CN104557955A - Tricyclic compound as PI3K/mTOR inhibitor as well as preparation method and application of tricyclic compound - Google Patents

Tricyclic compound as PI3K/mTOR inhibitor as well as preparation method and application of tricyclic compound Download PDF

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CN104557955A
CN104557955A CN201310504853.4A CN201310504853A CN104557955A CN 104557955 A CN104557955 A CN 104557955A CN 201310504853 A CN201310504853 A CN 201310504853A CN 104557955 A CN104557955 A CN 104557955A
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compound
cancer
pi3k
general formula
acid
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CN104557955B (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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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

Description

As the tricyclic compounds of PI3K/mTOR inhibitor, Preparation Method And The Use
Technical field
The present invention relates to a kind of tricyclic compounds as PI3K/mTOR inhibitor, its preparation method, containing they pharmaceutical compositions as activeconstituents, and their purposes of cancer of being correlated with in order to the treatment disease, particularly PI3K/mTOR relevant to PI3K/mTOR as medicine.
Background technology
Malignant tumour is the disease threatening global human health and lives.Modern study shows, in tumor development process, PI3K(phosphatidylinositol3-kinase)-Akt(PKB, protein kinase B)-mTOR(mammaliantarget 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 activation of this signal path can upset growth and the survival of cell, causes tumor cell proliferation quickening, pernicious transfer and produces common drug resistance.Block the growth of PI3K-Akt-mTOR signal path energy inhibition tumor cell and even promote apoptosis of tumor cells, therefore this path is the important target spot (Nature Reviews Drug Discovery2009,8,627-644.) of new type antineoplastic medicine research and development.
In PI3K-Akt-mTOR signal path, all studied confirmation of PI3K, Akt, mTOR can as antineoplastic target spot (Expert Opin.Ther.Targets2012,16 (1), 121-130.).PI3K is phosphatidyl inositol kinase in a kind of born of the same parents, can the 3-di of catalyze phospholipid acyl inositol and the activation of mediate downstream signal path.PI3K can be divided into I type, II type and type III, and research be the most widely can the I type PI3K that activates by cell surface receptor.I type PI3K mainly comprises PI3K α, PI3K β, PI3K δ and PI3K γ tetra-kinds of hypotypes, and wherein PI3K α, PI3K β, PI3K δ belong to IA type kinase, from transmission of signals such as receptor type tyrosine kinase (RTK), G-protein linked receptors; PI3K γ is IB type kinase, only from G-protein linked receptor (GPCR) transmission of signal.Research shows, I type PI3K is process LAN, activation or sudden change in multiple human tumor, with the generation of cancer, develops closely related (Science2004,304,554.).
In PI3K-Akt-mTOR signal path, mTOR, as the downstream signaling molecule of PI3K, is one of important substrate of Akt.MTOR is serine/threonine kinases, suppresses this signaling molecule to be proved can to produce the effect of inhibition tumor cell propagation.Act on some forms of rapamycin analogs of mTOR as medicine listing, therefore mTOR is also identified is the target spot (Cancer Letters2012,319,1-7) for the treatment of tumour.
At present, PI3K inhibitor, mTOR inhibitors, PI3K/mTOR double inhibitor have all been proved and can have grown by Tumor suppression, and tens compounds enter clinical study.The present invention will provide the PI3K and/or mTOR inhibitors compounds with new structure type, these compounds to have the potentiality for the treatment of PI3K/mTOR relative disease.
Summary of the invention
One of technical problem to be solved by this invention is to provide a kind of tricyclic compounds as PI3K/mTOR inhibitor.
Two of technical problem to be solved by this invention is to provide the preparation method of the tricyclic compounds as PI3K/mTOR inhibitor.
Three of technical problem to be solved by this invention is to provide containing the pharmaceutical composition as the tricyclic compounds 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 tricyclic compounds of PI3K/mTOR inhibitor.
As the tricyclic compounds of first aspect present invention, for having the compound of following general formula (I):
Wherein,
Ar is selected from aryl or heteroaryl, and can replace by 1 to 4 optional substituting group from amino, amido, amide group, sulfoamido, alkyl urea groups, aryl-ureido, heteroaryl urea groups, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, cyano group, carboxyl, ester group, amine formyl, nitro, heterocyclic radical;
X, Y, Z are independently selected from O, CR 2r 3, NR 4; Q is selected from O, CR 2r 3, NR 4or do not exist;
R 1for C 1to C 6alkyl; N is selected from the integer of 0-4; When n>=2, can by two R 1be combined as and ring, bridged ring or volution with morpholine ring; R 2, R 3be selected from hydrogen, C 1to C 6alkyl; R 4be selected from hydrogen, C 1to C 6alkyl, C 3to C 7cycloalkyl, heterocyclic radical, acyl group, alkylsulfonyl; Described alkyl, cycloalkyl, heterocyclic radical, acyl group, alkylsulfonyl all can by halogen, hydroxyl, amino, cyano group, ester group, amide group, sulfoamido replace.
In some embodiments of the present invention, Ar is any one below in structural formula (a) ~ (e) compound monomer in general formula (I):
Wherein, R 5for hydrogen, alkyl, cycloalkyl, aryl, heteroaryl; R 6for halogen, alkyl, alkoxyl group, amido.
In some embodiments of the present invention, in general formula (I), X, Y are O; Z is CH 2; Q is CH 2or do not exist.
In some embodiments of the present invention, in general formula (I) for any one in structural formula (f) ~ (m) compound monomer below:
Wherein, when containing chiral carbon atom in described structural formula (f) ~ (m) compound monomer, be the optically pure compound monomer of arbitrary configuration or the mixture of enantiomer and diastereomer.
General formula of the present invention (I) compound, can be following compound (I-1) to any one in (I-12):
Described general formula (I) compound is the mixture of any one or arbitrarily both or three in enantiomer, diastereomer, conformer.
Described general formula (I) compound is pharmacy acceptable derivates.
General formula of the present invention (I) compound can exist as a pharmaceutically acceptable salt form, comprise and salt formed by acid, such as hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate; Or acid proton the sodium salt, sylvite, magnesium salts, the calcium salt that replace by metal ion.
As the preparation method of the above-claimed cpd of second aspect present invention, be specially following synthetic method: the adjacent aminoaryl formic acid compound A of dicyclo and urea heat fusing altogether, obtain tricyclic antidepressants intermediate B, this intermediate is converted into two chloro intermediate C under the effect of phosphorus oxychloride, nucleophilic substitution is carried out with morpholine kind compound, obtain intermediate D, then carry out coupling or nucleophilic substitution reaction with aryl compound, general formula (I) compound can be obtained.(wherein Ar, X, Y, Z, Q, R as shown in reaction scheme below 1, the definition of n is as previously mentioned):
As the pharmaceutical composition contained as the aryl morpholine compounds of PI3K/mTOR inhibitor of third aspect present invention, wherein said pharmaceutical composition comprises general formula (I) compound and the acceptable vehicle of pharmacy for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable derivates and the acceptable vehicle of pharmacy of general formula (I) compound for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of general formula (I) compound for the treatment of significant quantity.
Described pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
As the application of fourth aspect present invention, be wherein that general formula (I) compound regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
As the application of fourth aspect present invention, be wherein the application of pharmacy acceptable derivates in preparation adjustment PI3K/mTOR signal path catalytic activity goods of general formula (I) compound.
As the application of fourth aspect present invention, be wherein the application of pharmaceutically useful salt in preparation adjustment PI3K/mTOR signal path catalytic activity goods of general formula (I) compound.
As the application of fourth aspect present invention, be wherein that pharmaceutical composition treats the application in the medicine of the disease relevant with PI3K/mTOR signal path in preparation.
The described disease relevant with PI3K/mTOR signal path is cancer, comprising:
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.
The compound of general formula (I) involved in the present invention also can be used for the biology of PI3K-Akt-mTOR signal path or the research of pharmacology phenomenon and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitor.
Embodiment
The invention provides general formula defined above (I) compound, prepare the method for these compounds, use the pharmaceutical composition of these compounds and use the method for these compounds.
Listed is below definition to the various terms for describing the compounds of this invention.These definition are applied to the term (unless separately having restriction on other occasions) used in each place of specification sheets, and no matter these terms are used alone or as the part of more macoradical.
