CN102153544A - Preparation method and application of novel tyrosine kinase inhibitors - Google Patents
Preparation method and application of novel tyrosine kinase inhibitors Download PDFInfo
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- CN102153544A CN102153544A CN2010101099923A CN201010109992A CN102153544A CN 102153544 A CN102153544 A CN 102153544A CN 2010101099923 A CN2010101099923 A CN 2010101099923A CN 201010109992 A CN201010109992 A CN 201010109992A CN 102153544 A CN102153544 A CN 102153544A
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- azetidine
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- piperidin
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- IIFNZMFZZLGYKS-UHFFFAOYSA-N O=C(Oc1ccccc1)I Chemical compound O=C(Oc1ccccc1)I IIFNZMFZZLGYKS-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a preparation method and application of novel tyrosine kinase inhibitors. Specifically, the invention relates to novel tyrosine kinase inhibitors shown as a formula I, wherein the definition of each substituent group is expressed in the specification. The invention also relates to the preparation method of the tyrosine kinase inhibitors and the application of the tyrosine kinase inhibitors to preparation of medicaments for treating tumors.
Description
Technical field
The invention belongs to pharmacology, pharmaceutical chemistry and area of pharmacology, more specifically, relate to the preparation method and the purposes in preparation medicine for treating tumor thing of the novel tyrosine kinase inhibitor of a class.
Background technology
The data presentation of China urban and rural residents major causes of death in 2006 of announcing according to the Ministry of Health, malignant tumour, cerebro-vascular diseases and heart trouble are the cause of the death of city resident's front three, urban residents' front three cause of the death then is respectively malignant tumour, cerebro-vascular diseases and respiratory system disease, and wherein malignant tumor mortality rose 18.6% and 23.1% respectively than 2005.This shows that malignant tumour has become China resident's the primary cause of death, and be accelerated development trend.
Protein tyrosine kinase (protein tyrosine kinases, PTKs) with the generation of tumour with develop closely related, the hyperactivity of Tyrosylprotein kinase, cause its downstream signal pathway activation, thereby cause cytodifferentiation, propagation, migration, inhibition apoptosis, finally cause the formation and the transfer [Top Med Chem, 2007 (1): 83-132.] of tumour.Therefore, tyrosine kinase inhibitor has become a development series antineoplastic medicament the most rapidly, to the end of the year 2008 existing lapatinibditosylate (lapatinib), Sutent (sunitimib) wait several small molecules tyrosine kinase inhibitors successively go on the market [Nature, 2006,441,457-462].Compare with traditional cell toxicant series antineoplastic medicament, this class drug selectivity is good, and curative effect height, toxic side effect are little, has become the focus of current antitumor drug research.
But all there are some shortcomings in these marketed drug, and as the further raising of medicine anti-tumor activity of early stage listing, imatinib the resistance problem occurs after using.There are some side effects that are difficult to overcome in the oxysuccinic acid Sutent, as: left ventricular dysfunction, hemorrhage, elevation of blood pressure, diarrhoea, feel sick, [Clin.Cancer Res. such as stomatitis, maldigestion, vomiting, skin disease, parageusia, brothers' syndromes, 2003,9 (1), 327-337.].Lapatinibditosylate is water-soluble relatively poor, and oral administration biaavailability is lower.
Therefore, this area presses for develops novel structure, active strong, the novel tyrosine kinase inhibitor that toxic side effect is little.
Summary of the invention
The purpose of this invention is to provide the novel tyrosine kinase inhibitor of a class, its preparation method and application thereof.
In a first aspect of the present invention, compound and various optical isomer thereof as general formula (I) expression are provided, various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain compound shown in the formula (I) and said derivative thereof pharmaceutical composition as main active ingredient.
In the formula:
X is O or NH;
R
1Can be selected from following structural unit:
R wherein
4, R
5Be H separately, F, Cl, Br, I, CH
3, OCH
3, NO
2, NH
2, SO
2NH
2, CF
3Or OCF
3
R
6Be selected from:
(1) hydrogen, C
1-6Alkyl and C
3-7Cycloalkyl, described alkyl or cycloalkyl are unsubstituted or are replaced by one to three halogen;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
(3) aryl or heteroaryl, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
R
2Can be selected from following structural unit:
M wherein, n, o are separately 1,2 or 3 integer, Y independently is selected from CO, CO
2, S, SO, SO
2, NHCO, NHSO
2, or Y is a chemical bond;
R
9Be selected from:
(1) hydrogen atom, C
1-6Chain or C
3-7Cyclic alkyl, described alkyl be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, O, N, S, SO, SO
2Or CN;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
(3) aryl or heteroaryl, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
In another preference, R
1Be selected from down group: 3-chloro-4-(3-fluorine benzyloxy) phenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-, 4-((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-, 1-(pyridine-2-ylmethyl)-1H-indazole-5-base, 2-(3-luorobenzyl)-1H-indazole-5-base, 1-(pyridine-2-ylmethyl)-2H-indazole-5-base, 2-(3-luorobenzyl)-2H-indazole-5-base, 4-methyl-3-sulfonamido phenyl, (R)-the 1-phenylethyl, the 5-chlorobenzene is [d] [1 also, 3] the assorted amyl group of dioxygen-4-base, 2,4-two chloro-5-p-methoxy-phenyls, 4-(6-picoline-3-base oxygen base)-3-aminomethyl phenyl.
In another preference, R
1Be 3-chloro-4-(3-fluorine benzyloxy) phenyl.
In another preference, X is O or NH; And/or
R
2Be selected from down group: 1-cyclohexyl piperidin-4-yl; 1-methyl piperidine-4-base; 1-cyclopentyl piperidin-4-yl; 1-isobutyl-piperidin-4-yl; 1-(amyl group-3-yl) piperidin-4-yl; 1-tertiary amyl piperidin-4-yl; 1-sec.-propyl piperidin-4-yl; 1-cyclobutyl piperidin-4-yl; 1-benzyl piepridine-4-base; 1-(4-methoxy-benzyl) piperidin-4-yl; 1-((pyridin-4-yl) methyl) piperidin-4-yl; 1-((furans-2-yl) methyl) piperidin-4-yl; 1-((thiophene-2-yl) methyl) piperidin-4-yl; 1-(4-tertiary butyl benzyl) piperidin-4-yl; 1-tertiary butyl piperidin-4-yl; 1-cyclopropyl piperidine-4-base; 1-(4-(dimethyl amido) but-2-ene-1-carbonyl) piperidin-4-yl; 1-((2-(dimethyl amido) ethyl) formamyl) piperidin-4-yl; 1-(pentane-3-yl) azetidine-3-base; 1-sec.-propyl azetidine-3-base; 1-cyclopentyl azetidine-3-base; 1-cyclobutyl azetidine-3-base; 1-(ring fourth oxygen-3-yl) azetidine-3-base; 1-methyl azetidine-3-base; 1-(cyclopropyl methyl) azetidine-3-base; 1-(2-(methyl sulfuryl) ethyl) azetidine-3-base; 1-benzyl azetidine-3-base; 1-(4-tertiary butyl benzyl) azetidine-3-base; 1-(pyridin-4-yl) azetidine-3-base; 1-(furans-2-yl) azetidine-3-base; 1-(thiophene-2-yl) azetidine-3-base; 1-(5-methyl furan-2-yl) azetidine-3-base; 1-cyclopropyl azetidine-3-base; 1-tertiary butyl azetidine-3-base; 2-(2-(first sulfo group) ethyl amido) ethyl; 2-(pyrroles-1-yl) ethyl; 2-(4-methylsulfonyl piperazine-1-yl) ethyl; 2-(4-methylpiperazine-1-yl) ethyl; 2-(4-methylamino formyl piperazine-1-yl) ethyl; 2-(4-formamyl piperazine-1-yl) ethyl; 2-(N; N-diethyl amido) ethyl; 2-(piperidines-1-yl) ethyl; 2-(morpholinyl) ethyl; 2-(4-(N; the N dimethylamine base) ethyl formyl piperazine-1-yl); 2-(4-(morpholinyl) formyl piperazine-1-yl) ethyl; 2-(4-(tetramethyleneimine-1 base) formyl piperazine-1-yl) ethyl; the 2-hydroxyethyl; (R)-1-benzyl-pyrrole alkane-3-base, (S)-1-benzyl-pyrrole alkane-3-base, (R)-1-ethyl pyrrolidine-3-base.
In another preference, X is NH.
In another preference, R
2It is 1-tertiary butyl azetidine-3-base.
In another preference, described compound is the compound 1 to 84 in the table 1.
In a second aspect of the present invention, provide the preparation method of pharmaceutically acceptable inorganic or organic salt, hydrate or solvate of above-mentioned novel benzo pyridine compound with anti-tumor activity or its.
The The compounds of this invention pharmacy acceptable salt, can enumerate the salt of mineral acids such as above-claimed cpd and hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid particularly, form salt with the acid of organic acid such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, p-methyl benzenesulfonic acid, ethyl sulfonic acid and acidic amino acids such as Tianmen propylhomoserin, L-glutamic acid.
In another preference, described compound is mesylate, p-methyl benzenesulfonic acid salt or hydrochloride.
In a third aspect of the present invention, a kind of pharmaceutical composition is provided, it contains acceptable vehicle or carrier on the pharmacology, and above-claimed cpd of the present invention (or its each optical isomer, each crystal formation) and pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
In a fourth aspect of the present invention, the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate is provided, it is used to prepare tyrosine kinase inhibitor.
In a fifth aspect of the present invention, the purposes of compound of the present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate is provided, and it is used to prepare the medicine that suppresses tyrosine kinase activity or is used to prepare the medicine of the too high relevant disease of treatment, prevention and alleviation and tyrosine kinase activity.
In another preference, describedly be selected from tumour with the too high relevant disease of tyrosine kinase activity.
In a fifth aspect of the present invention, a kind of method of inhibition growth of tumour cell of external non-therapeutic is provided, described method comprises the steps: the contacting of described tumour cell and the compound described in the first aspect present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, thereby suppresses the growth of tumour cell.
In a sixth aspect of the present invention, a kind of method that suppresses the growth of tumour cell of individuality is provided, described method comprises the steps: the described individuality that is applied to the compound described in the first aspect present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, thereby suppresses the growth of tumour cell.
In a seventh aspect of the present invention, provide the application in the medicine of preparation treatment tumor disease of above-mentioned novel benzo pyridine compound or its pharmacy acceptable salt.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and specifically described in below (eg embodiment) each technical characterictic can make up mutually, thereby constitute new or optimized technical scheme.
Embodiment
The inventor is through extensive studies, and is synthetic and screened a large amount of compounds, and that Tyrosylprotein kinase is had a very high inhibition is active and have very strong anti-tumor activity for discoverable type (I) compound first, is particularly suitable for preparing antitumor drug.The inventor has finished the present invention on this basis.
Preferably, the present invention is suc as formula in the compound shown in (I) structure, and representational compound title and structural formula see the following form 1.
Table 1 representative compounds and structural formula thereof
Detailed description of the invention
Unless otherwise specified, the following term that is used in specification sheets and claims has following implication:
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 6 carbon atom.The median size alkyl that preferably contains 1 to 6 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl etc.
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan or 6 yuan/6 yuan fused rings of carbon or encircles the fused rings group more, and wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.The cycloalkyl example has cyclopropyl, cyclobutyl, cyclopentyl, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.
" aryl " refers to have the group of at least one aromatic ring structure, promptly has the aromatic ring of conjugated πDian Zi system, comprises isocyclic aryl, heteroaryl.
" heteroaryl " refers to have 1 to 3 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur, nitrogen.Described ring can be 5 yuan or 6 yuan of rings.The heterocyclic aryl examples of groups includes but not limited to furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazyl, indyl, triazinyl, purine radicals, quinolyl, isoquinolyl etc.
" halogen " refers to fluorine, chlorine, bromine or iodine.
Therefore compound of the present invention can contain one or more asymmetric centers, and occurs with the form of raceme, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.The asymmetric center that can exist depends on various substituent character on the molecule.Each this asymmetric center will produce two optically active isomers independently, and all possible optically active isomer and non-enantiomer mixture and pure or partial-purified compound comprise within the scope of the present invention.The present invention means all this isomeric form that comprise these compounds.
Compounds more described herein can exist with tautomeric forms, and it has the different hydrogen interface with one or more migration of the double bond.
Activeconstituents
As used herein, term " activeconstituents " refers to compound shown in the formula (I)." activeconstituents " also comprises the various crystal formations of formula (I) compound, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.There are one or more unsymmetrical carbons in The compounds of this invention, and therefore, compound comprises the racemic modification thing shown in the formula (I), racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.
Pharmacy acceptable salt
" pharmacy acceptable salt " used herein be meant so long as pharmaceutically acceptable salt just there is no particular limitation, can enumerate The compounds of this invention and the sour salt that forms particularly, being fit to salifiable acid includes, but is not limited to: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, mineral acids such as phosphoric acid, formic acid, acetate, propionic acid, oxalic acid, trifluoroacetic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, organic acid and aspartic acids such as p-methyl benzenesulfonic acid, acidic amino acids such as L-glutamic acid.
The synthetic method of The compounds of this invention
Describe the preparation method of general formula of the present invention (I) structural compounds below particularly, but these concrete grammars do not constitute any restriction to the present invention.
General formula of the present invention (I) structural compounds can make by following method, however the condition of this method, and for example the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc. are not limited to following explanation.The compounds of this invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
In preparation method of the present invention, each reaction in inert solvent, is carried out to solvent refluxing temperature (preferred room temperature～80 ℃) at-30 ℃ usually.Reaction times is generally 0.1 hour～and 60 hours, preferably be 0.5～48 hour.
The preparation method of general formula of the present invention (I) compound can be by following each flow preparation, comprising:
The preparation of flow process I: intermediate compound I-3a-I-3n
Flow process 1
In the formula, representational R comprises following group:
(1) intermediate compound I-1 (US2005101617) under neutrality or alkaline condition, obtained intermediate compound I-2a-I-2n in 1-12 hour in-20 ℃-100 ℃ (or under reflux temperatures) and corresponding amine reaction in polar solvent (inert solvent).Polar solvent can be a methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile, DMF.Alkali can be selected from organic basess such as mineral alkali or DBU such as sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, diisopropyl ethyl amine, N-methylmorpholine.Optimum reaction condition is for being solvent with the Virahol, and 70-90 ℃ was reacted 1-5 hour.(2) intermediate compound I-2a-I-2n is in polar aprotic solvent, under suitable temperature, rare gas element and suitable alkali exist down, obtain a series of trimethylsilyl acetylene bases with palladium/copper mixed catalyst catalysis trimethylsilyl acetylene and halogenide cross-coupling and replace intermediate.Polar aprotic solvent is selected from tetrahydrofuran (THF), ether, methylene dichloride, toluene, 1,4-dioxane, dimethyl formamide, N-Methyl pyrrolidone, acetonitrile etc.; Temperature range is between 20-120 ℃; Alkali can be selected from yellow soda ash, salt of wormwood, cesium carbonate, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Palladium catalyst optional two (triphenylphosphine) palladium chloride, two (cyano group benzene) palladium chloride, tetrakis triphenylphosphine palladium, palladium etc.; Copper catalyst is selected cuprous iodide for use.Optimum condition is: with two (triphenylphosphine) palladium chlorides and cuprous iodide is catalyzer, and triethylamine is an alkali, and tetrahydrofuran (THF) is that solvent under refluxad reacted 6 hours.The tetrahydrofuran solution of this serial trimethylsilyl acetylene base replacement intermediate directly in the presence of fluorine reagent, in-20 ℃-50 ℃ reactions 0.1-4 hour, obtains intermediate compound I-3a-I-3n.Optimum reaction condition is that trifluoroacetic acid exists room temperature reaction 5-30 minute down.
The preparation of flow process II: intermediate II-3a-II-3d
Flow process 2
In the formula, representational R comprises following group:
(1) intermediate compound I-1 is in polar solvent (inert solvent), and under alkaline condition, reaction obtained intermediate II-2a-II-2d in 1-24 hour with the corresponding phenolic compound in-20 ℃-100 ℃.Polar solvent can be a methyl alcohol, ethanol, Virahol, the trimethyl carbinol, acetonitrile, DMF.Alkali can be selected from organic basess such as mineral alkali or DBU such as sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, diisopropyl ethyl amine, N-methylmorpholine.Optimum reaction condition is for being solvent with DMF, and salt of wormwood is done alkali, room temperature reaction 4-16 hour;
(2) intermediate II-2a-II-2d is in polar aprotic solvent, under suitable temperature, rare gas element and suitable alkali exist down, obtain a series of trimethylsilyl acetylene bases with palladium/copper mixed catalyst catalysis trimethylsilyl acetylene and halogenide cross-coupling and replace intermediate.Polar aprotic solvent is selected from tetrahydrofuran (THF), ether, methylene dichloride, toluene, 1,4-dioxane, dimethyl formamide, N-Methyl pyrrolidone, acetonitrile etc.; Temperature range is between 20-120 ℃; Alkali can be selected from yellow soda ash, salt of wormwood, cesium carbonate, triethylamine, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Palladium catalyst optional two (triphenylphosphine) palladium chloride, two (cyano group benzene) palladium chloride, tetrakis triphenylphosphine palladium, palladium etc.; Copper catalyst is selected cuprous iodide for use.Optimum condition is: with two (triphenylphosphine) palladium chlorides and cuprous iodide is catalyzer, and triethylamine is an alkali, and tetrahydrofuran (THF) is that solvent under refluxad reacted 6 hours.The tetrahydrofuran solution of this serial trimethylsilyl acetylene base replacement intermediate directly in the presence of fluorine reagent, in-20 ℃-50 ℃ reactions 0.1-4 hour, obtains intermediate II-3a-II-3d.Optimum reaction condition is that trifluoroacetic acid exists room temperature reaction 5-30 minute down.
The preparation of flow process III: intermediate III-3a-III-3n
Flow process 3
In the formula, R
1R
2The CH group is as follows:
(1) raw material II I-1 in polar solvent and corresponding aldehydes or ketones under-20 to 80 ℃, go back original reagent in the presence of carry out obtaining in reductive amination process 1-24 hour corresponding intermediate III-2a-III-2n.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methylene dichloride, 1,2-ethylene dichloride, 1,4-dioxane, DMF, acetonitrile, glycol dimethyl ether etc.Reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, sodium triacetoxy borohydride etc.Optimum reaction condition is, methylene dichloride is a solvent, and sodium triacetoxy borohydride is a reductive agent, at room temperature reacts 4-16 hour.
