CN102050824A - Piperazinoltriazole derivatives - Google Patents

Piperazinoltriazole derivatives Download PDF

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Publication number
CN102050824A
CN102050824A CN2009101982815A CN200910198281A CN102050824A CN 102050824 A CN102050824 A CN 102050824A CN 2009101982815 A CN2009101982815 A CN 2009101982815A CN 200910198281 A CN200910198281 A CN 200910198281A CN 102050824 A CN102050824 A CN 102050824A
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triazole
dihydro
amino
piperazines
trifluorophenyl
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卢鹏
赵传生
朱明杰
何宝林
於万松
史慧敏
陈义朗
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Abstract

The invention provides piperazinoltriazole derivatives, in particular dipeptidyl peptidase IV inhibitors shown by a formula (I) below. The substituents in the formula are defined in the description. The compounds can be used for treating or preventing diseases associated with dipeptidyl peptidase IV, such as diabetes, obesity and hyperlipidemia. The invention also provides methods for preparing the compounds shown by the formula (I), pharmaceutically acceptable salts of the compounds and medicinal compositions and the use of the compounds, the pharmaceutically acceptable salts of the compounds and the medicinal compositions in the preparation of medicaments for treating or preventing diseases associated with dipeptidyl peptidase IV.

Description

Piperazine and triazole derivative
Technical field
The present invention relates to a class novel dipeptidyl peptidase IV (Dipeptidyl peptidases, DPP-IV) inhibitor, its preparation method with and in preparation treatment DPP-IV relevant disease medicament, particularly preparation treatment diabetes, obesity, the application in the high blood cholesterol drug.
Background technology
Type ii diabetes be a kind of common be the chronic disease of feature with the hyperglycemia, it be accompanied by that insulin secretion in insulin resistant in the peripheral tissues, the body reduces relatively and the increase [Exp.0pin.Ther.Patents of liver glyconeogenesis, 2003,13 (4): 99-51].Existing pharmacological agent can not fundamentally address this problem, therefore, people are seeking new medicine, many new treatment target spots just under study for action, be particularly outstanding [the Medicinal Research Review of achievement that the drug research of target spot is obtained wherein with dipeptides peptidyl enzyme IV (DPP-IV), 2009,29 (1), 125-195].
Glucagon-like-peptide-1 (GLP-1) is a kind of hormone by pancreas islet A cells and enteron aisle L-emiocytosis, have glucose dependency insulin secretion accelerating and increase the biosynthetic effect of Regular Insulin, therefore use GLP-1 treatment diabetes to cause the very big interest of scientist.GLP-1 is except having the effect of the insulin secretion of promotion; also have physiological function [Trends Endocrinol Metab such as the generation that promotes beta cell hyperplasia, anti-beta cell apoptosis, glucagon suppression and glycogen, depress appetite, reduction gastrointestinal emptying speed, neuroprotective cell; 1999,10 (6): 229-235].These characteristics of GLP-1 make it become the ideal Remedies for diabetes, yet, only several minutes GLP-1 transformation period in vivo, rapidly by endogenous DPP IV (DPP-IV) degraded (removing N end dipeptides), and lose insulin secretion accelerating activity [Expert Opin.Investing.Drugs, 2004,13 (9): 1091-1102].DPP-IV extensively distributes in human body, is the main metabolic enzyme of GLP-1, is bringing into play important effect in regulation and control GLP-1 activity.Therefore the active compound that suppresses DPP-IV is the DPP-IV inhibitor, can strengthen the effect of GLP-1.
Existing document and patent disclosure many DPP-IV inhibitor [Current Medicinal Chemistry, 1999,6,311-327; Biochemistry 1999,38,11597-11603; Expert Opin.Ther.Patents, 2003,13 (4): 499-510; Expert Opin.Investing.Drugs, 2005,15 (10): 1387-1407].WO 00/34241 discloses to have DPP-IV and suppresses active N-replacement-2-cyanopyrrole compounds, and its diamantane partly is single replaces or simple alkyl replaces.US 2003/0100563 discloses the beta-amino heterocyclic DPP-IV inhibitor that is used for the treatment of diabetes.WO 03/057666 discloses Cyclopropanated 2-cyanopyrrole class DPP-IV inhibitor.US 2004/0171848 discloses a series of 2-cyanopyrrole compounds that contain together with the phenylbenzene side chain.WO2005/095381 discloses 2 of a class new texture, 4-dioxy-3,4-dihydropyridine DPP-IV inhibitor.DPP-IV inhibitor MK-0431 and LAF-237 in the US and European listing, are used for the treatment of type ii diabetes respectively.
Figure B2009101982815D0000021
Yet these compounds are satisfactory not enough to the inhibition activity of dipeptidyl peptidase in the prior art, and external activity and target spot enzyme selectivity are still not high, and its hypoglycemic and HbA 1cActivity does not have N1,N1-Dimethylbiguanide strong [MedicinalResearch Review, 2009,29 (1), 125-195] yet.Therefore this area presses for the active higher depeptidyl peptidase inhibitors of exploitation, so that the treatment various diseases relevant with dipeptidyl peptidase.
Summary of the invention
The purpose of this invention is to provide a class novel dipeptidyl peptidase IV inhibitor, its preparation method and application thereof.
A first aspect of the present invention provides the compound shown in a kind of formula (I), or its various optical isomers, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate:
Figure B2009101982815D0000022
In the formula, R 1, R 2And R 3Be selected from hydrogen atom, C unsubstituted or that replaced arbitrarily by 1 to 2 five yuan or hexa-atomic aromatic ring respectively 1-6Alkyl;
R 4Be selected from:
(1) hydrogen, cyano group, CO 2R 5, carboxyl, CONR 6R 7, NR 6R 7,
(2) C 1-6Alkyl and C 1-6Cycloalkyl, and described alkyl or cycloalkyl is unsubstituted or partly replaced by halogen or replace entirely,
(3) phenyl, it is unsubstituted or independently is selected from following substituting group by one to three and replaces: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl,
(4) contain one to four heteroatomic 5 yuan or 6 yuan of heterocycle that independently are selected from N, S and O, above-mentioned 5 yuan or 6 yuan of heterocycles are unsubstituted or independently are selected from following substituting group by one to three and replace: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl.
R 5Be C 1-6Alkyl, it is unsubstituted or by halogen, COOH and CO 2C 1-6Moieties replaces or replaces entirely;
R 6And R 7Be selected from independently of one another:
(1) hydrogen,
(2) phenyl, it is unsubstituted or independently is selected from halogen, hydroxyl, C by one to three 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or are partly replaced or replace entirely by halogen,
(3) C 1-6Alkyl, and described alkyl is unsubstituted or is partly replaced by halogen or replace entirely;
(4) C 1-6Alkyl, and described alkyl is unsubstituted or is replaced by hydroxylic moiety or replace entirely.
There are four unsymmetrical carbons in The compounds of this invention, so general formula (I) comprises single optically active form, single enantiomer, single diastereomer, non-enantiomer mixture and raceme mixture.
A second aspect of the present invention provides the compound shown in a kind of formula (I), or the preparation method of its various optical isomers pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
A third aspect of the present invention provides a kind of pharmaceutical composition, 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, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
A fourth aspect of the present invention, provide above-claimed cpd of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate to be used for preparation treatment, prevent diabetes, obesity, the purposes of the medicine of hyperlipidemia and other disease relevant with DPP IV (DPP-IV).
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 discoverable type (I) compound has very high inhibition activity to DPP-IV first, is particularly suitable as the inhibitor of DPP-IV.The inventor has finished the present invention on this basis.
Compound title and structural formula representative in the compound shown in the formula of the present invention (I) are as follows
Figure B2009101982815D0000031
Table 1: The compounds of this invention concrete structure formula is as follows
Figure B2009101982815D0000032
Figure B2009101982815D0000051
Figure B2009101982815D0000061
Figure B2009101982815D0000071
Figure B2009101982815D0000081
Figure B2009101982815D0000091
Figure B2009101982815D0000101
Figure B2009101982815D0000111
Figure B2009101982815D0000121
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, ring heptan three rare 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.
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl).Representative example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy 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
" activeconstituents " refers to compound shown in the formula (I) in the literary composition." 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, be fit to salifiable acid and include, but is not limited to mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acidic amino acids such as organic acid such as 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, Phenylsulfonic acid and aspartic acid, 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 0 ℃ usually.Reaction times is generally 0.1 hour～and 60 hours, preferably be 0.5～48 hour.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route I preparation
The preparation of route I: intermediate compound I-5a-o
Figure B2009101982815D0000141
Figure B2009101982815D0000151
Reagent and reaction conditions: a:K 2CO 3, CH 3CN refluxes; B:CuI, Pd (PPh 3) 2Cl 2, Et 3N, DMF; C:SOCl 2, DCM; D:NaN 3, DMSO, 150 ℃; E:TFA, Me 3SiH.
(1) in polar aprotic solvent, under suitable temp, with the available 2-(2 of commerce, 4-dimethoxy-benzyl amino) ethanol and propargyl chloride, in the presence of alkali, react, obtain 2-(N-(2, the 4-veratryl)-N-(Propargyl) amido) ethanol (1-1).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 salt of wormwood is alkali, is solvent with the acetonitrile, and heating reflux reaction spends the night.
(2) in polar aprotic solvent, under suitable temperature, under rare gas element and the suitable alkali, obtain compound (I-2) with terminal alkynes of palladium/copper mixed catalyst catalysis and halogenide cross-coupling.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 N, dinethylformamide are solvent, and bromo-derivative is 100 ℃ of reactions, and the iodo thing is at room temperature reaction.
(3) in polar aprotic solvent, select the appropriate condition chloro to obtain chloro thing (I-3), chloro thing and sodiumazide obtain compound (I-4) by intramolecularly [3+2] cycloaddition under certain condition.The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; The solvent of intramolecularly [3+2] cycloaddition reaction can be selected ether, toluene, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide etc. for use; Temperature range is 0-200 ℃.Optimum condition is: be solvent with the methylene dichloride, sulfur oxychloride/pyridine is a chlorinating agent, and the chloro thing and the sodiumazide that obtain are made solvent with methyl-sulphoxide, 150 ℃ of reactions.
(4) in protic solvent, under suitable temperature, make solvent with acid, under the triethyl silicane effect, obtain sloughing the compound (I-5) of N-protected base.Acid can be selected trifluoroacetic acid, Glacial acetic acid, formic acid etc. for use; Temperature range 0-100 ℃.Optimum condition is: make solvent with trifluoroacetic acid, add triethyl silicane, room temperature reaction spends the night.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route II preparation.
Route II: the preparation of intermediate II-5 and II-9a-9p
Figure B2009101982815D0000161
Reagent and reaction conditions: a:K 2CO 3, CH 3CN refluxes; B:SOCl 2, DCM; C:NaN 3, DMSO, 150 ℃; D:Pd (OH) 2, H 2E:Boc 2O, TEA; F:NBS, MeCN; G:Pd (PPh 3) 4, K 2CO 3, 1,4-diox/H 2O; H:HCl-1,4-diox, DCM.
(1) in polar aprotic solvent, under suitable temp,, in the presence of alkali, react the available 2-of commerce (benzyl amino) ethanol and propargyl chloride, obtain 2-(N-benzyl-N-(Propargyl) amino) ethanol (II-2).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 salt of wormwood is alkali, is solvent with the acetonitrile, and heating reflux reaction spends the night.
(2) in polar aprotic solvent, select the appropriate condition chloro to obtain chloro thing (II-3), chloro thing and sodiumazide obtain compound (II-4) by intramolecularly [3+2] cycloaddition under certain condition.The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; The solvent of intramolecularly [3+2] cycloaddition reaction can be selected ether, toluene, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide etc. for use; Temperature range is 0-200 ℃.Optimum condition is: be solvent with the methylene dichloride, sulfur oxychloride/pyridine is a chlorinating agent, and the chloro thing and the sodiumazide that obtain are made solvent with methyl-sulphoxide, 150 ℃ of reactions.
(3) in proton or non-protonic solvent, in atmosphere of hydrogen with the palladium for the catalyzer hydrogenolysis obtains 4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-α] pyrazine (II-5).Solvent can be selected methyl alcohol, ethanol, Virahol, formic acid, Glacial acetic acid, tetrahydrofuran (THF), acetonitrile etc. for use; Catalyzer can be selected palladium/carbon or palladium hydroxide/carbon etc. for use; Temperature range is 20-80 ℃.Optimum condition is: be solvent with methyl alcohol, 10% palladium/carbon is made catalyzer, room temperature synthesis under normal pressure in atmosphere of hydrogen.
(4) in non-protonic solvent, under the alkali effect, obtain the compound tertiary butyl-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (II-6) with the tert-Butyl dicarbonate effect.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane etc.; Alkali can be selected triethylamine for use, Diisopropylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine, piperazine etc.; Temperature range is 20-70 ℃.Priority condition is: with the methylene dichloride is solvent, and triethylamine is done alkali, at room temperature reaction.