Unless otherwise defined, term as used herein " alkyl " (be used alone or as the part of another group) refers to the univalent perssad comprising 1 to 12 carbon atom that alkane derives.Preferred alkyl has 1 to 6 carbon atom.Alkyl is the optional straight chain, side chain or the cyclic saturated hydrocarbon base that replace.Exemplary alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.And described " alkyl " can be selected from following group replaces arbitrarily: alkyl, halogen (as fluorine, chlorine, bromine, iodine), alkoxyl group, amino/amido, haloalkyl (as trichloromethyl, trifluoromethyl), aryl, aryloxy, alkylthio, hydroxyl, cyano group, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, carbamyl, urea or sulfydryl.
Term as used herein " cycloalkyl " (be used alone or as the part of another group) refers to 3 to 10 carbon atoms, is preferably the hydrocarbon ring of the completely saturated or fractional saturation of 3 to 7 carbon atoms.In addition, cycloalkyl can be replace." cycloalkyl of replacement " refer to have once, two or three be selected from following substituent ring: the alkyl of halogen, alkyl, replacement (wherein substituting group as above alkyl substituent define), thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO 2h ,-C (=O) H ,-CO 2-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, five or hexa-atomic ketal (i.e. 1,3-dioxane or 1,3-diox) ,-NR'R " ,-C (=O) NR'R " ,-CO 2nR'R'' ,-C (=O) NR'R " ,-NR'CO 2r " ,-NR'C (=O) R " ,-SO 2nR'R " and-NR'SO 2r ", wherein R' and R " independently is selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl separately, or R' and R ", formation Heterocyclylalkyl or heteroaryl ring together.
Index number after symbol " C " defines the number of the carbon atom that concrete group can comprise.Such as " C 1to C 6alkyl ", refer to the straight or branched saturated carbon chains with one to six carbon atom; Example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl and n-hexyl.Based on context, " C 1to C 6alkyl " also can refer to the C of connection two groups 1to C 6alkylidene group.
Term as used herein " aryl " (be used alone or as the part of another group) refers to monocyclic aromatic ring or polycyclic aromatic ring, the phenyl of such as phenyl, replacement etc. and the group such as naphthyl, the phenanthryl etc. that condense.Thus, aryl comprises the ring that at least one has at least 6 atoms, comprises five such rings (wherein comprising 22 atoms at the most) at the most, and has (conjugation) double bond alternately between adjacent carbon atom or suitable heteroatoms.Preferred aryl comprises 6 to 14 carbon atoms in ring.And described " aryl " can be optionally substituted one or more group, described group has included but not limited to halogen (such as fluorine, chlorine, bromine), alkyl (such as methyl, ethyl, propyl group), substituted alkyl (as trifluoromethyl), cycloalkyl, alkoxyl group (such as methoxy or ethoxy), hydroxyl, carboxyl, amine formyl (-C (=O) NR'R "), alkoxy carbonyl (-CO 2r), amino/amido, nitro, cyano group, thiazolinyl oxygen base, aryl, heteroaryl, alkylsulfonyl (-SO 2r) etc., wherein, R, R', R " is described alkyl.
Term as used herein " heteroaryl " (be used alone or as the part of another group) refers to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 8 to 10 yuan of bicyclic radicals and 11 to 14 yuan of three cyclic group, and these groups have at least one heteroatoms (N, O or S) at least one ring.The each ring comprising heteroatomic heteroaryl can comprise one to four nitrogen-atoms, one or two Sauerstoffatoms and/or sulphur atom, 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 at least one complete aromatic ring, 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 (including but not limited to difluoromethyl) 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'CO 2r " ,-NR'C (=O) R " ,-SO 2nR'R " and-NR'SO 2r ", wherein R' and R " independently is selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl separately, or R' with R " together with formation Heterocyclylalkyl or heteroaryl ring.
The example of bicyclic heteroaryl comprises pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazolyl etc.
The example of bicyclic heteroaryl comprises indyl, indazolyl, 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, 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 N, O or S 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 N, O and/or S).Heterocycle can be 5,6 or 7 yuan of monocycles, and comprises the heteroatoms that, two or three is selected from N, O and/or S.Heterocycle can be optional replacement; this means that heterocycle can have one or more to be independently selected from following group in one or more commutable ring position replacement: alkyl, Heterocyclylalkyl, heteroaryl, alkoxyl group, nitro, monoalkyl amido, dialkyl amino, cyano group, halogen, haloalkyl, alkyloyl, ammonia/amino-carbonyl, monoalkyl amino-carbonyl, dialkyl amino carbonyl, alkylamidoalkyl, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl oxygen base and aryl, described aryl optionally replaces halogen, alkyl and alkoxyl group.The example of these Heterocyclylalkyls includes but not limited to: piperidines, morpholine, high morpholine, piperazine, parathiazan, tetramethyleneimine and azetidine.
Term as used herein " alkoxyl group " (be used alone or as the part of another group) refers to the alkyl preferably with 1 to 6 carbon atom connected by Sauerstoffatom, and such as-OR, wherein R is described alkyl.
Term as used herein " amino " (be used alone or as the part of another group) refers to-NH 2." amido " can optionally replace one or two substituting groups (-NR'R "); wherein R' and R " can be identical or different, such as alkyl, aryl, arylalkyl, thiazolinyl, alkynyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, carbonyl or carboxyl.These substituting groups can replace any one in the alkyl or aryl substituting group had listed by carboxylic acid or the application further.In some embodiments, there are carboxyl or carbonyl amino replacement, forms N-acyl group or N-carbamyl deriveding group.
Term " halogen " refers to independent fluorine, chlorine, the bromine or iodine selected.
Term " anticarcinogen " comprises the medicine known arbitrarily that can be used for Therapeutic cancer, comprising: (1) cytotoxic drug: chlormethine series pharmaceuticals, as melphalan, endoxan; Platinum coordination complex, such as cis-platinum, carboplatin and oxaliplatin; (2) anti-metabolism antitumour drug: 5 FU 5 fluorouracil, capecitabine, methotrexate, Calciumlevofolinate, Raltitrexed, purine antagonist (such as 6-thioguanine and Ismipur); (3) hormones: the female alcohol of 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene; (4) tyrosine kinase inhibitor: EGFR inhibitor, comprises Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cetuximab (Cetuximab), Trastuzumab (Herceptin) etc.; VEGF inhibitor, such as VEGF antibody (Avastin (Avastin)) and micromolecular inhibitor such as Sunitinib, Sorafenib, Vandetanib, Pazopanib, Axitinib etc.; Bcr-Abl inhibitor is as Imatinib, Nilotinib, Dasatinib; B-Raf inhibitor is as Sorafenib, Vemurafenib, Dabrafenib etc.; MEK kinase inhibitor is as Trametinib, Selumetinib etc.; And mapk kinase inhibitor, PI3K kinase inhibitor, c-Met inhibitor, ALK inhibitor, Src 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, glu famine antagonist, angiogenesis inhibitor and anti-vascular medicine, matrix metallo-proteinase inhibitor etc.
" Mammals " comprises the mankind and domestic animal, as cat, dog, pig, ox, sheep, goat, horse, rabbit etc.Preferably, for the purposes of the present invention, described Mammals is the mankind.
When " pharmacy acceptable derivates " represents to recipient's administration, directly or indirectly can provide salt or other derivatives of the salt of any nontoxic salt of the active metabolite of compound of the present invention or its inhibition or resistates, ester, ester, acid amides, acid amides.
" the acceptable vehicle of pharmacy " includes but not limited to be ratified as any assistant agent that can be used for the mankind or domestic animal, carrier, vehicle, glidant, sweeting agent, dispersion agent, thinner, sanitas, suspending agent, stablizer, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, isotonic agent, solvent or emulsifying agent by state food and Drug Administration.
" pharmacologically acceptable salts " comprises acid salt and base addition salt.
" the acceptable acid salt of pharmacy " refers to such salt, and they remain biological effect and the character of free alkali, can not produce adverse consequences in biology or other, and is such as but not limited to hydrochloric acid with mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid is such as but not limited to following acid: formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2,2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, phenylformic acid, paraacetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane-1,2-disulfonic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, glyconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-oxo-pentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, glactaric acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, palm fibre eleostearic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, 4-ASA, sebacic acid, stearic acid, fumaric acid, succsinic acid, tartrate, thiocyanic acid, the formation such as undecylenic acid.