(2) intermediate III-2a-III-2n in the presence of triphenylphosphine and azide reagent carry out Mitsunobu reaction and obtain intermediate III-3a-III-3n.Solvent can be selected tetrahydrofuran (THF) for use, and 1,4-dioxane, methyl tert-butyl ether etc.; Azide reagent can be selected from sodiumazide, DPPA etc.Optimum reaction condition is, in the presence of triphenylphosphine, is solvent with the tetrahydrofuran (THF), and DPPA is an azide reagent, room temperature reaction 4-16 hour.
The preparation of flow process IV: intermediate compound IV-4a and IV-4b
Flow process 4
(1) raw material IV-1 (J.Org.Chem., 2005,70 (5), 1930-1933) in the presence of vinylformic acid, under alkaline condition, make solvent and corresponding amine obtained intermediate compound IV-2a and IV-2b in 2-24 hour in room temperature-80 a ℃ reaction with water.Alkali can be selected from organic basess such as lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta, and optimum reaction condition is for being alkali with sodium hydroxide, 40-70 ℃ of reaction 6-16 hour.
(2) raw material IV-2a and IV-2b obtained intermediate compound IV-3a and IV-3b with reductive agent in 2-12 hour-20 ℃ to 50 ℃ reactions in polar aprotic solvent.Polar aprotic solvent can be selected from methyl alcohol, ethanol, and Virahol, the trimethyl carbinol etc., reductive agent can be selected from sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE etc.Optimum reaction condition is that ethanol is made solvent, and sodium borohydride was done the reductive agent room temperature reaction 2-6 hour.
(3) intermediate compound IV-3a and IV-3b in the presence of triphenylphosphine and azide reagent carry out Mitsunobu reaction and obtain intermediate compound IV-4a and IV-4b.Solvent can be selected tetrahydrofuran (THF) for use, and 1,4-dioxane, methyl tert-butyl ether etc.; Azide reagent can be selected from sodiumazide, DPPA etc.Optimum reaction condition is, in the presence of triphenylphosphine, is solvent with the tetrahydrofuran (THF), and DPPA is an azide reagent, room temperature reaction 6-16 hour.
Flow process V: the preparation of intermediate V-2b and V-3a
Flow process 5
(1) in polar aprotic solvent, under suitable temp, V-1 (Tetrahrdron Lett., 2005,46 (16), 2911-2914), in the presence of alkali, react with corresponding acyl chlorides, obtain intermediate V-2a and V-2b.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Optimum condition is: with the triethylamine is alkali, is solvent with the tetrahydrofuran (THF), and room temperature reaction spends the night.
(2) intermediate V-2a is in the non-polarity proton solvent, under alkaline condition and N
1, N
1-dimethyl-ethylenediamine is reflected to react under the suitable temp and obtained intermediate V-3a in 1-24 hour.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Alkali can be selected from yellow soda ash, salt of wormwood, imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Optimum condition is: with salt of wormwood is alkali, is solvent with the dimethyl formamide, and 30-60 ℃ of reaction spent the night.
Flow process VI: the preparation of intermediate VI-3a-VI-3q
Flow process 6
In the formula, R
1R
2The CH group is as follows:
(1) raw material VI-1 (WO2006021881) in polar solvent and corresponding aldehydes or ketones under-20-80 ℃, go back original reagent in the presence of carry out obtaining in reductive amination process 1-24 hour corresponding intermediate VI-2a-VI-2o.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methylene dichloride, 1, the 2-ethylene dichloride, 1,4-dioxane, DMF, acetonitrile, glycol dimethyl ethers etc., reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, sodium triacetoxy borohydride etc.Optimum reaction condition is, methylene dichloride is a solvent, and sodium triacetoxy borohydride is a reductive agent, at room temperature reacts 2-16 hour.
(2) intermediate VI-2a-VI-2o, 1-cyclopropyl aza-cyclobutane-3-alcohol (SyntheticCommunications, 2003,22 (24), 4297-4302.), 1-tertiary butyl aza-cyclobutane-3-alcohol (Synthetic Communications, 2003,22 (24), 4297-4302.) in polar aprotic solvent, under suitable temp, in the presence of alkali, react and methylsulfonyl chloride reaction obtains corresponding methanesulfonates intermediate.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Optimum condition is: with the triethylamine is alkali, is solvent with the methylene dichloride, 0 ℃-room temperature reaction 3 hours.The methanesulfonates intermediate that obtains in polar aprotic solvent, under suitable temp and the azide reagent react obtain intermediate VI-3a-VI-3q, polar aprotic solvent is selected from methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1, the 4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0 ℃-100 ℃; Azide reagent can be selected from sodiumazide, potassium azide etc.; Top condition was, is solvent with DMF, and sodiumazide is an azide reagent, 30-80 ℃ of reaction 2-8 hour.
Flow process VII: the preparation of intermediate VII-2a-VII-2l
Flow process 7
(1) in polar aprotic solvent, under suitable temp, VII-1 (Org.Lett., 2001,3 (25), 4091-4094), in the presence of alkali, react with corresponding amine, obtain intermediate VII-2a-VII-2l.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Alkali can be selected from imidazoles, triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine etc.; Optimum condition is: with the triethylamine is alkali, is solvent with the acetonitrile, and the back flow reaction reaction is spent the night.
Flow process VIII: the preparation of compound 1-14
Flow process 8
Raw material I-3a-I-3n is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, under protection of inert gas, carries out D-A reacting generating compound 1-14 at suitable temp and raw material VI-3q.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
Flow process IX: the preparation of compound 15-18
Flow process 9
Raw material II-3a-II-3d is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, under protection of inert gas, carries out D-A reacting generating compound 15-18 at suitable temp and raw material VI-3q.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
Flow process X: the preparation of compound 19-68
Flow process 10
Raw material I-3a is in polar solvent; at Tong Shiji and sodium ascorbate is catalyzer; under protection of inert gas, at suitable temp and raw material II I-3a-3n, IV-4a; IV-4b; V-2b, V-3a, VI-3a-3p; VII-2a-2l; (R)-3-nitrine-1-benzyl-pyrrole (J.Med.Chem., 1992,35 (22); 4205-4213.); (S)-3-nitrine-1-benzyl-pyrrole (WO2004056767), (S)-3-nitrine-1-N-ethyl pyrrole N-(J.Org.Chem., 1998; 63 (23), 8266-8275.) carry out D-A reacting generating compound 19-68.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
Flow process XI: the preparation of compound 69-76
Flow process 11
Raw material I-3b is a catalyzer at Tong Shiji and sodium ascorbate, under protection of inert gas in polar solvent; at suitable temp and raw material II I-3e; IV-4a, VI-3a, VI-3b; VI-3j VII-2a; VII-2f, 2-azidoethyl alcohol (Org.Lett., 2001; 3 (25), 4091-4094) carry out D-A reacting generating compound 69-76.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
Flow process XII: the preparation of compound 77-80
Flow process 12
Raw material I-3d is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, under protection of inert gas, and at suitable temp and raw material II I-3e, IV-3a, VI-3a, VI-3b carry out D-A reacting generating compound 77-80.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
Flow process XIII: the preparation of compound 81-84
Flow process 13
Raw material I-3g is a catalyzer at Tong Shiji and sodium ascorbate in polar solvent, under protection of inert gas, and at suitable temp and raw material II I-3e, IV-3a, VI-3a, VI-3b carry out D-A reacting generating compound 81-84.Polar solvent can be selected from methyl alcohol, ethanol, Virahol, trimethyl carbinol isopolarity protonic solvent and methylene dichloride, chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, DMF, dimethyl sulfoxide (DMSO), acetonitrile isopolarity aprotic solvent; Tong Shiji can be selected from anhydrous cupric sulfate, cupric sulfate pentahydrate, neutralized verdigris, cuprous iodide; Temperature is a room temperature-120 ℃, and the reaction times is 0.1-24 hour.Optimum reaction condition is, is solvent with DMF, with cupric sulfate pentahydrate and sodium ascorbate be catalyzer under argon shield, be heated to 40-80 ℃ the reaction 0.2-4 hour.
As required, can be in the polar protic solvent with compound of the present invention, as methyl alcohol, ethanol, Virahol and pharmaceutically the acceptable acid-respons generate pharmacy acceptable salt and prepare.Described pharmaceutically acceptable inorganic or organic acid is: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, aspartic acid or L-glutamic acid.
Pharmaceutical composition and application process
Because The compounds of this invention has excellent tyrosine kinase inhibitory activity, therefore The compounds of this invention and various crystal formation thereof, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and to contain The compounds of this invention be that the pharmaceutical composition of main active ingredient can be used for treatment, prevention and alleviates tyrosine kinase related disorder.Particularly, The compounds of this invention can be used for suppressing the growth of tumour (cell).
Pharmaceutical composition of the present invention comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-1000mg The compounds of this invention/agent, and preferably 5-500mg The compounds of this invention/agent more preferably, contains 10-200mg The compounds of this invention/agent.
Acceptable salt can be made into various preparations on compound of the present invention and the pharmacology thereof, wherein comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.The safety of compound, significant quantity are determined according to particular cases such as age of treatment target, the state of an illness, the courses of treatment.
" acceptable vehicle or carrier on the pharmacology " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as in the composition each component can and compound of the present invention and blending mutually between them, and the drug effect of not obvious reduction compound.Acceptable vehicle or carrier part example have Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween on the pharmacology
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
When using The compounds of this invention, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
The compounds of this invention can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.
When making pharmaceutical composition, it is the Mammals (as the people) that the The compounds of this invention of safe and effective amount is applicable to the needs treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using, for the people of 60kg body weight, day dosage is generally 1～1000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Major advantage of the present invention comprises:
(1) The compounds of this invention is the tyrosine kinase inhibitor of a class recruit structure.
(2) The compounds of this invention has stronger inhibition activity to Tyrosylprotein kinase.
(3) The compounds of this invention has stronger inhibition activity to tumour cell.
(4) The compounds of this invention has excellent pharmacokinetic property.
More specifically explain the present invention in the following embodiments.Yet, should be appreciated that these embodiment are in order to demonstrate the invention, and be not to limit the scope of the invention by any way.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Among all embodiment, fusing point is measured with X-4 fusing point instrument, and thermometer is not proofreaied and correct;
1H-NMR VarianMercury 300 or 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate with the undeclared 200-300 order that is of silica gel, the proportioning of elutriant is volume ratio.
Embodiment 1 N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine (I-2a)
(1.0g 3.44mmol) is dissolved in the Virahol (50mL), stirs to add 3-chloro-4-(3-fluorine benzyloxy) aniline (0.87g down with raw material I-1,3.44mmol), reflux 3h is cooled to room temperature, leaves standstill 6 hours, there are a large amount of solids to separate out, filter a small amount of washed with isopropyl alcohol of filter cake, oven dry, obtain intermediate compound I-2a (yellow solid (1.7g, 98%).
1H?NMR(DMSO-d
6，400MHz)：δ5.21(s，2H)，7.15(m，1H)，7.29(m，3H)，7.46(m，1H)，7.64(m，1H)，7.70(m，1H)，7.90(s，1H)，8.36(d，J＝6.30Hz，1H)，8.92(s，1H)，9.26(s，1H)，11.53(br?s，1H).
Be similar to the synthetic of intermediate compound I-2a, following intermediate compound I-2b to I-2n can be synthesized with various arylamine by raw material I-1 and obtains.
Table 2
| Numbering | Name | 1H?NMR(DMSO-d 6，400MHz)δ | Yield |
| I-2b | N-(3-chloro-4-fluorophenyl)-6-iodine quinazoline-4-amine | 7.42(d，J＝8.9Hz，1H)，7.78-7.82(m，1H)， 8.20(m，3H)，8.75(s，1H)，9.22(s，1H)， 11.15(s，1H). | 96％ |
| I-2c | N-(4-bromo-2-fluorophenyl)-6-iodine quinazoline-4-amine | 7.49-7.57(m，2H)，7.74-7.80(m，2H)， 8.36-8.39(m，1H)，8.90(d，J＝4.0Hz，1H)， 9.27(d，J＝8.4Hz，1H). | 99％ |
| I-2d | N-(4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine | 5.34(s，2H)，7.33-7.43(m，2H)，7.60-7.68(m， 3H)，7.90-7.95(m，2H)，8.34(d，J＝9.1Hz， 1H)，8.61(d，J＝3.6Hz，1H)，8.93(s，1H)， 9.20(s，1H)，11.43(s，1H). | 99％ |
| I-2e | N-(4-((pyridine-3-yl) methoxyl group)-3-chloro-phenyl-)-6-iodine quinazoline-4-amine | 5.35(s，2H)，7.37(d，J＝4.8Hz，1H)， 7.62-7.71(m，3H)，7.94(d，J＝2.4Hz，1H)， 8.10(d，J＝6.0Hz，1H)，8.29(d，J＝8.4Hz， 1H)，8.66(d，J＝4.4Hz，1H)，8.79(s，1H)， 8.87(s，1H)，9.22(m，1H)，11.26(br?s，1H). | 99％ |
| I-2f | N-(1-(pyridine-2-ylmethyl)-1H-indazole-5-yl)-6-iodine quinazoline-4-amine | 5.72(s，2H)，7.23(d，J＝8.4Hz，1H)， 7.35-7.36(m，1H)，7.49(d，J＝9.2Hz，1H)， 7.65-7.71(m，2H)，7.79-7.82(m，1H)，8.07(s， 1H)，8.34(d，J＝8.7Hz，1H)，8.55(s，1H)， 8.63(s，1H)，8.77-8.89(m，1H)，9.23(s，1H)， 11.35(s，1H). | 93％ |
| I-2g | N-(2-(3-fluorine benzyl | 5.74(s，2H)，7.06-7.15(m，3H)， | 98％ |
| Base)-1H-indazole-5-yl)-6-iodine quinazoline-4-amine | 7.34-7.40(m，1H)，7.63-7.74(m，2H)， 7.84-7.87(d，J＝8.5Hz，1H)，8.10(s，1H)， 8.24(s，1H)，8.36-8.38(d，J＝8.6Hz，1H)， 8.89(s，1H)，9.27(s，1H)，11.62-11.67(m， 1H). | ||
| I-2h | N-(1-(pyridine-2-ylmethyl)-2H-indazole-5-yl)-6-iodine quinazoline-4-amine | 5.79(s，2H)，7.23(d，J＝8.4Hz，1H)， 7.35-7.36(m，1H)，7.49(d，J＝9.3Hz，1H)， 7.65-7.71(m，2H)，7.79-7.82(m，1H)，8.07(s， 1H)，8.34(d，J＝8.7Hz，1H)，8.55(s，1H)， 8.63(s，1H)，8.77-8.89(m，1H)，9.22(s，1H)， 11.41(s，1H). | 91％ |
| I-2i | N-(2-(3-luorobenzyl)-2H-indazole-5-yl)-6-iodine quinazoline-4-amine | 5.74(s，2H)，7.06-7.15(m，3H)， 7.34-7.41(m，1H)，7.63-7.74(m，2H)， 7.84-7.88(d，J＝14.7Hz，1H)，8.10(s，1H)， 8.24(s，1H)，8.38(d，J＝1.6Hz，1H)， 8.89(s，1H)，9.22(s，1H)，11.50(s，1H). | 99％ |
| I-2j | 5-(6-iodine quinazoline-4-base is amino)-2-methyl benzenesulfonamide | 2.61(s，3H)，7.48(t，J＝5.6Hz，4H)，7.74(d， J＝7.2Hz，1H)，7.90(dd，J 1＝2.4Hz，J 2＝7.6 Hz，1H)，8.21(d，J＝2.4Hz，1H)，8.35(dd.J 1 ＝2.0Hz，J 2＝8.8Hz，1H)，8.93(s，1H)， 9.28(d，J＝0.4Hz，1H)，11.63(s，1H). | 91％ |
| I-2k | N-((R)-1-phenylethyl)-6-iodine quinazoline-4-amine | 1.58(d，J＝7.0Hz，3H)，5.57(m，1H)， 7.21(t，J＝7.8Hz，1H)，7.32(d，J＝7.8Hz， 2H)，7.44(m，3H)，8.02(dd，J＝2.1，6.7Hz， 1H)，8.42(s，1H)，8.60(d，J＝8.0Hz，1H)， 8.92(d，J＝2.1Hz，1H). | 87％ |
| I-2l | N-(the 5-chlorobenzene is the assorted amyl group of [d] [1,3] dioxygen-4-yl also)-6-iodine quinazoline-4-amine | 5.72(s，2H)，6.12(d，J＝2.5Hz，1H)， 6.58(dd，J 1＝2.5Hz，J 2＝6.7Hz，1H)，7.98(d， J＝2.1Hz，1H)，8.21(m，1H)，8.32(d，J＝6.2 Hz，1H)，9.21(s，1H)，11.25(m，1H). | 88％ |
| I-2m | N-(2,4-two chloro-5-p-methoxy-phenyls)-6- | 3.84(s，3H)，6.34(s，1H)，7.34(m，1H)， 7.96(d，J＝2.1Hz，1H)，8.21(m，1H)，8.32(d， | 92％ |
| Quinazoline-4-amine | J＝6.2Hz，1H)，9.23(s，1H)，11.35(m，1H). | ||
| I-2n | N-(4-(6-picoline-3-base oxygen base)-3-aminomethyl phenyl)-6-iodine quinazoline-4-amine | 2.38(s，3H)，2.73(s，3H)，6.54(s，1H)， 6.68(d，J＝2.4Hz，1H)，6.74(d，J＝2.5Hz， 1H)，7.47(d，J＝2.7Hz，1H)，7.56(d，J＝2.7 Hz，1H)，7.96(d，J＝2.3Hz，1H)，8.21(m，1H)， 8.32(d，J＝6.2Hz，1H)，8.64(s，1H)，9.23(s， 1H)，11.35(m，1H). | 93％ |
Embodiment 2 N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-ethynyl quinazoline-4-amine (I-3a)
With I-2a (2.0g 4.2mmol) is dissolved among the THF (120mL), stir add down CuI (70mg, 0.36mol), Pd (PPh
3)
2Cl
2(164mg, 0.3mmol), Et
3N (1.42mL), and trimethylsilyl acetylene (0.98mL, 4.2mmol), under the protection of argon gas, heating refluxes, and the control oil bath temperature is about 80 ℃, and reaction is spent the night, and after the TLC monitoring reaction was complete, cool to room temperature filtered, and filter cake washs with THF.Filtrate is changed in the 250mL there-necked flask, feed argon gas, stir.(2.0g 7.6mg), adds system fast with a small amount of THF dissolving tetra-n-butyl Neutral ammonium fluoride, after reacting 5min under the room temperature, react completely, reaction solution is poured in the Erlenmeyer flask that cold water (1200mL) is housed, have a large amount of brownish black solids to separate out, filter, consider cake and wash with water, oven dry is with a small amount of THF dissolving, silica gel mixed sample, column chromatography (V
PE:THF=5/1), obtains yellow solid I-3a (yellow solid 530mg, 34%).