(5) in non-protonic solvent, obtain the compound tertiary butyl-3-bromo-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (II-7) with the effect of bromine source.Solvent can be selected chloroform, tetracol phenixin, tetrahydrofuran (THF), acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide etc. for use; The bromine source can be selected the liquid bromine for use, N-bromo-succinimide, 1,3-two bromo-5,5-dimethyl hydantion etc.; Temperature range is 20-80 ℃.Optimum condition is: be solvent with the acetonitrile, the N-bromo-succinimide is the bromine source, 40 ℃ of reactions.
(6) in appropriate solvent, under suitable temperature, under rare gas element and the suitable alkali, obtain compound (II-8) with palladium catalyst catalysis bromo-derivative and aryl boric acid (or boric acid ester) coupling.Solvent can select 1 for use, the 4-dioxane, and N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, water-toluene, benzene, dimethylbenzene, tetrahydrofuran (THF), glycol dimethyl ether is medium, can be single solvent, also can be mixed solvent; Alkali can be selected salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide, potassium hydroxide etc. for use; Palladium catalyst can be selected tetrakis triphenylphosphine palladium for use, palladium, two (dibenzalacetone) palladium, 1, two (diphenylphosphine) ferrocene of 1-] palladium chloride etc.; Temperature range is 20-150 ℃.Optimum condition is: with 1,4-dioxane/water is solvent, is alkali between carbonic acid, and tetrakis triphenylphosphine palladium is a catalyzer, 80 ℃ of reactions.
(7) in non-protonic solvent, slough protecting group with suitable acid effect, obtain compound (II-9).Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds the HCl-dioxane, at room temperature reaction.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route III preparation.
Route III: the preparation of intermediate III-10
Reagent and reaction conditions: a:NaH, Ac 2O, THF; B:SOCl 2, Py; C:BnNHCH 2CH 2OH, K 2CO 3, CH 3CN; D:SOCl 2, Py; E:NaN 3, DMF; F:Pd/C, Boc 2O, H 2G:LiOH, MeOH/H 2O; H:SOCl 2, Py, DCM; I:Pd/C, H 2J:HCl-1,4-diox, DCM.
(1) in polar aprotic solvent, with fourth-2-alkynes 1, the 4-glycol is a raw material, adds suitable alkali and acylating reagent, and reaction obtains 4-hydroxyl-2-butyne alcohol acetic ester (III-1) under suitable temperature.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Acylating reagent can be selected from Acetyl Chloride 98Min., diacetyl oxide, and acetate mixes acid anhydride etc.Alkali can be selected from sodium hydrogen, hydrogen potassium, n-Butyl Lithium, lithium diisopropyl amido, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium ethylate etc.; Optimum condition is: make alkali with sodium hydrogen, tetrahydrofuran (THF) is a solvent, and diacetyl oxide is an acylating reagent, and room temperature reaction spends the night.
(2) in polar aprotic solvent, be raw material with 4-hydroxyl-2-butyne alcohol acetic ester (III-1), add suitable chlorinating agent, reaction obtains 4-chloro-2-butyne alcohol acetic ester (III-2) under suitable temperature.The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Optimum condition is: with sulfur oxychloride/pyridine is chlorinating agent, and methylene dichloride is a solvent, room temperature reaction.
(3) in polar aprotic solvent, under suitable temp, with the available 2-of commerce (benzyl amino) ethanol and 4-chloro-2-butyne alcohol acetic ester (III-2), in the presence of alkali, react, obtain 4-(N-benzyl-N-(3-hydroxypropyl) amino)-2-butyne alcohol acetic ester (III-3).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 salt of wormwood is alkali, is solvent with the acetonitrile, and heating reflux reaction spends the night.
(4) in polar aprotic solvent, (N-benzyl-N-(3-hydroxypropyl) amino)-2-butyne alcohol acetic ester (III-3) is a raw material with 4-, add suitable chlorinating agent, reaction obtains 4-(N-benzyl-N-(3-chloropropyl) amino)-2-butyne alcohol acetic ester (I II-4) under suitable temperature.Chloro thing and sodiumazide obtain (5-benzyl-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-a] pyrazine-3-yl) methanol acetic acid ester (III-5) by intramolecularly [3+2] cycloaddition under certain condition.The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; The solvent of intramolecularly [3+2] cycloaddition reaction can be selected ether, toluene, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide etc. for use; Temperature range is 0-200 ℃.Optimum condition is: be solvent with the methylene dichloride, sulfur oxychloride/pyridine is a chlorinating agent, and the chloro thing and the sodiumazide that obtain are made solvent with methyl-sulphoxide, 150 ℃ of reactions.
(5) in proton or non-protonic solvent, in atmosphere of hydrogen, be catalyzer with the palladium, compound (III-5) and commercial available tert-Butyl dicarbonate reaction obtain 3-(acetyl-o-methyl)-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (III-6).Solvent can be selected methyl alcohol, ethanol, Virahol, formic acid, Glacial acetic acid, tetrahydrofuran (THF), acetonitrile etc. for use; Catalyzer can be selected palladium/carbon or palladium hydroxide/carbon etc. for use; Temperature range is 20-80 ℃.Optimum condition is: be solvent with methyl alcohol, 10% palladium/carbon is made catalyzer, room temperature synthesis under normal pressure in atmosphere of hydrogen.
(6) in proton or non-protonic solvent, obtain 6 with suitable alkali, 7-dihydro-3-(methylol)-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (III-7).Solvent can be selected methyl alcohol, ethanol, water, formic acid, Glacial acetic acid, tetrahydrofuran (THF), methylene dichloride, acetonitrile etc. for use; Alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta, sodium methylate, potassium tert.-butoxide etc.; Temperature range is 20-80 ℃.Optimum condition is; The mixed solution of first alcohol and water is a solvent, and lithium hydroxide is an alkali, room temperature reaction.
(7) in polar aprotic solvent, with 6,7-dihydro-3-(methylol)-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (III-7) is raw material, adds suitable chlorinating agent, reaction obtains 3-(chloromethyl)-6 under suitable temperature, 7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (III-8).The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Temperature range is 0-200 ℃.Optimum condition is: with sulfur oxychloride/pyridine is chlorinating agent, and methylene dichloride is a solvent, room temperature reaction.
(8) in proton or non-protonic solvent, in atmosphere of hydrogen with the palladium for the catalyzer hydrogenolysis obtains 6,7-dihydro-3-(methyl)-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (III-9).Solvent can be selected methyl alcohol, ethanol, Virahol, formic acid, Glacial acetic acid, tetrahydrofuran (THF), acetonitrile etc. for use; Catalyzer can be selected palladium/carbon or palladium hydroxide/carbon etc. for use; Temperature range is 20-80 ℃.Optimum condition is: be solvent with methyl alcohol, 10% palladium/carbon is made catalyzer, room temperature synthesis under normal pressure in atmosphere of hydrogen.
(9) in non-protonic solvent, slough protecting group with suitable acid effect, obtain compound 4,5,6,7-tetrahydrochysene-3-methyl-[1,2,3] triazole [1,5-α] pyrazine (III-10).Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-100 ℃.Optimum condition is: with methylene dichloride is solvent, and hydrochloric acid is acid, at room temperature reaction.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route IV preparation.
The preparation of route IV: intermediate compound IV-8-12
Reagent and reaction conditions: a:(COCl) 2, DMSO, DIPEA, CH 2Cl 2B:CF 3CH 2OH, I 2, K 2CO 3C:NH 3Aq; D:K 2CO 3, NH (CH 3) 2E:NH 2NH 2F:I 2, NH 3Aq; G:DAST, DCM; The h:HCl-dioxane, DCM; I:HC (OMe) 3.
(1) in proton or non-protonic solvent, in the presence of alkali, use oxidising agent to obtain 3-aldehyde radical-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (IV-2).Solvent can be selected acetone for use, 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.; Alkali can be selected from triethylamine, pyridine, N-methylmorpholine, morpholine, N, N-diisopropylethylamine (DIPEA) etc.Oxidising agent can be selected methyl-sulphoxide/oxalyl chloride for use, methyl-sulphoxide/trifluoracetic acid, and methyl-sulphoxide/dicyclohexyl carbonization diimine, potassium bichromate/sulfuric acid, chromium trioxide/pyridine, Manganse Dioxide, tetrapropyl ammonium is crossed nail acid/4-methylmorpholine-N-oxide compound.Temperature range is-80-50 ℃.Optimum condition is: methylene dichloride is a solvent, and methyl-sulphoxide/oxalyl chloride is an oxidising agent, and N, N-diisopropylethylamine are alkali, and-78 ℃ were reacted room temperature reaction 1 hour 2 hours.
(2) in proton or aprotic solvent, in the presence of oxygenant and alkali, obtain 6, the 7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-3,5 (the 4H)-two carbonic acid-5-tert-butyl ester-3-(2,2, the 2-trifluoro ethyl ester) is (IV-1).Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, trifluoroethanol etc.Oxidising agent can be selected iodine, Periodic acid etc. for use.Alkali can be used salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide, potassium hydroxide etc.Temperature range is 0-100 ℃.Optimum condition is: trifluoroethanol is a solvent, and iodine is oxygenant, and salt of wormwood is alkali, and temperature of reaction is 50 ℃.
(3) in aprotic solvent, compound (IV-1) and ammoniacal liquor reaction obtain 3-carbamyl-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (IV-3).Solvent can be selected methylene dichloride for use, chloroform, and 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1, the 4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitriles etc. also can directly use ammoniacal liquor as reaction solvent.Temperature range is 0-80 ℃.Optimum condition is: ammoniacal liquor is as reaction solvent, room temperature reaction.
(4) in aprotic solvent, add suitable alkali and obtain 3-dimethylamine formyl radical-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (IV-4) with the reaction of the hydrochloride of compound (IV-1) and dimethylamine or dimethylamine.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.Alkali can be used salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, Tripotassium phosphate, cesium carbonate, cesium fluoride, sodium hydroxide, potassium hydroxide etc.Temperature range is 0-100 ℃.Optimum condition is: acetonitrile is as reaction solvent, and salt of wormwood is alkali, 80 ℃ of reactions.
(5) in aprotic solvent, compound (IV-1) and hydrazine hydrate reaction obtain 3-hydrazine formyl radical-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (IV-5).Solvent can be selected methylene dichloride for use, chloroform, and 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1, the 4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitriles etc. also can directly use hydrazine hydrate as reaction solvent.Temperature range is 0-80 ℃.Optimum condition is: hydrazine hydrate is as reaction solvent, room temperature reaction.
(6) in aprotic solvent, compound (IV-2) and ammoniacal liquor reaction obtain 3-cyano group-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic acid tert-butyl ester (IV-6) under oxygenant participates in.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1, the 4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc., oxygenant can be selected iodine, Periodic acid, potassium bichromate/sulfuric acid for use, chromium trioxide/pyridine, Manganse Dioxide, tetrapropyl ammonium is crossed nail acid/4-methylmorpholine-N-oxide compound etc.Temperature range is 0-100 ℃.Optimum condition is: tetrahydrofuran (THF) is as reaction solvent, and iodine is oxygenant, room temperature reaction.
(7) in aprotic solvent, compound (IV-2) obtains 6,7-dihydro-3-(difluoromethyl)-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-7) under fluorination reagent participates in.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.Fluorination reagent can be selected hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine, hydrogen fluoride/Trimethylamine for use, the tribromide fluorine, silicon tetrafluoride, diethylamide sulfur trifluoride (DAST), the dimethyl amine sulfur trifluoride, 1,1,2,3,3,3-hexafluoro propyl group quadrol, two 2-methoxy ethyl amine sulfur trifluorides, sulfur trifluoride piperidines, sulfur trifluoride tetramethyleneimine etc.Temperature range is-50-80 ℃.Select condition to be: methylene dichloride is a solvent, and the diethylamide sulfur trifluoride is a fluorination reagent, 0 ℃ of reaction.
(8) in non-protonic solvent, slough protecting group with suitable acid effect, (IV-9) (IV-11) (IV-12) to obtain compound (IV-8).Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-100 ℃.Optimum condition is: with methylene dichloride is solvent, and hydrochloric acid is acid, at room temperature reaction.
(9) in non-protonic solvent, compound (IV-5) is sloughed protecting group with triethyl orthoformate reaction back with suitable acid and is obtained 4,5,6,7-tetrahydrochysene-3-(1,3,4-oxadiazole-2-yl)-[1,2,3] triazole [1,5-a] pyrazines (IV-10).Solvent can be selected acetone for use, methylene dichloride, and chloroform, 1, the 2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,4-dioxane etc., or use triethyl orthoformate to be solvent.Slough in the protecting group reaction acid and can select hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-200 ℃.Optimum condition is: triethyl orthoformate is a reaction solvent, 150 ℃ of reactions, and the gained compound is acid with hydrochloric acid, methylene dichloride is that solvent at room temperature reacts and sloughs protecting group.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route V preparation.