" the acceptable base addition salt of pharmacy " refers to such salt, and they remain biological effect and the character of free acid, can not be improper in biology or other.These salt obtain by mineral alkali or organic bases being added on free acid.The salt being derived from mineral alkali includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Preferred inorganic salt are ammonium, sodium, potassium, calcium and magnesium salts.The salt being derived from organic bases includes but not limited to the salt of following substances: primary amine, secondary amine and tertiary amine, the amine replaced, comprise naturally occurring replacement amine, cyclammonium and deacidite, as ammonia, methylamine, dimethylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, Isopropylamine, diethanolamine, thanomin, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, Benethamine diacetale, quadrol, glycosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperidines, piperazine, N-ethylpiperidine, versamid 900 etc.Preferred organic bases is Isopropylamine, diethylamine, thanomin, triethylamine, dicyclohexyl amine, choline and caffeine.
" pharmaceutical composition " refer to compound of the present invention with biologically active cpds is delivered to Mammals as the medium of the usual acceptance in the mankind the preparation that forms.Such medium comprises all pharmaceutically acceptable carrier, thinner or vehicle to this.
" treatment significant quantity " refers to when to (the preferred mankind) during Mammals administration, be enough to the relative disease of Mammals (the preferred mankind) or illness realize as hereafter the amount of the compound of the present invention for the treatment of that defines.The amount forming the compound of the present invention of " treatment significant quantity " can according to the activity of such as applied particular compound; The metabolic stability of described compound and effect duration; Age of patient, body weight, holistic health, sex and diet; Mode of administration and time; Discharge rate; Drug combination; The seriousness of specific illness or illness; And experience the individuality for the treatment of and change, but it can be determined according to himself knowledge and the disclosure routinely by those of ordinary skill in the art.
" treat " or " treatment " for containing the Mammals to having relative disease or illness during this paper, the relative disease of the preferred mankind or the treatment of illness, and comprise:
(1) prevent disease or illness to occur in Mammals, especially when such Mammals is ill but when also not diagnosing out ill;
(2) suppress disease or illness, namely stop it to develop;
(3) alleviate disease or illness, namely cause disease or illness to disappear;
(4) stable disease or illness.
During for this paper, term " disease " and " illness " can be exchanged and to be used or can be different, reason is the inducement (thus also not working out the cause of disease) that specified disease or illness may not have oneself to know, therefore also disease is not considered to and only as improper situation or syndrome, wherein clinician have identified concrete syndrome more or less.
The compounds of this invention shown in this article and their structure also represent and comprise all isomer (such as enantiomer, diastereomer, rotamerism or conformational isomerism) form, they can according to amino acid whose absolute stereochemical being defined as to (R)-/(S)-or (D)-/(L)-or (R, R)-/(R, S)-/(S, S)-.The present invention represents and comprises all these possible isomer, and their racemic, enantiomorph enrichment and optional pure form.Optically-active (+) and (-), (R)-and (S)-and (R, R)-/(R, S)-/(S, S)-or (D)-chiral synthesize, chiral separation can be used to prepare with (L)-isomer, or routine techniques can be used to split such as but not limited to using the high performance liquid phase (HPLC) of chiral column.When compound as herein described comprises thiazolinyl double bond or other geometry asymmetric centers, except as otherwise noted, described compound comprises E and Z geometrical isomer.Equally, all tautomeric forms are also comprised.
" steric isomer " refers to be made up of with identical chemical bonding identical atom but to have the compound of different three-dimensional structure, and they are not interchangeable.The present invention is contained various steric isomer and composition thereof and is comprised " enantiomer " and " diastereomer ", and enantiomer refers to two kinds of steric isomers of the mirror image that its molecule each other can not be overlapping; Diastereomer refers to that molecule has two or more chiral centre, and intermolecular be the steric isomer of non-mirror.
" tautomer " refers to that proton moves to another position of same a part from an atom of molecule from original position.The present invention includes the tautomer of any described compound.
In addition, except as otherwise noted, compound of the present invention also comprises the compound that structure difference is only to exist one or more isotopic enrichment atoms.Such as, there is structure of the present invention, except replacing hydrogen with " deuterium " or " tritium ", or using 18f-fluorine mark ( 18f isotropic substance) replace fluorine, or use 11c-, 13c-, or 14the carbon of C-enrichment ( 11c-, 13c-, or 14c-carbon markings; 11c-, 13c-, or 14c-isotropic substance) replace the compound of carbon atom to be in scope of the present invention.Such compound can be used as biological example measure in analysis tool or probe, or can the diagnostic imaging in vivo tracer agent of disease be used as, or as the tracer agent of pharmacodynamics, pharmacokinetics or acceptor research.
The present invention also provides following methods: (simultaneously or successively) needs the patient of this treatment by (I) compound of general formula as defined above and other anticancer agents of at least one for the treatment of significant quantity being given, and treats proliferative disease (such as cancer) via regulating PI3K/mTOR signal path.In preferred embodiments, proliferative disease is cancer.
Particularly, general formula (I) compound can be used for treating kinds cancer, is most specifically those cancers depending on the activation of PI3K/mTOR signal.Usually, compound of the present invention can be used for the treatment of following cancer:
1. incidence cancer, comprises thyroid carcinoma, nasopharyngeal carcinoma, meninx cancer, acoustic tumor, pituitary tumor, oral carcinoma, craniopharyngioma, thalamus and brain stem tumor, angiogenic tumour, intracranial metastatic tumor;
2. respiratory system cancer, comprises lung cancer;
3. cancer in digestive system, comprises liver cancer, cancer of the stomach, the esophageal carcinoma, large bowel cancer, the rectum cancer, colorectal carcinoma, carcinoma of the pancreas;
4. urinary system cancer, comprises kidney, bladder cancer, prostate cancer, carcinoma of testis;
5. Skeletal system cancer, osteocarcinoma;
6. gynecological cancer, comprises mammary cancer, cervical cancer, ovarian cancer;
7. hematological cancer, comprises leukemia, malignant lymphoma, multiple myeloma;
8. other types cancer, comprises malignant melanoma, neurospongioma, skin carcinoma.
General formula (I) compound also can be used for treating any lysis being characterized as abnormal cell proliferation, the restenosis such as, occurred after benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or vascular surgery, inflammatory bowel, graft-rejection, endotoxin shock and fungi infestation.
The level of the adjustable cell RNA of general formula (I) compound and DNA synthesis.Therefore, these materials can be used for the treatment of virus infection (including but not limited to HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, sindbis alphavirus and adenovirus).
General formula (I) compound can be used for the chemoprophylaxis of cancer.Chemoprophylaxis is defined through and blocks initial mutagenesis event or by blocking the progress of pre-malignant cells damaged and carry out the development of anti-invasion cancer or Tumor suppression recurring.
General formula (I) compound can be used for Tumor suppression vasculogenesis and transfer.
Compound of the present invention also can combinationally use with known anticarcinogen (include but not limited to mention in above-mentioned " anticarcinogen " those) or anticancer therapy (such as radiotherapy) (together with give or successively give).
Some general formula (I) compound can be prepared according to following route usually.The tautomer of general formula (I) compound and solvate (such as hydrate, ethanolates) are also within the scope of the invention.The preparation method of solvate is normally known in the art.Therefore, compound of the present invention can be free form or hydrate forms.
In method hereinafter described, the functional group of midbody compound may need the protecting group by being suitable for protect.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.The protecting group be applicable to for hydroxyl comprise trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl, to methoxy-benzyl etc.Suitable protecting groups for amino comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, trifluoroacetyl group, to methoxy-benzyl etc.Suitable protecting groups for carboxylic acid comprises alkyl, aryl or alkyl aryl.Suitable protecting groups for the heteroaryl such as NH functional group of such as indoles or indazole ring comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, 2-trimethylsilyl-ethoxy methyl, to methoxy-benzyl etc.
Protecting group can be added according to method known to those skilled in the art (Greene, T.W., Protective Groups inOrganic Sythesis, the 3rd edition, Wiley in 1999) and standard technique as herein described or remove.Described protecting group also can be that fluoropolymer resin is as Wang resin, Rink resin or 2-chlorine trityl chloride resin.
Meanwhile, although these protected derivatives of the compounds of this invention itself may not have pharmacological activity, they can be administered to Mammals, and then metabolism has the compounds of this invention of pharmacological activity with formation in vivo.Therefore such derivative is described to " prodrug ".All prodrugs of the compounds of this invention include within the scope of the invention.