1H?NMR(400MHz，CDCl
3)：δ4.42(s，1H)，5.18(s，2H)，6.99-7.06(m，2H)7.21-7.26(m，2H)，7.34-7.40(m，2H)，7.52(dd，J
1＝2.7Hz，J
2＝8.8Hz，1H)，7.86(d，J＝3.2Hz，3H)，8.03(s，1H)，8.75(s，1H).
Be similar to the synthetic of intermediate compound I-3a, following intermediate compound I-3b to I-3n can be synthesized by raw material I-2b to I-2n and obtains.
Table 3
| Numbering | Name | 1H?NMR(CDCl 3，400MHz)δ | Yield |
| I-3b | N-(3-chloro-4-fluorophenyl)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，7.42(d，J＝8.9Hz，1H)， 8.20(m，3H)，8.62(s，1H)，8.75(s，1H)， 9.92(s，1H). | 78％ |
| I-3c | N-(4-bromo-2-fluorophenyl)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，7.47-7.55(m，3H)，7.68(d，J ＝9.2Hz，1H)，7.78(d，J＝7.9Hz，1H)， 7.89(d，J＝8.7Hz，1H)，8.52(s，1H)， | 62％ |
| 8.69(s，1H)，10.02(s，1H). | |||
| I-3d | N-(4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，5.27(s，2H)，7.26(d，J＝8.4 Hz，1H)，7.33-7.36(m，1H)，7.55- 7.60(m，1H)，7.72(dd，J 1＝2.8Hz，J 2＝ 8.8Hz，2H)，7.83-7.88(m，2H)，8.04(d，J ＝5.2Hz，1H)，8.58(d，J＝5.2Hz，2H)， 8.73(s，1H)，9.86(s，1H). | 47％ |
| I-3e | N-(4-((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-6-ethynyl quinazoline-4-amine | 4.43(s，1H)，5.28(s，2H)，7.33(d，J＝9.2 Hz，1H)，7.7.44-7.46(m，1H)，7.56- 7.63(m，1H)，7.75-7.79(m，2H)，7.86- 7.92(m，2H)，8.05(s，1H)，8.56-8.62(m， 2H)，8.71-8.76(m，2H)，9.81(s，1H). | 66％ |
| I-3f | N-(1-(pyridine-2-ylmethyl)-1H-indazole-5-yl)-6-ethynyl quinazoline-4-amine | 4.40(s，1H)，5.75(s，2H)，6.96(d，J＝6.4 Hz，1H)，7.26-7.29(m，4H)，7.84(dd，J 1＝ 2.0Hz，J 2＝8.4Hz，1H)，8.14(s，1H)， 8.23(s，1H)，8.51(t，J＝8.4Hz，2H)， 8.78(d，J＝1.6Hz，1H)，9.98(s，1H). | 91％ |
| I-3g | N-(2-(3-luorobenzyl)-1H-indazole-5-yl)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，5.67(s，2H)，7.15-7.18(m， 3H)，7.56-7.60(m，3H)，7.85-7.87(m，2H)， 8.25(s，1H)，8.52-8.58(d，J＝18.4Hz， 2H)，8.82(s，1H)，9.92(s，1H). | 58％ |
| I-3h | N-(1-(pyridine-2-ylmethyl)-2H-indazole-5-yl)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，5.75(s，2H)，7.16(d，J＝7.8 Hz，1H)，7.34(t，J＝6.0Hz，1H)， 7.55-7.64(m，2H)，7.73-7.81(m，2H)， 7.86(dd，J 1＝1.5Hz，J 2＝9.0Hz，1H)， 8.25(s，1H)，8.53(d，J＝7.5Hz，2H)， 8.58(s，1H)，8.82(s，1H)，9.92(s，1H). | 56％ |
| I-3i | N-(2-(3-luorobenzyl)-2H-indazole-5-yl)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，5.69(s，2H)，7.03-7.12(m， 3H)，7.33-7.36(m，1H)，7.71-7.75(m，2H)， 7.98-8.00(m，1H)，8.16(s，2H)， 8.24-8.28(m，1H)，8.59(s，1H)，8.92- 8.95(m，1H)，9.92(s，1H). | 44％ |
| I-3j | 5-(6-ethynyl quinazoline-4-base is amino)-2-methyl benzenesulfonamide | 2.59(s，3H)，4.44(s，1H)，7.38-7.41(m， 3H)，7.78(d，J＝8.6Hz，1H)，8.14(dd，J 1 ＝0.9Hz，J 2＝8.6Hz，1H)，7.89(dd，J 1＝ 2.4Hz，J 2＝8.2Hz，1H)，8.11(dd，J 1＝2.4 Hz，J 2＝8.2Hz，1H)，8.4(t，J＝2.4Hz， 1H)，8.65(d，J＝14.5Hz，1H)，8.83(d，J ＝1.5Hz，1H)，10.09(s，1H). | 84％ |
| I-3k | N-((R)-1-phenylethyl)-6-ethynyl quinazoline-4-amine | 1.52(d，J＝6.8Hz，3H)，4.43(s，1H)， 5.57(m，1H)，7.21(t，J＝7.6Hz，1H)， 7.32(d，J＝7.8Hz，2H)，7.34(m，3H)， 8.02(dd，J＝2.1，6.7Hz，1H)，8.22(s， 1H)，8.41(d，J＝8.0Hz，1H)，8.82(d，J ＝2.1Hz，1H). | 37％ |
| I-3l | N-(the 5-chlorobenzene is the assorted amyl group of [d] [1,3] dioxygen-4-yl also)-6-ethynyl quinazoline-4-amine | 4.42(s，1H)，5.52(s，2H)，6.12(d，J＝2.5 Hz，1H)，6.58(dd，J 1＝2.5Hz，J 2＝6.7Hz， 1H)，7.76(d，J＝2.1Hz，1H)，8.21(m，1H)， 8.32(d，J＝6.2Hz，1H)，8.83(s，1H)， 10.02(s，1H). | 46％ |
| I-3m | N-(2,4-two chloro-5-p-methoxy-phenyls)-6-ethynyl azoles quinoline-4-amine | 3.84(s，3H)，4.43(s，1H)，6.34(s，1H)， 7.34(m，1H)，7.96(d，J＝2.1Hz，1H)， 8.21(m，1H)，8.32(d，J＝6.2Hz，1H)， 8.89(s，1H)，9.94(s，1H). | 58％ |
| I-3n | N-(4-(6-picoline-3-base oxygen base)-3-aminomethyl phenyl)-6-ethynyl quinazoline-4-amine | 2.38(s，3H)，2.73(s，3H)，4.43(s，1H)， 6.54(s，1H)，6.68(d，J ＝2.4Hz，1H)， 6.74(d，J＝2.5Hz，1H)，7.47(d，J＝2.7Hz， 1H)，7.56(d，J＝2.7Hz，1H)，7.96(d，J＝ 2.3Hz，1H)，8.21(m，1H)，8.32(d，J＝6.2 Hz，1H)，8.64(s，1H)，8..92(s，1H)，9.82(s， 1H). | 71％ |
Embodiment 3 4-(4-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-iodine quinazoline (II-2a) adds I-1 (3.35g in DMF (50mL), 1mmol), 4-fluoro-2-Methyl-1H-indole-5-phenol (2.0g, 1.05mmol), salt of wormwood (1.91g, 1.2mmol), react 40h under the stirring at room.Add entry dilution, ethyl acetate and the extraction of tetrahydrofuran (THF) mixed solution, organic layer is washed 4 times again, anhydrous sodium sulfate drying, filtration, concentrates, mixes sample column chromatography (V
Normal hexane: V
Ethyl acetate=3/1).Obtain product II-2a (1.62g, 33%).
1H?NMR(400MHz，DMSO-d
6)：δ2.42(s，3H)，6.24(s，1H)，7.01(t，J＝8.0Hz，1H)，7.16(d，J＝8.8Hz，1H)，7.78(d，J＝8.8Hz，1H)，8.30(dd，J＝8.8，2.0Hz，1H)，8.72(s，1H)，8.74(d，J＝1.4Hz，1H)，11.37(s，1H).
Be similar to the synthetic of intermediate II-2a, following intermediate II-2b to II-2d can be synthesized with various substituted phenol by raw material I-1 and obtains.
Table 4
| Numbering | Name | 1H?NMR(DMSO-d 6，400MHz)δ | Yield |
| II-2b | 4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-iodine quinazoline | 5.21(s，2H)，7.15(m，1H)，7.24-7.32(m，3H)， 7.46(m，1H)，7.64(m，1H)，7.70(m，1H)， 7.90(s，1H)，8.36(d，J＝6.30Hz，1H)， 8.92(s，1H)，9.12(s，1H). | 38％ |
| II-2c | 4-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl)-6-iodine quinazoline | 5.24(s，2H)，7.33-7.43(m，2H)，7.60-7.68(m， 3H)，7.90-7.95(m，2H)，8.34(d，J＝9.1Hz， 1H)，8.61(d，J＝3.6Hz，1H)，8.83(s，1H)， 9.08(s，1H). | 42％ |
| II-2d | 4-(2-(3-luorobenzyl)-2H-indazole-5-yl)-6-iodine quinazoline | 2.61(s，3H)，7.36(t，J＝5.6Hz，4H)，7.74(d， J＝7.2Hz，1H)，7.85(dd，J 1＝2.4Hz，J 2＝7.6 Hz，1H)，8.15(d，J＝2.4Hz，1H)，8.26(dd.J 1 ＝2.0Hz，J 2＝8.8Hz，1H)，8.83(s，1H)，9.12(d， J＝0.4Hz，1H). | 37％ |
Embodiment 44-(4--2-fluoro-2-Methyl-1H-indole-5-base oxygen base)-6-ethynyl quinazoline (II-3a)
In tetrahydrofuran (THF) (130mL), add YF-50-184 (1.62g under the argon gas, 3.86mmol), cuprous iodide (55mg, 0.286mmol), two (triphenylphosphine) palladium chloride (130mg, 0.278mmol), triethylamine (1.34mL), trimethyl silicane ethyl-acetylene (1.30mL) stir back flow reaction down.Stopped reaction behind the 3h, suction filtration, a small amount of tetrahydrofuran solution is washed.(room temperature reaction 5min pours in the frozen water (800mL) and stirs, suction filtration, washing, oven dry for 2.02g, tetrahydrofuran solution 7.72mmol) (20mL) to add the tetra-n-butyl Neutral ammonium fluoride under the argon gas in above-mentioned tetrahydrofuran solution (180mL).Obtain brownish black solids YF-50-190 (1.22g, 99%).
1H?NMR(400MHz，DMSO-d
6)：δ(ppm)2.41(s，3H)，4.50(s，1H)，6.26(d，J＝0.6Hz，1H)，7.01-7.05(m，1H)，7.17-7.20(m，1H)，7.55-7.65(m，1H)，8.00-8.09(m，2H)，8.49(d，J＝2.2Hz，1H)，8.73(s，1H)，11.38(s，1H).
Be similar to the synthetic of intermediate II-3a, following intermediate II-3b to II-3d can be synthesized by raw material II-2b to II-2d and obtains.
Table 5
| Numbering | Name | 1H?NMR(CDCl 3，400MHz)δ | Yield |
| II-3b | 4-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-ethynyl quinazoline | 4.45(s，1H)，5.21(s，2H)，6.85(m，1H)， 7.24-7.32(m，3H)，7.43(m，1H)，7.54(m，1H)， 7.62(m，1H)，7.78(s，1H)，8.16(d，J＝6.5Hz， 1H)，8.62(s，1H)，8.92(s，1H). | 86％ |
| II-3c | 4-(3-chloro-4-(pyridine-2-ylmethoxy) phenyl)-6-ethynyl quinazoline | 4.43(s，1H)，5.24(s，2H)，7.33-7.43(m，2H)， 7.60-7.68(m，3H)，7.90-7.95(m，2H)，8.34(d，J ＝9.1Hz，1H)，8.61(d，J＝3.6Hz，1H)，8.83(s， 1H)，8.93(s，1H). | 76％ |
| II-3d | 4-(2-(3-luorobenzyl)-2H-indazole-5-yl)-6-ethynyl quinazoline | 2.61(s，3H)，4.42(s，1H)，7.16(t，J＝5.6Hz， 4H)，7.53(d，J＝7.2Hz，1H)，7.65(dd，J 1＝2.5 Hz，J 2＝7.6Hz，1H)，8.05(d，J＝2.4Hz，1H)， 8.26(dd.J 1＝2.3Hz，J 2＝8.8Hz，1H)，8.76(s， 1H)，8.93(s，1H). | 79％ |
Embodiment 5 1-cyclohexyl-4-hydroxy piperidine (III-2a)
(4.05g 40mmol) is dissolved in the exsiccant methylene dichloride (100mL), and (5.8g 60mmol), adds and stirred 15 minutes, adds NaBH (OAc) to add pimelinketone again with the 4-hydroxy piperidine
3(16.93g 80mmol), stirs under the room temperature and spends the night, and the TLC detection reaction finishes, and adds saturated sodium bicarbonate, methylene dichloride (80mL*3) extraction, and anhydrous sodium sulfate drying filters, and evaporate to dryness filtrate gets crude product YF-230-80 (2.1g, 40%).
MS(ESI-LR)m/z：184.2(M+1)
+.
Be similar to the synthetic of intermediate III-2a, following intermediate III-2b to III-2n can be obtained by raw material II I-1 and the reaction of various amine.
Table 6
| Numbering | Name | MS(ESI-LR)m/z | Yield |
| III-2b | 1-methyl-4-hydroxy piperidine | 116.1(M+1) + | 23％ |
| III-2c | 1-cyclopentyl-4-hydroxy piperidine | 170.2(M+1) + | 65％ |
| III-2d | 1-isobutyl--4-hydroxy piperidine | 158.2(M+1) + | 42％ |
| III-2e | 1-(amyl group-3-yl)-4-hydroxy piperidine | 172.2(M+1) + | 45％ |
| III-2f | 1-tertiary amyl-4-hydroxy piperidine | 172.2(M+1) + | 52％ |
| III-2g | 1-sec.-propyl-4-hydroxy piperidine | 143.1(M+1) + | 38％ |
| III-2h | 1-cyclobutyl-4-hydroxy piperidine | 156.1(M+1) + | 54％ |
| III-2i | 1-benzyl-4-hydroxy piperidine | 192.1(M+1) + | 68％ |
| III-2j | 1-(4-methoxy-benzyl)-4-hydroxy piperidine | 221.1(M+1) + | 76％ |
| III-2k | 1-(pyridin-4-yl)-4-hydroxy piperidine | 193.1(M+1) + | 63％ |
| III-2l | 1-(furans-2-yl)-4-hydroxy piperidine | 182.2(M+1) + | 72％ |
| III-2m | 1-(thiophene-2-yl)--4-hydroxy piperidine | 198.1(M+1) + | 74％ |
| III-2n | 1-(4-tertiary butyl benzyl)-4-hydroxy piperidine | 248.2(M+1) + | 73％ |
Embodiment 6 1-cyclohexyl-4-nitrine piperidines (III-3a)
(1.83g 10mmol) is dissolved among the THF (30mL) of new steaming, stirs to add PPh down with III-2a
3(3.94g, 15mmol), argon shield; dropping DIAD under cryosel is bathed (3mL, 15mmol), DPPA (3.3mL; 15mmol); shift out ice bath behind the 10min, stirred overnight at room temperature, the TLC monitoring reaction finishes; concentrate; remove solvent, add ethyl acetate (60mL), water (100mL) and dilute hydrochloric acid (18mL); separatory; water is washed with methylene dichloride, and making solution with the adjusting of NaOH solution is strong basicity, is extracting with methylene dichloride (100mL*3); anhydrous sodium sulfate drying; concentrate, obtain brown liquid YF-230-111 (0.89g, 46%).
1H?NMR(400MHz，CDCl
3)：δ1.22-1.25(m，4H)，1.61-1.72(m，4H)，1.79-1.83(m，4H)，1.90-1.93(m，2H)，2.36-2.39(m，3H)，2.82-2.87(m，2H)，3.36(s，1H).
Be similar to the synthetic of intermediate III-3a, following intermediate III-3b to III-3n can be obtained by raw material II I-2b to III-2n reaction.