Route V: the preparation of intermediate V-5a-5b
Figure B2009101982815D0000231
Reagent and reaction conditions: a:K 2CO 3, CH 3CN refluxes; B:SOCl 2, DCM; C:NaN 3, DMSO, 150 ℃; D:TFA, Me 3SiH.
(1) in polar aprotic solvent, under suitable temp, to discuss inferior available 2, the 2-(2 of 3 replacements, 4-dimethoxy-benzyl amino) ethanol and propargyl chloride react in the presence of alkali, obtain 2, the 2-of 3 replacements (N-(2, the 4-veratryl)-N-(Propargyl) amido) ethanol (V-1).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 salt of wormwood is alkali, is solvent with the acetonitrile, and heating reflux reaction spends the night.
(2) in polar aprotic solvent, select the appropriate condition chloro to obtain chloro thing (V-3), chloro thing and sodiumazide obtain compound (V-4) by intramolecularly [3+2] cycloaddition under certain condition.The reagent of chloro can be selected sulfur oxychloride, sulfur oxychloride/pyridine, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride etc. for use; Reaction conditions can be pure chlorinating agent, also can add chlorinating agent in solvent, and solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; The solvent of intramolecularly [3+2] cycloaddition reaction can be selected ether, toluene, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide etc. for use; Temperature range is 0-200 ℃.Optimum condition is: be solvent with the methylene dichloride, sulfur oxychloride/pyridine is a chlorinating agent, and the chloro thing and the sodiumazide that obtain are made solvent with methyl-sulphoxide, 150 ℃ of reactions.
(3) in protic solvent, under suitable temperature, make solvent with acid, under the triethyl silicane effect, obtain sloughing the compound (V-5) of N-protected base.Acid can be selected trifluoroacetic acid, Glacial acetic acid, formic acid etc. for use; Temperature range 0-100 ℃.Optimum condition is: make solvent with trifluoroacetic acid, add triethyl silicane, room temperature reaction spends the night.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route VI preparation.
Route VI: the preparation of intermediate VI2a-2c
Figure B2009101982815D0000241
Reagent and reaction conditions: a:n-BuLi, TMEDA, MeI or BnBr or 4-F-BnBr, THF; B:HCl-1,4-diox, DCM.
(1) is raw material with the preparation-obtained intermediate of route II, in polar aprotic solvent, under the suitable temperature, in the presence of highly basic and Tetramethyl Ethylene Diamine (TMEDA), obtains intermediate VI-1 with the reaction of the halogenated alkane of various replacements.Polar aprotic solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, glycol dimethyl ether etc.; Highly basic can be selected from n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, lithium diisopropylamine, hexamethyl two silica-based Lithamides, hexamethyl two silica-based sodium amides, hexamethyl two silica-based potassium amides, potassium tert.-butoxide, sodium methylate, sodium ethylate, sodium hydrogen, hydrogen potassium etc.; Temperature range is-100-40 ℃.Halogenated alkane can be selected from various chloro things, bromo-derivative and the iodo thing relevant with The compounds of this invention.Optimum condition is, n-Butyl Lithium is done alkali, and tetrahydrofuran (THF) is a solvent ,-78 ℃ of reactions 3 hours, room temperature reaction 3 hours.
(2) in non-protonic solvent, slough protecting group with suitable acid effect, obtain intermediate V-2.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, and hydrochloric acid is acid, at room temperature reaction.
In a preference, the required intermediate of formula of the present invention (I) compound can be by following route VII preparation.
Route VII: the preparation of intermediate VII-5
Figure B2009101982815D0000251
Reagent and reaction conditions: a:K 2CO 3, H 2O/1, the 4-dioxane; B:NaN 3, DMF; C: toluene, room temperature; D:Pd/C, H 2, room temperature～backflow; F:LiAlH 4, THF refluxes.
(1) in water soluble polar solvent, add an amount of water, 2-bromine ethylamine hydrobromide and benzyl chloride manthanoate in the presence of alkali, obtain 2-bromine ethylamino-benzyl formate (VII-1).Water soluble polar solvent can be selected from tetrahydrofuran (THF), and 1,4-dioxane, ether, glycol dimethyl ether 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: salt of wormwood is made alkali, water and 1, and 4-dioxane (volume ratio 1: 1) is a solvent, room temperature reaction spends the night.
(2) in polar aprotic solvent, 2-bromine ethylamino-benzyl formate (VII-1) and sodiumazide, under suitable temperature, reaction obtains 2-nitrine ethylamino-benzyl formate (VII-2).Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Optimum condition is: with the dimethyl formamide is solvent, adds 1.2 normal sodiumazide, and 85 ℃ of reactions are spent the night.
(3) in non-polar solvent, under suitable temperature, 2-nitrine ethylamino-benzyl formate (VII-2) and 4,4,4-trifluoro fourth-2-acetylenic acid ethyl ester reaction obtains positional isomers VII-3a and VII-3b.Non-polar solvent can be selected from benzene, toluene, dimethylbenzene, sherwood oil, normal hexane, hexanaphthene etc.; Temperature range is between 0-100 ℃; Optimum condition is: with toluene solvent, and stirred overnight at room temperature.
(4) in the polar protic solvent, under the suitable temperature, hydrogen removes the Cbz protecting group down transition metal-catalyzed with isomer VII-3a and VII-3b, and cyclization synchronously obtains mixture VII-4a and VII-4b.The polar protic solvent can be selected from methyl alcohol, ethanol, acetate, Virahol, formic acid etc.; Temperature range is between 0-100 ℃; Transition-metal catalyst can be selected from palladium, nickel, platinum or its alloy.Optimum condition is: with methyl alcohol is solvent, and selecting Pd/C for use is catalyzer, and reflux is spent the night.
(5) in polar aprotic solvent, be raw material with VII-4a, add the metallicity reductive agent, obtain intermediate 3-(trifluoromethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-a] and piperazine (VII-5).Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.; Temperature range is between 0-100 ℃; Metallic reducing agent can be selected from boron sodium cyanide and calcium chloride, mix reagents such as zinc chloride, POTASSIUM BOROHYDRIDE, diisobutyl aluminium hydride, lithium aluminum hydride, triacetyl oxygen base lithium aluminum hydride, aluminum chloride, red aluminium etc.Optimum condition is: be solvent with the tetrahydrofuran (THF), lithium aluminum hydride is a reductive agent, reflux 3 hours.
In a preference, formula of the present invention (I) compound required compound can be by following route VIII preparation.
Route VIII:
Figure B2009101982815D0000261
Reagent and reaction conditions: a:Pd (PPh 3) 4, toluene refluxes; B:DCM, HCl/ ether (ether).
(1) in appropriate solvent, under suitable temperature, under the protection of inert gas, obtains compound (VIII-1) with palladium catalyst catalysis bromo-derivative and the coupling of stannane compound.Solvent can be selected benzene for use, toluene, and 1, the 4-dioxane, N, dinethylformamide, N,N-dimethylacetamide, methyl-sulphoxide, acetonitrile, dimethylbenzene, tetrahydrofuran (THF), glycol dimethyl ether is medium, can be single solvent, also can be mixed solvent; Palladium catalyst can be selected tetrakis triphenylphosphine palladium for use, palladium, two (dibenzalacetone) palladium, 1, two (diphenylphosphine) ferrocene of 1-] palladium chloride etc.; Temperature range is 20-150 ℃.Optimum condition is: be solvent with toluene, tetrakis triphenylphosphine palladium is a catalyzer, 140 ℃ of reactions.
(2) in non-protonic solvent, slough protecting group with suitable acid effect, obtain compound (VIII-2).Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds the HCl-dioxane, at room temperature reaction.
In a preference, formula of the present invention (I) compound required compound can be by following route IX preparation.
Route IX: compound 1-33, the preparation of 52-65
Figure B2009101982815D0000271
Reagent and reaction conditions: a:HOBT, EDC, TEA, CH 2Cl 2, room temperature; B:HCl-1,4-diox, DCM.
(1) Compound I X-1 is according to document J.Med.Chem.2005, and 48,141-151 prepares.
(2) in polar aprotic solvent, Compound I X-1 and various heterocycle are under standard peptide coupling condition, for example use 1-ethyl-3-(3-dimethylin) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBT) or phosphofluoric acid (7-azepine benzo triazol-1-yl)-N, N, N ', N ' ,-tetramethyl-urea and 1-hydroxyl azepine benzotriazole, reaction 1-36h can obtain Compound I X-2.Temperature of reaction is-20-40 ℃ between.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.Optimum condition is for being solvent with the methylene dichloride, and in the presence of the EDC/HOBT coupler, room temperature reaction spends the night.
In a preference, formula of the present invention (I) compound required compound can be by following route X preparation.
Route X: the preparation of compound 34-43
Figure B2009101982815D0000272
Reagent and reaction conditions: a:HOBT, EDC, TEA, CH 2Cl 2, room temperature; B:CF 3COOH, DCM, NaHCO 3C: fumaric acid, EtOH.
(1) in polar aprotic solvent, Compound I X-1 and various heterocycle are under standard peptide coupling condition, for example use 1-ethyl-3-(3-dimethylin) carbodiimide and I-hydroxybenzotriazole (EDC/HOBT) or phosphofluoric acid (7-pyridine ' and triazol-1-yl)-N, N, N ', N ' ,-tetramethyl-urea and 1-hydroxyl azepine benzotriazole (EDC/HATU), reaction 1-36h can obtain intermediate X-1.Temperature of reaction is-20-40 ℃ between.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.Optimum condition is for being solvent with the methylene dichloride, and in the presence of the EDC/HOBT coupler, room temperature reaction spends the night.
(2) in non-protonic solvent, slough the Boc protecting group with suitable acid effect, use the alkali liquid washing organic phase, obtain free alkali compound 34-38.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Alkali lye can be selected from sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta etc.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds excessive trifluoroacetic acid, reaction at room temperature, and organic phase is washed with saturated sodium bicarbonate solution, concentrates to obtain free alkali.
(3) as required, free alkali compound 34-38 in the polar protic solvent, as methyl alcohol, ethanol, Virahol and pharmaceutically the acceptable acid-respons generate pharmacy acceptable salt, obtain compound 39-43.Optimum condition is: in ethanol, add the fumaric acid of equivalent, stirring at room is separated out solid, filters.
In a preference, formula of the present invention (I) compound required compound can be by following route XI preparation.
Route XI: the preparation of compound 44-48
Figure B2009101982815D0000281
Reagent and reaction conditions: a:HOBT, EDC, TEA, CH 2Cl 2, room temperature; B:CF 3COOH, DCM.
(1) in polar aprotic solvent, Compound I X-1 and various heterocycle are under standard peptide coupling condition, for example use 1-ethyl-3-(3-dimethylin) carbodiimide and I-hydroxybenzotriazole (EDC/HOBT) or phosphofluoric acid (7-pyridine ' and triazol-1-yl)-N, N, N ', N ' ,-tetramethyl-urea and 1-hydroxyl azepine benzotriazole, reaction 1-36h can obtain intermediate X I-1.Temperature of reaction is-20-40 ℃ between.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.Optimum condition is for being solvent with the methylene dichloride, and in the presence of the EDC/HOBT coupler, room temperature reaction spends the night.
(2) in non-protonic solvent, slough the Boc protecting group with suitable acid effect, obtain compound 44-48.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds excessive trifluoroacetic acid, at room temperature reaction.
In a preference, formula of the present invention (I) compound required compound can be by following route XII preparation.
Route XII: compound 49 and 50 preparation
Figure B2009101982815D0000291
Reagent and reaction conditions: a:NaN 3, NH 4Cl, LiCl, DMF, 95 ℃; B:HCl-1,4-diox, DCM; C:NaHCO 3, L-aspartic acid, EtOH.
(1) in polar aprotic solvent, be starting raw material with general formula X-1 gained intermediate, under condition of saltouing and suitable temperature,, obtain intermediate X II-1 with many nitrogen reagent react.Polar aprotic solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether, 1,6-dioxane, dimethyl formamide, dimethyl sulfoxide (DMSO), acetonitrile etc.The reagent of saltouing can be selected from ammonia chloride, lithium chloride, lithiumbromide, lithium iodide, sulfuric acid amine, sodium sulfate etc.Many nitrogen reagent can be selected from sodium azide, trimethyl silicon based sodium azide.The temperature temperature range is 50-150 ℃.Optimum condition is: be solvent with the dimethyl formamide, add sodiumazide, add lithium chloride and ammonia chloride, 95 ℃ of reactions.