The compound of general formula of the present invention (I), be prepared by following method: the adjacent aminoaryl formic acid compound A of dicyclo and urea heat fusing altogether, obtain tricyclic antidepressants intermediate B, this intermediate is converted into two chloro intermediate C under the effect of phosphorus oxychloride, nucleophilic substitution is carried out with morpholine kind compound, obtain intermediate D, then carry out linked reaction or nucleophilic substitution with aryl compound, general formula (I) compound can be obtained.(wherein Ar, X, Y, Z, Q, R as shown in reaction scheme below 1, the definition of n is as previously mentioned):
Wherein, following is abbreviation conventional in statement process of the present invention:
DMF:N, dinethylformamide;
DMSO: dimethyl sulfoxide (DMSO);
THF: tetrahydrofuran (THF)
CDCl 3: deuterochloroform;
LC-MS: LC-MS chromatogram;
TLC: tlc;
1H NMR: proton nmr spectra;
S: unimodal;
D: bimodal;
T: triplet;
Dd: doublet of doublet;
Br: broad peak;
M: multiplet;
DEG C: degree Celsius;
Mol: mole;
Mmol: mmole.
Those skilled in the art can use suitable raw material, adopt similar method, prepare in reaction scheme above with no specific disclosure of other compounds of the present invention.
By with suitable inorganic or organic bases or acid treatment, can by according to preparing all the compounds of this invention existed with free alkali or sour form above and change into their pharmacologically acceptable salts.The salt of the compound prepared above can change into their free alkali or sour form by standard technique.
Compound of the present invention comprises its all crystal formations, amorphous forms, dehydrate, hydrate, solvate and salt.In addition, all compounds of the present invention comprising ester group and amide group can oneself knows by those skilled in the art method or change into corresponding acid by method described herein.Equally, the compounds of this invention comprising hydroxy-acid group oneself knows by those skilled in the art method can be converted into corresponding ester and acid amides.Also can oneself knows by those skilled in the art method (such as hydrogenation, alkylation, with acyl chloride reaction etc.) carry out on molecule other replace and replace.
Prepare cyclodextrin inclusion compound of the present invention, can the compound of the general formula (I) defined in summary of the invention be above dissolved in the acceptable solvent of pharmacology such as (but being not limited to) alcohol (preferred alcohol), ketone (such as acetone) or ether (such as ether), and at 20 DEG C to 80 DEG C and alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin, the aqueous solution of preferred beta-cyclodextrin; Or can by the acid of the compound of general formula (I) that defines in summary of the invention above with the aqueous solution form of its salt (such as sodium or sylvite) and cyclodextrin blended, then with the solution blending of equivalent acid (such as hydrochloric acid or sulfuric acid), to provide corresponding cyclodextrin inclusion compound.
Now or after the cooling period, corresponding cyclodextrin inclusion compound crystal can crystallization.Or when general formula (I) compound be oily and crystallization time, by room temperature for a long time stir (such as 1 is little of 14 days), add the aqueous solution process of cyclodextrin, also can be converted into corresponding cyclodextrin inclusion compound.Then by filtering and drying, inclusion compound can be separated into solid or crystal.
For cyclodextrin of the present invention commercially available (such as from Aldrich Chemical Co.), or adopt known method preparation by those skilled in the art.See people such as such as Croft, A.P., " Sy-hesis of ChemicallyModified Cyclodextrins ", Tetrahedron1983,39,9,1417-1474.Suitable cyclodextrin comprises all kinds preparing inclusion compound with the compound of institute's column (I) above.
By selecting appropriate cyclodextrin and water, the inclusion compound of repeatably active substance content can be obtained according to stoichiometric composition.Inclusion compound can use for dry water suction form or the moisture but form more do not absorbed water.The Typical mole ratios of the compound of cyclodextrin and general formula (I) is 2:1(cyclodextrin: compound).
Comprising general formula (I) compound as the pharmaceutical composition of activeconstituents can be suitable for oral form, such as, be tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis or granule, syrup etc.The composition that can orally use can be prepared according to any means for the preparation of pharmaceutical composition known in the art, and these compositions can comprise the material that one or more is selected from sweeting agent, seasonings, tinting material and sanitas, to provide pharmaceutical elegant and agreeable to the taste preparation.
Tablet comprises activeconstituents, and is mixed with the nontoxic pharmaceutically acceptable vehicle or carrier that are suitable for preparing tablet.These vehicle or carrier can be inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as Celluloasun Microcrystallisatum, carmethose, W-Gum or alginic acid; Tackiness agent, such as starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum powder.Tablet can be non-dressing, or carrys out dressing by known technology, thus covers and make us unhappy drug tastes, or postpones disintegration and absorption in the gastrointestinal tract, provides lasting effect thus within the longer period.Such as, water miscible taste can be used to cover material (such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose) or time lag material (such as ethyl cellulose, cellulose acetate butyrate).
Capsule comprises hard-gelatin capsules, Gelseal.Hard-gelatin capsules is mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin by activeconstituents; Gelseal is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oily medium (such as peanut oil, whiteruss or sweet oil) by activeconstituents.
Aqueous suspension comprises active substance and is suitable for preparing the vehicle of aqueous suspension.These vehicle are suspending agent, such as Xylo-Mucine, methylcellulose gum, hydroxypropyl methyl-cellulose, sodiun alginate, polyvinylpyrrolidone and gum arabic; Dispersion agent or wetting agent, the condensation product (such as polyethylene sorbitan monoleate) of partial ester that can be the condensation product (such as polyoxyethylene stearic acid ester) of naturally occurring phosphatide (such as Yelkin TTS) or oxyalkylene and lipid acid or the condensation product (such as 17 oxygen ethene hexadecanols (heptadecaethylene-oxycetanol)) of ethylene oxide and long chain aliphatic alcohol or ethylene oxide and the condensation product (such as polyoxyethylene 80 sorbitan monooleate) of partial ester derived from lipid acid and hexitol or ethylene oxide and derive from lipid acid and 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 (I) compound also can give by the form of the suppository for rectal administration.These compositions are prepared by hybrid medicine and suitable nonirritant excipient, and described vehicle is solid at normal temperature but is liquid in rectal temperature, therefore melts in the rectum, thus release medicine.These materials comprise theobroma oil, glycogelatin, hydrogenated vegetable oil, the mixture of polyoxyethylene glycol of different molecular weight and the fatty acid ester of polyoxyethylene glycol.
With regard to local uses, can to prepare and use comprises the ointment of general formula (I) compound, ointment, jelly, solution or suspensoid etc.
Compound of the present invention uses suitable nasal carrier and doser to give with intranasal form by local, or use those skilled in the art the form of well-known transdermal skin patches given by cutaneous routes.Compound of the present invention also can give by the form of the suppository using all matrix as described below: the mixture of the polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight and the fatty acid ester of polyoxyethylene glycol.
When being administered in human subject body by compound of the present invention, every per daily dose is generally determined by the doctor of prescription, and described dosage usually with the symptom of age of patient, body weight, sex and reaction and patient severity and change.Usually, the effective per daily dose of the patient for 70kg is about 0.001mg/kg to 100mg/kg, is preferably 0.01mg/kg to 50mg/kg.
If be mixed with fixed dosage, so these combined prods are used in the compounds of this invention in dosage range described above and other medical active agent treatment in the dosage range of its approval.When combination preparation is improper, general formula (I) compound also successively can give with known anticarcinogen or cytotoxicity medicine.The present invention is not by the restriction of order of administration; General formula (I) compound can give before or after giving known anticarcinogen (multiple anticarcinogen) or cytotoxicity medicine (various kinds of cell toxicity medicine).
Compound of the present invention is the inhibitor of the disease of PI3K/mTOR mediation or the illness of PI3K/mTOR mediation.Term " disease of PI3K/mTOR mediation " and " illness of PI3K/mTOR mediation " represent the effective any morbid state of known PI3K/mTOR tool or other adverse conditions.Term " PI3K/mTOR mediation disease " and " illness that PI3K/mTOR mediates " also represent those diseases by being eased with PI3K/mTOR inhibitor for treating or illness.These diseases and illness include but not limited to cancer and other proliferative disorder.
Therefore, described compound can be used for treating such as Mammals, the following disease especially in the mankind or illness: cancer of the stomach, lung cancer, esophagus cancer, carcinoma of the pancreas, kidney, colorectal carcinoma, thyroid carcinoma, the cancer of the brain, mammary cancer, prostate cancer and other solid tumors; Lymphoma; Leukemia; Adjustment blood vessel occurs; Regulate thrombosis and pulmonary fibrosis.
Compound involved in the present invention also can be used for the biology of PI3K-Akt-mTOR signal path or the research of pharmacology phenomenon and the comparative evaluation for new PI3K or PI3K/mTOR double inhibitor.