Table 7
| Numbering | Name | 1H?NMR(CDCl 3，400MHz)δ | Yield |
| III-3b | 1-methyl-4-nitrine piperidines | 1.63-1.72(m，2H)，1.86-1.92(m，2H)， 2.09-2.15(m，2H)，2.26(s，3H)，2.70(d， J＝4.0Hz，2H)，3.37(d，J＝4.4Hz，1H). | 38％ |
| III-3c | 1-cyclopentyl-4-nitrine piperidines | 1.34-1.40(m，2H)，1.49-1.53(m，2H)， 1.62-1.71(m，4H)，1.80-1.92(m，4H)， 2.14(d，J＝1.2Hz，2H)，2.43-2.50(m， 1H)，2.84(s，2H)，3.36(s，1H). | 46％ |
| III-3d | 1-isobutyl--4-nitrine piperidines | 0.84-0.88(m，6H)，1.27-1.29(m，2H)， 1.62-1.68(m，2H)，1.69-1.81(m，1H)， 2.03-2.08(m，4H)，2.67-2.76(m，2H)， 3.31-3.40(m，1H). | 39％ |
| III-3e | 1-(amyl group-3-yl)-4-nitrine piperidines | 0.88(t，J＝7.2Hz，6H)，1.63～1.54(m， 2H)，1.89-1.83(m，2H)，2.18～2.12(m， 1H)，2.36-2.29(m，2H)，2.73～2.68(m， 2H)，3.33-3.28(m，1H). | 55％ |
| III-3f | 1-tertiary amyl-4-nitrine piperidines | 0.84(s，9H)，1.69-1.56(m，2H)， 1.85-1.79(m，2H)，2.02(s，2H)， 2.34-2.26(m，2H)，2.77-2.70(m，2H)， 3.33-3.27(m，1H). | 56％ |
| III-3g | 1-sec.-propyl-4-nitrine piperidines | 0.95-0.99(m，6H)，1.56-1.62(m， 2H)，1.83-1.87(m，2H)，2.18 -2.23(m，2H)，2.64-2.74(m，3H)， 2.97(s，3H)，3.26-3.30(m，1H). | 70％ |
| III-3h | 1-cyclobutyl-4-nitrine piperidines | 1.62-1.71(m，4H)，1.80-1.92(m，6H)， 2.23(m，2H)，2.43-2.50(m，1H)，2.82(s， 2H)，3.36(s，1H). | 57％ |
| III-3i | 1-benzyl-4-nitrine piperidines | 1.58-1.65(m，4H)，2.34-2.42(m，4H)， 3.32(m，1H)，3.78(s，2H)，7.06-7.21(m， 5H). | 63％ |
| III-3j | 1-(4-methoxy-benzyl)-4-nitrine | 1.56-1.65(m，4H)，2.34-2.43(m，4H)， 3.32(m，1H)，3.68(s，2H)，3.94(s，3H)， | 58％ |
| Piperidines | 6.75(d，J＝5.6Hz，2H)，7.12(d，J＝5.6 Hz，2H). | ||
| III-3k | 1-(pyridine-4-yl)-4-nitrine piperidines | 1.56-1.63(m，4H)，2.34-2.44(m，4H)， 3.32(m，1H)，3.68(s，2H)，7.42(d，J＝ 5.7Hz，2H)，7.98(d，J＝5.7Hz，2H). | 45％ |
| III-3l | 1-(furans-2-yl)-4-nitrine piperidines | 1.56-1.63(m，4H)，2.34-2.43(m，4H)， 3.32(m，1H)，3.42(s，2H)，6.52(d，J＝ 2.4Hz，1H)，6.84(m，1H)，7.28(d，J＝ 3.7Hz，1H). | 62％ |
| III-3m | 1-(thiophene-2-yl)-4-nitrine piperidines | 1.56-1.63(m，4H)，2.34-2.43(m，4H)， 3.32(m，1H)，3.42(s，2H)，6.42(m，1H)， 6.74(m，1H)，7.08(d，J＝2.7Hz，1H). | 68％ |
| III-3n | 1-(4-tertiary butyl benzyl)-4-nitrine piperidines | 1.31(s，9H)，1.56-1.65(m，4H)， 2.34-2.43(m，4H)，3.32(m，1H)，3.68(s， 2H)，6.75(d，J＝5.6Hz，2H)，7.12(d， J＝5.6Hz，2H). | 65％ |
Embodiment 7 1-tertiary butyl piperidin-4-one-s (IV-2a)
(34.5mL 0.5mol) is added dropwise to 10N sodium hydroxide (46mL) under the stirring, and the back that finishes adds IV-1, and (24.51g, 0.1mol), TERTIARY BUTYL AMINE (200mL) is warming up to back flow reaction and spends the night to add vinylformic acid in water (100mL).Reaction finishes the back decompression and removes low boilers, and resistates adds uses ethyl acetate extraction, and the organic layer anhydrous sodium sulfate drying filters, concentrates, and underpressure distillation obtains product IV-2a (5.05g, 32%).
1H?NMR(300MHz，CDCl
3)：δ1.06(s，9H)，2.36(t，J＝6.0Hz，4H)，2.78(t，J＝6.0Hz，4H).
Embodiment 8 1-cyclopropyl piperidine-4-ketone (IV-2b)
The operation of similar embodiment 7 obtains intermediate compound IV-2b (4.8g, 40%).
1H?NMR(400MHz，CDCl
3)：δ0.37-0.47(m，4H)，1.64-1.68(m，1H)，2.33-2.36(m，4H)，2.83-2.86(m，4H).
Embodiment 9 1-tertiary butyl piperidines-4-alcohol (IV-3a)
(2.0g, 12.88mmol), add sodium borohydride under the water-bath (0.75g 19.32mmol) stirs reaction 3.5h down in batches to add IV-2a in ethanol (100mL).Ethanol is removed in decompression, after resistates adds diluted hydrochloric acid dissolution, and the sodium carbonate solution neutralization, dichloromethane extraction, the organic layer anhydrous sodium sulfate drying filters, concentrates.Obtain product IV-3a (1.875g, 92%).
1H?NMR(300MHz，CDCl
3)：δ1.02(s，9H)，1.50-1.59(m，2H)，1.83-1.90(m，2H)，2.17-2.25(m，2H)，2.82-2.88(m，2H)，3.57-3.51(m，1H).
Embodiment 10 1-cyclopropyl piperidine-4-alcohol (IV-3b)
The operation of similar embodiment 9 obtains intermediate compound IV-3b (4.58g, 94%).
The embodiment 11 1-tertiary butyl-4-nitrine piperidines (IV-4a)
The operation of similar embodiment 6 can obtain intermediate compound IV-4a (2.6g, 95%).
1H?NMR(400MHz，CDCl
3)：δ1.03(s，9H)，1.56-1.65(m，2H)，1.86-1.89(m，2H)，2.20-2.26(m，2H)，2.84-2.88(m，2H)，3.28-3.32(m，1H).
Embodiment 12 1-cyclopropyl-4-nitrine piperidines (YF-50-194)
The operation of similar embodiment 6 can obtain intermediate compound IV-4b (2.8g, 96%).
1H?NMR(400MHz，CDCl
3)：δ0.32-0.39(m，4H)，1.51-1.59(m，3H)，1.80-1.83(m，2H)，2.25-2.31(m，2H)，2.81-2.87(m，2H)，3.30-3.34(m，1H).
Embodiment 13 4-nitrine piperidines-1 phenyl formates (V-2a)
(2.52g 20mmol) is dissolved in the tetrahydrofuran (THF) (50mL) raw material V-1, adds triethylamine (3mL), cryosel is bathed cooling, and adding rate phenyl formate (3.14g, 20mmol), add room temperature reaction 3 hours, stopped reaction, be spin-dried for solvent, residue is dissolved in the ethyl acetate (100mL), washing, saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying is spin-dried for, obtain intermediate V-2a (3.12g, 63%).
1H?NMR(400MHz，CDCl
3)：δ1.42(m，2H)，1.63(m，2H)，3.36(m，4H)，3.78(m，1H)，7.10-7.23(m，5H).
Embodiment 14 (E)-1-(4-nitrine piperidines-1-yl)-4-(dimethyl amido)-but-2-ene-1-ketone (V-2b)
The operation of similar embodiment 13 can obtain intermediate V-2b (0.86g, 25%).
1H?NMR(400MHz，CDCl
3)：δ1.41(m，2H)，1.63(m，2H)，2.28(s，6H)，3.14(d，J＝6.1Hz，2H)，3.34(m，4H)，3.75(m，1H)，6.25(d，J＝15.3Hz，1H)，6.54(m，1H).
Embodiment 15 4-nitrine-N-(2-(dimethyl amido) ethyl) piperidines-1-methane amide (V-3a)
Raw material V-2a (2.46g 10mmol) is dissolved among the dry DMF (20mL), and adding salt of wormwood (2.76g, 20mmol), N
1, N
1-dimethyl-ethylenediamine (1.06g 12mol), is heated to 50 ℃ of reactions and spends the night, and stopped reaction adds water (100mL) dilution, methylene dichloride (50mL*2) extraction, and the combined dichloromethane layer, the saturated common salt washing, the anhydrous sodium drying is spin-dried for, column chromatography (V
Methylene dichloride/ V
Methyl alcohol=20/1), obtains intermediate V-3a (1.12g, 47%).
1H?NMR(400MHz，CDCl
3)：δ1.41(m，2H)，1.63(m，2H)，2.34(s，6H)，2.56(t，J＝6.5Hz，2H)，3.26(m，2H)，3.34(m，4H)，3.75(m，1H)，6.23(t，J＝6.10Hz，1H).
Synthetic (VI-2a) of embodiment 16 1-(pentane-3-yl) aza-cyclobutane-3-alcohol
(2.5g 0.022mol) is dissolved among the DCM (100mL) VI-1, adds propione (1.9g, 0.022mol), adding sodium triacetoxy borohydride under stirring (7g, 0.033mol), salt of wormwood (3.78g, 0.027mol) and a small amount of activated molecular sieve, room temperature reaction spends the night, and the TLC raw material reaction is complete, adding EA after the filtering and concentrating stirs, filter once more, filtrate obtains intermediate VI-2a (1.6g, 49%) after concentrating.MS(ESI-LR)：142.2(M+1)
+.
Be similar to the synthetic of intermediate VI-2a, following intermediate VI-2b to VI-2o can be obtained by raw material VI-1 and the reaction of various aldehyde ketone compound.
Table 8
| Numbering | Name | MS(ESI-LR)m/z | Yield |
| VI-2b | 1-sec.-propyl aza-cyclobutane-3-alcohol | 116.1(M+1) + | 58％ |
| VI-2c | 1-cyclopentyl aza-cyclobutane-3-alcohol | 142.1(M+1) + | 73％ |
| VI-2d | 1-cyclohexyl azetidin-3-alcohol | 155.2(M+1) + | 63％ |
| VI-2e | 1-cyclobutyl aza-cyclobutane-3-alcohol | 128.1(M+1) + | 62％ |
| VI-2f | 1-(ring fourth oxygen-3-yl) aza-cyclobutane-3-alcohol | 130.1(M+1) + | 34％ |
| VI-2g | 1-methyl azetidine-3-alcohol | 88.1(M+1) + | 25％ |
| VI-2h | 1-(cyclopropyl methyl) aza-cyclobutane-3-alcohol | 128.2(M+1) + | 53％ |
| VI-2i | 1-(2-(methyl sulfuryl) ethyl) aza-cyclobutane-3-alcohol | 180.1(M+1) + | 26％ |
| VI-2j | 1-benzyl aza-cyclobutane-3-alcohol | 164.1(M+1) + | 64％ |
| VI-2k | 1-(4-tertiary butyl benzyl) aza-cyclobutane-3-alcohol | 220.2(M+1) + | 62％ |
| VI-2l | 1-(pyridin-4-yl) aza-cyclobutane-3-alcohol | 165.1(M+1) + | 58％ |
| VI-2m | 1-(furans-2-yl) aza-cyclobutane-3-alcohol | 153.1(M+1) + | 72％ |
| VI-2n | 1-(thiophene-2-yl) aza-cyclobutane-3-alcohol | 170.1(M+1) + | 68％ |
| VI-2o | 1-(5-methyl furan-2-yl) aza-cyclobutane-3-alcohol | 168.1(M+1) + | 74％ |
Synthetic (VI-3a) of embodiment 17 3-nitrine-1-(3-amyl group) ring butylamine
With VI-2a (1.6g, 0.011mol) be dissolved among the exsiccant DCM (25mL). add triethylamine (3mL, 0.022mol) cryosel cooling down, drip methane sulfonyl chloride (1mL, 0.013mol) and the mixed solution of DCM (10mL), it is complete to drip two hours TLC raw material reactions of Bi Fanying, add saturated sodium bicarbonate solution, layering is also used the DCM aqueous phase extracted once, merges organic phase, each washs saturated sodium bicarbonate and water once, and dry concentrating obtains the methanesulfonates intermediate.(1.7g 0.0076mol) adds DMF (30mL), and (1g 0.015mol), is heated to 60 ℃ of reactions and spends the night under argon shield to add sodiumazide with above-mentioned intermediate.After raw material reaction is complete, add entry (100mL), the DCM extracting twice with using saturated sodium bicarbonate solution and water washing respectively once, obtains VI-3a (0.25g, 19%) behind evaporating column chromatography (hex-hex:EA=10/1) purifying of dry back.
1H?NMR(400MHz，CDCl
3)：δ0.80-0.85(m，6H)，1.28-1.42(m，4H)，2.00-2.04(m，1H)，2.92-2.97(m，2H)，3.57-3.62(m，2H)，3.96-4.00(m，1H).
Be similar to the synthetic of intermediate VI-3a, following intermediate VI-3b to VI-3o can be respectively by raw material VI-2b to VI-2o, 1-cyclopropyl aza-cyclobutane-3-alcohol, and the reaction of 1-tertiary butyl aza-cyclobutane-3-alcohol obtains.
Table 9
| Numbering | Name | 1H?NMR(CDCl 3，400MHz)δ | Yield |
| VI-3b | 3-nitrine-1-sec.-propyl azetidine | 0.87(d，J＝6.5Hz，6H)，2.20-2.28(m，1H)， 2.89(m，2H)，3.50-3.55(m，2H)， 3.89-3.95(m，1H). | 23％ |
| VI-3c | 3-nitrine-1-cyclopentyl azetidine | 1.36-1.56(m，6H)，1.68-1.74(m，2H)，2.34(m， 1H)，2.74-2.83(m，2H)，3.50-3.55(m，2H)， 3.89-3.95(m，1H). | 34％ |
| VI-3d | 3-nitrine-1-cyclohexyl azetidin | 1.34-1.52(m，6H)，1.68-1.76(m，4H)，2.32(m， 1H)，2.74-2.83(m，2H)，3.50-3.56(m，2H)， 3.89-3.98(m，1H). | 45％ |
| VI-3e | 3-nitrine-1-cyclobutyl azetidine | 1.89-2.01(m，4H)，2.10-2.26(m，2H)，2.34(m， 1H)，2.74-2.83(m，2H)，3.50-3.56(m，2H)， 3.89-3.98(m，1H). | 24％ |
| VI-3f | 3-nitrine-1-(ring fourth oxygen-3-yl) azetidine | 2.34(m，1H)，2.74-2.83(m，2H)，3.50-3.56(m， 2H)，3.89-3.98(m，1H)，4.56-4.68(m，4H). | 18％ |
| VI-3g | 3-nitrine-1-methyl azetidine | 2.36(s，1H)，2.74-2.83(m，2H)，3.50-3.56(m， 2H)，3.89-3.98(m，1H). | 12％ |
| VI-3h | 3-nitrine-1-(cyclopropyl methyl) azetidine | 0.35-0.48(m，3H)，0.62(m，2H)，2.38(m，1H)， 2.74-2.83(m，2H)，3.50-3.56(m，2H)， | 28％ |
| 3.89-3.98(m，1H). | |||
| VI-3i | 3-nitrine-1-(2-(methyl sulfuryl) ethyl) azetidine | 2.84(s，3H)，2.74-2.86(m，4H)，3.50-3.56(m， 2H)，3.58(t，J＝6.7Hz，2H)，3.89-3.98(m， 1H). | 13％ |
| VI-3j | 3-nitrine-1-benzyl azetidine | 3.05-3.1(m，2H)，3.57-3.61(m，4H)，3.99- 4.08(m，1H)，7.27-7.34(m，5H). | 54％ |
| VI-3k | 3-nitrine-1-(4-tertiary butyl benzyl) azetidine | 1.31(s，9H)，3.05-3.1(m，2H)， 3.57-3.61(m，4H)，3.99-4.08(m，1H)， 6.78(d，J＝5.4Hz，2H)，7.14(d，J＝5.4 Hz，2H). | 52％ |
| VI-3l | 3-nitrine-1-(pyridin-4-yl) azetidine | 3.05-3.12(m，2H)，3.57-3.61(m，4H)，3.99- 4.08(m，1H)，7.28(d，J ＝6.6Hz，2H)， 7.96(d，J＝6.5Hz，2H). | 39％ |
| VI-3m | 3-nitrine-1-(furans-2-yl) azetidine | 3.05-3.12(m，2H)，3.57-3.61(m，4H)，3.99- 4.08(m，1H)，6.32(d，J＝2.6Hz，1H)， 6.58(m，1H)，7.14(d，J＝3.5Hz，1H). | 57％ |
| VI-3n | 3-nitrine-1-(thiophene-2-yl) azetidine | 3.05-3.13(m，2H)，3.57-3.61(m，4H)，3.99- 4.08(m，1H)，6.32(d，J＝2.4Hz，1H)， 6.58(m，1H)，6.84(d，J＝3.6Hz，1H). | 47％ |
| VI-3o | 3-nitrine-1-(5-methyl furan-2-yl) azetidine | 2.16(s，3H)，3.05-3.12(m，2H)，3.57-3.61(m， 4H)，3.99-4.08(m，1H)，6.32(d，J＝3.6Hz， 1H)，6.54(d，J＝3.5Hz，1H). | 54％ |
| VI-3p | 3-nitrine-1-cyclopropyl azetidine | 0.45(m，2H)，0.82(m，2H)，1.56(m，1H)， 2.74-2.83(m，2H)，3.50-3.56(m，2H)， 3.89-3.98(m，1H). | 31％ |
| VI-3q | 3-nitrine-1-tertiary butyl azetidine | 0.94(s，9H)，3.12-3.17(m，2H)， 3.41-3.46(m，2H)，3.95-4.00(m，1H). | 63％ |
Embodiment 18 N-(2-azidoethyl)-2-(methyl sulphonyl) ethamine (VII-2a)
(2.46g 20mmol) is dissolved in the dry acetonitrile (30mL) raw material VII-1, and (2.76g, 20mmol), (4.82g 20mmol), is heated to 50 ℃ of reactions and spends the night 2-(methyl sulphonyl) ethamine to add Anhydrous potassium carbonate.Stopped reaction, TLC (CH
2Cl
2/ MeOH=50/1) monitoring reaction, after question response was finished, stopped reaction filtered, and ethyl acetate is washed, and concentrates residue column chromatography (CH
2Cl
2/ MeOH=50/1), obtain intermediate VII-2a (oily matter 1.48g, productive rate 39%).