(2) in non-protonic solvent, slough the Boc protecting group with suitable acid effect, use the alkali liquid washing organic phase, obtain free alkali compound 49.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Alkali lye can be selected from sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta etc.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds excessive trifluoroacetic acid, reaction at room temperature, and organic phase is washed with saturated sodium bicarbonate solution, concentrates to obtain free alkali.
(3) as required, free alkali compound 49 in the polar protic solvent, as methyl alcohol, ethanol, Virahol and pharmaceutically the acceptable acid-respons generate pharmacy acceptable salt, obtain compound 50.Optimum condition is: in ethanol, add the aspartic acid of equivalent, stirring at room is separated out solid, filters.
In a preference, formula of the present invention (I) compound required compound can be by following route XIII preparation.
Route XIII: the preparation of compound 51
Figure B2009101982815D0000301
Reagent and reaction conditions: a:PhI (OCOCH 3) 2, MeCN/H 2O; B:HCl-1,4-diox, DCM;
(1) in the mixed solvent of polar solvent and water, be raw material with general formula X-1, under suitable temperature, the application standard Hofmann reagent of degrading obtains amino intermediate X III-1.Polar solvent can be selected from methyl alcohol, ethanol, acetate, isopropyl alcohol, acetonitrile, formic acid etc.Standard Hofmann degraded reagent can be selected from Br 2/ NaOH, 1.8-diazabicylo (DBU)/bromo-succinimide (NBS), two (ethanoyl) iodo phenyl ester (PIDA), Cl 2, two (trifluoromethyl) iodo phenyl ester (BTI) etc.Temperature of reaction is between 0-100 ℃.Optimum condition serves as degraded reagent for being mixed solvent in acetonitrile/water with two (ethanoyl) iodo phenyl ester, and 20 ℃ were reacted 4 hours.
(2) in non-protonic solvent, slough the Boc protecting group with suitable acid effect, obtain compound 51.Solvent can be selected methylene dichloride for use, chloroform, 1,2-ethylene dichloride, ethyl acetate, tetrahydrofuran (THF), ether, methyl tert-butyl ether etc.; Acid can be selected hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic etc. for use.Temperature range is 0-50 ℃.Optimum condition is: with methylene dichloride is solvent, adds the HCl-dioxane, at room temperature reaction.
As required, according to the method described above, compound 1-65 in the polar protic solvent, 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, Phenylsulfonic acid, aspartic acid or L-glutamic acid.
Pharmaceutical composition and application process
Because The compounds of this invention has excellent DPP-IV restraining effect, 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 the DPP-IV relative disease.According to prior art, The compounds of this invention can be used for treating diabetes B, obesity, hyperlipidemia.
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
Figure B2009101982815D0000311
), 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 DPP IV (DPP-IV) inhibitor of a class recruit structure.
(2) The compounds of this invention has stronger inhibition activity to DPP IV (DPP-IV).
(3) The compounds of this invention has the better choice ratio for pepx.It is relevant with immunotoxicity that the homology enzyme DPP8 that has confirmed to suppress DPP-IV and DPP9 can produce gi tract.Therefore, The compounds of this invention preferably the target spot selectivity show that such compound has better security.
(4) the The compounds of this invention preparation method is simple.By building-up process of the present invention as can be seen, synthetic route of the present invention has shorter synthetic route and more excellent synthesis condition than existing marketed drug.
Embodiment
In following preparation example and embodiment, more specifically explain the present invention.Yet, should be appreciated that these preparation examples and 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 preparation examples and the embodiment, fusing point is measured with X-4 fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR VarianMercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); The mensuration of MS Tianjin, island LC-MS-2020 mass spectrograph.Separate with the undeclared 200-300 order that is of silica gel, the proportioning of elutriant is volume ratio.
Preparation example 1:2-(N-(2, the 4-veratryl)-N-(Propargyl) amido) ethanol (I-1)
Figure B2009101982815D0000331
(62.7g, 0.842mol), (148.0g 0.702mol) is dissolved in the acetonitrile (1500mL) 2-(2,4-veratryl amido) ethanol, adds K with 3-chloroallylene 2CO 3(backflow is spent the night for 176.0g, 1.276mol) powder.After reaction finishes, filter, with the filtrate decompression distillation as for, column chromatography (normal hexane: ethyl acetate=5: 1), obtain title compound, be yellow oil (125.8g, 72%). 1H?NMR(CDCl 3，400MHz)δ：2.23(t，1H)，2.76(t，2H)，3.27(d，2H)，3.62(s，2H)，3.64(t，2H)，3.80(s，6H)，6.41-6.45(m，2H)，7.14(s，1H).
Preparation example 2:2-(N-(2, the 4-veratryl)-N-(3-(pyridine-2-yl) Propargyl) amido) ethanol (I-2a)
Figure B2009101982815D0000332
With the 2-bromopyridine (3.79g 24mmol) is dissolved among the DMF (50mL), Ar protection add down CuI (228mg, 1.2mmol), Pd (PPh 3) 3Cl 2(336mg, 0.48mmol), triethylamine (7.27g, 72mmol), under agitation with 2-(N-(2, the 4-veratryl)-N-(Propargyl) amido) ethanol (5.97g, DMF 24mmol) (25mL) drips of solution adds in the reaction solution, heats 100 ℃ of reaction 16h.Be chilled to room temperature, add water (150mL), ethyl acetate (200mL), separatory, water layer merges organic phase, the saturated common salt water washing with ethyl acetate (100mL * 2) extraction, dry, concentrate column chromatography (normal hexane: ethyl acetate=5: 1), obtain title compound, be yellow oil (5.8g, 74%). 1H?NMR(CDCl 3，400MHz)δ：2.76(t，2H)，3.27(s，2H)，3.62(s，2H)，3.64(t，2H)，3.80(s，6H)，6.41-6.45(m，2H)，7.14-7.18(m，2H)，7.72-7.76(m，1H)，8.18(d，1H)，8.55(d，1H).
Preparation example 3-16:
Figure B2009101982815D0000341
The listed compound of following table can be by 2-(N-(2, the 4-veratryl)-N-(Propargyl) amido) ethanol and various bromo-derivative, at Pd (PPh 3) 3Cl 2With prepare according to preparation example 2 identical steps under the existence of triethylamine.
Figure B2009101982815D0000342
Figure B2009101982815D0000351
Preparation example 17:5-(2, the 4-veratryl)-4,5,6,7-tetrahydrochysene-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-α] pyrazine (I-4a)
(118mg 15mmol) is dissolved in the methylene dichloride (20mL), adds SOCl down at 0 ℃ with pyridine 2(214mg 18mmol), continues to stir 15min.(3.51g 10mmol) is dissolved in the methylene dichloride (30mL), the ice bath cooling with 2-(N-(2, the 4-veratryl)-N-(3-(pyridine-2-yl) Propargyl) amido) ethanol.Above-mentioned solution is added in the reaction solution, rise to room temperature after finishing, stir 3h.Add water 30ml, separatory, the DCM extraction merges organic layer, MgSO 4Drying is filtered, be concentrated into dried, the not purified the next step that is directly used in.
Above-mentioned oily matter is dissolved in DMSO (50mL), adds NaN 3(650mg, 1.0mmol), 150 ℃ of reaction 3h.Revolve and steam to doing column chromatography (normal hexane: ethyl acetate=8: 1), obtain title compound, be yellow solid (2.41g, 71%). 1H?NMR(CDCl 3，400MHz)δ：2.91(t，2H)，3.69(s，2H)，3.80(s，6H)，3.91(s，2H)，4.31(t，2H)，6.41-6.45(m，2H)，7.14-7.18(m，2H)，7.72-7.76(m，1H)，8.18(d，1H)，8.55(d，1H).
Preparation example 18-31:
Figure B2009101982815D0000353
The listed compound of following table can be prepared according to preparation example 17 identical steps by 2-(N-(2, the 4-veratryl)-N-(3-(pyridine-2-yl) Propargyl) amido) ethanol.
Figure B2009101982815D0000354
Preparation example 32:4,5,6,7-tetrahydrochysene-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-α] pyrazine ((I-5a)
Figure B2009101982815D0000371
With 5-(2, the 4-veratryl)-4,5,6,7-tetrahydrochysene-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-α] pyrazine (1.75g 5mmol) is dissolved in the trifluoroacetic acid (20mL), under agitation add triethyl silicane (370mg, 5mmol), room temperature reaction 16h.Concentrate, resistates is used saturated NaHCO with ethyl acetate (30mL) dissolving 3Washing, separatory, water layer EA extraction merges organic phase, Na 2SO 4Drying concentrates back column chromatography (methylene dichloride: methyl alcohol=50: 1), obtain title compound, be white solid (743mg, 74%). 1H?NMR(CDCl 3，400MHz)δ：3.35(t，2H)，4.43(t，2H)，4.54(s，2H)，7.14-7.18(m，1H)，7.72-7.76(m，1H)，8.18(d，1H)，8.55(d，1H).
Preparation example 33-46:
Figure B2009101982815D0000372
The listed compound of following table can be prepared according to preparation example 32 identical steps by preparation example 18-31 gained compound.
Figure B2009101982815D0000373
Figure B2009101982815D0000381
Preparation example 47:2-(N-benzyl-N-(Propargyl) amido) ethanol (II-2)
(44.7g, 0.60mol), (75.5g 0.50mol) is dissolved in the acetonitrile (1000mL) 2-(N-benzyl-N-(Propargyl) amido) ethanol, adds K with 3-chloroallylene 2CO 3(backflow is spent the night for 103.5g, 0.75mol) powder.After reaction finishes, filter, filtrate decompression is distilled to dried, column chromatography (sherwood oil: ethyl acetate=5: 1), obtain title compound, be yellow oil (70.8g, 75%). 1H?NMR(CDCl 3，400MHz)δ：2.23(t，1H)，2.76(t，2H)，3.27(d，2H)，3.62(s，2H)，3.64(t，2H)，77.06-7.14(s，1H).
Preparation example 48:5-benzyl-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-α] pyrazine (II-4)
Figure B2009101982815D0000383
(23.6g 0.3mol) is dissolved in the methylene dichloride (400mL), adds SOCl down at 0 ℃ with pyridine 2(42.8g 0.36mol), continues to stir 30min.(37.8g 0.2mol) is dissolved in the methylene dichloride (180mL), the ice bath cooling with 2-(N-benzyl-N-(Propargyl) amido) ethanol.Above-mentioned solution is added in the reaction solution, rise to room temperature after finishing, stir 3h.Add water 300ml, separatory, the DCM extraction merges organic layer, MgSO 4Drying is filtered, be concentrated into dried, the not purified the next step that is directly used in.
Above-mentioned oily matter is dissolved in DMSO (800mL), adds NaN 3(13g, 0.2mol), 150 ℃ of reaction 3h.Concentrate resistates column chromatography (sherwood oil: ethyl acetate=5: 1), obtain title compound, be white solid (33.4g, 78%). 1H?NMR(CDCl 3，400MHz)δ：2.97(t，2H)，3.72(s，2H)，3.75(s，2H)，4.42(t，2H)，7.34-7.36(m，5H)，7.42(s，1H).
Preparation example 49:4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-α] pyrazine (II-5)
Figure B2009101982815D0000391
With 5-benzyl-4,5,6, (21.4g 0.10mol) is dissolved in the methyl alcohol (400mL) 7-tetrahydrochysene-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-α] pyrazine, adds 10% Pd/C (2.14g), H 2Replace three times, at H 2Room temperature reaction 20h under the atmosphere.After reaction finishes, remove by filter palladium carbon, concentrate colourless viscous liquid, the not purified the next step that is directly used in.
Preparation example 50: the tertiary butyl-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (II-6)
Figure B2009101982815D0000392
(II-5) is dissolved in the methylene dichloride (400mL), add triethylamine (12.1g, 0.12mol), ice bath, drip below 5 ℃ tert-Butyl dicarbonate (23.9g, 0.11mol).Rise to room temperature after dropwising, stirring reaction spends the night.Add H 2O (250mL), the saturated common salt water washing of separatory, organic layer, drying is filtered, and concentrates column chromatography (sherwood oil: ethyl acetate=5: 1), get title compound, be white solid (16.3g, 73%). 1H?NMR(CDCl 3，400MHz)δ：1.51(s，9H)，3.91(t，2H)，4.42(t，2H)，4.71(s，2H)，7.42(s，1H).
Preparation example 51: the tertiary butyl-3-bromo-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5-(4H)-carbonic ether (II-7)
With the tertiary butyl-6, (13.4g 0.06mol) is dissolved in the acetonitrile (150mL) 7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether, and (12.8g 0.072mol), slowly is raised to room temperature to add NBS down at 0 ℃.Reaction is spent the night.Concentrate resistates column chromatography (sherwood oil: ethyl acetate=5: 1), get title compound, be faint yellow solid (8.9g, 49%). 1H?NMR(CDCl 3，400MHz)δ：1.48(s，9H)，3.89(t，2H)，4.38(t，2H)，4.57(s，2H).