Compound is herein including, but not limited to the structure type given by 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: the preparation of the 5-of structural formula (I-1) (8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases) pyrimidine-2-ammonia, concrete reaction formula is as follows:
Step 1: be dissolved in by piperinic acid (20g, 0.12mmol) in methyl alcohol (160mL), drips the vitriol oil (16mL), is heated to 70 DEG C and stirs 5 hours.TLC shows raw material disappearance, is cooled to room temperature, concentrating under reduced pressure, and the aqueous sodium hydroxide solution with 5% regulates pH to alkalescence, is extracted with ethyl acetate, dry, concentrates to obtain methyl piperate (white needles 21.0g, 97%).
Step 2: methyl piperate (21.0g, 0.117mmol) is dissolved in Glacial acetic acid (130mL), drips nitrosonitric acid (44.8mL), finishes under stirring, be warming up to 70 DEG C and stir 1 hour.Be chilled to room temperature, concentrated, with the aqueous sodium hydroxide solution neutralization of 5%, solid is separated out, and filters, and filter cake distillation washing is dry, obtains 6-nitro benzo [d] [1,3] diox-5-methyl-formiate (19.6g, 75%).
Step 3:6-nitro benzo [d] [1,3] diox-5-methyl-formiate (18.0g, 79.9mmol) adds in ethanol (200mL) and water (40mL), heating makes dissolving, take a policy powder (48.0g, 276mmol), is warming up to 80 DEG C and stirs 2 hours.Cooling, filter, filter cake methylene dichloride/ethanol is washed, and collects filtrate, concentrated, add methylene dichloride/ethanol more fully to stir, filter, filter cake methylene dichloride/ethanol is washed, and collects filtrate, concentrated, obtain amino benzo [d] [1, the 3] diox-5-carboxylate methyl ester (12.3g, 79%) of 6-.
Step 4: by NaOH(2.95g, 73.8mmol) add in water (75mL), add amino benzo [d] [1,3] diox-5-carboxylate methyl ester (12.0g, 61.5mmol) of 6-after stirring and dissolving, be warming up to 90 DEG C and stir 2 hours.Frozen water cools, and regulates pH to 2, have solid to separate out, fully stir with concentrated hydrochloric acid, and filter, filter cake washes with water, dries to obtain amino benzo [d] [1, the 3] diox-5-formic acid (7.2g, 65%) of 6-.
Step 5: nitrogen protection, is placed in single port bottle by urea (4.97g, 82.8mmol), is heated to 160 DEG C and makes it melting, adds amino benzo [d] [1,3] diox-5-formic acid (1.0g, 5.52mmol) of 6-, stirs 3 hours.Be cooled to 100 DEG C, carefully add water (5mL), stirs 10 minutes, filters, filter cake washes with water, collects solid, adds in the aqueous sodium hydroxide solution of 5%, be heated to 100 DEG C, stir to clarify, cooling, regulate pH to 2 with concentrated hydrochloric acid, abundant stirring, filter, filter cake washes with water, dry [1,3] diox [4,5-g] quinazolines-6,8 (5H, 7H)-diketone (600mg, 53%).
Step 6: nitrogen protection, by [1,3] dioxs [4,5-g] quinazoline-6; 8 (5H, 7H)-diketone (1.2g, 5.82mmol) adds in phosphorus oxychloride (20mL), adds DIPEA(752mg; 5.82mmol), be heated to backflow, stir 5 hours.TLC shows raw material and disappears, and be cooled to room temperature, concentrating under reduced pressure, the careful shrend on the rocks of resistates is gone out, and is extracted with ethyl acetate, and dry, steaming desolventizes, and obtains 6,8-bis-chloro-[1,3] diox [4,5-g] quinazoline (900mg, 64%).
Step 7: nitrogen protection, by chloro-for 6,8-bis-[1,3] diox [4; 5-g] quinazoline (900mg, 3.7mmol) adds in methylene dichloride (25mL), adds morpholine (387mg, 4.44mmol); triethylamine (450mg, 4.44mmol), stirred overnight at room temperature.TLC shows raw material and disappears, and concentrated, residue by silicagel column chromatography obtains the chloro-8-morpholine of 6--[1,3] bis-Evil [4,5-g] quinazolines (560mg, 52%).
Step 8: nitrogen protection, the chloro-8-morpholine of 6--[1,3] diox [4,5-g] quinazolines (100mg, 0.34mmol), 2-aminopyrimidine-5-boric acid pinacol ester (113mg, 0.51mmol), Cs 2cO 3(150mg, 0.51mmol), Pd (dppf) Cl 2(23mg, 0.034mmol) is mixed in the mixed solvent of Isosorbide-5-Nitrae-dioxane (9mL) and water (1.5mL), is heated to 100 DEG C, stirs 1 hour.Be cooled to room temperature, concentrating under reduced pressure, through purification by silica gel column chromatography, obtain 5-(8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases) pyrimidine-2-ammonia (56mg, 47%).MS(ESI)m/z=353[M+H]； 1H NMR(300MHz,DMSO-d 6)9.14(s,2H),7.32(s,1H),7.23(s,1H),7.15(s,2H),6.23(s,2H),3.82(m,4H),3.59(m,4H)。
Embodiment 2: the preparation of the 5-of structural formula (I-2) (8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases)-4-(trifluoromethyl) pyridine-2-ammonia, concrete reaction formula is as follows:
Nitrogen protection; the chloro-8-morpholine-[1 of 6-; 3] dioxs [4; 5-g] quinazoline (100mg, 0.34mmol), 4-trifluoromethyl-PA-5-pinacol borate ([reference literature is prepared ACS Med.Chem.Lett.2011,2; 774 – 779.]; 198mg, 0.68mmol), aqueous sodium carbonate (2N, 0.74mL), Pd (dppf) Cl 2(36mg), glycol dimethyl ether (2mL) mixes, and tube sealing is heated to 90 DEG C, and stirring is spent the night, and TLC shows raw material and substantially disappears, and adds diluted ethyl acetate, uses saturated Na 2cO 3solution/water/strong aqua=5/4/1(10mL) washing, then use saturated aqueous ammonium chloride (20mL) to wash, then use saturated aqueous common salt (20mL) to wash, dry, concentrated.Residue by silicagel column chromatography purification, obtains 5-(8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases)-4-(trifluoromethyl) pyridine-2-ammonia (31mg, 55%).MS(ESI)m/z=420[M+H]； 1H NMR(500MHz,DMSO-d 6)8.58(s,1H),7.34(s,1H),7.23(s,1H),6.84(s,1H),6.81(br,2H),6.24(s,2H),3.77(m,4H)，3.56(m,4H)。
Embodiment 3: 6-(1H-indazole-4-the base)-8-morpholine of structural formula (I-3)-[preparation of 1,3] diox [4,5-g] quinazolines, concrete reaction formula is as follows:
Under nitrogen protection, the chloro-8-morpholine of 6--[1,3] diox [4,5-g] quinazolines (100mg, 0.34mmol), 1H-indazole-4-pinacol borate (209mg, 0.51mmol), Cs 2cO 3(167mg, 0.52mmol), Pd (dppf) Cl 2(23mg, 0.034mmol) is mixed in the mixed solvent of Isosorbide-5-Nitrae-dioxane (9mL) and water (1.5mL), is heated to 100 DEG C, stirs 1 hour.TLC shows raw material and disappears, and concentrated, residue by silicagel column chromatography purification, obtains 6-(1H-indazole-4-base)-8-morpholine-[1,3] diox [4,5-g] quinazolines (54mg, 43%).MS(ESI)m/z=376[M+H]； 1H NMR(300MHz,DMSO-d 6)13.18(s,1H),9.00(s,1H),8.27(d,1H，J=6.6Hz),7.65(d,1H，J=7.8Hz),7.42-7.48(m,2H),7.33(s,1H),6.23(s,2H),3.84(m,4H),3.59(m,4H)。
Embodiment 4: the preparation of the 1-ethyl-3-of structural formula (I-4) (4-(8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases) phenyl) urea, concrete reaction formula is as follows:
Step 1:4-bromaniline (10.0g, 58mmol) is dissolved in DMF(100mL) in, add 4-DMAP(7.1g, 58mmol successively), DIPEA(15.0g, 116mmol), add ethyl isocyanate (8.25g, 116mmol), stirring at room temperature 3 hours.Concentrating under reduced pressure, resistates adds water making beating, filters, gets solid, with ethyl acetate/methanol=100:1(50mL), making beating, filters.Drying, obtains 1-(4-bromophenyl)-3-ethyl carbamide (8.8g, 62%).