1H?NMR(400MHz，CDCl
3)：δ3.38(t，J＝5.6Hz，2H)，3.15(m，4H)，2.98(s，3H)，2.76(t，J＝5.6Hz，2H)，1.55(br?s，1H)。
Be similar to the synthetic of intermediate VII-2a, following intermediate VII-2b-3f can be obtained with the amine reaction of different replacements by raw material VII-1 respectively.
Table 10
| Numbering | Name | 1H?NMR(CDCl 3，400MHz)δ | Yield |
| VII-2b | 1-(2-azidoethyl) tetramethyleneimine | 3.36(t，J＝6.1Hz，2H)，3.68(t，J＝6.1 Hz，2H)，2.55(m，4H)，1.78(m，4H). | 38％ |
| VII-2c | 1-(2-azidoethyl)-4-(methylsulfonyl) piperazine | 2.59-2.66(m，6H)，2.76(s，3H)，3.24(t， ＝4.8Hz，4H)，3.35(t，J＝6.4Hz，2H) | 31％ |
| VII-2d | 1-(2-azidoethyl)-4-methylpiperazine | 2.20(s，3H)，2.37-2.47(m，8H)， 2.50-2.53(t，J＝12.4Hz，2H)， 3.25-3.28(t，J＝12.0Hz，2H). | 48％ |
| VII-2e | 4-(2-azidoethyl)-N methyl piperazine-1-methane amide | 2.38(s，3H)，2.59-2.66(m，6H)，3.24(t，J ＝4.8Hz，4H)，3.35(t，J＝6.4Hz，2H)， 6.12(br?s，1H). | 36％ |
| VII-2f | 4-(2-azidoethyl) piperazine-1-methane amide | 2.59-2.68(m，6H)，3.26(t，J＝4.8Hz，4 H)，3.35(t，J＝6.4Hz，2H)，5.62(br?s， 2H). | 23％ |
| VII-2g | 2-nitrine-N, N-diethyl ethamine | 3.36(t，J＝6.1Hz，2H)，3.68(t，J＝6.1 Hz，2H)，2.35(q，J＝5.6Hz，4H)， 1.21(t，J＝5.6Hz，4H). | 29％ |
| VII-2h | 1-(2-azidoethyl) piperidines | 3.36(t，J＝6.1Hz，2H)，3.68(t，J＝6.1 Hz，2H)，2.45(m，4H)，1.64(m，4H)， 1.25(m，2H). | 47％ |
| VII-2i | 4-(2-azidoethyl) morpholine | 3.36(t，J＝6.1Hz，2H)，3.68(t，J＝6.1 Hz，2H)，3.98(m，4H)，2.45(m，4H). | 43％ |
| VII-2j | 4-(2-azidoethyl)-N, N-lupetazin-1-methane amide | 2.35(s，6H)，2.59-2.66(m，6H)，3.25(t，J ＝5.8Hz，4H)，3.38(t，J＝6.2Hz，2H)， | 28％ |
| VII-2k | (4-(2-azidoethyl) piperazine-1-yl) (morpholinyl) methyl ketone | 2.59-2.68(m，10H)，3.24(t，J＝5.8Hz，4 H)，3.35(t，J＝6.3Hz，2H)，4.02(m，4H). | 31％ |
| VII-2l | (4-(2-azidoethyl) piperazine-1-yl) (tetramethyleneimine-1-yl) methyl ketone | 1.56(m，4H)，2.59-2.68(m，10H)，3.26(t， J＝5.7Hz，4H)，3.36(t，J＝6.4Hz，2H). | 35％ |
Embodiment 19N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-6-(1-(1-tertiary butyl azetidine-3-yl)-1H-1,2,3-triazole-4-yl) quinazoline-4-amine (compound 1)
(238mg 0.5mmol) is dissolved among the DMF (5mL), adds CuSO with I-3a
4.5H
2O (38mg, 0.15mmol), L-(+) sodium ascorbate (50mg; 25mmol), add again VI-3q (155mg, 1.5mmol); be heated to 60 ℃ of reaction 0.5h under the protection of argon gas, the TLC detection reaction is complete, cooling; reaction solution is poured in the ice entry (50mL), separated out a large amount of solids, filter; washing behind the solid drying, is dissolved in a small amount of methylene dichloride; adding silica gel is spin-dried for and mixes sample, column chromatography (V
Methylene dichloride/ V
Methyl alcohol=20/1), obtains yellow solid YF-230-34 (178mg, 64%).
1H?NMR(300MHz，DMSO-d
6)：δ1.04(s，9H)，3.79-3.84(m，4H)，5.24(s，2H)，5.31-5.36(m，1H)，7.13-7.20(m，1H)，7.24-7.33(m，3H)，7.42-7.49(m，1H)，7.76(dd，J
1＝1.4Hz，J
2＝9.0Hz，1H)，8.03(d，J＝2.4Hz，1H)，8.32(s，1H)，8.82(s，1H)，9.12(s，H)，10.0(s，1H)；ESI-LR：558.2[M+1]
+.
Embodiment 20-32
Synthesizing of similar compound 1, compound 2-14 can be obtained with the VI-3q reaction by raw material I-3b to I-3n respectively.
Table 11
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR)m/z | Yield |
| 2 | 1.1(s，9H)，3.72-3.81(m，2H)，3.94(t，J ＝8.3Hz，2H)，5.29-5.33(m，1H)，7.19(d， J＝8.8Hz，1H)，7.60-7.66(m，1H)， 7.95-8.14(m，4H)，8.27(s，1H)，8.73(s，1 H)，8.77(s，1H). | 452.2(M+1) + | 67％ |
| 3 | 1.01(s，9H)，3.56(t，J＝6.4Hz，2H)， 3.68(t，J＝7.2Hz，2H)，5.29(t，J＝6.4 Hz，1H)，7.46-7.56(m，2H)，7.66(dd，J 1＝1.0 | 498.1(M+1) + | 26％ |
| Hz，J 2＝10.0Hz，1H)，7.86(d，J＝8.4Hz， 1H)，8.34(dd，J 1＝1.0Hz，J 2＝8.4Hz，1H)， 8.48(s，1H)，8.80(s，1H)，9.00(d，J＝0.8 Hz，1H)，10.08(s，J＝8.8Hz，1H)； | |||
| 4 | 1.15(s，9H)，3.58(s，2H)，3.64(s，2H)， 5.29(s，3H)，7.27(d，J＝9.2Hz，1H)， 7.36(t，J＝6.0Hz，1H)，7.57(d，J＝8.0Hz， 1H)，7.75(d，J＝8.4Hz，1H)，7.83- 7.89(m，2H)，8.04(s，1H)，8.32(d，J＝8.8 Hz，1H)，8.58(t，J＝8.8Hz，2H)，8.82(s， 1H)，9.05(s，1H)，10.00(s，1H). | 541.2(M+1) + | 54％ |
| 5 | 1.00(s，9H)，3.59(t，J＝6.6Hz，2H)， 3.70(t，J＝7.2Hz，2H)，5.26-5.30(m，2H)， 7.34(d，J＝3.0Hz，1H)，7.44-7.49(m，1H)， 7.78-7.93(m，3H)，8.05(d，J＝2.1Hz，1H)， 8.33(dd，J 1＝2.1Hz，J 2＝8.7Hz，1H)， 8.56-8.59(m，2H)，8.72(d，J＝1.2Hz，1H)， 8.83(s，1H)，9.06(d，J＝1.2Hz，1H)， 10.01(s，1H). | 541.2(M+1) + | 49％ |
| 6 | 0.98(s，9H)，3.57(s，2H)，3.69(s，2H)， 5.27(t，J＝6.0Hz，1H)，5.75(s，2H)， 6.97(d，J＝8.0Hz，1H)，7.28(t，J＝6.4Hz， 1H)，7.66-7.74(m，3H)，7.83(d，J＝8.4Hz， 1H)，8.14(s，1H)，8.21(s，1H)，8.32(d，J＝ 8.4Hz，1H)，8.51(m，2H)，8.80(s，1H)， 9.01(s，1H)，10.01(s，1H). | 531.3(M+1) + | 26％ |
| 7 | 0.98(s，9H)，3.57(t，J＝4.0Hz，2H)， 3.69(t，J＝12.0Hz，2H)，5.25-5.30(m，1 H)，5.69(s，2H)，7.04-7.11(m，3H)， 7.35(dd，J＝14.0，7.5Hz，1H)，7.70- 7.77(m，2H)，8.15(s，1H)，8.21(s，1H)， 8.34(s，1H)，8.80(s，1H)，9.16(s，1H)， | 548.3(M+1) + | 15％ |
| 10.09(s，1H). | |||
| 8 | 1.00(s，9H)，3.32-3.70(m，4H)，5.38(s， 1H)，5.74(s，2H)，7.15(d，J＝8.0Hz，1H)， 7.30-7.33(m，1H)，7.60(m，2H)， 7.75-7.85(m，2H)，8.21(s，1H)，8.32(d，J ＝9.6Hz，1H)，8.51-8.54(m，3H)， 8.85(s，1H)，9.12(s，1H)，10.06(s，1H). | 531.3(M+1) + | 12％ |
| 9 | 0.98(s，9H)，3.57(t，J＝12.0Hz，2H)， 3.69(t，J＝13.2Hz，2H)，5.25-5.30(m， 1H)，5.66(s，1H)，7.13-7.16(m，3H)， 7.38-7.41(m，1H)，7.79(dd，J＝8.5Hz， 9.0Hz，2H)，7.91(d，J＝8.5Hz，1H)， 8.20(s，1H)，8.33(d，J＝8.4Hz，1H)， 8.50(s，1H)，8.53(s，1H)，8.80(s，1H)， 9.07(s，1H)，10.00(s，1H). | 548.3(M+1) + | 14％ |
| 10 | 0.99(s，9H)，2.58(s，3H)，3.59(s，2H)， 3.70(s，2H)，5.28(s，1H)，7.39(t，J＝4.0 Hz，3H)，7.87(d，J＝8.4Hz，1H)，8.07(dd， J 1＝2.4Hz，J 2＝8.0Hz，1H)，8.34(d，J＝ 8.0Hz，1H)，8.38(d，J＝2.4Hz，1H)，8.59(s， 1H)，8.82(s，1H)，9.09(s，1H)，10.19(s， 1H). | 493.2(M+1) + | 43％ |
| 11 | 1.05(s，9H)，1.70(d，J＝6.7Hz，3H)， 3.62(t，J＝2.7Hz，2H)，3.80(t，J＝8.2 Hz，2H)，5.21(m，1H)，5.66(m，1H)， 6.25(d，J＝7.5Hz，1H)，7.20- 7.40(m，3H)，7.43(m，2H)，7.87(d，J＝8.6 Hz，1H)，8.00(m，1H)，8.14(s，1H)， 8.48(s，1H)，8.63(s，1H). | 414.2(M+1) + | 25％ |
| 12 | 1.02(s，9H)，3.72-3.81(m，2H)，3.94(t，J＝ 8.3Hz，2H)，5.31(m，1H)，5.52(s，2H)，6.12 (d，J＝2.5Hz，1H)，6.56(dd，J 1＝2.3Hz， | 478.2(M+1) + | 48％ |
| J 2＝6.7Hz，1H)，7.76(d，J＝2.1Hz，1H)， 8.21(m，1H)，8.32(d，J＝6.2Hz，1H)， 8.83(s，1H)，9.82(s，1H). | |||
| 13 | 0.99(s，1H)，3.72-3.81(m，2H)，3.94(t，J＝ 8.3Hz，2H)，4.12(s，3H)，5.27(m，1H)， 6.34(s，1H)，7.34(m，1H)，7.96(d，J＝2.5 Hz，1H)，8.21(m，1H)，8.32(d，J＝6.3Hz， 1H)，8.89(s，1H)，9.92(s，1H). | 498.2(M+1) + | 37％ |
| 14 | 1.02(s，1H)，2.38(s，3H)，2.73(s，3H)， 3.72-3.81(m，2H)，3.94(t，J＝8.3Hz，2H)， 5.31(m，1H)，6.54(s，1H)，6.65(d，J＝2.4 Hz，1H)，6.74(d，J＝2.5Hz，1H)，7.47(d， J＝2.7Hz，1H)，7.56(d，J＝2.7Hz，1H)， 7.96(d，J＝2.3Hz，1H)，8.21(m，1H)， 8.32(d，J＝6.2Hz，1H)，8.64(s，1H)， 8..92(s，1H)，9.82(s，1H). | 521.3(M+1) + | 43％ |
Embodiment 33-46
Synthesizing of similar compound 1, compound 5-18 can be obtained with the VI-3q reaction by raw material II-3a to II-3d respectively.
Table 12
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR)m/z | Yield |
| 15 | 0.98(s，9H)，2.41(s，3H)，3.57-3.70(m， 4H)，5.22-5.26(m，1H)，6.26(s，1H)， 7.05(t，J＝8.2Hz，1H)，7.19(d，J＝8.6 Hz，1H)，8.10(d，J＝8.7Hz，1H)，8.59(dd， J＝8.8，1.8Hz，1H)，8.68(s，1H)，8.87(d， J＝1.5Hz，1H)，9.10(s，1H)，11.37(s，1H) | 472.2(M+1) + | 21％ |
| 16 | 0.99(s，9H)，3.54-3.68(m，4H)，5.21(s， 2H)，5.33(m，1H)，6.85(m，1H)，7.24- 7.32(m，3H)，7.43(m，1H)，7.54(m，1H)， 7.62(m，1H)，7.78(s，1H)，8.16(d，J＝6.5 | 559.2(M+1) + | 38％ |
| Hz，1H)，8.62(s，1H)，8.92(s，1H). | |||
| 17 | 1.01(s，9H)，3.56-3.68(m，4H)，5.24(s， 2H)，5.34(m，1H)，7.33-7.43(m，2H)， 7.60-7.68(m，3H)，7.90-7.95(m，2H)， 8.34(d，J＝9.1Hz，1H)，8.61(d，J＝3.6 Hz，1H)，8.83(s，1H)，8.94(s，1H). | 542.2(M+1) + | 35％ |
| 18 | 1.00(s，9H)，2.61(s，3H)，3.56-3.68(m， 4H)，5.32(m，1H)，7.16(t，J＝5.6Hz，4H)， 7.53(d，J＝7.2Hz，1H)，7.65(dd，J 1＝2.5 Hz，J 2＝7.6Hz，1H)，8.05(d，J＝2.6Hz， 1H)，8.26(dd.J 1＝2.4Hz，J 2＝8.8Hz，1H)， 8.76(s，1H)，8.98(s，1H). | 549.2(M+1) + | 46％ |
Embodiment 47-96
Synthesizing of similar compound 1, compound 19-68 can by raw material I-3a respectively with III-3a to III-3n, IV-4a, IV-4b, V-2b, V-3a, VI-3a-3p, VII-2a-21, (R)-3-nitrine-1-benzyl-pyrrole, (S)-3-nitrine-1-benzyl-pyrrole, (S)-the 3-nitrine-reaction of 1-N-ethyl pyrrole N-obtains.
