstill, separate organic phase, aqueous phase dichloromethane extraction, merge organic phase, wash with saturated common salt, drying, concentrated, resistates column chromatography (methylene dichloride: methyl alcohol=80:1), obtain the bromo-3-methyl of 8--2-oxygen-2,3-dihydro-oxazole is [4,5-c] quinoline-5-oxynitride (1.21g, 41%) also.
The bromo-3-methyl of step 2:8--2-oxygen-2,3-dihydro-oxazole also [4,5-c] quinoline-5-oxynitride (1.21g, 4.1mmol) be dissolved in the mixed solvent of methylene dichloride (60mL) and methyl alcohol (30mL), be cooled to 0 DEG C, add ammoniacal liquor (10mL), then drip methylene dichloride (20mL) solution of p-methyl benzene sulfonic chloride (2.35g, 12.3mmol).Drip Bi Shengzhi stirring at room temperature 2 hours.By concentrated for reaction solution dry, resistates column chromatography (methylene dichloride: methyl alcohol=20:1) obtains 4-amino-8-bromo-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (470mg, 39%).LC-MS(ESI+):294,296[M+1] +。
Step 3:4-amino-8-bromo-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one (147mg, 0.50mmol) be dissolved in 1, in 4-dioxane (10mL) and water (2.0mL), add quinoline-3-boric acid (173mg, 1.0mmol), Pd (dppf) Cl 2(36mg, 0.05mmol) and Cs 2cO 3(489mg, 1.50mmol).Nitrogen replacement three post-heating to 100 DEG C reaction 3 hours, be cooled to room temperature, extraction into ethyl acetate, extraction liquid merges, anhydrous sodium sulfate drying, concentrated, column chromatography purification (methylene dichloride: methyl alcohol=50:1) 4-amino-3-methyl-8-(quinoline-3-base) oxazole also [4,5-c] quinoline-2 (3H)-one (80mg, 47%).MS(ESI+):343[M+1] +。 1H NMR(300MHz,DMSO-d 6)8.67(d,1H,J=3.6Hz),8.34-8.03(m,5H),7.90-7.61(m,3H),6.49(br,2H),3.51(s,3H)。
Copy the method for embodiment 25, by 4-amino-8-bromo-3-Jia Ji oxazole also [4,5-c] quinoline-2 (3H)-one carries out Suzuki linked reaction with (the chloro-5-of 6-(4-fluorobenzenesulfonamide base) pyridin-3-yl) boric acid, the fluoro-N-of 4-(2-methoxyl group-5-(tetramethyl ethylene ketone boronate) pyridin-3-yl) benzsulfamide respectively, can prepare Compound I-26, Compound I-27 respectively:
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 (IA) described in our face, (IB) compound.
Biological examples 1:
The compounds of this invention is to the half-inhibition concentration (IC of PI3K α, PI3K β, PI3K δ, PI3K γ and mTOR 50) measure
1. raw material
P110 α/p85a, purchased from Invitrogen, cat No.PV4788;
P110 δ/p85a, purchased from Millipore, cat No.14-604-K;
P110 β, purchased from Millipore, cat No.14-603-K;
P110 γ, purchased from Invitrogen, cat No.PR8641C;
MTOR, purchased from Millipore, cat No.14-770;
Kinase-Glo Plus L μM of inesce-Kinase Assay, purchased from Promege, cat No.V3771;
ADP-Glo Kinase Assay, purchased from Promege, cat No.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) 1x mTOR kinase buffer liquid
50mM HEPES,pH7.5
10mM MgCl 2
1mM EGTA
3mM MnCl
0.01%Tween-20
2mM DTT
2) 1x PI3K α, PI3K δ kinase buffer liquid
50mM HEPES,pH7.5
3mM MgCl 2
1mM EGTA
100mM NaCl
0.03%CHAPS
2mM DTT
3) 1x PI3K β, PI3K γ kinase buffer liquid
50mM HEPES,pH7.5
3mM MgCl 2
1mM EGTA
100mM NaCl
0.03%CHAPS
2mM DTT
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 L Kinase-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 L ADP-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:
Percent inhibition=(Lance signal-min)/(max-min)*100
PI3K α, PI3K β, PI3K γ and PI3K δ conversion formula:
Percent inhibition=(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 MS Excel.