Step 2: under nitrogen protection, 1-(4-bromophenyl)-3-ethyl carbamide (2.0g, 8.22mmol), connection boric acid pinacol ester (4.18g, 16.5mmol), Pd (dppf) Cl 2(600mg, 0.82mmol), Potassium ethanoate (1.21g, 12.3mmol) mix with Isosorbide-5-Nitrae-dioxane (50mL), are heated to 100 DEG C and stir 2 hours.Be cooled to room temperature, concentrating under reduced pressure.Add water in resistates, be extracted with ethyl acetate, dry, concentrated, silica gel column chromatography obtains 1-ethyl-3-(4-pinacol borate-2-base) phenyl) urea (2.0g, 84%).
Step 3: nitrogen protection, the chloro-8-morpholine of 6--[1,3] diox [4,5-g] quinazolines (100mg, 0.34mmol), 1-ethyl-3-(4-pinacol borate-2-base) phenyl) urea (58mg, 0.34mmol), Cs 2cO 3(166mg, 0.51mmol), Pd (dppf) Cl 2(25mg) be mixed in the mixed solvent of Isosorbide-5-Nitrae-dioxane (9mL) and water (1.5mL), be heated to 100 DEG C, stir 2 hours.TLC shows raw material and substantially disappears, and concentrated, add water cancellation, with dichloromethane extraction, drying, concentrated, through silica gel column chromatography, obtain 1-ethyl-3-(4-(8-morpholine-[1,3] diox [4,5-g] quinazoline-6-bases) phenyl) urea (79mg, 55%).MS(ESI)m/z=422[M+H]； 1H NMR(500MHz,DMSO-d 6)8.65(brs,1H),8.29(d,2H,J=8.5Hz),7.50(d,2H,J=8.5Hz),7.31(s,1H),7.24(s,1H),6.21(s,2H),6.16(br,1H),3.83(t,4H,J=5.5Hz),3.59(t,4H,J=5.0Hz),3.12-3.17(q,2H),1.05-1.08(t,3H)。
Embodiment 5: 6-(2-(difluoromethyl)-1H-benzo [d] imidazoles-1-the base)-8-morpholine of structural formula (I-5)-[preparation of 1,3] bis-Evil [4,5-g] quinazolines, concrete reaction formula is as follows:
Nitrogen protection, the chloro-8-morpholine of 6--[1,3] bis-Evil [4; 5-g] quinazoline (100mg, 0.34mmol), 2-(difluoromethyl)-1H-benzo [d] imidazoles ([reference prepare: J.Med.Chem.2011,54; 7105 – 7126] 113mg, 0.68mmol), K 2cO 3(188mg, 1.36mmol) is mixed in DMSO, is heated to 130 DEG C, stirs 4 hours.Be cooled to room temperature, add water cancellation, be extracted with ethyl acetate, drying, concentrated, residue by silicagel column chromatography purification, obtain 6-(2-(difluoromethyl)-1H-benzo [d] imidazoles-1-base)-8-morpholine-[1,3] bis-Evil [4,5-g] quinazolines (62mg, 43%).MS(ESI)m/z=426[M+H]； 1H NMR(300MHz,CDCl 3),8.54(m,1H),7.94(d,1H),7.45(m,3H),7.29(s,1H),7.19(s,1H),6.18(s,2H),3.97(m,4H),3.75(m,4H)。
Embodiment 6: the preparation of the 5-of structural formula (I-6) (4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline-2-base) pyrimidine-2-ammonia, concrete reaction formula is as follows:
Step 1:1,4-benzodioxane-6-formic acid (25.0g, 139mmol) is dissolved in methyl alcohol (180mL), drips the vitriol oil (17.5mL), is heated to 70 DEG C and stirs 5 hours.Be chilled to room temperature, concentrating under reduced pressure, the aqueous sodium hydroxide solution with 5% regulates pH to alkalescence, is extracted with ethyl acetate, dry, concentrates to obtain Isosorbide-5-Nitrae-benzodioxane-6-methyl-formiate (white solid 26.8g, 99%).
Step 2: added in acetic acid (150mL) by Isosorbide-5-Nitrae-benzodioxane-6-methyl-formiate (26.0g, 133.9mmol), be stirred to dissolve, drips nitrosonitric acid (51mL), finishes, and is warming up to 70 DEG C and stirs 1 hour.Be cooled to room temperature, concentrating under reduced pressure, the aqueous sodium hydroxide solution with 5% regulates pH to 7, adds extraction into ethyl acetate, and organic phase is through washing, dry, concentrated, obtains 7-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-carboxylate methyl ester (31.1g, 97%).
Step 3:7-nitro-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-carboxylate methyl ester (32g, 134mmol) add in ethanol (350mL) and water (70mL), heating for dissolving, take a policy powder (80.4g, 462mmol), be warming up to 80 DEG C to stir 2 hours.Cooling, filter, filter cake methylene dichloride/ethanol is washed, and collects filtrate, concentrated, add methylene dichloride again to dissolve, organic phase is through washing, and saturated common salt is washed, dry, concentrated, obtain amino-2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxin-6-carboxylate methyl ester (10.9g, 39%) of 7-.
Step 4: by NaOH(2.43g, 61mmol) add in water (70mL), [Isosorbide-5-Nitrae] dioxin-6-carboxylate methyl ester (10.6g, 51mmol) is warming up to 90 DEG C and stirs 2 hours to add 7-amino-2,3-dihydrobenzo [b].TLC shows raw material and disappears, and cooling regulates pH to 2 with concentrated hydrochloric acid, and solid is separated out, and fully stirs, and filter, filter cake washes with water, dries to obtain amino-2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxin-6-formic acid (8.66g, 88%) of 7-.
Step 5: nitrogen protection; by 7-amino-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-formic acid (9.17g, 47mmol), urea (22.57g; 376mmol) with phenol (35.4g; 376mmol) be placed in single port bottle, be heated to 150 DEG C and make it melting, stir 2 hours at this temperature.Be cooled to 100 DEG C, add ethanol (100mL) and water (100mL), stir 10 minutes, filter, filter cake washes with water, then washes with a small amount of ethanol, collect solid, dry, obtain 7,8-dihydro-[1,4] dioxin [2,3-g] quinazoline-2,4 (1H, 3H)-diketone (4.1g, 40%).
Step 6: nitrogen protection, by 7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2; 3-g] quinazoline-2,4 (1H, 3H)-diketone (4.0g, 18.2mmol) adds in phosphorus oxychloride (30mL); add DIPEA(2.35g, 18.2mmol), return stirring 5 hours.Be cooled to room temperature, concentrating under reduced pressure, the careful shrend on the rocks of resistates is gone out, and is extracted with ethyl acetate, and extraction liquid merges, dry, concentrated, obtains chloro-7, the 8-dihydros of 2,4-bis--[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline (4.47g, 96%).
Step 7: nitrogen protection, by 2, 4-bis-chloro-7, 8-dihydro-[1, 4] dioxin [2, 3-g] quinazoline (4.5g, 17.5mmol) add in methylene dichloride (30mL) and methyl alcohol (50mL), add morpholine (1.83g, 21mmol), triethylamine (2.12g, 21mmol), room temperature reaction 2 hours, TLC shows raw material and disappears, concentrated, methylene dichloride and water is added in resistates, organic phase washes with water respectively, saturated common salt is washed, dry, concentrated, obtain the chloro-4-morpholine-7 of 2-, 8-dihydro-[1, 4] dioxin [2, 3-g] quinazoline (4.9g, 92%).