Table 13
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR) m/z | Yield |
| 19 | 1.14-1.28(m，5H)，1.57(d，J ＝12.0Hz， 1H)，1.70-1.77(m，4H)，1.97-2.03(m，2H)， 2.11-2.19(m，2H)，2.32-2.49(m，3H)，2.95-2.96(m， 2H)，4.53-4.54(m，1H)，5.25(s，2H)，7.15-7.19(m， 1H)，7.25-7.33(m，3H)，7.43-7.49(m，1H)，7.76(dd， J 1＝2.8Hz，J 2＝8.8Hz，1H)，7.83(d，J＝8.8Hz，1H)， 8.24(dd，J 1＝1.6Hz，J 2＝8.8Hz，1H)，8.56(s，1H)， 8.76(s，1H)，9.02(d，J＝1.6Hz，1H)，9.99(s，1H). | 612.3(M+1) + | 39％ |
| 20 | 2.02-2.15(m，6H)，2.22(s，3H)，6.50(t，J＝2.0Hz， 2H)，4.52-4.56(m，1H)，5.25(s，2H)，7.14-7.19(m， 1H)，7.25-7.33(m，3H)，7.43-7.49(m，1H)，7.76(dd， J 1＝2.4Hz，J 2＝9.6Hz，1H)，8.02(d，J＝2.8Hz，1H)， | 544.2(M+1) + | 46％ |
| 8.25(dd，J 1＝1.6Hz，J 2＝8.8Hz，1H)，8.56(s，1H)， 8.74(s，1H)，9.02(d，J＝1.6Hz，1H)，9.98(d，J＝4.0 Hz，1H). |
| 21 | 1.35-1.37(m，2H)，1.49-1.55(m，2H)，1.56-1.65(m， 2H)，1.79-1.85(m，2H)，2.02-2.06(m，2H)， 2.10-2.19(m，4H)，4.59(s，1H)，5.27(s，2H)， 7.19-7.22(m，1H)，7.27-7.35(m，3H)，7.44-7.52(m， 1H)，7.78(dd，J 1＝2.6Hz，J 2＝9.2Hz，1H)，7.85(d， J＝2.4Hz，1H)，8.05(d，J＝2.4Hz，1H)，8.25(t， J＝5.1Hz，1H)，8.59(d，J＝0.6Hz，1H)，8.77(s， 1H)，9.05(s，1H)，10.08(s，1H). | 598.3(M+1) + | 32％ |
| 22 | 0.88(t，J＝6.6Hz，6H)，1.75-1.84(m，1H)， 1.99-2.12(m，8H)，2.94(t，J＝7.5Hz，2H)， 4.55-4.61(m，1H)，5.27(s，2H)，7.16-7.22(m，1H)， 7.27-7.35(m，3H)，7.44-7.51(m，1H)，7.78(dd，J 1＝2.4 Hz，J 2＝9.0Hz，1H)，7.87(t，J＝6.0Hz，1H)，8.04(d， J＝2.1Hz，1H)，8.27(d，J＝5.1Hz，1H)，8.78(s， 1H)，9.06(s，1H)，10.0(s，1H). | 586.3(M+1) + | 64％ |
| 23 | 0.93(t，J＝7.2Hz，6H)，1.24(s，2H)，1.29～ 1.37(m，2H)，2.05～2.12(m，2H)，2.22～2.30(m， 3H)，2.49～2.53(m，2H)，2.91(d，J＝8.4Hz，2H)， 4.50～4.57(m，1H)，5.17(s，2H)，6.99～7.05(m， 2H)，7.32～7.40(m，2H)，7.54(dd，J＝3.2，6.0Hz， 1H)，7.62(s，1H)，7.96(t，J＝3.4Hz，3H)，8.03(dd， J＝1.6，7.2Hz，1H)，8.62(s，1H)，8.75(s，1H). | 600.3(M+1) + | 30％ |
| 24 | 9.32(s，1H)，8.84(br s，1H)，8.03(br?s，1H)， 7.98(s，1H)，7.58(dd，J＝2.4，6.4Hz，1H)，7.20～ 7.15(m，1H)，7.07～7.01(m，2H)，6.84～6.80(m， 2H)，4.97(s，2H)，4.34～4.29(m，1H)，2.78(d，J＝ 13.6Hz，2H)，2.32～2.26(m，2H)，1.99～1.91(m， 6H)，0.69(s，9H). | 600.3(M+1) + | 42％ |
| 25 | 1.02(d，J＝6.4Hz，6H)，1.98-2.05(m，2H)， | 572.2(M+1) + | 28％ |
| 2.17-2.20(m，2H)，2.32-2.38(m，2H)，2.82(br s， 1H)，2.88-2.95(m，2H)，4.57(br?s，1H)，5.26(s， 2H)，7.16-7.21(m，1H)，7.26-7.34(m，3H)， 7.44-7.50(m，1H)，7.79(dd，J＝9.0，2.5Hz，1H)， 7.84(d，J＝9.0Hz，1H)，8.26(dd，J＝8.4，1.1Hz， 1H)，8.55(s，1H)，8.78(s，1H)，9.06(s，1H)， 10.01(s，1H). |
| 26 | 1.78-1.85(m，4H)，1.92-2.05(m，2H)，2.14-2.25(m， 4H)，3.17-3.30(m，4H)，3.45(m，1H)，4.64-4.66(m， 1H)，5.25(s，2H)，7.15-7.20(m，1H)，7.25-7.34(m， 3H)，7.79(dd，J＝8.8，2.8Hz，1H)，7.84(d，J＝8.8 Hz，1H)，8.05(d，J＝2.0Hz，1H)，8.28(dd，J＝8.8， 1.6Hz，1H)，8.57(s，1H)，8.78(s，1H)，9.08(s，1H)， 10.04(s，1H). | 584.3(M+1) + | 46％ |
| 27 | 2.14-2.25(m，4H)，3.17-3.30(m，4H)，3.54(s，2H)， 4.64-4.66(m，1H)，5.25(s，2H)，7.05-7.23(m，6H)， 7.25-7.34(m，3H)，7.79(dd，J＝8.8，2.8Hz，1H)， 7.84(d，J＝8.8Hz，1H)，8.05(d，J＝2.0Hz，1H)， 8.28(dd，J＝8.8，1.6Hz，1H)，8.57(s，1H)，8.78(s， 1H)，9.08(s，1H)，10.04(s，1H). | 620.2(M+1) + | 58％ |
| 28 | 2.14-2.25(m，4H)，3.17-3.30(m，4H)，6.52(s，2H)， 4.12(s，3H)，4.64-4.66(m，1H)，5.25(s，2H)，6.64(d， J＝5.6Hz，2H)，6.95(d，J＝5.6Hz，2H)，7.15-7.20(m， 1H)，7.25-7.34(m，3H)，7.79(dd，J＝8.8，2.8Hz，1H)， 7.84(d，J＝8.8Hz，1H)，8.05(d，J＝2.0Hz，1H)， 8.28(dd，J＝8.8，1.6Hz，1H)，8.57(s，1H)，8.78(s， 1H)，9.08(s，1H)，10.04(s，1H) | 650.2(M+1) + | 74％ |
| 29 | 2.06-2.15(m，4H)，2.20-2.34(m，2H)，2.92(t，J＝ 11.3Hz，2H)，3.59(s，2H)，4.58-4.62(m，1H)， 5.25(s，2H)，7.15-7.19(m，1H)，7.24-7.37(m，5H)， 7.42-7.49(m，1H)，7.78(dd，J 1＝2.3，J 2＝9.1Hz， 1H)，7.81(d，J＝8.7Hz，1H)，8.03(d，J＝2.1Hz， | 621.2(M+1) + | 61％ |
| 1H)，8.24(dd，J 1＝2.6，J 2＝8.8Hz，1H)，8.53(d， J＝5.5Hz，2H)，8.57(s，1H)，8.79(s，1H)，9.03(s， 1H)，10.00(s，1H) | |||
| 30 | 2.03-2.24(m，6H)，2.95(d，J＝10.5Hz，2H)， 3.57(s，2H)，4.08-4.60(m，1H)，5.25(s，2H)， 6.31(d，J＝2.9Hz，1H)，6.41(d，J＝2.3Hz，1H)， 7.18(dd，J＝8.7Hz，1H)，7.25-7.34(m，3H)， 7.43-7.51(m，1H)，7.60(s，1H)，7.77(d，J＝8.5Hz， 1H)，8.04(d，J＝1.5Hz，1H)，8.27(s，1H)，8.74(s， 1H)，9.14(br?s，1H)，10.01(s，1H). | 610.2(M+1) + | 65％ |
| 31 | 2.14-2.25(m，4H)，3.17-3.30(m，4H)，4.64-4.66(m， 1H)，5.25(s，2H)，6.54(d，J＝2.6Hz，1H)，6.76(m， 1H)，7.15-7.23(m，2H)，7.25-7.34(m，3H)，7.79(dd， J＝8.8，2.8Hz，1H)，7.84(d，J＝8.8Hz，1H)，8.05(d， J＝2.0Hz，1H)，8.28(dd，J＝8.8，1.6Hz，1H)， 8.57(s，1H)，8.78(s，1H)，9.08(s，1H)，10.04(s，1H). | 626.2(M+1) + | 63％ |
| 32 | 1.26(s，9H)，2.02-2.06(m，2H)，2.13-2.20(m，4H)， 2.93(t，J＝11.2Hz，2H)，3.50(s，2H)， 4.58-4.62(m，1H)，5.24(s，2H)，7.16-7.17(m，1H)， 7.23-7.27(m，3H)，7.29-7.35(m，4H)，7.43-7.47(m， 1H)，7.76(dd，J 1＝3.2，J 2＝9.2Hz，1H)，7.83(d， J＝8.4Hz，1H)，8.02(d，J＝2.4Hz，1H)，8.24(dd， J 1＝1.2，J 2＝8.4Hz，1H)，8.56(s，1H)，8.75(s，1H)， 9.01(d，J＝1.2，1H)，9.98(s，1H). | 676.2(M+1) + | 67％ |
| 33 | 1.05(s，9H)，2.14-2.25(m，4H)，3.17-3.30(m，4H)， 4.64-4.66(m，1H)，5.25(s，2H)，7.15-7.20(m，1H)， 7.25-7.34(m，3H)，7.79(dd，J＝8.8，2.8Hz，1H)， 7.84(d，J＝8.8Hz，1H)，8.05(d，J＝2.0Hz，1H)， 8.28(dd，J＝8.8，1.6Hz，1H)，8.57(s，1H)，8.78(s， 1H)，9.08(s，1H)，10.04(s，1H). | 586.2(M+1) + | 33％ |
| 34 | 0.32-0.35(m，2H)，0.42-0.46(m，2H)，1.66-1.70(m， 1H)，1.95-2.00(m，2H)，2.11-2.15(m，2H)， | 570.2(M+1) + | 31％ |
| 2.38-2.45(m，2H)，3.03-3.06(m，2H)，4.55-4.64(m， 1H)，5.24(s，2H)，7.15-7.19(m，1H)，7.25-7.33(m， 4H)，7.43-7.49(m，1H)，7.75(dd，J＝9.0，2.4Hz，1H)， 8.01(d，J＝2.4Hz，1H)，8.25(d，J＝7.5Hz，1H)， 8.70(s，1H)，9.00(s，1H)，10.00(s，1H) | |||
| 35 | 2.04-2.15(m，4H)，2.28(s，6H)，2.98(d，J＝5.6Hz， 2H)，3.17-3.30(m，4H)，6.54(d，J＝12.6Hz，2H)， 4.64-4.66(m，1H)，5.25(s，2H)，7.15-7.20(m，2H)， 7.25-7.34(m，3H)，7.79(dd，J＝8.8，2.8Hz，1H)， 7.84(d，J＝8.8Hz，1H)，8.05(d，J＝2.0Hz，1H)， 8.28(dd，J＝8.8，1.6Hz，1H)，8.57(s，1H)，8.78(s， 1H)，9.08(s，1H)，10.04(s，1H). | 641.3(M+1) + | 23％ |
| 36 | 2.04-2.15(m，4H)，2.28(s，6H)，2.62(d，J＝6.4Hz， 2H)，3.05(d，J＝6.4Hz，2H)，3.17-3.30(m，4H)， 4.64-4.66(m，1H)，5.25(s，2H)，7.15-7.20(m，1H)， 7.25-7.34(m，3H)，7.79(dd，J＝8.8，2.8Hz，1H)， 7.84(d，J＝8.8Hz，1H)，8.05(d，J＝2.0Hz，1H)， 8.28(dd，J＝8.8，1.6Hz，1H)，8.57(s，1H)，8.78(s， 1H)，9.08(s，1H)，10.04(s，1H). | 644.3(M+1) + | 35％ |
| 37 | 0.81(t，J＝8.0Hz，6H)，1.26-1.41(m，4H)， 2.19-2.22(m，1H)，3.43(t，J＝8.4Hz，2H)，3.78(t， J＝2.0Hz，2H)，5.25(s，2H)，5.28-5.32(m，1H)， 7.14-7.19(m，1H)，7.25-7.32(m，3H)，7.43-7.50(m， 1H)，7.75(d-d，J＝6.0Hz，2.8Hz，1H)，7.84(d， J＝8.8Hz，1H)，8.02(d，J＝2.4Hz，1H)，8.30(d， J＝2.8Hz，1.6Hz，1H)，8.57(s，1H)，8.86(s，1H)， 9.03(d，J＝1.2Hz，1H)，10.00(s，1H). | 572.2(M+1) + | 28％ |
| 38 | 0.93(d，J＝8.2Hz，6H)，2.47-2.50(m，1H)，3.46(t， J＝6.4Hz，2H)，3.79(t，J＝6.8Hz，2H)， 5.26-5.32(m，3H)，7.17-7.21(m，1H)，7.28-7.35(m， 3H)，7.48(dd，J＝8.0Hz，5.9Hz，1H)，7.77(q，J ＝6.2Hz，2.8Hz，1H)，7.86(d，J＝8.9Hz，1H)， | 544.2(M+1) + | 28％ |
| 8.05(d，1H)，8.32(q，J＝2.6Hz，1H)，8.59(s，1H)， 8.89(s，1H)，9.06(s，1H)，10.02(s，1H). | |||
| 39 | 1.48-1.59(m，8H)，2.87(s，1H)，3.75(t，J＝7.5Hz， 4H)，5.24(s，2H)，5.27-5.29(m，1H)，7.25-7.33(m， 4H)，7.45(m，1H)，7.74(d，J＝7.4Hz，1H)，7.84(d， J＝7.6Hz，1H)，8.00(s，1H)，8.30(d，J＝9.1Hz， 1H)，8.56(s，1H)，8.84(s，1H)，9.02(s，1H)， 9.9(s，1H). | 570.2(M+1) + | 18％ |
| 40 | 0.97-0.99(m，2H)，1.15-1.22(m，4H)，1.68(s，4H)， 3.50-3.60(m，2H)，3.78-3.80(m，2H)，5.25(s，2H)， 5.30-5.34(m，1H)，7.17-7.20(m，1H)，7.26-7.34(m， 3H)，7.44-7.48(s，1H)，7.74-7.76(m，1H)，8.01(d， J＝2.8Hz，1H)，8.30(d，J＝7.2Hz，1H)，8.85(s， 1H)，9.03(s，1H)，10.0(s，1H). | 584.2(M+1) + | 14％ |
| 41 | 1.85-1.94(m，2H)，2.05-2.14(m，4H)，3.12(m，1H)， 3.46(t，J＝6.4Hz，2H)，3.79(t，J＝6.8Hz，2H)， 5.26-5.32(m，3H)，7.17-7.21(m，1H)，7.28-7.35(m， 3H)，7.48(dd，J＝8.0Hz，5.9Hz，1H)，7.77(q，J ＝6.2Hz，2.8Hz，1H)，7.86(d，J＝8.9Hz，1H)， 8.05(d，1H)，8.32(q，J＝2.6Hz，1H)，8.59(s，1H)， 8.89(s，1H)，9.06(s，1H)，10.02(s，1H). | 556.2(M+1) + | 25％ |
| 42 | 3.46(t，J＝6.4Hz，2H)，3.65(m，1H)，3.79(t，J＝6.8 Hz，2H)，4.72-4.83(m，4H)，5.26-5.32(m，3H)， 7.17-7.21(m，1H)，7.28-7.35(m，3H)，7.48(dd，J＝8.0 Hz，5.9Hz，1H)，7.77(q，J＝6.2Hz，2.8Hz，1H)， 7.86(d，J＝8.9Hz，1H)，8.05(d，1H)，8.32(q，J＝ 2.6Hz，1H)，8.59(s，1H)，8.89(s，1H)，9.06(s，1H)， 10.02(s，1H). | 558.2(M+1) + | 23％ |
| 43 | 2.38(s，3H)，3.46(t，J＝6.4Hz，2H)，3.79(t，J＝ 6.8Hz，2H)，5.26-5.32(m，3H)，7.17-7.21(m，1H)， 7.28-7.35(m，3H)，7.48(dd，J＝8.0Hz，5.9Hz，1H)， 7.77(q，J＝6.2Hz，2.8Hz，1H)，7.86(d，J＝8.9Hz， | 516.2(M+1) + | 28％ |
| 1H)，8.05(d，1H)，8.32(q，J＝2.6Hz，1H)，8.59(s， 1H)，8.89(s，1H)，9.06(s，1H)，10.02(s，1H). | |||
| 44 | 0.26(m，2H)，0.54-0.65(m，3H)，2.38(d，J＝5.6Hz， 2H)，3.46(t，J＝6.4Hz，2H)，3.79(t，J＝6.8Hz， 2H)，5.26-5.32(m，3H)，7.17-7.21(m，1H)， 7.28-7.35(m，3H)，7.48(dd，J＝8.0Hz，5.9Hz，1H)， 7.77(q，J＝6.2Hz，2.8Hz，1H)，7.86(d，J＝8.9Hz， 1H)，8.05(d，1H)，8.32(q，J＝2.6Hz，1H)，8.59(s， 1H)，8.89(s，1H)，9.06(s，1H)，10.02(s，1H). | 556.2(M+1) + | 62％ |
| 45 | 2.84(s，3H)，2.74-2.86(m，4H)，3.46(t，J＝6.4Hz， 2H)，3.79(t，J＝6.8Hz，2H)，5.26-5.32(m，3H)， 7.17-7.21(m，1H)，7.28-7.35(m，3H)，7.48(dd，J＝8.0 Hz，5.9Hz，1H)，7.77(q，J＝6.2Hz，2.8Hz，1H)， 7.86(d，J＝8.9Hz，1H)，8.05(d，1H)，8.32(q，J＝ 2.6Hz，1H)，8.59(s，1H)，8.89(s，1H)，9.06(s，1H)， 10.02(s，1H). | 608.2(M+1) + | 42％ |
| 46 | 3.42(s，2H)，3.63-3.65(m，2H)，3.77(s，2H)， 3.85(t，J＝7.3Hz，2H)，5.15(s，2H)，5.29-5.33(m， 1H)，6.97(d，J＝8.8Hz，1H)，7.05-7.14(m，6H)， 7.20-7.25(m，2H)，7.28-7.39(m，6H)，7.53(dd，J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)，7.90(d， J＝2.5Hz，1H)，7.92(d，J＝8.8Hz，1H)，8.04(dd， J 1＝1.6Hz，J 2＝8.7Hz，1H)，8.22(s，1H)，8.68(s， 1H)，8.73(s，1H). | 592.2(M+1) + | 61％ |