Preparation example 52: the tertiary butyl-3-phenyl-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (II-8a)
With the tertiary butyl-3-bromo-6,7-dihydro-[1,2; 3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (303mg, 1mmol); phenylo boric acid (134mg; 1.1mmol), tetrakis triphenylphosphine palladium (34mg, 0.03mmol); salt of wormwood (276mg; 2.0mmol) be dissolved in the aqueous solution (8mL, 4: 1) of dioxane the following 80 ℃ of reaction 12h of nitrogen protection.Be concentrated into driedly, add ethyl acetate and water (each 20mL), separatory, water layer ethyl acetate extraction (10mL * 2), merge organic layer, use the saturated common salt water washing, drying, filter, concentrate column chromatography (sherwood oil: ethyl acetate=5: 1), get title compound, be white solid (220mg, 75%). 1H?NMR(CDCl 3，400MHz)δ：1.45(s，9H)，2.91(t，2H)，3.65(s，2H)，4.42(t，2H)，7.34-7.36(m，5H).
Preparation example 53-67:
The listed compound of following table can be by the tertiary butyl-3-bromo-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether and various boric acid ester or boric acid, in the presence of tetrakis triphenylphosphine palladium and salt of wormwood, prepare according to preparation example 52 identical steps.
Figure B2009101982815D0000411
Preparation example 68:4,5,6,7-tetrahydrochysene-3-phenyl-[1,2,3] triazole [1,5-α] pyrazine hydrochloride (II-9a)
Figure B2009101982815D0000412
With the tertiary butyl-3-phenyl-6, (210mg 0.7mmol) is dissolved in the methylene dichloride (5mL) 7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether, adds salt acid ether (3mL).Room temperature reaction 3h.Be concentrated into dried, white solid (157mg, 95%)., be directly used in the next step. 1H?NMR(D 2O，400MHz)δ：2.81(t，2H)，3.62(s，2H)，4.38(t，2H)，7.31-7.33(m，5H).
Preparation example 69-83:
Figure B2009101982815D0000413
The listed compound of following table can be prepared according to preparation example 68 identical steps by preparation example 53-67 gained compound.
Figure B2009101982815D0000414
Figure B2009101982815D0000421
Preparation example 84:4-hydroxyl-2-butyne alcohol acetic ester (III-1)
With 1, the 4-butynediol (30.0g 0.35mol) is dissolved in tetrahydrofuran (THF) (1L), and ice-water bath is cooled to 0 ℃, add in batches NaH (13.9g 0.35mol), stirred 15 minutes, slowly drip diacetyl oxide (23.3mL, 0.35mol).Stirred 12 hours, the TLC detection reaction is complete, concentrates, and adds entry (1L), and with methylene dichloride (300mL * 3) extraction, organic phase is washed with saturated sodium-chloride salt solution (200mL), and anhydrous sodium sulfate drying concentrates.The use eluent (normal hexane: ethyl acetate=2: 1) column chromatography, obtain title compound, be colourless liquid (21.3g, yield 48%). 1H?NMR(CDCl 3，400MHz)δ：2.09(s，3H)，4.28(t，2H)，4.69(t，2H).
Preparation example 85:4-(N-benzyl-N-(3-hydroxypropyl) amino)-2-butyne alcohol acetic ester (III-3)
Figure B2009101982815D0000431
(14.5g, 99mmol), (15.0g 99mmol) is dissolved in acetonitrile (300mL) to N-benzyl ethyl alcohol amine, and (17.7g 130mmol), stirs, and is warming up to back flow reaction 2.5 hours, and the TLC detection reaction is complete to add salt of wormwood with 4-chloro-2-butyne alcohol acetic ester.Filter, filtrate concentrates, and the usefulness eluent (normal hexane: ethyl acetate=4: 1) column chromatography, obtain title compound, be colourless liquid (19.4g, yield 75%). 1H?NMR(CDCl 3，400MHz)δ：2.10(s，3H)，2.75(t，2H)，3.35(t，2H)，3.62(t，2H)，3.66(s，2H)，4.71(t，2H)，7.26-7.31(m，5H).
Preparation example 86:(5-benzyl-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-a] pyrazine-3-yl) methanol acetic acid ester (III-5)
(4.60g 164mmol) is dissolved in dry DMF (100mL), and (1.60g 246mmol), is warming up to 100 ℃ of reactions 2 hours, and the TLC detection reaction is complete to add sodiumazide with 4-(N-benzyl-N-(3-chloropropyl) amino)-2-butyne alcohol acetic ester.In reaction solution impouring frozen water (300mL), ethyl acetate (100mL * 3) extraction, organic phase is water (200mL) successively, saturated sodium-chloride salt solution (200mL) washing, anhydrous sodium sulfate drying concentrates.Use eluent (normal hexane: ethyl acetate=5: 1) carry out column chromatography, obtain title compound, be colourless liquid (1.58g, yield 35%). 1H?NMR(CDCl 3，300MHz)δ：2.00(s，3H)，2.92(t，2H)，3.75(s，2H)，3.77(s，2H)，4.37(t，2H)，5.10(s，2H)，7.26-7.34(m，5H).
Preparation example 87:3-(acetyl-o-methyl)-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (III-6)
(3.70g 12.9mmol) is dissolved in methyl alcohol (30mL), adds (Boc) with (5-benzyl-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-a] pyrazine-3-yl) methanol acetic acid ester 2O (3.10g, 14.2mmol), 10%Pd/C (1.8g) vacuumizes logical hydrogen in 40 ℃ of reactions 5 hours, and the TLC detection reaction is complete, remove by filter catalyzer, filtrate concentrates, and (normal hexane: ethyl acetate=2: 1) column chromatography obtains title compound to use eluent, be colourless liquid (2.90g, yield 76%). 1H?NMR(CDCl 3，300MHz)δ：1.50(s，9H)，2.06(s，3H)，3.89(t，2H)，4.39(t，2H)，4.76(s，2H)，5.16(s，2H).
Preparation example 88:6,7-dihydro-3-(methylol)-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (III-7)
Figure B2009101982815D0000441
With 3-(acetyl-o-methyl)-6,7-dihydro-[1,2,3] triazole [1,5-a] (3.2g 10.8mmol), is dissolved in methyl alcohol to pyrazine-5 (the 4H)-carbonic acid tert-butyl ester: in the mixing solutions (25mL) of water=4: 1, (1.36g, 32.4mmol), stirring at room is reacted to add a hydronium(ion) oxidation lithium.The TLC detection reaction is complete, removes methyl alcohol, adds water (50mL), with ethyl acetate (20mL * 3) extraction.The organic phase anhydrous sodium sulfate drying concentrates and obtains title compound, is white solid (2.43g, yield 88%). 1HNMR(CDCl 3，300MHz)δ：1.50(s，9H)，3.90(t，2H)，4.99(t，2H)，4.76(s，2H)，4.78(s，2H).
Preparation example 89:3-(chloromethyl)-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (III-8)
Figure B2009101982815D0000442
With 6,7-dihydro-3-(methylol)-[1,2,3] triazole [1,5-a] (600mg 2.36mmol) is dissolved in methylene dichloride (5mL) to pyrazine-5 (the 4H)-carbonic acid tert-butyl ester, adds pyridine (560mg, 7.08mmol), drip under the condition of ice bath thionyl chloride (0.4mL, 5.66mmol).Dropwise, be warming up to 40 ℃ of reactions 2 hours, the TLC detection reaction is complete, 1N HCl solution (5mL) washing organic phase, the organic phase anhydrous sodium sulfate drying, (methylene dichloride: column chromatography methyl alcohol=50: 1) obtains title compound to use eluent, be white solid (450mg, yield 70%). 1HNMR(CDCl 3，400MHz)δ：1.51(s，9H)，3.91(t，2H)，4.41(t，2H)，4.72(s，2H)，4.76(s，2H).
Preparation example 90:6,7-dihydro-3-(methyl)-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (III-9)
With 3-(chloromethyl)-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazine-5 (the 4H)-carbonic acid tert-butyl ester (190mg, 0,70mmol) be dissolved in methyl alcohol (7mL), add 10%Pd/C (145mg), vacuumize logical hydrogen in room temperature reaction 3 hours, the TLC detection reaction is complete, remove by filter catalyzer, filtrate concentrating obtains title compound, is white solid (163mg, yield 100%). 1H?NMR(CDCl 3，400MHz)δ：1.49(s，9H)，2.47(s，3H)，4.09(t，2H)，4.54(t，2H)，4.85(s，2H).
Preparation example 91:4,5,6,7-tetrahydrochysene-3-methyl-[1,2,3] triazole [1,5-a] pyrazines (III-10)
Figure B2009101982815D0000451
With 4,5,6, (163mg 0.70mmol), is dissolved in methylene dichloride (2mL) to 7-tetrahydrochysene-3-methyl-[1,2,3] triazole [1,5-a] pyrazine, adds saturated HCl-dioxane solution (10mL), and stirring at room is separated out solid.The TLC detection reaction is complete, filters, and adds ether (10mL) washing solid, and drying obtains title compound, is white solid (87mg, yield 71%). 1H?NMR(CDCl 3，400MHz)δ：2.25(s，3H)，3.28(t，2H)，4.04(s，2H)，4.33(t，2H).
Preparation example 92:6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-3,5 (the 4H)-two carbonic acid-5-tert-butyl ester-3-(2,2, the 2-trifluoro ethyl ester) (IV-1)
Figure B2009101982815D0000452
Under the nitrogen protection, with 6,7-dihydro-3-(methylol)-[1; 2,3] triazole [1,5-a] pyrazine-5 (the 4H)-carbonic acid tert-butyl ester (1.0g; 3.94mmol) be dissolved in trifluoroethanol (20mL), add iodine (2.5g, 9.85mmol); (1.36g 9.85mmol), is warming up to 50 ℃ of reactions 2 hours to salt of wormwood; add iodine (2.5g again; 9.85mmol), (1.36g 9.85mmol) continues reaction 1 hour to salt of wormwood.The TLC detection reaction is complete, with saturated sodium bisulfite solution (20mL) washing organic phase.The organic phase anhydrous sodium sulfate drying concentrates, and the use eluent (normal hexane: ethyl acetate=3: 1) column chromatography, obtain title compound, be white solid (422mg, yield 35%). 1H?NMR(CDCl 3，400MHz)δ：1.50(s，9H)，3.94(t，2H)，4.47(t，2H)，4.69-4.77(q，2H)，4.93(s，2H).
Preparation example 93:3-aldehyde radical-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-2)
Under the nitrogen protection, (730mg 5.74mmol) is dissolved in methylene dichloride (2mL) to oxalyl chloride, is cooled to-78 ℃, and (897mg, dichloromethane solution 11.5mmol) (2mL) dropwise and stirred 15 minutes slowly to drip DMSO.Slowly drip 6 then, (temperature is no more than-60 ℃ to 7-dihydro-3-(methylol)-[1,2,3] triazole [1,5-a] pyrazines-5 (4H)-carbonic acid tert-butyl ester for 730g, dichloromethane solution 2.87mmol) (5mL).Dropwise and stirred 30 minutes, add diisopropyl ethyl amine (2mL), slowly rise to room temperature, add saturated aqueous ammonium chloride cancellation reaction.Add methylene dichloride (20mL), with 1N HCl solution (10mL * 2) washing organic phase, the organic phase anhydrous sodium sulfate drying concentrates and obtains title compound, is faint yellow solid (570mg, yield 78%). 1H?NMR(CDCl 3，300MHz)δ：1.50(s，9H)，3.94(t，2H)，4.47(t，2H)，4.94(s，2H)，10.17(s，1H).
Preparation example 94:3-carbamyl-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-3)
Figure B2009101982815D0000461
With 6, (800mg 2.28mmol) is dissolved in tetrahydrofuran (THF) (15mL) to 7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-3,5 (the 4H)-two carbonic acid-5-tert-butyl ester-3-(2,2, the 2-trifluoro ethyl ester), adds ammoniacal liquor (45mL), the stirring at room reaction.The TLC detection reaction is complete, ethyl acetate (20mL * 2) extraction, and the organic phase anhydrous sodium sulfate drying concentrates and obtains title compound, is white solid (528mg, yield 86%). 1H?NMR(CDCl 3，400MHz)δ：1.48(s，9H)，3.91(t，2H)，4.42(t，2H)，4.95(s，2H)，5.66(br，1H)，6.98(br，1H).