Part of compounds of the present invention is to the IC of PI3K α, PI3K β, PI3K γ, PI3K δ and mTOR five enzymes 50test result is as shown in the table:
Biological examples 2: adopt Cell Titer-Glo luciferase kit to measure the compounds of this invention to tumor cell proliferation half-inhibition concentration (IC 50)
1. raw material
U-87MG cell strain, purchased from ATCC, Cat.No.HTB-14, Lot No.5018014;
A549 cell strain, purchased from ATCC, Cat.No.CCL-185, Lot No.7502546;
PC-3 cell strain, purchased from ATCC, Cat.No.CRL-1435, Lot No.7348670;
BT474 cell strain, purchased from ATCC, Cat.No.HTB-20, Lot No.5188737;
F-12K nutrient solution, purchased from Invitrogen, Cat.No.21127-022;
EMEM nutrient solution, purchased from Invitrogen, Cat.No.11095;
96 orifice plates, purchased from Corning, Cat.No.CLS3903;
CellTiter Glo assay kit, purchased from Promega, Cat.No.G7571, Lot.No.256984;
Foetal calf serum, purchased from Invitrogen, Cat.No.10099-141, Lot.No.8153379.
2. experimental technique
2.1 plating cells
Preparation perfect medium:, fully mix.
The cell strain that growth selection is in good condition.
Tissue Culture Flask is taken out from incubator, checks the Cell Name that bottle marks, type of culture medium and cell algebraically.
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.
Inhale the cell conditioned medium liquid abandoned in centrifuge tube.
In centrifuge tube, add the substratum of proper volume, soft piping and druming makes cell evenly resuspended.
Use Vi-Cell XR cell counter counting.
Cell suspension is adjusted to suitable concn.
Cell suspension is added in 96 white orifice plates of the saturating wall in the end, 100uL/ 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:
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).
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.
Cell adds the substratum containing different compound when changing liquid.
The specified time is hatched in 37 DEG C of incubators.
2.4 detect and analyze
Observation of cell form under inverted microscope.
Tissue Culture Plate is placed in room temperature and balance 30 minutes.
Cytoactive detection reagent 100 μ L/ hole is added in culture plate.
Vibration plate machine mixes 2 minutes, inducing cell lysis.
96 orifice plates are placed 10 minutes at room temperature, its luminous signal is stablized.
Paste the counterdie of white bottom culture plate, use Flexstation3 drafting board. (be correlated with and be set to: be luminous, integrating time 500ms).
The 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 (40)

1. as a compound for PI3K/mTOR inhibitor, for having the compound of following general formula (IA) or (IB):
Wherein,
R 1be selected from hydrogen, halogen, alkyl, alkoxyl group, amido, or and R 2formed and ring;
R 2be selected from hydrogen, amido, sulfoamido, sulfonylurea group, alkyl, alkoxyl group, or and R 1formed and ring;
R 3be selected from hydrogen, C 1-C 6alkyl;
R 4be selected from hydrogen, amido, amide group or sulfoamido;
R 5be selected from hydrogen, halogen, alkyl or alkoxyl group.
2. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 1~ R 5described in alkyl, alkoxyl group, amido, amide group, urea groups, sulfoamido, sulfonylurea group all optionally can be replaced by one or more group, these groups comprise alkyl, thiazolinyl, alkynyl, halogen, alkoxyl group, aryl, heteroaryl, heterocyclic radical, amino, amido, cyano group, nitro, carboxyl, ester group, amine formyl, alkylsulfonyl or sulfoamido.
3. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 1be selected from chlorine, methoxyl group or and R 2and be phenyl ring.
4. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 2be selected from sulfoamido, sulfonylurea group or and R 1and be phenyl ring.
5. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 3be selected from hydrogen, methyl.
6. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 4be selected from hydrogen, amido.
7. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, described R 5for hydrogen.
8. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, R in the compound of described general formula (IA) or (IB) 1be selected from chlorine, methoxyl group or and R 2and be phenyl ring, R simultaneously 2be selected from sulfoamido, sulfonylurea group or and R 1and be phenyl ring; R 3be selected from methyl; R 4be selected from hydrogen or amido; R 5for hydrogen.
9. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, is characterized in that, the compound of described general formula (IA) or (IB) be following structure (I-1) to any one in (I-27):
10. a kind of compound as PI3K/mTOR inhibitor as claimed in claim 1, it is characterized in that, the compound of described general formula (IA) or (IB) is the mixture of any one or both or three arbitrarily in enantiomer, diastereomer, conformer.
11. a kind of compounds as PI3K/mTOR inhibitor as claimed in claim 1, it is characterized in that, described general formula (IA) or (IB) compound are pharmacy acceptable derivates.
12. a kind of compounds as PI3K/mTOR inhibitor as claimed in claim 1, it is characterized in that, described general formula (IA) or (IB) compound exist as a pharmaceutically acceptable salt form.
13. a kind of compounds as PI3K/mTOR inhibitor as claimed in claim 12, it is characterized in that, described exist as a pharmaceutically acceptable salt form comprise with salt formed by acid or acid proton the sodium salt, sylvite, magnesium salts, the calcium salt that replace by metal ion.
14. a kind of compounds as PI3K/mTOR inhibitor as claimed in claim 13, it is characterized in that, described is hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate with salt formed by acid.
15. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IA), is characterized in that, work as R 4for H, R 1, R 2, R 3, R 5time as claimed in claim 1, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepares quinolinoxazole compounds (B), and bromine atoms and boric acid ester (C) will be utilized further to carry out Suzuki linked reaction, and prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
16. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IA), is characterized in that, work as R 4for H, R 1, R 2, R 3, R 5time as claimed in claim 1, the preparation process of the compound shown in general formula (IA) is: by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), the bromine then Jiang oxazole and in quinolines (B) molecule is converted into boric acid ester (D), carries out Suzuki coupling further with bromide (E), prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
17. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IA), is characterized in that, work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as claimed in claim 1, by 3-amino-4-hydroxy-6-bromoquinoline compounds (A) and carboxylic acid R 3cOOH carries out cyclization, prepare quinolinoxazole compounds (B), quinolinoxazole compounds (B) is carried out the activation of-2, quinoline by nitrogen-atoms oxidation, and then introduce quinoline-2-amino (J), compound (K) is prepared by corresponding conversion, further itself and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IA), concrete reaction formula is as follows:
Above-mentioned group
18. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IB), is characterized in that, work as R 4for H, R 1, R 2, R 3, R 5time as claimed in claim 1,3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, quinolinoxazole-2-the ketone compounds (G) of bromo and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
19. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IB), is characterized in that, work as R 4for H, R 1, R 2, R 3, R 5time as claimed in claim 1,3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then quinolinoxazole-2-the ketone compounds (G) of bromo is converted into corresponding boric acid ester (H), then Suzuki coupling is carried out with bromide (E), prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
20. 1 kinds of methods preparing the compound shown in general formula according to claim 1 (IB), is characterized in that, work as R 4for amido, amide group, sulfoamido, urea groups, R 1, R 2, R 3, R 5time as claimed in claim 1, 3-amino-4-hydroxy-6-bromoquinoline compounds (A) is carried out cyclization with carbonyl dimidazoles (CDI) reagent, prepare quinolinoxazole-2-ketone compounds (F), further amide nitrogen atom alkylation is obtained the quinolinoxazole-2-ketone compounds (G) of bromo, then the quinoline nitrogen-atoms oxidized activating of the quinolinoxazole-2-ketone compounds (G) of bromo, and then introduce quinoline-2-amino (L), compound (M) is prepared by corresponding conversion, then 6 bromine atoms and boric acid ester (C) are carried out Suzuki coupling, prepare the compound shown in general formula (IB), concrete reaction formula is as follows:
Above-mentioned group
21. pharmaceutical compositions, wherein said pharmaceutical composition comprises the general formula (IA) described in any one of claim 1 to 10 claim for the treatment of significant quantity or/and general formula (IB) compound and the acceptable vehicle of pharmacy.
22. pharmaceutical compositions as claimed in claim 21, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
23. pharmaceutical compositions, wherein said pharmaceutical composition comprises the general formula according to claim 11 (IA) for the treatment of significant quantity or/and the pharmacy acceptable derivates of general formula (IB) compound and the acceptable vehicle of pharmacy.
24. pharmaceutical compositions as claimed in claim 23, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
25. pharmaceutical compositions, wherein said pharmaceutical composition comprises the general formula (IA) described in any one of claim 12 to 14 claim for the treatment of significant quantity or/and the pharmacy acceptable salt of general formula (IB) compound and the acceptable vehicle of pharmacy.
26. pharmaceutical compositions as claimed in claim 25, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
General formula (IA) described in 27. any one of claim 1 to 10 claims is or/and general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
28. general formulas according to claim 11 (IA) are or/and the pharmacy acceptable derivates of general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
General formula (IA) described in 29. any one of claim 12 to 14 claims is or/and the pharmaceutically useful salt of general formula (IB) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
Pharmaceutical composition described in 30. any one of claim 21 to 26 claims treats the application in the medicine of the disease relevant with PI3K/mTOR signal path in preparation.
31. application according to claim 30, the wherein said disease relevant with PI3K/mTOR signal path is cancer.
32. application according to claim 31, 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.
33. application according to claim 32, 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.
34. application according to claim 32, wherein said respiratory system cancer is lung cancer.
35. application according to claim 32, 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.
36. application according to claim 32, wherein said urinary system cancer is kidney, bladder cancer, prostate cancer or carcinoma of testis.
37. application according to claim 32, wherein said Skeletal system cancer is osteocarcinoma.
38. application according to claim 32, wherein said gynecological cancer is mammary cancer, cervical cancer or ovarian cancer.
39. application according to claim 32, wherein said hematological cancer is leukemia, malignant lymphoma or multiple myeloma.
40. application according to claim 32, wherein said other types cancer is malignant melanoma, neurospongioma or skin carcinoma.
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