| 47 | 1.34(s，9H)，3.43(s，2H)，3.63-3.65(m，2H)， 3.77(s，2H)，3.85(t，J＝7.3Hz，2H)，5.15(s， 2H)，5.29-5.33(m，1H)，6.97(d，J＝8.8Hz，1H)， 6.68(d，J＝6.5Hz，2H)，7.02(m，1H)，7.12(d，J ＝6.5Hz，2H)，7.20-7.25(m，2H)，7.28-7.39(m，6H)， 7.53(dd，J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)， 7.90(d，J＝2.5Hz，1H)，7.92(d，J＝8.8Hz，1H)， 8.04(dd，J 1＝1.6Hz，J 2＝8.7Hz，1H)，8.22(s，1H)， | 648.3(M+1) + | 67％ |
| 8.68(s，1H)，8.73(s，1H). | |||
| 48 | 3.43(s，2H)，3.63-3.65(m，2H)，3.77(s，2H)，3.85(t， J＝7.3Hz，2H)，5.15(s，2H)，5.29-5.33(m，1H)， 6.97(d，J＝8.8Hz，1H)，7.08(m，1H)，7.12(d，J＝ 6.5Hz，2H)，7.20-7.25(m，2H)，7.28-7.39(m，6H)， 7.53(dd，J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)， 7.86(m，2H)，7.96(d，J＝6.3Hz，2H)，8.04(dd，J 1＝ 1.6Hz，J 2＝8.7Hz，1H)，8.22(s，1H)，8.68(s，1H)， 8.73(s，1H). | 593.2(M+1) + | 54％ |
| 49 | 3.43(s，2H)，3.63-3.65(m，2H)，3.77(s，2H)， 3.85(t，J＝7.3Hz，2H)，5.15(s，2H)，5.29-5.33(m， 1H)，6.31(d，J＝3.5Hz，1H)，6.64(m，1H)，6.97(d， J＝8.8Hz，1H)，7.08(m，1H)，7.15(d，J＝2.6Hz， 1H)，7.20-7.25(m，2H)，7.28-7.39(m，6H)，7.53(dd， J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)，7.86(m， 2H)，8.04(dd，J 1＝1.6Hz，J 2＝8.7Hz，1H)，8.22(s， 1H)，8.68(s，1H)，8.73(s，1H). | 581.2(M+1) + | 61％ |
| 50 | 3.43(s，2H)，3.63-3.65(m，2H)，3.77(s，2H)，3.85(t， J＝7.3Hz，2H)，5.15(s，2H)，5.29-5.33(m，1H)， 6.35(d，J＝3.5Hz，1H)，6.64(m，1H)，6.97(d，J＝ 8.8Hz，1H)，7.02-7.08(m，2H)，7.15(d，J＝2.6Hz， 1H)，7.20-7.25(m，2H)，7.28-7.39(m，6H)，7.53(dd， J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)，7.86(m， 2H)，8.04(dd，J 1＝1.6Hz，J 2＝8.7Hz，1H)，8.22(s， 1H)， | 598.2(M+1) + | 67％ |
| 51 | 2.14(s，3H)，3.43(s，2H)，3.63-3.65(m，2H)，3.77(s， 2H)，3.85(t，J＝7.3Hz，2H)，5.15(s，2H)， 5.29-5.33(m，1H)，6.31(d，J＝3.5Hz，1H)，6.64(m， 1H)，6.97(d，J＝8.8Hz，1H)，7.08(m，1H)，7.15(d， J＝2.6Hz，1H)，7.20-7.25(m，2H)，7.28-7.39(m，6H)， 7.53(dd，J 1＝2.7Hz，J 2＝8.9Hz，1H)，7.86(s?1H)， 7.86(m，2H)，8.04(dd，J 1＝1.6Hz，J 2＝8.7Hz，1H)， | 596.2(M+1) + | 71％ |
| 8.22(s，1H)，8.68(s，1H)，8.73(s，1H). | |||
| 52 | 0.36(s，2H)，0.83(dd，J＝5.6Hz，3.8Hz，2H)， 2.08-2.10(m，1H)，3.64-3.67(m，2H)，3.86-3.87(m， 2H)，5.24(s，2H)，5.29-5.32(m，1H)，7.14-7.19(m， 1H)，7.25-7.32(m，3H)，7.43-7.48(m，1H)， 7.75(d-d，J＝7.7Hz，6.4Hz，1H)，8.00-8.02(m， 1H)，8.30(s，1H)，8.87(s，1H)，9.09(s，1H)， 10.00(s，1H). | 542.2(M+1) + | 26％ |
| 53 | 2.89(s，3H)，2.96-3.00(m，2H)，3.04- 3.08(m，2H)，2.65(t，J＝6.5Hz，2H)，4.51(t，J ＝5.9Hz，2H)，5.25(s，2H)，7.14-7.19(m，1H)， 7.25-7.33(m，3H)，7.42-7.50(m，1H)，7.76(dd，J＝ 1.6Hz，1H)，8.03(d，J＝8.3Hz，1H)，8.26(dd， J 1＝1.1Hz，J 2＝8.8Hz，1H)，8.57(s，1H)，8.64(s， 1H)，9.03(s，1H)，10.0(s，1H). | 582.2(M+1) + | 63％ |
| 54 | 1.69-1.87(m，4H)，2.62(s，4H)，3.04(t，J＝6.4Hz， 2H)，4.58(t，J＝6.2Hz，2H)，5.16(s，2H)， 6.97-7.05(m，2H)，7.21-7.26(m，1H)，7.33-7.40(m， 1H)，7.56(dd，J 1＝2.6Hz，J 2＝8.8Hz，1H)， 7.91-7.96(m，3H)，8.02(d，J＝8.6Hz，1H)，8.08(s， 1H)，8.72(d，J＝12.2Hz，2H). | 544.2(M+1) + | 54％ |
| 55 | 2.59(t，J＝4.8Hz，4H)，2.86(s，3H)，2.91(t，J＝ 6.4Hz，2H)，3.10(t，J＝4.8Hz，4H)，4.62(t，J＝ 6.0Hz，2H)，5.27(s，2H)，7.14-7.19(m，1H)， 7.27-7.35(m，4H)，7.45-7.51(m，1H)，7.77(dd，J 1＝2.8 Hz，J 2＝8.8Hz，1H)，8.04(d，J＝2.8Hz，1H)，8.27(d， J＝7.6Hz，1H)，8.65(s，1H)，9.05(s，1H)，10.02(s， 1H). | 637.2(M+1) + | 47％ |
| 56 | 2.21(s，3H)，2.50(s，8H)，2.82-2.86(t，J＝12.9 Hz，2H)，4.57-4.61(t，J＝13.2Hz，2H)，5.27(s， 2H)，7.27-7.30(m，1H)，7.33-7.35(m，3H)， 7.47-7.49(m，1H)，7.77-7.82(m，2H)，8.05-8.06(d， | 573.2(M+1) + | 28％ |
| J＝2.7Hz，1H)，8.25-8.28(m，1H)，8.59(s，1H)， 8.56(s，1H)，9.06(s，1H)，10.04(s，1H). |
| 57 | 2.49(t，J＝4.8Hz，4H)，2.56(d，J＝6.1Hz，3H)， 2.91(t，J＝6.4Hz，2H)，3.10(t，J＝4.8Hz，4H)， 4.62(t，J＝6.0Hz，2H)，5.27(s，2H)，7.14-7.19(m， 1H)，7.27-7.35(m，4H)，7.45-7.51(m，1H)，7.77(dd， J 1＝2.8Hz，J 2＝8.8Hz，1H)，8.04(d，J＝2.8Hz，1H)， 8.27(d，J＝7.6Hz，1H)，8.65(s，1H)，8.76(br?s?1H)， 9.05(s，1H)，10.02(s，1H). | 616.2(M+1) + | 39％ |
| 58 | 2.49(t，J＝4.8Hz，4H)，2.91(t，J＝6.4Hz，2H)， 3.10(t，J＝4.8Hz，4H)，4.62(t，J＝6.0Hz，2H)， 5.27(s，2H)，7.14-7.19(m，1H)，7.27-7.35(m，4H)， 7.45-7.51(m，1H)，7.77(dd，J 1＝2.8Hz，J 2＝8.8Hz， 1H)，8.04(d，J＝2.8Hz，1H)，8.27(d，J＝7.6Hz，1H)， 8.35(br?s，2H)，8.65(s，1H)，9.05(s，1H)，10.02(s， 1H). | 602.2(M+1) + | 35％ |
| 59 | 0.89(t，J＝7.0Hz，6H)，2.48(m，4H)，2.89(m，2H)， 4.49(t，J＝5.9Hz，2H)，5.24(s，2H)，7.13-7.18(m， 1H)，7.24-7.32(m，4H)，7.45(m，1H)，7.73(dd，J 1＝ 2.3Hz，J 2＝9.3Hz，1H)，8.01(d，J＝3.2Hz，1H)， 8.28(s，1H)，8.60(s，1H)，9.12(s，1H)，10.01(s， 1H). | 646.2(M+1) + | 48％ |
| 60 | 1.36-1.39(m，2H)，1.45-1.50(m，4H)，2.42(s，4H)， 2.78(t，J＝6.0Hz，2H)，4.57(t，J＝6.0Hz，2H)， 5.26(s，2H)，7.16-7.20(m，1H)，7.27-7.34(m，3H)， 7.44-7.50(m，1H)，7.76(dd，J 1＝2.0，J 2＝8.4Hz， 1H)，7.88(s，1H)，8.03(d，J＝2.8Hz，1H)， 8.27(s，1H)，8.61(s，1H)，9.05(d，J＝1.2Hz，1H)， 10.02(s，1H). | 676.2(M+1) + | 43％ |
| 61 | 2.56(t，J＝4.6Hz，4H)，2.91(t，J＝6.1Hz，2H)， 3.74(t，J＝7.9Hz，4H)，4.56(t，J＝6.1Hz，2H)， 5.18(s，2H)，6.97-7.07(m，2H)，7.20-7.26(m，2H)， | 660.2(M+1) + | 53％ |
| 7.34-7.38(m，1H)，7.56(dd，J 1＝2.2Hz，J 2＝9.0 Hz，1H)，7.81(s，1H)，7.93-8.02(m，3H)，8.06(s， 1H)，8.70(s，1H)，8.75(s，1H). | |||
| 62 | 2.55(t，J＝4.8Hz，4H)，2.82(s，6H)，2.92(t，J ＝6.0Hz，2H)，3.26(t，J＝4.6Hz，4H)，4.56(t， J＝6.2Hz，2H)，5.17(s，2H)，6.96-7.02(m，2H)， 7.24(m，2H)，7.28(m，1H)，7.55(dd，J 1＝2.8，J 2＝ 8.8Hz，1H)，7.80(s，1H)，7.94(m，2H)，7.99(m， 1H)，8.06(s，1H)，8.66(s，1H)，8.73(s，1H). | 630.2(M+1) + | 49％ |
| 63 | 2.44-2.48(m，4H)，2.85(t，J＝6.4Hz，2H)，3.09(t， J＝4.3Hz，4H)，3.16(t，J＝4.2Hz，4H)，3.55(t， J＝4.5Hz，4H)，4.59(t，J＝6.2Hz，2H)，5.26(s， 2H)，7.18(m，1H)，7.26-7.35(m，3H)，7.43-7.51(m， 1H)，7.70(dd，J 1＝2.2Hz，J 2＝8.8Hz，1H)， 7.84(d，J＝8.7Hz，1H)，8.04(d，J＝2.4Hz，1H)， 8.26(m，1H)，8.58(s，1H)，8.64(s，1H)，9.03(s， 1H)，10.01(s，1H). | 672.2(M+1) + | 52％ |
| 64 | 1.72(t，J＝6.7Hz，4H)，2.46(m，4H)，2.85(t，J ＝6.2Hz，2H)，3.13(t，J＝4.8Hz，4H)，3.25(t， J＝7.2Hz，4H)，4.58(t，J＝6.2Hz，2H)，5.26(s， 2H)，7.18(m，1H)，7.26-7.35(m，3H)，7.47(m，1H)， 7.76(dd，J 1＝3.0Hz，J 2＝8.8Hz，1H)，7.83(m，1H)， 8.03(d，J＝2.8Hz，1H)，8.27(d，J＝6.0Hz，1H)， 8.64(s，2H)，9.05(s，1H)，10.02(s，1H). | 656.2(M+1) + | 47％ |
| 65 | 3.15(d，J＝5.1Hz，1H)，3.82-3.86(m，2H)，4.15(t， J＝5.3Hz，2H)，5.18(t，J＝5.1Hz，1H)，5.24(s， 2H)，7.14-7.19(m，6H)，7.25-7.33(m，3H)， 7.43-7.49(m，1H)，7.74(dd，J 1＝2.3Hz，J 2＝8.6Hz， 1H)，7.86(s，1H)，8.02(d，J＝2.4Hz，1H)，8.31(s， 1H)，8.61(s，1H)，9.03(s，1H)，9.99(s，1H). | 491.1(M+1) + | 64％ |
| 66 | 1.94-2.08(m，2H)，2.34-2.42(m，4H)，3.78(s，2H)， 4.54(m，1H)，5.24(s，2H)，7.14-7.19(m，6H)， | 606.2(M+1) + | 55％ |
| 7.25-7.33(m，3H)，7.43-7.49(m，1H)，7.74(dd，J 1＝ 2.3Hz，J 2＝8.6Hz，1H)，7.86(s，1H)，8.02(d，J＝ 2.4Hz，1H)，8.31(s，1H)，8.61(s，1H)，9.03(s，1H)， 9.99(s，1H). | |||
| 67 | 1.94-2.06(m，2H)，2.34-2.45(m，4H)，3.78(s，2H)， 4.54(m，1H)，5.24(s，2H)，7.14-7.19(m，1H)， 7.25-7.34(m，3H)，7.43-7.49(m，1H)，7.76(dd，J 1＝2.3 Hz，J 2＝8.6Hz，1H)，7.86(s，1H)，8.02(d，J＝2.4 Hz，1H)，8.31(s，1H)，8.61(s，1H)，9.03(s，1H)， 10.02(s，1H). | 606.2(M+1) + | 53％ |
| 68 | 1.06(t，J＝5.6Hz，3H)，1.94-2.06(m，2H)， 2.34-2.48(m，6H)，4.54(m，1H)，5.24(s，2H)， 7.14-7.19(m，1H)，7.25-7.34(m，3H)，7.43-7.49(m， 1H)，7.76(dd，J 1＝2.3Hz，J 2＝8.6Hz，1H)，7.86(s， 1H)，8.02(d，J＝2.4Hz，1H)，8.31(s，1H)，8.61(s， 1H)，9.03(s，1H)，10.02(s，1H). | 594.2(M+1) + | 47％ |
Embodiment 97-104
Similar compound 1 synthetic, compound 69-76 can by raw material I-3b respectively with III-3e, IV-4a, VI-3a, VI-3b, VI-3j VII-2a, VII-2f, the reaction of 2-azidoethyl alcohol obtains.
Table 14
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR) | Yield |
| 69 | 1.02(d，J＝6.4Hz，6H)，1.98-2.05(m，2H)， 2.17-2.20(m，2H)，2.32-2.38(m，2H)，2.82(br?s，1H)， 2.88-2.95(m，2H)，4.57(m，1H)，7.19(d，J＝8.8Hz， 1H)，7.60-7.66(m，1H)，7.95-8.14(m，4H)，8.27(s， 1H)，8.73(s，1H)，8.77(s，1H). | 466.2(M+1) + | 49％ |
| 70 | 1.05(s，9H)，2.14-2.25(m，4H)，3.17-3.30(m，4H)， 4.64-4.66(m，1H)，7.19(d，J＝8.8Hz，1H)， 7.60-7.66(m，1H)，7.95-8.14(m，4H)，8.27(s，1H)， 8.73(s，1H)，8.77(s，1H). | 480.2(M+1) + | 53％ |
| 71 | 1.14(d，J＝5.1Hz，6H)，2.35(m，1H)， 3.72-3.81(m，2H)，3.94(t，J＝8.3Hz，2H)， 5.29-5.33(m，1H)，7.19(d，J＝8.8Hz，1H)， 7.60-7.66(m，1H)，7.95-8.14(m，4H)，8.27(s， 1H)，8.73(s，1H)，8.77(s，1H). | 438.2(M+1) + | 69％ |
| 72 | 0.98(d，J＝4.8Hz，4H)，1.36(m，4H)，3.35(m，1H)， 3.55(m，1H)，3.72-3.81(m，2H)，3.94(t，J＝8.3Hz， 2H)，5.29-5.33(m，1H)，7.19(d，J＝8.8Hz，1H)， 7.60-7.66(m，1H)，7.95-8.14(m，4H)，8.27(s，1H)， 8.73(s，1H)，8.77(s，1H). | 466.2(M+1) + | 53％ |
| 73 | 8.72(s，1H)，8.40(br?s，1H)，8.30(s，1H)，8.16(d， J＝8.7Hz，1H)，8.06(m，1H)，7.92(d，J＝8.5Hz， 1H)，7.15(m，2H)，4.70(t，J＝5.4Hz，1H)， 3.30(t，J＝5.4Hz，2H)，2.82(br?s，4H)，1.90(br s，4H). | 438.2(M+1) + | 62％ |
| 74 | 3.36(s，2H)，3.82(br s，2H)，3.88(s，2H)， 5.34(t，J＝5.3Hz，1H)，7.18(t，J＝8.9Hz，1H)， 7.28-7.40(m，5H)，7.66-7.71(m，1H)，7.97(s， 1H)，8.03(d，J＝7.1Hz，1H)，8.08(dd，J＝8.6 Hz，2.3Hz，1H)，8.21(s，1H)，8.77(s ，1H)， 8.85(s，1H). | 486.2(M+1) + | 58％ |
| 75 | 2.95(s，3H)，3.13(t，J＝5.5Hz，2H)， 3.18-3.20(m，2H)，3.26-3.30(m，2H)，4.60(t，J＝ 6.0Hz，2H)，7.26(t，J＝8.8Hz，1H)，7.70-7.74(m， 1H)，7.83(d，J＝9.1Hz，1H)，8.08(dd，J 1＝2.6 Hz，J 2＝6.5Hz，1H)，8.28(dd，J 1＝1.4Hz，J 2＝ 8.5Hz，1H)，8.49(s，1H)，8.55(s，1H)，8.77(s， 1H). | 490.1(M+1) + | 43％ |
| 76 | 4.02(t，J＝2.9Hz，2H)，4.58-4.62(m，2H)， 7.30(t，J＝9.0Hz，1H)，7.74-7.79(m，1H)， 7.86(d，J＝8.4Hz，1H)，8.12(dd，J 1＝2.9Hz，J 2＝7.0Hz，1H)，8.35(dd，J 1＝1.5Hz，J 2＝8.9Hz， | 385.1(M+1) + | 37％ |
| 1H)，8.50(s，1H)，8.59(s，1H)，8.86(s，1H). |
Embodiment 105-108
Similar compound 1 synthetic, compound 77-80 can by raw material I-3d respectively with III-3e, IV-3a, VI-3a, the VI-3b reaction obtains.