Preparation example 95:3-dimethylamine formyl radical-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-4)
Figure B2009101982815D0000462
With 6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazine-3,5 (the 4H)-two carbonic acid-5-tert-butyl ester-3-(2,2, the 2-trifluoro ethyl ester) (350mg, 1.00mmol) be dissolved in acetonitrile (20mL), add salt of wormwood (1.65g, 12mmol), dimethylamine hydrochloride (489mg, 6mmol), 70 ℃ of stirring reactions are 12 hours.The TLC detection reaction is complete, ethyl acetate (20mL * 2) extraction, and the organic phase anhydrous sodium sulfate drying, concentrated title compound is weak yellow liquid (292mg, yield 100%). 1HNMR(CDCl 3，400MHz)δ：1.49(s，9H)，3.11(s，3H)，3.60(s，3H)，3.91(t，2H)，4.42(t，2H)，4.95(s，2H).
Preparation example 96:3-hydrazine formyl radical-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-5)
With 6, (350mg 1.00mmol) is dissolved in tetrahydrofuran (THF) (5mL) to 7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-3,5 (the 4H)-two carbonic acid-5-tert-butyl ester-3-(2,2, the 2-trifluoro ethyl ester), adds hydrazine hydrate (30mL), stirring at room.The TLC detection reaction is complete, ethyl acetate (20mL * 2) extraction, and the organic phase anhydrous sodium sulfate drying concentrates and obtains title compound, is white solid (231mg, yield 82%). 1HNMR(CDCl 3，400MHz)δ：1.49(s，9H)，3.92(t，2H)，4.42(t，2H)，4.95(s，2H)，5.74(br，1H)，7.13(br，1H)，7.35(br，1H)，
Preparation example 97:3-cyano group-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-6)
With 3-aldehyde radical-6,7-dihydro-[1,2,3] triazole [1,5-a] pyrazines-5 (4H)-carbonic acid tert-butyl ester (100mg 0.4mmol) is dissolved in tetrahydrofuran (THF) (0.5mL), adds ammoniacal liquor (4mL), and iodine (111mg, 0.44mmol), stirring at room.The TLC detection reaction is complete, add 5% hypo solution (10mL), ethyl acetate (10mL * 2) extraction, the organic phase anhydrous sodium sulfate drying, concentrate, (normal hexane: ethyl acetate=2: 1) column chromatography obtains title compound to use eluent, be white solid (46mg, yield 46%). 1HNMR(CDCl 3，400MHz)δ：1.51(s，9H)，3.95(t，2H)，4.47(t，2H)，4.85(s，2H).
Preparation example 98:6,7-dihydro-3-(difluoromethyl)-[1,2,3] triazole [1,5-a] pyrazines-5 (the 4H)-carbonic acid tert-butyl ester (IV-7)
Figure B2009101982815D0000471
Under the nitrogen protection, (911mg 5.65mmol) is dissolved in methylene dichloride (6mL) to DAST, is cooled to-60 ℃; drip 3-aldehyde radical-6,7-dihydro-[1,2; 3] triazole [1,5-a] pyrazine-5 (4H)-carbonic acid tert-butyl ester (570mg, dichloromethane solution 2.26mmol) (4mL).Dropwise and slowly be warming up to room temperature, stirring reaction 5 hours, the TLC detection reaction is complete, in reaction solution impouring frozen water (10mL), and separatory, the organic phase anhydrous sodium sulfate drying, concentrate, (normal hexane: ethyl acetate=5: 1) column chromatography obtains title compound to use eluent, be white solid (314mg, yield 51%). 1HNMR(CDCl 3，400MHz)：δ1.48(s，9H)，3.91(t，2H)，4.42(t，2H)，4.81(s，2H)，6.88(t，1H).
Preparation example 99-103.:
Figure B2009101982815D0000472
The listed compound of following table can be prepared according to preparation example 68 identical steps by preparation example 94-98 gained compound.
Figure B2009101982815D0000473
Preparation example 104:2-(2,4-dimethoxy-benzyl amino) third-1-alcohol (V-1a)
Figure B2009101982815D0000481
2, (20g 0.12mol) is dissolved in the methyl alcohol (200mL) the 4-dimethoxy benzaldehyde, adds 2-amino third-1-alcohol (9.1mL, 0.144mol), Zinc Chloride Anhydrous (9.82g, 0.072mol), stirring at room 2h, under the ice bath, add sodium cyanoborohydride (11.35g, 0.18mol), room temperature reaction spends the night in batches.Under the ice bath, regulate pH=2, concentrate, add entry with concentrated hydrochloric acid, dichloromethane extraction, water is regulated pH=10 with sodium hydroxide, uses ethyl acetate extraction, the organic phase anhydrous magnesium sulfate drying, filter, filtrate concentrating obtains title compound, is colourless liquid (25.1g, 90%). 1H?NMR(CDCl 3，400MHz)：δ1.10(d，3H)，2.88(m，1H)，3.75(s，6H)，3.73，3.84(m，2H)，3.81(s，2H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H).
Preparation example 105:2-(N-(2, the 4-dimethoxy-benzyl)-N-(Propargyl) amino) third-1-alcohol (V-2a)
Figure B2009101982815D0000482
With preparation example 104 products therefroms and propargyl chloride, salt of wormwood is made alkali, prepares according to preparation example 1 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.14(d，3H)，2.23(t，1H)，3.05(s，1H)，3.17(m，1H)，3.30(d，2H)，3.49(m，2H)，3.59(d，1H)，3.75(s，6H)，3.83(d，1H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H).
Preparation example 106:5-(2, the 4-dimethoxy-benzyl)-4,5,6,7-tetrahydrochysene-6-methyl-[1,2,3] triazole [1,5a] piperazines (V-4a)
Figure B2009101982815D0000483
Preparation example 105 products therefroms are prepared according to preparation example 17 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.21(d，3H)，2.59(q，1H)，3.36(m，2H)，3.60(s，2H)，3.75(s，6H)，4.19(s，2H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H)，7.41(s，1H).
Preparation example 107:4,5,6.7-tetrahydrochysene-6-methyl-[1,2,3] triazole [1,5a] piperazines (V-5a)
Figure B2009101982815D0000484
Preparation example 106 products therefroms are prepared according to preparation example 32 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.21(d，3H)，2.1(br，1H)，2.59(q，1H)，3.36(m，2H)，3.60(s，2H)，7.41(s，1H).
Preparation example 108:1-(2,4-dimethoxy-benzyl amino) propan-2-ol (V-1b)
With the amino propan-2-ol of 1-is that raw material prepares according to preparation example 100 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.21(d，3H)，2.58，2.83(m，2H)，3.63(m，1H)，3.75(s，6H)，3.81(s，2H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H).
Preparation example 109:1-(N-(2, the 4-dimethoxy-benzyl)-N-(Propargyl) amino) propan-2-ol (V-2b)
Figure B2009101982815D0000492
With preparation example 104 products therefroms and propargyl chloride, salt of wormwood is made alkali, prepares according to preparation example 1 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.21(d，3H)，2.23(t，1H)，2.58，2.83(m，2H)，3.63(d，1H)，3.10(m，2H)，3.75(s，6H)，3.62(s，2H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H).
Preparation example 110:5-(2, the 4-dimethoxy-benzyl)-4,5,6,7-tetrahydrochysene-7-methyl-[1,2,3] triazole [1,5a] piperazines (V-4b)
Preparation example 105 products therefroms are prepared according to preparation example 17 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.61(d，3H)，2.59(t，2H)，3.60(s，2H)，3.73(s，2H)，3.75(s，6H)，6.16(s，1H)，6.21(d，1H)，6.84(d，1H)，7.30(s，1H).
Preparation example 111:4,5,6.7-tetrahydrochysene-7-methyl-[1,2,3] triazole [1,5a] piperazines (V-5b)
Figure B2009101982815D0000494
Preparation example 106 products therefroms are prepared according to preparation example 32 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.61(d，3H)，2.1(br，1H)，2.87(m，2H)，4.10(m，1H)，3.79(s，2H)，7.31(s，1H).
Preparation example 112: the tertiary butyl 6,7-dihydro-4-methyl-[1,2,3] triazole [1,5-a] piperazine-5-(4H)-carboxylicesters (VI-1a)
Figure B2009101982815D0000495
Under the nitrogen protection ,-78 ℃, with the tertiary butyl 6; 7-dihydro-[1,2,3] triazole [1; 5-a] (4.4g 19.6mmol) is dissolved among the THF piperazine-5-(4H)-carboxylicesters, adds Tetramethyl Ethylene Diamine (2.93mL; 19.6mmol) stir 10min, add n-Butyl Lithium (2.5M, 8.65mL again; 21.6mmol), restir 0.5h adds methyl iodide (1.57mL again; 21.6mmol), reaction 3h.Rise to room temperature, add the saturated ammonium chloride solution cancellation, ethyl acetate extraction, the anhydrous magnesium sulfate drying organic layer filters, and removes and desolvates, and column chromatography purification gets title compound, is white solid (2.52g, 60%). 1H?NMR(CDCl 3，400MHz)：δ1.40(s，9H)，1.58(d，3H)，3.49(t，2H)，3.98(t，2H)，5.05(q，1H)，7.30(s，1H).
Preparation example 113:4,5,6.7-tetrahydrochysene-4-methyl-[1,2,3] triazole [1,5a] piperazines (VI-2a)
Preparation example 108 products therefroms are prepared according to preparation example 66 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.38(d，3H)，2.98(t，2H)，3.83(t，2H)，4.08(q，1H)，7.30(s，1H).LC-MS?139(M+1)。
Preparation example 114: the tertiary butyl 6,7-dihydro-4-benzyl-[1,2,3] triazole [1,5-a] piperazine-5-(4H)-carboxylicesters (VI-1b)
Figure B2009101982815D0000502
Prepare according to preparation example 112 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.40(s，9H)，3.22(m，2H)，3.49(t，2H)，3.98(t，2H)，5.26(q，1H)，7.08-7.21(m，5H)，7.30(s，1H).
Preparation example 115: the tertiary butyl 6,7-dihydro-4-(4-fluorobenzene methylene)-[1,2,3] triazole [1,5-a] piperazine-5-(4H)-carboxylicesters (VI-1c)
Figure B2009101982815D0000503
Prepare according to preparation example 112 identical operations. 1H?NMR(CDCl 3，400MHz)：δ1.40(s，9H)，3.22(m，2H)，3.49(t，2H)，3.98(t，2H)，5.26(q，1H)，6.92(d，2H)，7.10(d，2H)，7.30(s，1H).
Preparation example 116:4,5,6.7-tetrahydrochysene-4-benzyl-[1,2,3] triazole [1,5a] piperazines (VI-2b)
Preparation example 110 products therefroms are prepared according to preparation example 66 identical operations. 1H?NMR(CDCl 3，400MHz)：δ2.1(br，1H)，3.09(m，2H)，3.08(t，2H)，3.86(t，2H)，4.29(q，1H)，7.08-7.21(m，5H)，7.30(s，1H).
Preparation example 117:4,5,6.7-tetrahydrochysene-4-benzyl-[1,2,3] triazole [1,5a] piperazines (VI-2c)
Figure B2009101982815D0000512
Preparation example 115 products therefroms are prepared according to preparation example 66 identical operations. 1H?NMR(CDCl 3，400MHz)：δ2.1(br，1H)，3.09(m，2H)，3.08(t，2H)，3.86(t，2H)，4.29(q，1H)，6.91(d，2H)，7.10(d，2H)，7.30(s，1H).
Preparation example 118:2-bromine ethylamino-benzyl formate (VII-1)
Figure B2009101982815D0000513
(20.5g 100mmol) is dissolved in 100mL water/1, in the mixed solution of 4-dioxane=1/1 with the hydrobromate of 2-bromine ethamine, under the room temperature, under the vigorous stirring, drip chloroformic acid benzyl ester (21.0g simultaneously, 120mmol) 1, the K of 4-dioxane solution (50mL) and 3.5M 2CO 3The aqueous solution remains between the 6-7 pH value of mixed solution, and after dropwising, stirring at room 0.5h drips the K of 3.5M again 2CO 3The aqueous solution, making the pH value is 8, stirring at room is to reacting completely again.With extracted with diethyl ether 3 times, organic phase with the NaOH solution washing of 1N once, saturated NaCl solution washing twice is used anhydrous Na again 2SO 4Drying, last underpressure distillation is to doing, and is standby.
Preparation example 119:2-nitrine ethylamino-benzyl formate (VII-2)
2-bromine ethylamino-benzyl formate (100mmol) is dissolved among the DMF (150mL), adds NaN 3(11.6g 180mmol), is heated to 85 ℃ of stirrings and spends the night.After reaction finishes, add entry and ethyl acetate, water merges organic phase with ethyl acetate extraction 2 times, with saturated NaCl solution washing 2 times, uses anhydrous Na again 2SO 4Drying, underpressure distillation gets title compound to doing, and is yellow oil (21.6g, two step productive rates 97%).