Step 8: nitrogen protection, 2-chloro-4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline (150mg, 0.487mmol), 2-aminopyrimidine-5-boric acid pinacol ester (161mg, 0.73mmol), Cs 2cO 3(238mg, 0.73mmol), Pd (dppf) Cl 2(36mg, 0.049mmol) is mixed in the mixed solvent of Isosorbide-5-Nitrae-dioxane (15mL) and water (2.5mL), is heated to 100 DEG C, stirs 1 hour.Be cooled to room temperature, concentrating under reduced pressure, through purification by silica gel column chromatography, obtain 5-(4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline-2-base) pyrimidine-2-ammonia (106mg, 59%).MS(ESI+)m/z=367[M+1]； 1H NMR(400MHz,DMSO-d 6)δ9.13(s,2H),7.34(s,1H),7.22(s,1H),7.09(br,2H),4.35-4.40(m,4H),3.86(t,4H,J=2.8Hz),3.67(t,4H,J=4.0Hz)。
Embodiment 7: the preparation of the 5-of structural formula (I-7) (4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline-2-base)-4-(trifluoromethyl) pyridine-2-ammonia, concrete reaction formula is as follows:
Nitrogen protection, 2-chloro-4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline (194mg, 0.632mmol), 4-trifluoromethyl-PA-5-pinacol borate (140mg, 0.486mmol), Cs 2cO 3(238mg, 0.73mmol), Pd (dppf) Cl 2(36mg, 0.049mmol) is mixed in the mixed solvent of Isosorbide-5-Nitrae-dioxane (18mL) and water (3mL), is heated to 100 DEG C, stirs 1 hour.Be cooled to room temperature, concentrating under reduced pressure, through purification by silica gel column chromatography, obtain 5-(4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline-2-base)-4-(trifluoromethyl) pyridine-2-ammonia (71mg, 26%).MS(ESI+)m/z=434[M+1]； 1H NMR(300MHz,DMSO-d 6)δ8.54(s,1H),7.35(s,1H),7.20(s,1H),6.81(s,1H),6.75(br,2H),4.38(t,4H,J=6.9Hz),3.75(t,4H,J=4.1Hz),3.60(t,4H,J=2.9Hz)。
Embodiment 8: 2-(1H-indazole-4-base)-4-morpholine-7, the 8-dihydro of structural formula (I-8)-[preparation of Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline, concrete reaction formula is as follows:
Copy the method for embodiment 3, with the chloro-4-morpholine-7 of 2-, 8-dihydro-[1,4] dioxin [2,3-g] quinazoline, 1H-indazole-4-pinacol borate be raw material, can prepare 2-(1H-indazole-4-base)-4-morpholine-7,8-dihydro-[1,4] dioxin [2,3-g] quinazolines.MS(ESI+)m/z=390[M+1]； 1H NMR(400MHz,DMSO-d 6)δ13.2(br,1H),9.01(s,1H),8.29(d,1H,J=8.0Hz),7.67(d,1H,J=8.0Hz),7.48(t,1H,J=5.9Hz),7.44(s,1H),7.39(s,1H),4.39-4.43(m,4H),3.86(t,4H,J=3.2Hz),3.70(d,4H,J=4.4Hz)。
Embodiment 9: the preparation of the 1-ethyl-3-of structural formula (I-9) (4-(4-morpholine-7,8-dihydro-[Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline-2-base) phenyl) urea, concrete reaction formula is as follows:
Copy the method for embodiment 4, with the chloro-4-morpholine-7 of 2-, 8-dihydro-[1,4] dioxin [2,3-g] quinazoline, 1-ethyl-3-(4-pinacol borate-2-base) phenyl) urea is raw material, can prepare 1-ethyl-3-(4-(4-morpholine-7,8-dihydro-[1,4] dioxin [2,3-g] quinazoline-2-bases) phenyl) urea.MS(ESI+)m/z=436[M+1]； 1H NMR(400MHz,DMSO-d 6)δ8.67(br,1H),8.3(d,2H,J=8.8Hz),7.51(d,2H,J=8.8Hz),7.33(s,1H),7.23(s,1H),6.18(br,1H),4.36-4.40(m,4H),3.81(t,4H,J=3.2Hz),3.66(d,4H,J=4.4Hz),3.11-3.14(m,2H),1.06(t,3H,J=5.3Hz)。
Embodiment 10: 2-(2-(difluoromethyl)-1H-benzo [d] imidazoles-1-base)-4-morpholine-7, the 8-dihydro of structural formula (I-10)-[preparation of Isosorbide-5-Nitrae] dioxin [2,3-g] quinazoline, concrete reaction formula is as follows:
Copy the method for embodiment 5, with the chloro-4-morpholine-7 of 2-, 8-dihydro-[1,4] dioxin [2,3-g] quinazoline, 2-(difluoromethyl)-1H-benzo [d] imidazoles be raw material, can prepare 2-(2-(difluoromethyl)-1H-benzo [d] imidazoles-1-base)-4-morpholine-7,8-dihydro-[1,4] dioxin [2,3-g] quinazolines.MS(ESI+)m/z=440[M+1]； 1H NMR(400MHz,DMSO-d 6)δ8.49(d,1H,J=8.0Hz),7.91(t,1H,J=39.8Hz),7.84(d,1H,J=8.0Hz),7.49(t,1H,J=5.7Hz),7.41(t,2H,J=5.7Hz),7.33(s,1H),4.37-4.43(m,4H),3.79(d,8H,J=8.0Hz)。
Embodiment 11: (S)-1-ethyl-3-(4-(8-(3-methylmorpholine)-[1 of structural formula (I-11), 3] dioxs [4,5-g] quinazoline-6-base) phenyl) preparation of urea, concrete reaction formula is as follows:
Step 1: nitrogen protection, by 6, 8-bis-chloro-[1, 3] bis-Evil [4, 5-g] quinazoline (589mg, 2.42mmol) add in methylene dichloride (15mL) and methyl alcohol (15mL), add (S)-3-methylmorpholine (491mg, 4.85mmol), triethylamine (491mg, 4.85mmol), room temperature reaction 5 hours, TLC shows raw material and disappears, concentrated, methylene dichloride and water is added in resistates, organic phase washes with water respectively, saturated common salt is washed, dry, concentrated, obtain the chloro-8-of (S)-6-(3-methylmorpholine)-[1, 3] dioxs [4, 5-g] quinazoline (168mg, 22%).
Step 2:(S) the chloro-8-of-6-(3-methylmorpholine)-[1,3] dioxs [4,5-g] quinazoline (168mg, 0.546mmol), 1-ethyl-3-(4-pinacol borate-2-base) phenyl) urea (174mg, 0.60mmol), Cs 2cO 3(267mg, 0.819mmol), Pd (dppf) Cl 2(40mg, 0.055mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (18mL) with the mixed solvent of water (3mL), is heated to 100 DEG C, stirs 2 hours.TLC shows raw material and disappears, and concentrated, residue by silicagel column chromatography purification, obtains title compound (111mg, 47%).LC-MS(ESI+)m/z=436[M+1]； 1H NMR(300MHz,CDCl 3)δ8.39(d,2H,J=8.4Hz),7.41(d,2H,J=8.4Hz),7.20(s,1H),7.11(s,1H),6.09(s,2H),5.31(br,1H),4.23(s,1H),3.85-3.98(m,3H),3.64(s,3H),3.28(t,2H,J=6.5Hz),2.14(br,1H),1.34(d,3H,J=6.6Hz),1.13(t,3H,J=6.8Hz)。
Embodiment 12: (S)-1-ethyl-3-(5-(4-(3-methylmorpholine)-7 of structural formula (I-11), 8-dihydro-[1,4] dioxin [2,3-g] quinazoline-2-bases) pyrimidine-2-base) preparation of urea, concrete reaction formula is as follows:
Copy the method for embodiment 11, with 2,4-bis-chloro-7,8-dihydro-[1,4] dioxin [2,3-g] quinazoline replaces 6,8-bis-chloro-[1 wherein, 3] bis-Evil [4,5-g] quinazoline, (S)-1-ethyl-3-(5-(4-(3-methylmorpholine)-7,8-dihydros-[1 can be prepared, 4] dioxin [2,3-g] quinazoline-2-bases) pyrimidine-2-base) urea.MS(ESI+)m/z:450[M+1]； 1H NMR(300MHz,CDCl 3)δ8.38(d,2H,J=8.1Hz),7.37-7.42(m,4H),5.33(br,1H),4.37(m,5H),3.68-3.98(m,6H),3.24-3.33(m,2H),2.06(br,1H),1.40(d,3H,J=5.7Hz),1.11(t,3H,J=6.9Hz)。
Biology test case 1: utilize the method test compounds of Kinase-Glo Luminescent Kinase Assay to the inhibit activities of PI3K α
1. prepare the kinase buffer liquid of 1 times of PI3K α: 50mM HEPES, pH7.5; 3mM MgCl 2; 1mM EGTA; 100mM NaCl; 0.03%CHAPS; 2mM DTT.
2. compound preparation
1) compound test final concentration is 100nM and 10nM, is first configured to 100 times of concentration, namely 10 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.The 1mM compound of 10 μ L is added respectively in the second perform hole of 96 orifice plates, add the 100%DMSO of 90 μ L, be made into the 100uM compound of 100 μ L, 100 μMs of compounds of 10 μ L are added respectively in the third line hole of 96 orifice plates, add the 100%DMSO of 90 μ L, be made into 10 μMs of compounds of 100 μ L, redilution 10 times, is made into the compound solution of 1 μM.
2) 100 μ L100%DMSO are added respectively in the first hole and the 12 hole.
3) compound intermediate dilute.Shift 4 μ L compounds in new 96 orifice plates, add the kinase buffer liquid of 1 times of 96 μ L, mixing 10 minutes that vibration plate machine vibrates.