Table 15
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR) | Yield |
| 77 | 1.02(d，J＝6.4Hz，6H)，1.98-2.05(m，2H)， 2.17-2.20(m，2H)，2.32-2.38(m，2H)，2.82(br?s， 1H)，2.88-2.95(m，2H)，4.57(m，1H)，5.24(s，2H)， 7.27(d，J＝9.2Hz，1H)，7.36(t，J＝6.0Hz，1H)， 7.57(d，J＝8.0Hz，1H)，7.75(d，J＝8.4Hz，1H)， 7.83-7.89(m，2H)，8.04(s，1H)，8.32(d，J＝8.8Hz， 1H)，8.58(t，J＝8.8Hz，2H)，8.82(s，1H)，9.05(s， 1H)，10.00(s，1H). | 555.2(M+1) + | 61％ |
| 78 | 1.05(s，9H)，2.14-2.25(m，4H)，3.17-3.30(m，4H)， 4.64-4.66(m，1H)，5.24(s，2H)，7.27(d，J＝9.2Hz， 1H)，7.36(t，J＝6.0Hz，1H)，7.57(d，J＝8.0Hz， 1H)，7.75(d，J＝8.4Hz，1H)，7.83-7.89(m，2H)， 8.04(s，1H)，8.32(d，J＝8.8Hz，1H)，8.58(t，J＝ 8.8Hz，2H)，8.82(s，1H)，9.05(s，1H)，10.00(s， 1H). | 569.3(M+1) + | 57％ |
| 79 | 1.14(d，J＝5.1Hz，6H)，2.35(m，1H)，3.72-3.81(m， 2H)，3.94(t，J＝8.3Hz，2H)，5.29-5.33(m，1H)， 5.24(s，2H)，7.27(d，J＝9.2Hz，1H)，7.36(t，J＝ 6.0Hz，1H)，7.57(d，J＝8.0Hz，1H)，7.75(d，J＝ 8.4Hz，1H)，7.83-7.89(m，2H)，8.04(s，1H)， 8.32(d，J＝8.8Hz，1H)，8.58(t，J＝8.8Hz，2H)， 8.82(s，1H)，9.05(s，1H)，10.00(s，1H). | 527.2(M+1) + | 53％ |
| 80 | 0.98(d，J＝4.8Hz，4H)，1.36(m，4H)，3.35(m，1H)， 3.55(m，1H)，3.72-3.81(m，2H)，3.94(t，J＝8.3Hz， 2H)，5.29-5.33(m，1H)，5.24(s，2H)，7.27(d，J＝9.2 | 555.2(M+1) + | 60％ |
| Hz，1H)，7.36(t，J＝6.0Hz，1H)，7.57(d，J＝8.0 Hz，1H)，7.75(d，J＝8.4Hz，1H)，7.83-7.89(m，2H)， 8.04(s，1H)，8.32(d，J＝8.8Hz，1H)，8.58(t，J＝ 8.8Hz，2H)，8.82(s，1H)，9.05(s，1H)，10.00(s， 1H). |
Embodiment 109-112
Similar compound 1 synthetic, compound 81-84 can by raw material I-3g respectively with III-3e, IV-3a, VI-3a, the VI-3b reaction obtains.
Table 16
| Numbering | 1H?NMR(DMSO-d 6，400MHz)δ | MS(ESI-LR) | Yield |
| 81 | 1.02(d，J＝6.4Hz，6H)，1.98-2.05(m，2H)， 2.17-2.20(m，2H)，2.32-2.38(m，2H)，2.82(br?s， 1H)，2.88-2.95(m，2H)，4.57(m，1H)，5.69(s，2H)， 7.04-7.11(m，3H)，7.35(dd，J＝14.0，7.5Hz，1H)， 7.70-7.77(m，2H)，8.15(s，1H)，8.21(s，1H)， 8.34(s，1H)，8.80(s，1H)，9.16(s，1H)，10.08(s， 1H). | 562.3(M+1) + | 66％ |
| 82 | 1.05(s，9H)，2.14-2.25(m，4H)，3.17-3.30(m，4H)， 4.64-4.66(m，1H)，5.69(s，2H)，7.04-7.11(m，3H)， 7.35(dd，J＝14.0，7.3Hz，1H)，7.70-7.77(m，2H)， 8.15(s，1H)，8.21(s，1H)，8.34(s，1H)，8.80(s， 1H)，9.12(s，1H)，10.06(s，1H). | 576.3(M+1) + | 61％ |
| 83 | 1.12(d，J＝5.1Hz，6H)，2.35(m，1H)，3.72-3.81(m， 2H)，3.94(t，J＝8.3Hz，2H)，5.29-5.33(m，1H)， 5.69(s，2H)，7.04-7.12(m，3H)，7.35(dd，J＝14.0， 7.5Hz，1H)，7.70-7.77(m，2H)，8.16(s，1H)， 8.21(s，1H)，8.34(s，1H)，8.80(s，1H)，9.12(s， 1H)，10.05(s，1H). | 534.3(M+1) + | 54％ |
| 84 | 0.98(d，J＝4.8Hz，4H)，1.36(m，4H)，3.35(m，1H)， 3.55(m，1H)，3.72-3.81(m，2H)，3.92(t，J＝8.1Hz， 2H)，5.29-5.33(m，1H)，5.69(s，2H)，7.04-7.11(m， | 562.3(M+1) + | 53％ |
| 3H)，7.35(dd，J＝14.0，7.5Hz，1H)，7.70-7.76(m， 2H)，8.15(s，1H)，8.21(s，1H)，8.34(s，1H)， 8.80(s，1H)，9.08(s，1H)，10.02(s，1H). |
The preparation of embodiment 113 compound salt
(5.58g 10mmol) is dissolved in the mixed solvent of ethyl acetate (160mL) and methyl alcohol (40mL) compound 1, after heating is molten entirely, (0.96g 10mmol), adds to drip methylsulfonic acid, the evaporated under reduced pressure solvent, residue suspended 0.5 hour with dehydrated alcohol (100mL) heating, be cooled to room temperature after, filter, solid is washed with a small amount of dehydrated alcohol, collect solid, vacuum-drying obtains the mesylate (faint yellow solid 5.98g, productive rate 91%) of compound 1.Fusing point: 208-209 ℃, liquid phase purity: 99.602%.
Embodiment 114 pharmaceutical compositions
Compound 1 20g
Starch 140g
Microcrystalline Cellulose 60g
According to a conventional method, after each component of aforementioned pharmaceutical compositions mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound 25.
Embodiment 115: the preparation of capsule
Compound 150g
Starch 400g
Microcrystalline Cellulose 200g
According to a conventional method, after each component of aforementioned pharmaceutical compositions mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound 25.
Experimental example
1. tumors inhibition activity (IC
50)
Behind the nonsmall-cell lung cancer A549 cell of logarithmic phase and human breast carcinoma SKBR3 cell dissociation, blow and beat into single cell suspension, be inoculated in 96 well culture plates respectively; Every hole 5 * 10
3Individual cell, every hole adds substratum 100 μ L, 37 ℃, 5%CO
2Overnight incubation in the incubator.After treating cell attachment, add the test-compound and the lapatinibditosylate of high, medium and low three dosage respectively, the sample of three kinds of different concns of configuration is organized negative control group with blank, with the positive control group of lapatinibditosylate, cultivates 72h again in incubator.Then, it is the MTT liquid of 5mg/mL that every hole adds 20 μ L mass concentrations, cultured continuously 4h.Supernatant liquor is removed in suction, and every hole adds 100 μ L methyl-sulphoxides, and culture plate is placed the 10min that vibrates on the microwell plate vibrator, makes the crystallisate dissolving.Survey the absorbance A value at 570nm wavelength place with microplate reader, calculate inhibiting rate; Press the Bliss method and calculate IC
50Test-results sees the following form 17.
Table 17 part of compounds is to nonsmall-cell lung cancer A549 cell and human breast carcinoma SKBR3 cell inhibiting activity
By the data in the last table as can be seen, this The compounds of this invention all has comparison according to the stronger anti-tumor activity of medicine lapatinibditosylate.
2. anti-tumor in vivo activity
The A549 lung carcinoma cell with contain 10% foetal calf serum 1640 in 37 ℃, 5%CO
2The conventional cultivation in the incubator, after going down to posterity, when treating that cell reaches aequum, the digestion collecting cell.With 3 * 10
6Individual A549 human lung carcinoma cell is injected into oxter, every nude mouse left side, treats tumor growth to 100～200mm
3After, the animal random packet is begun administration.Inoculate in advance the A549 nude mouse from 30 and to select 21 consistent nude mouses of tumor growth to be divided into 3 groups at random, be respectively 1) the solvent control group, 7; 2) compound 1100mg/kg group, 7; 4) lapatinibditosylate 100mg/kg group, 7.The solvent control group is irritated stomach CMCNa solvent every day; Compound 1100mg/kg group is irritated the compound solution 0.1mL/10g of stomach 10mg/mL every day; Lapatinibditosylate 100mg/kg group is irritated the lapatinibditosylate solution 0.1mL/10g of stomach 10mg/mL every day.On every Mondays, three, five weigh and measure gross tumor volume, put to death nude mouse on the 24th day in administration, weigh, it is long-pending to measure the knurl block, calculates relative tumour volume (RTV), tumour appreciation rate (T/C) and tumor suppression percentage relatively, does the statistics detection.Test-results sees the following form 18.
The experimental therapy effect of 1 pair of people's lung cancer of table 18. compound A549 Nude Mice
Compared with the control
*: P＜0.05;
*: P＜0.01;
* *: P＜0.001
D1: divide the cage administration time.RTV: relative tumour volume, calculation formula is: RTV=V
t/ V
0.
T/C (%)=T
RTV/ C
RTV* 100.T
RTV: be treatment group RTV; C
RTV: negative control group RTV.
Therapeutic evaluation standard: T/C (%)＞60 is invalid; T/C (%)≤60, and processing P＜0.05 is effective by statistics.
Compound 1 has comparison according to the stronger anti-tumor in vivo activity of medicine lapatinibditosylate as can be seen from the above table, significantly is better than the blank group.
3. pharmacokinetic
Compound 1 has carried out pharmacokinetic in the rat body.
Compound 1 adopts irritates stomach and two kinds of administering modes of quiet notes, and dosage is 15mg/kg, 4 of every group of healthy SD rats, male and female half and half.The administration volume is 10ml/kg, wherein irritates stomach and prepares with 0.5%CMC-Na, and quiet notes are with DMSO, tween 80 and physiological saline preparation.Fasting 12h before the administration freely drinks water 5min after administration, 15min, 0.5,1.0,2.0,3.0,4.0,5.0,7.0,9.0,24 and 48h through rat eye rear vein beard extracting vein blood 0.3mL, put in the heparinization test tube, the centrifugal 10min of 3500rpm, separated plasma ,-20 ℃ of preservations are to be measured.With the concentration of compound 1 in the liquid chromatography-tandem mass spectrometry method mensuration blood plasma, obtain corresponding pharmacokinetic parameter according to plasma concentration-time curve.See the following form 19.
The main pharmacokinetic parameter of table 19 compound 1
| Compound | Dosage (mg/kg) | Route of administration | t 1/2 (h) | C max (ng/mL) | AUC 0-∞ (ng.h/mL) | F(％) |
| 1 | 15 | Irritate stomach | 12.7±3.9 | 338±66 | 9469±4057 | 62.7％ |
| 1 | 15 | Quiet notes | 18.8±0.5 | 4412±132 | 15103±4654 | - |
| Lapatinibditosylate | 10 | Irritate stomach | 3.91±3.98 | 228±224 | 861±420 | 24.0％ |
| Lapatinibditosylate | 10 | Quiet notes | 12.3±8.24 | 4557±1210 | 3596±924 | - |
By last table data as can be seen, The compounds of this invention 1 has comparison according to the more excellent pharmacokinetic property of medicine lapatinibditosylate (prior art).The rat oral administration biaavailability of The compounds of this invention 1 is 62.7%, and lapatinibditosylate is 24.0%, and therefore, The compounds of this invention might become better clinical antitumor drug.
Advantages such as in a word, this series compound has comparison and shines stronger anti-tumor activity of medicine lapatinibditosylate and more excellent pharmacokinetic property, and simultaneously, compound has novel structure, and synthesis technique is simple.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the compound shown in the formula (I), or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate:
In the formula:
X is O or NH;
R
1Can be selected from following structural unit:
R wherein
4, R
5Be H separately, F, Cl, Br, I, CH
3, OCH
3, NO
2, NH
2, SO
2NH
2, CF
3Or OCF
3
R
6Be selected from:
(1) hydrogen, C
1-6Alkyl and C
3-7Cycloalkyl, described alkyl or cycloalkyl are unsubstituted or are replaced by one to three halogen;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
(3) aryl or heteroaryl, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
R
2Can be selected from following structural unit:
M wherein, n, o are separately 1,2 or 3 integer, Y independently is selected from CO, CO
2, S, SO, SO
2, NHCO, NHSO
2, or Y is a chemical bond;
R
9Be selected from:
(1) hydrogen atom, C
1-6Chain or C
3-7Cyclic alkyl, described alkyl be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, O, N, S, SO, SO
2Or CN;
(2) aryl methylene or hetero-aromatic ring methylene radical, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
(3) aryl or heteroaryl, its be unsubstituted or by one to three independently be selected from down the group group replace: halogen, OH, NH
2, NO
2, CH
3, C
2H
5, (CH
3)
2CH,
tBu, CN, CF
3, OCH
3, or OCF
3
2. compound as claimed in claim 1 is characterized in that R
1Be selected from down group: 3-chloro-4-(3-fluorine benzyloxy) phenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-, 4-((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-, 1-(pyridine-2-ylmethyl)-1H-indazole-5-base, 2-(3-luorobenzyl)-1H-indazole-5-base, 1-(pyridine-2-ylmethyl)-2H-indazole-5-base, 2-(3-luorobenzyl)-2H-indazole-5-base, 4-methyl-3-sulfonamido phenyl, (R)-the 1-phenylethyl, the 5-chlorobenzene is [d] [1 also, 3] the assorted amyl group of dioxygen-4-base, 2,4-two chloro-5-p-methoxy-phenyls, 4-(6-picoline-3-base oxygen base)-3-aminomethyl phenyl.
3. compound as claimed in claim 1 is characterized in that, X is O or NH; And/or
R
2Be selected from down group: 1-cyclohexyl piperidin-4-yl; 1-methyl piperidine-4-base; 1-cyclopentyl piperidin-4-yl; 1-isobutyl-piperidin-4-yl; 1-(amyl group-3-yl) piperidin-4-yl; 1-tertiary amyl piperidin-4-yl; 1-sec.-propyl piperidin-4-yl; 1-cyclobutyl piperidin-4-yl; 1-benzyl piepridine-4-base; 1-(4-methoxy-benzyl) piperidin-4-yl; 1-((pyridin-4-yl) methyl) piperidin-4-yl; 1-((furans-2-yl) methyl) piperidin-4-yl; 1-((thiophene-2-yl) methyl) piperidin-4-yl; 1-(4-tertiary butyl benzyl) piperidin-4-yl; 1-tertiary butyl piperidin-4-yl; 1-cyclopropyl piperidine-4-base; 1-(4-(dimethyl amido) but-2-ene-1-carbonyl) piperidin-4-yl; 1-((2-(dimethyl amido) ethyl) formamyl) piperidin-4-yl; 1-(pentane-3-yl) azetidine-3-base; 1-sec.-propyl azetidine-3-base; 1-cyclopentyl azetidine-3-base; 1-cyclobutyl azetidine-3-base; 1-(ring fourth oxygen-3-yl) azetidine-3-base; 1-methyl azetidine-3-base; 1-(cyclopropyl methyl) azetidine-3-base; 1-(2-(methyl sulfuryl) ethyl) azetidine-3-base; 1-benzyl azetidine-3-base; 1-(4-tertiary butyl benzyl) azetidine-3-base; 1-(pyridin-4-yl) azetidine-3-base; 1-(furans-2-yl) azetidine-3-base; 1-(thiophene-2-yl) azetidine-3-base; 1-(5-methyl furan-2-yl) azetidine-3-base; 1-cyclopropyl azetidine-3-base; 1-tertiary butyl azetidine-3-base; 2-(2-(first sulfo group) ethyl amido) ethyl; 2-(pyrroles-1-yl) ethyl; 2-(4-methylsulfonyl piperazine-1-yl) ethyl; 2-(4-methylpiperazine-1-yl) ethyl; 2-(4-methylamino formyl piperazine-1-yl) ethyl; 2-(4-formamyl piperazine-1-yl) ethyl; 2-(N; N-diethyl amido) ethyl; 2-(piperidines-1-yl) ethyl; 2-(morpholinyl) ethyl; 2-(4-(N; the N dimethylamine base) ethyl formyl piperazine-1-yl); 2-(4-(morpholinyl) formyl piperazine-1-yl) ethyl; 2-(4-(tetramethyleneimine-1 base) formyl piperazine-1-yl) ethyl; the 2-hydroxyethyl; (R)-1-benzyl-pyrrole alkane-3-base, (S)-1-benzyl-pyrrole alkane-3-base, (R)-1-ethyl pyrrolidine-3-base.
4. compound as claimed in claim 1 is characterized in that, described compound is mesylate, p-methyl benzenesulfonic acid salt or hydrochloride.
5. compound as claimed in claim 1 is characterized in that, described compound is the compound 1 to 84 in the table 1.
6. pharmaceutical composition, it is characterized in that, it contains acceptable vehicle or carrier on the pharmacology, and the described compound of claim 1 or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
7. the purposes of the described compound of claim 1 or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate is characterized in that, is used to prepare tyrosine kinase inhibitor.
8. the purposes of the described compound of claim 1 or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, it is characterized in that, be used to prepare the medicine that suppresses tyrosine kinase activity or be used to prepare the medicine of the too high relevant disease of treatment, prevention and alleviation and tyrosine kinase activity.
9. purposes as claimed in claim 8 is characterized in that, describedly is selected from tumour with the too high relevant disease of tyrosine kinase activity.
10. the method for the inhibition growth of tumour cell of an external non-therapeutic, it is characterized in that, described method comprises the steps: the contacting of the described compound of described tumour cell and claim 1 or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, thereby suppresses the growth of tumour cell.
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| CN103159748A (en) * | 2011-12-19 | 2013-06-19 | 天津市国际生物医药联合研究院 | Preparation and application of 2-(1H-1, 2, 3-triazole-4-group) aniline compounds |
| JP2017507951A (en) * | 2014-02-27 | 2017-03-23 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Heterocyclic compounds and their use as NAV channel inhibitors |
| JP2017518352A (en) * | 2014-06-19 | 2017-07-06 | メリアル インコーポレイテッド | Parasiticidal compositions containing indole derivatives, parasite control methods and uses thereof |
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| JP2017507951A (en) * | 2014-02-27 | 2017-03-23 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Heterocyclic compounds and their use as NAV channel inhibitors |
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| JP2017518352A (en) * | 2014-06-19 | 2017-07-06 | メリアル インコーポレイテッド | Parasiticidal compositions containing indole derivatives, parasite control methods and uses thereof |
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