Preparation example 120: benzyl 2-(5-(ethoxy carbonyl)-4-Trifluoromethyl-1 H-1,2, the 3-triazol-1-yl) ethyl carbamate (VII-3a) and benzyl 2-(4-(ethoxy carbonyl)-5-Trifluoromethyl-1 H-1,2,3-triazol-1-yl) ethyl carbamate (VII-3b)
(8.1g 36.6mmol) is dissolved in the dry toluene (25mL), adds 4,4,4-three fluoro-2-alkynes-ethyl butyrates (6.2g, toluene solution 36.6mmol) (15mL), stirred overnight at room temperature with 2-nitrine ethylamino-benzyl formate.After reaction finished, underpressure distillation obtained title compound to doing, and is yellow oil (13.7g, 97%). 1H?NMR(CDCl 3，400MHz)：δ2.87-2.94(t，2H)，3.35-3.45(dd，2H)，5.11(s，2H)，7.26-7.37(m，5H).
Preparation example 121:3-(trifluoromethyl)-6,7-dihydro-[1,2,3] triazole [1,5-a] and piperazine-4 (5H)-ketone (VII-4a)
Figure B2009101982815D0000522
(13.6g 35.1mmol) is added in the ethanol (200ml), adds 10%Pd/C (2.80g), the room temperature catalytic hydrogenation with raw material YF-234-20.After TLC monitoring raw material reaction finishes, leach Pd/C, be evaporated to dried, standby.Reactant is dissolved in the ethanol reflux.After the TLC monitoring reaction finishes, be evaporated to driedly, add 1N dilute hydrochloric acid solution 50mL, dichloromethane extraction, anhydrous magnesium sulfate drying, underpressure distillation is to doing, title compound, be white solid (2.50g, two step yields 35%). 1H?NMR(CDCl 3，400MHz)：δ3.78(t，J＝6.0Hz，2H)，4.71(t，J＝6.0Hz，2H).
Preparation example 122:3-(trifluoromethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazole [1,5-a] and piperazine (VII-5)
Figure B2009101982815D0000523
With 3-(trifluoromethyl)-6, (2.50g 12.1mmol) is dissolved among the THF (50ml), slowly drips LiAlH for 7-dihydro-[1,2,3] triazole [1,5-a] and piperazine-4 (5H)-ketone 4(692mg, THF solution 18.2mmol), stirring at room.After the TLC monitoring reaction finishes, add sal glauberi and stir 30min, add entry, dichloromethane extraction, anhydrous magnesium sulfate drying, underpressure distillation is to doing, and column chromatography purification gets title compound, is white solid powder (1.00g, 43%). 1H?NMR(CDCl 3，400MHz)：δ1.83(br，1H)，3.30(t，J＝5.6Hz，2H)，4.19(s，2H)，4.37(t，J＝5.6Hz，2H).
Preparation example 123: the tertiary butyl-3-phenyl-6,7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether (VIII-1a)
Figure B2009101982815D0000531
With the tertiary butyl-3-bromo-6; 7-dihydro-[1,2,3] triazole [1; 5-α] pyrazine-5 (4H)-carbonic ether (606mg; 2mmol), and 1-methyl-2-(tributyl tinbase)-1H-pyrroles (848mg, 2.2mmol); tetrakis triphenylphosphine palladium (70mg; 0.06mmol), be dissolved in the toluene (20mL) the following 140 ℃ of reaction 4h of nitrogen protection.Be concentrated into driedly, add ethyl acetate (20mL) and water (20mL), separatory, water layer ethyl acetate extraction (10mL * 2), merge organic layer, use the saturated common salt water washing, drying, filter, concentrate column chromatography (sherwood oil: ethyl acetate=5: 1), obtain title compound, be beige look solid (322mg, 53%). 1H?NMR(CDCl 3，400MHz)δ：1.45(s，9H)，2.91(t，2H)，3.50(s，3H)，3.65(s，2H)，4.42(t，2H)，5.90(d，1H)，5.95(m，1H)，6.42(d，2H).
Preparation example 124-136:
Figure B2009101982815D0000532
The listed compound of following table can be by the tertiary butyl-3-bromo-6, and 7-dihydro-[1,2,3] triazole [1,5-α] pyrazine-5 (4H)-carbonic ether and stannane prepares according to preparation example 123 identical steps in the presence of tetrakis triphenylphosphine palladium.
Figure B2009101982815D0000533
Preparation example 137-149:
Figure B2009101982815D0000542
The listed compound of following table can be prepared according to preparation example 68 identical steps by preparation example 124-136 gained intermediate.
Figure B2009101982815D0000543
Figure B2009101982815D0000551
Embodiment 1:(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-4-methyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride (compound 1)
Figure B2009101982815D0000552
Room temperature is with 3-(uncle's fourth oxanamide base)-3-(2,4, the 5-trifluorophenyl) propionic acid (225mg, 0.63mmol) add in the methylene dichloride (30ml), adding EDC (160mg, 0.83mmol), HOBT (35mg, 0.26mmo]), triethylamine (170mg, 1.7mmol), stirring at room adds 4,5,6.7-tetrahydrochysene-4-methyl-[1,2,3] triazole [1,5a] and piperazine (97mg, 0.70mmol), ambient temperature overnight.Reaction is used dilute hydrochloric acid respectively after finishing, the saturated sodium bicarbonate solution washing, and anhydrous magnesium sulfate drying, underpressure distillation obtains Boc protection intermediate to doing through column chromatography purification.Be dissolved in methylene dichloride (10mL) again, add the hydrochloric acid dioxane solution, behind the stirring 30min, separate out solid, suction filtration, solid washs with ether, and drying obtains title compound, is white solid (103mg, two step yields 42%). 1H?NMR(D 2O，400MHz)δ1.58(d，3H)，2.43-2.53(m，2H)，2.58-2.83(m，3H)，3.93-4.15(m，2H)，4.44-4.54(m，2H)，5.05(m，1H)，6.90-6.96(m，1H)，7.02-7.11(d，1H)，7.30(s，1H).MS(ESI)m/z：354(M+1).
Embodiment 2-47:
The listed compound of following table can be prepared according to embodiment 1 identical step by preparation example gained intermediate.
Figure B2009101982815D0000553
Figure B2009101982815D0000571
Figure B2009101982815D0000581
Figure B2009101982815D0000591
Figure B2009101982815D0000601
Embodiment 48:(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone (compound 34)
Figure B2009101982815D0000602
Room temperature is with 3-(uncle's fourth oxanamide base)-3-(2,4, the 5-trifluorophenyl) propionic acid (200mg, 0.55mmol) add in the methylene dichloride (30ml), adding EDC (141mg, 0.73mmol), HOBT (74mg, 0.55mmol), triethylamine (150mg, 1.50mmol), stirring at room adds 4,5,6.7-tetrahydrochysene-4-(pyridine-2-yl)-[1,2,3] triazole [1,5a] and piperazine (111mg, 0.55mmol), ambient temperature overnight.Reaction is used dilute hydrochloric acid respectively after finishing, the saturated sodium bicarbonate solution washing, and anhydrous magnesium sulfate drying, underpressure distillation obtains Boc protection intermediate to doing through column chromatography purification.Be dissolved in methylene dichloride (10mL) again, add trifluoroacetic acid (10mL), behind the stirring 30min, concentrate, add saturated solution of sodium bicarbonate, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate and obtain title compound, be colorless oil (100mg, two step yields 43%). 1H?NMR(D 2O，400MHz)：δ2.83-2.90(m，1H)，2.94-2.99(q，1H)，3.04-3.07(t，2H)，3.86-3.88(m，1H)，4.02-4.05(m，1H)，4.14-4.16(m，1H)，4.47-4.56(m，2H)，5.13-5.30(m，2H)，7.12-7.22(m，1H)，7.31-7.38(m，2H)，7.86-7.88(m，1H)，8.05-8.09(t，1H)，8.61(d，1H).MS(ESI)m/z：417.1[M+1].
Embodiment 49-52:
Following compounds can be prepared according to embodiment 48 identical steps by preparation example 3-6 gained intermediate.
Figure B2009101982815D0000611
Embodiment 53:(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate (compound 39)
Figure B2009101982815D0000612
(100mg 0.24mmol), is dissolved in the dehydrated alcohol (3mL), adds fumaric acid (28mg with resulting free alkali among the embodiment 34,0.24mmol), stir until separating out solid, suction filtration, solid washs with anhydrous diethyl ether, drying obtains title compound, is white solid (42mg, 33%). 1H?NMR(D 2O，400MHz)：δ2.83-2.90(m，1H)，2.94-2.99(q，1H)，3.04-3.07(t，2H)，3.86-3.88(m，1H)，4.02-4.05(m，1H)，4.14-4.16(m，1H)，4.47-4.56(m，2H)，5.13-5.30(m，2H)，6.81(s，2H)，7.12-7.22(m，1H)，7.31-7.38(m，2H)，7.86-7.88(m，1H)，8.05-8.09(t，1H)，8.61(d，1H).MS (ESI)m/z：417.1[M+1].
Embodiment 54-57:
Following compounds can be prepared according to embodiment 53 identical steps by embodiment 49-52 gained free alkali.
Embodiment 58:(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiazol-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate (compound 44)
Figure B2009101982815D0000622
Room temperature is with 3-(uncle's fourth oxanamide base)-3-(2,4, the 5-trifluorophenyl) propionic acid (150mg, 0.41mmol) add in the methylene dichloride (10ml), adding EDC (105mg, 0.55mmol), HOBT (55mg, 0.41mmol), triethylamine (112mg, 1.12mmol), stirring at room adds 4,5,6.7-tetrahydrochysene-4-(pyridine-2-yl)-[1,2,3] triazole [1,5a] and piperazine (84mg, 0.41mmol), ambient temperature overnight.Reaction is used dilute hydrochloric acid respectively after finishing, the saturated sodium bicarbonate solution washing, and anhydrous magnesium sulfate drying, underpressure distillation obtains Boc protection intermediate to doing through column chromatography purification.Being dissolved in methylene dichloride (10mL) again, adding trifluoroacetic acid (10mL), behind the stirring 30min, concentrate, add ether, separate out the solid suction filtration, obtain title compound, is white solid (56mg, two step yields 32%). 1H?NMR(D 2O，400MHz)：3.07(m，4H)，4.16(m，2H)，4.45(m，1H)，5.00(m，2H)，7.16(m，2H)，7.32(m，2H)，7.48(m，1H).MS(ESI)m/z：422[M+1].
Embodiment: 59-62:
Following compounds can be prepared according to embodiment 58 identical steps with 46 gained intermediates by preparation example 40-43.
Figure B2009101982815D0000631
Embodiment 63:(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-(3-(2H-tetrazole-5-yl)-6,7-dihydro-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone (compound 49)
Figure B2009101982815D0000632
With N-Boc-(R)-3-amino-4-(2; 4; the 5-trifluorophenyl)-1-(6; 7-dihydro-3-cyano group-[1,2,3] triazole [1; 5-a] piperazine-5 (4H)-yl) fourth-1-ketone (464mg; 1mmol) among the molten DMF (10mL), add anhydrous chlorides of rase amine (53mg, 1mmol) and lithium chloride (42mg; 1mmol); stirring at room 10min, and the adding sodiumazide (65mg, 1mmol); in 95 ℃ of reactions 4 hours; be concentrated into dried, column chromatography (methylene dichloride: methyl alcohol=20: 1) obtain Boc protection intermediate (500mg, 95%).The above-mentioned intermediate for preparing is dissolved in the methylene dichloride (10mL), add trifluoroacetic acid (10mL) stirring at room 30min, be concentrated into dried, add saturated sodium bicarbonate solution, use ethyl acetate extraction, dried over sodium sulfate, be concentrated into dried, obtain title compound, be white solid (235mg, 57%). 1H?NMR(D 2O，400MHz)：δ2.28-2.85(m，4H)，3.23(m，1H)，3.68(m，2H)，3.99(m，2H)，4.46(s，2H)，6.61(m，1H)，6.79(d，1H).MS(ESI)m/z：408.2(M+1).
Embodiment 64:(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-(3-(2H-tetrazole-5-yl)-6,7-dihydro-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone aspartate (compound 50)
Figure B2009101982815D0000641
(235mg 0.57mmol) is dissolved in the ethanol (10mL), adds the aspartic acid (76mg of equivalent with embodiment gained free alkali, 0.57mmol), stirring at room is until separating out solid, suction filtration, obtain title compound, be white solid (120mg, yield 22%). 1H?NMR(D 2O，400MHz)：δ2.28-2.85(m，6H)，3.23(m，1H)，3.82(m，1H)，3.68(m，2H)，3.99(m，2H)，4.46(s，2H，)，6.61(m，1H)，6.79(d，1H).MS(ESI)m/z：408.2(M+1).