3. prepare 4 times of kinase solution
1) 1 times of kinase buffer liquid is used to configure 4 times of PI3K α solution.Kinase solution final concentration is 1.65nM;
2) transferase 12 .5 μ L4 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.
4. prepare 2 times of substrate solutions
1) 1 times of kinase buffer liquid is used to configure 2 times of substrate solutions.Substrate solution final concentration is PIP2 (50 μMs); ATP (25 μMs);
2) initial action in transferase 45 μ L2 times substrate solution to 384 orifice plate reacting holes;
3) vibrate, mixing.
5. kinase reaction
By 96 orifice plate cover lids, in incubated at room temperature 1 hour.
6. the detection of reaction result
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. digital independent
The luminous numerical value of sample is read at Flexstation.
8. fitting of a curve
1) data of luminous reading are copied from Flexstation program;
2) value of luminous reading is converted to inhibition percentage by 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.
Biology test case 2: utilize the method test compounds of Lance Ultra Assay to the kinase whose inhibit activities of mTOR
1. prepare the kinase buffer liquid of 1 times: 50mM HEPES, pH7.5; 10mM MgCl 2; 1mM EGTA; 3mMMnCl 2; 0.01%Tween-20; 2mM DTT.
2. compound preparation
1) compound test final concentration is 100nM and 10nM, is first configured to 100 times of concentration, i.e. 10uM and 1uM.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.The 1mM compound of 10 μ L is added respectively in the second perform hole of 96 orifice plates, add the 100%DMSO of 90 μ L, be made into 100 μMs of compounds of 100 μ L, 100 μMs of compounds of 10 μ L are added respectively in the third line hole of 96 orifice plates, add the 100%DMSO of 90 μ L, be made into 10 μMs of compounds of 100 μ L, redilution 10 times, is made into the compound of 1 μM.
2) 100 μ L100%DMSO are added respectively in the first hole and the 12 hole.
3) compound intermediate dilute.Shift 4 μ L compounds in new 96 orifice plates, add 1 times of kinase buffer liquid of 96 μ L, mixing 10 minutes that vibration plate machine vibrates.
3. prepare 4 times of kinase solution
1) 1 times of kinase buffer liquid is used to configure 4 times of mTOR solution.Kinase solution final concentration is 2.5nM;
2) transferase 12 .5 μ L4 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.
4. prepare 2 times of substrate solutions
1) 1 times of kinase buffer liquid is used to configure 2 times of substrate solutions.Substrate solution final concentration is ULight-4E-BP150nM; ATP10.8 μM;
2) initial action in transferase 45 μ L2 times substrate solution to 384 orifice plate reacting holes;
3) vibrate, mixing.
5. kinase reaction
By 96 orifice plate cover lids, in incubated at room temperature 1 hour.
6. the detection of reaction result
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. digital independent
The luminous numerical value of sample is read at Envision.
8. 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;
Percent inhibition=(Lance signal-min)/(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 as shown in the table to the inhibiting rate of PI3K α and mTOR under 100nM and 10nM two concentration:

Claims (32)

1. as a tricyclic compounds for PI3K/mTOR inhibitor, it is characterized in that, for having the compound of following general formula (I):
Wherein,
Ar is selected from aryl or heteroaryl, and can replace by 1 to 4 optional substituting group from amino, amido, amide group, sulfoamido, alkyl urea groups, aryl-ureido, heteroaryl urea groups, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, cyano group, carboxyl, ester group, amine formyl, nitro, heterocyclic radical;
X, Y, Z are independently selected from O, CR 2r 3, NR 4; Q is selected from O, CR 2r 3, NR 4or do not exist;
R 1for C 1to C 6alkyl; N is selected from the integer of 0-4; When n>=2, can by two R 1be combined as and ring, bridged ring or volution with morpholine ring; R 2, R 3be selected from hydrogen, C 1to C 6alkyl; R 4be selected from hydrogen, C 1to C 6alkyl, C 3to C 7cycloalkyl, heterocyclic radical, acyl group, alkylsulfonyl; Described alkyl, cycloalkyl, heterocyclic radical, acyl group, alkylsulfonyl all can by halogen, hydroxyl, amino, cyano group, ester group, amide group, sulfoamido replace.
2. as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, in general formula (I), Ar is any one below in structural formula (a) ~ (e) compound monomer:
Wherein, R 5for hydrogen, alkyl, cycloalkyl, aryl, heteroaryl; R 6for halogen, alkyl, alkoxyl group, amido.
3. as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, in general formula (I), X, Y are O; Z is CH 2; Q is CH 2or do not exist.
4., as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, in some embodiments of the present invention, in general formula (I) for any one in structural formula (f) ~ (m) compound monomer below:
5. as claimed in claim 4 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, when containing chiral carbon atom in described structural formula (f) ~ (m) compound monomer, be the optically pure compound monomer of arbitrary configuration or the mixture of enantiomer and diastereomer.
6., as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, general formula (I) compound, be following compound (I-1) to any one in (I-12):
7. as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, described general formula (I) compound is the mixture of any one or arbitrarily both or three in enantiomer, diastereomer, conformer.
8., as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, described general formula (I) compound is pharmacy acceptable derivates.
9., as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, described general formula (I) compound exists as a pharmaceutically acceptable salt form.
10. as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, described general formula (I) compound comprise as a pharmaceutically acceptable salt form salt formed by general formula (I) compound and acid or acid proton the sodium salt, sylvite, magnesium salts, the calcium salt that replace by metal ion.
11. as claimed in claim 1 as the tricyclic compounds of PI3K/mTOR inhibitor, it is characterized in that, formed by described general formula (I) compound and acid, salt is hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate.
The preparation method of 12. tricyclic compoundses as PI3K/mTOR inhibitor according to claim 1, it is characterized in that, concrete steps are: the adjacent aminoaryl formic acid compound A of dicyclo and urea heat fusing altogether, obtain tricyclic antidepressants intermediate B, this intermediate is converted into two chloro intermediate C under the effect of phosphorus oxychloride, carries out nucleophilic substitution, obtain intermediate D with morpholine kind compound, carry out coupling or nucleophilic substitution reaction with aryl compound again, general formula (I) compound can be obtained; Concrete reaction formula is as follows:
13. pharmaceutical compositions, wherein said pharmaceutical composition comprises general formula (I) compound described in any one of claim 1 to 7 claim and the acceptable vehicle of pharmacy for the treatment of significant quantity.
14. pharmaceutical compositions as claimed in claim 13, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
15. pharmaceutical compositions, wherein said pharmaceutical composition comprises pharmacy acceptable derivates and the acceptable vehicle of pharmacy of general formula according to claim 8 (I) compound for the treatment of significant quantity.
16. pharmaceutical compositions as claimed in claim 15, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
17. pharmaceutical compositions, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of general formula (I) compound described in any one of claim 9 to 11 claim for the treatment of significant quantity.
18. pharmaceutical compositions as claimed in claim 17, wherein said pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
General formula (I) compound described in 19. any one of claim 1 to 7 claims regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
The pharmacy acceptable derivates of 20. general formula according to claim 8 (I) compounds regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
The pharmaceutically useful salt of general formula (I) compound described in 21. any one of claim 9 to 11 claims regulates the application in PI3K/mTOR signal path catalytic activity goods in preparation.
Pharmaceutical composition described in 22. any one of claim 13 to 18 claims treats the application in the medicine of the disease relevant with PI3K/mTOR signal path in preparation.
23. apply as claimed in claim 22, and the wherein said disease relevant with PI3K/mTOR signal path is cancer.
24. apply as claimed in claim 23, and wherein said cancer is for being incidence cancer, respiratory system cancer, cancer in digestive system, urinary system cancer, Skeletal system cancer, gynecological cancer, hematological cancer or other types cancer.
25. application according to claim 24, 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.
26. application according to claim 24, wherein said respiratory system cancer is lung cancer.
27. application according to claim 24, 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.
28. application according to claim 24, wherein said urinary system cancer is kidney, bladder cancer, prostate cancer or carcinoma of testis.
29. application according to claim 24, wherein said Skeletal system cancer is osteocarcinoma.
30. application according to claim 24, wherein said gynecological cancer is mammary cancer, cervical cancer or ovarian cancer.
31. application according to claim 24, wherein said hematological cancer is leukemia, malignant lymphoma or multiple myeloma.
32. application according to claim 24, wherein said other types cancer is malignant melanoma, neurospongioma or skin carcinoma.
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