Embodiment 65:(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-amino-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride (compound 51)
Figure B2009101982815D0000642
With N-Boc-(R)-3-amino-4-(2; 4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-aminocarboxyl-[1; 2; 3] (400mg 0.83mmol) is dissolved in acetonitrile (5mL) to triazole [1,5-a] piperazine-5 (4H)-yl) fourth-1-ketone; in the mixed solvent of ethyl acetate (5mL) and water (3mL); adding diacetyl group iodobenzene (322mg, 1mmol), stirring at room 4h.Be concentrated into dried, column chromatography (methylene dichloride: methyl alcohol=15: 1) obtain intermediate X-1 (300mg, 81%).The above-mentioned target intermediate for preparing is dissolved in the methylene dichloride, adds hydrochloric acid 1, the 4-dioxane solution, stirring at room 4 hours is separated out solid, and suction filtration obtains title compound, is white solid (52mg, yield 15%). 1H?NMR(D 2O，400MHz)：δ2.28-2.89(m，4H)，3.25(m，1H)，3.68(m，2H)，3.99(m，2H)，4.20(br，2H)，4.66(s，2H)，6.61-6.79(m，2H).MS(ESI)m/z：355.1(M+1).
Embodiment 66: Compound D PP-IV suppresses active
DPP-IV suppresses determination of activity can carry out with ordinary method.DPP-IV expresses and purified pure enzyme the K of pure enzyme for using baculovirus expression system m, K CatAll conform to, show that the pure enzyme of DPP-IV that expression and purification obtains is normal fully on zymologic property with bibliographical information.Reaction system is carried out in the damping fluid of PH7.5, and enzyme reaction substrate is L-Ala-proline(Pro)-7-amino-4-methylcoumarin (Ala-Pro-AMC).
DPP-IV degradable substrate A la-Pro-AMC generates product A MC, and AMC is produced the emission light of 460nm by the ultraviolet excitation of 355nm.Measure the activity of DPP-IV in the speed of the rising of 460nm place fluorescent value by dynamic measurement AMC.
With test-compound, enzyme and reaction buffer mixing, incubate 15min in advance at 37 ℃, add substrate and start reaction, METHOD FOR CONTINUOUS DETERMINATION 460nm fluorescent value 5min.The blank group do not add substrate is set simultaneously, substitutes the solvent control group and the LAF-237[Bioorg.Med.Chem.Lett. of test-compound with DMSO, 2005,15,4770-4773] positive control group.The final volume that responds is 100uL.Each concentration of each sample is established 3 multiple holes.
At first calculate unit time fluorescence intensity in the enzyme initial velocity phase increment (unit: RFU/sec), represent the initial velocity of enzyme with this, the active percentage ratio of each concentration group of calculation sample then, formula is as follows:
Figure B2009101982815D0000651
V wherein SampleThe initial velocity of each concentration group of expression sample, v DMSOThe initial velocity of expression DMSO group
Logarithmic value with concentration is mapped to active percentage ratio, adopts non-linear regression to calculate then and fits curve, calculates IC 50Value.
The molecular structural formula of representative compounds of the present invention and the biological activity test of compound the results are shown in Table 2.
Table 2: The compounds of this invention suppresses active to DPP-IV
Figure B2009101982815D0000652
Figure B2009101982815D0000661
By the compound of the present invention as can be seen of the data in the table 2 the inhibition activity of DPP-IV obviously is better than LAF-237 and MK-0431, especially the DPP-IV of compound 45 inhibition specific activity LAF-237 is strong 14 times, stronger 3 times than MK-0431, therefore, The compounds of this invention has more excellent biological activity with respect to existing medicine.
Embodiment 67: compound is to the selectivity of DPP-IV
Recent study finds, the albumen (DASH) of some and DPPIV activity and/or similar is arranged in the human body, comprises DPP8, DPP9 and FAP etc.Experiment shows that the activity that suppresses these DASH members will cause toxicity even deadly before clinical.Therefore, screening has highly selective, the inhibitor of DPPIV has important value for treatment of diabetes efficiently.
Use insect expression system, express the recombinant protein that obtains DPPIV, DPP8, DPP9 and PAP.Adopt fluorogenic substrate to detect the activity of these 5 kinds of enzymes.Observe different compounds the activity of enzyme is suppressed inhibition effect with assessing compound.The positive that adopts is LAF237 with reference to medicine.Experimental technique reference literature J.Med.Chem.2006,49, the described method of 3520-3535.The results are shown in Table 3 and table 4.
Table 3: test-compound and positive control are to the IC of five kinds of pepxs 50Value (μ M)
Compound DPPIV DPP8 DPP9 FAP
Compound 21 0.0124±0.00 35.25±7.65 9.09±3.47 21.38±4.02
Compound 45 0.0058±0.00 15.63±3.61 2.14±1.02 2.47±0.28
LAF-237 0.080±0.006 2.94±0.39 0.18±0.10 5.00±0.17
Table 4: test-compound and positive control suppress active selection ratio to pepx
Compound DPP8/DPPIV DPP9/DPPIV FAP/DPPIV
Compound 21 2842 733 1724
Compound 45 2694 369 426
LAF-237 37 2 63
By table 3 and table 4 data as can be seen: compound 21 and 45 is for DPP8, the selection ratio of DPP9 and FAP is all than positive drug LAF-237 height, show that The compounds of this invention has better security than existing positive control medicine, more be applicable to treatment or the prevention disease relevant than existing medicine with DPP IV, as diabetes, obesity, hyperlipidemia etc.
Embodiment 68 pharmaceutical compositions
Compound 45 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 21 respectively.
Embodiment 69: the preparation of capsule
Compound 45 50g
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 21 respectively.
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:
Figure F2009101982815C0000011
In the formula, R 1, R 2And R 3Be selected from hydrogen atom, C unsubstituted or that replaced arbitrarily by 1 to 2 five yuan or hexa-atomic aromatic ring respectively 1-5Alkyl;
R 4Be selected from
(1) hydrogen, cyano group, CO 2R 5, carboxyl, CONR 6R 7, NR 6R 7,
(2) C 1-6Alkyl and C 1-6Cycloalkyl, and described alkyl or cycloalkyl is unsubstituted or partly replaced by halogen or replace entirely,
(3) phenyl, it is unsubstituted or independently is selected from following substituting group by one to three and replaces: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl,
(4) contain one to four heteroatomic 5 yuan or 6 yuan of heterocycle that independently are selected from N, S and O, above-mentioned 5 yuan or 6 yuan of heterocycles are unsubstituted or independently are selected from following substituting group by one to three and replace: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl.
R 5Be C 1-6Alkyl, it is unsubstituted or by halogen, COOH and CO 2C 1-6Moieties replaces or replaces entirely;
R 6And R 7Be selected from independently of one another:
(1) hydrogen,
(2) phenyl, it is unsubstituted or independently is selected from halogen, hydroxyl, C by one to three 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or are partly replaced or replace entirely by halogen,
(3) C 1-6Alkyl, and described alkyl is unsubstituted or is partly replaced by halogen or replace entirely;
(4) C 1-6Alkyl, and described alkyl is unsubstituted or is replaced by hydroxylic moiety or replace entirely.
2. compound as claimed in claim 1 is characterized in that R 4Be to contain one to four heteroatomic 5 yuan or 6 yuan of heterocycle that independently are selected from N, S and O, above-mentioned 5 yuan or 6 yuan of heterocycles are unsubstituted or independently are selected from following substituting group by one to three and replace: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl.
3. compound as claimed in claim 1 is characterized in that R 4Be phenyl, it is unsubstituted or independently is selected from following substituting group by one to three and replaces: halogen, NO 2, cyano group, hydroxyl, R 5, OR 5, NHSO 2R 5, N (C 1-6Alkyl) SO 2R 5, SO 2R 5, SO 2NR 6R 7, NR 6R 7, CONR 6R 7, CO 2H and CO 2R 5Alkyl.
4. compound as claimed in claim 1 is characterized in that, described compound is hydrochloride, fumarate or trifluoroacetate.
5. compound as claimed in claim 1 is characterized in that, described compound is selected from down group:
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-4-methyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-4-benzyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-4-(4-fluorobenzene methylene)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-6-methyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-7-methyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-trifluoromethyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-difluoromethyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-methyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-cyano group-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-aminocarboxyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-dimethylamino carbonyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-phenyl-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-chlorophenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-fluoro phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-p-methoxy-phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-methylsulfonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-trifluoromethyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-cyano-phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-aminocarbonyl-phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-dimethylamino carbonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-methoxycarbonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-hydroxycarbonyl group phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-(1,3,4-oxygen ribavirin-2-yl) phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(3-methoxycarbonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-methoxycarbonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyrimidine-4-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyrazine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyrimidine-2-base)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1H-imidazol-4 yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-pyrazole-3-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-amino-sulfonyl phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(4-methyl sulphur sulfonamido phenyl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridin-3-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridin-4-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-methoxycarbonyl pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-cyanopyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridin-3-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyridin-4-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-methoxycarbonyl pyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-cyanopyridine-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone fumarate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiazol-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(furans-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-methyl furan-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-chloro furans-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-nitrofuran-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone trifluoroacetate;
(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-(3-(2H-tetrazole-5-yl)-6,7-dihydro-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone aspartate;
(R)-3-amino-4-(2,4, the 5-trifluorophenyl)-1-(3-(2H-tetrazole-5-yl)-6,7-dihydro-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-ketone aspartate;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-amino-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-pyrroles-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiazole-5-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(5-thiotolene-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(oxazole-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(furans-3-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(oxazole-5-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiene-3-yl-)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-imidazoles-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-imidazol-4 yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiazol-2-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(pyrimidine-5-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(thiazole-4-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride;
(R)-and 3-amino-4-(2,4, the 5-trifluorophenyl)-1-(6,7-dihydro-3-(1-methyl isophthalic acid H-pyrimid-2-one-5-yl)-[1,2,3] triazole [1,5-a] piperazines-5 (4H)-yl) fourth-1-keto hydrochloride.
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 the DPP-IV 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 is characterized in that, is used to prepare the medicine of treatment, prevention and the alleviation disease relevant with DPP-IV.
9. purposes as claimed in claim 8 is characterized in that, the described disease relevant with DPP-IV is selected from diabetes, obesity or hyperlipidemia.
10. the method for compound shown in the preparation formula (I) is characterized in that described method comprises the steps:
(a) in inertia solution, under the peptide coupling condition, make compound shown in the reaction production of compound shown in compound shown in the formula (II) and the formula (III) (Ia),
Wherein, R 1, R 2, R 3And R 4Definition with claim 1, Z is a protecting group,
(b) protecting group of sloughing formula Ia compound with acid forms formula I compound,
Reagent and reaction conditions: a:HOBT, EDC, TEA, CH 2Cl 2, room temperature; B:CF 3COOH, DCM, NaHCO 3. in the formula, R 1, R 2, R 3And R 4Definition with claim 1.
CN2009101982815A 2009-11-04 2009-11-04 Piperazinoltriazole derivatives Pending CN102050824A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304504A (en) * 2013-06-02 2013-09-18 张远强 Anti-diabetic compound, as well as preparation method and application thereof
CN103833760A (en) * 2013-12-20 2014-06-04 南京华威医药科技开发有限公司 Piperazidines derivate
CN111807994A (en) * 2020-07-27 2020-10-23 四川嘉瑛莱科技有限责任公司 L-glutamic acid derivative and synthesis method and application thereof
CN112996792A (en) * 2018-11-12 2021-06-18 伊缪诺金公司 Process for the preparation of cytotoxic benzodiazepine derivatives
CN114591333A (en) * 2020-12-04 2022-06-07 广州嘉越医药科技有限公司 Preparation method of pyrrolopyrimidine compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304504A (en) * 2013-06-02 2013-09-18 张远强 Anti-diabetic compound, as well as preparation method and application thereof
CN103833760A (en) * 2013-12-20 2014-06-04 南京华威医药科技开发有限公司 Piperazidines derivate
CN103833760B (en) * 2013-12-20 2016-01-20 南京华威医药科技开发有限公司 Piperazine derivative
CN112996792A (en) * 2018-11-12 2021-06-18 伊缪诺金公司 Process for the preparation of cytotoxic benzodiazepine derivatives
CN112996792B (en) * 2018-11-12 2024-04-26 伊缪诺金公司 Process for preparing cytotoxic benzodiazepine derivatives
US11981688B2 (en) 2018-11-12 2024-05-14 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
CN111807994A (en) * 2020-07-27 2020-10-23 四川嘉瑛莱科技有限责任公司 L-glutamic acid derivative and synthesis method and application thereof
CN114591333A (en) * 2020-12-04 2022-06-07 广州嘉越医药科技有限公司 Preparation method of pyrrolopyrimidine compounds
CN114591333B (en) * 2020-12-04 2023-08-01 广州嘉越医药科技有限公司 Preparation method of pyrrolopyrimidine compound

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