CN105017213B - Uracil derivative - Google Patents

Uracil derivative Download PDF

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Publication number
CN105017213B
CN105017213B CN201510193889.4A CN201510193889A CN105017213B CN 105017213 B CN105017213 B CN 105017213B CN 201510193889 A CN201510193889 A CN 201510193889A CN 105017213 B CN105017213 B CN 105017213B
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straight
compound
branched alkyl
preparation
hydroxyl
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CN105017213A (en
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王颖
向永哲
周宁
刘建
付海霞
黄龙
岑国栋
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Chengdu Easton Biopharmaceuticals Co Ltd
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Chengdu Easton Biopharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present invention relates to medicinal chemistry art, and in particular to a kind of uracil derivative and the purposes of its stereoisomer, its preparation method and its derivative as dipeptidyl peptidase IV (DPP IV) inhibitor.

Description

Uracil derivative
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of uracil derivative and its stereoisomer, its preparation The purposes of method and its derivative as dipeptidyl peptidase IV (DPP-IV) inhibitor.
Background technology
China diabetic accounts for the 1/3 of global diabetes sum, and wherein patients with NIDDM accounts for more than 90%.Two Peptidyl peptidase IV (DPP-IV) is the novel targets for treating type ii diabetes, and it being capable of rapid inactivation incretin hyperglycemic factor A variety of hormones such as sample peptide -1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and DPP-IV inhibitor then extends and improved Endogenous GLP-1 and GIP activity, promote insulin secretion, reduce blood glucose.The DPP-IV inhibitor listed both at home and abroad at present There are Xi Gelieting, vildagliptin, BMS-477118, Li Gelieting and Egelieting, gigue row spit of fland, for Ge Lieting etc..Above-mentioned DPP-4 Inhibitor must take medicine daily, and from the angle of diabetic's maximum benefit, it is still necessary to one or more depot drug products, However, hypoglycemic medicine long-acting on the market is seldom at present, only insulin glargine injecta, Exenatide parenteral solution etc., and be mostly Injection, uses and carries for diabetic and easily cause inconvenience, therefore, a kind of oral long-acting drug of market in urgent need Thing changes this situation, and the compounds of this invention is a kind of DPP-IV inhibitor, shows the effect of excellent reduction blood glucose, fits Share in diabetes B, and long-acting is maintained after disclosure satisfy that administration, so as to improve patient medication compliance.
The content of the invention
Application the present invention relates to a kind of uracil substitutive derivative and preparation method thereof and in medicine, more particularly to Uracil substitutive derivative or stereoisomer shown in below formula (I), preparing, treatment is related to dipeptidyl peptidase IV Purposes in disease medicament, especially as the purposes of dipeptidyl peptidase IV (DPP-IV) inhibitor, especially preparing treatment Purposes in type II diabetes or impaired glucose tolerance disease medicament.
Present invention relates particularly to the compound shown in following logical formula (I) structure or stereoisomer：
R1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；
Preferably, R1Selected from-SO2R2Or-PO (OR2)2, wherein：
R2For hydrogen atom, metal ion or C1-C5Straight or branched alkyl, wherein C1-C5It is any in straight or branched alkyl Hydrogen atom further can be substituted by hydroxyl, sulfydryl or amino；Further, R2For C1-C5Straight or branched alkyl, wherein C1-C5 Any hydrogen atom further can be substituted by hydroxyl or amino in straight or branched alkyl；Further R2For C1-C5Straight chain or branch Alkyl group；Preferably, R2For C1-C3Straight chained alkyl.
Or preferable, R1Selected from-COR3, wherein：
R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom or carbon atom can enter on alkyl One step is substituted by hydroxyl, sulfydryl or amino；Further, R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Alkane Any hydrogen atom or carbon atom further can be substituted by hydroxyl or amino on base；Further, R3For C1-C6Straight chain, branched alkane Base or cycloalkyl, wherein C1-C6Any hydrogen atom or carbon atom further can be substituted by hydroxyl or amino on alkyl；
Or preferable, R1Selected from-COO (CH2)nOR4, wherein：
R4For C1-C10Straight or branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom can in straight or branched alkyl Further substituted by hydroxyl, sulfydryl or amino, n 1,2,3 or 4；Further, R4For C1-C10Straight or branched alkyl, wherein C1-C10Any hydrogen atom further can be substituted by hydroxyl or amino in straight or branched alkyl, n 2,3 or 4；Further, R4For C1-C10Straight or branched alkyl；N is 2 or 3；Preferably, R4For C1-C10Straight chained alkyl；N is 2.
Or preferable, R1Selected from-COOR5, wherein：
R5For C1-C20Straight or branched alkyl or cycloalkyl, wherein C1-C20Any hydrogen atom can in straight or branched alkyl Further substituted by hydroxyl, sulfydryl or amino；Further, R5For C1-C20Straight or branched alkyl, wherein C1-C20Straight chain or Any hydrogen atom further can be substituted by hydroxyl or amino on branched alkyl；Further, R5For C1-C10Straight or branched alkane Base；Preferable R5For C1-C10Straight chained alkyl.
In addition, invention also discloses R1The residue of amido link is formed for the carboxyl of amino acid, wherein amino acid includes day Right amino acid and artificial synthesized amino acid, amino acid can be stereoisomer and raceme.
In addition, invention also discloses the stereoisomer of compound of the present invention and its pharmaceutically available salt.
In uracil derivative shown in the logical formula (I) of the present invention, preferred compound includes, but are not limited to compound：
Further, the compounds of this invention is preferably but not limited to following compound：
Another object of the present invention is to, there is provided the preparation method of above-mentioned formula (I) compound is prepared, methods described includes Following steps：
Under the conditions of room temperature (10~25 DEG C), by initiation material a and R1-X(XSO2R2Or XPO (OR2)2Or XCOR3Or XCOR3Or X COO (CH2)nOR4Or XCOOR5, it is chlorine atom, hydroxyl, imidazoles -1- bases that wherein X, which is selected from) and reaction generation product b. If raw material R1- X is XSO2R2Or XPO (OR2)2, R is just obtained after the product hydrolysis of generation2For the corresponding product of hydrogen atom, the product With alkali into corresponding R can be obtained after salt2For the product salt of metal ion.If raw material R1- X contains blocking group, and the product of generation enters One step sloughs protection, you can obtains target compound I.
Wherein described raw material R1R in-X1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5。 Wherein：
R2For hydrogen atom, metal ion or C1-C5Straight or branched alkyl, wherein C1-C5It is any in straight or branched alkyl Hydrogen atom further can be substituted by hydroxyl, sulfydryl or amino；Further, R2For C1-C5Straight or branched alkyl, wherein C1-C5 Any hydrogen atom further can be substituted by hydroxyl or amino in straight or branched alkyl；Further R2For C1-C5Straight chain or branch Alkyl group；Preferably, R2For C1-C3Straight chained alkyl.
R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom or carbon atom can enter on alkyl One step is substituted by hydroxyl, sulfydryl or amino；Further, R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Alkane Any hydrogen atom or carbon atom further can be substituted by hydroxyl or amino on base；Further, R3For C1-C6Straight chain, branched alkane Base or cycloalkyl, wherein C1-C6Any hydrogen atom or carbon atom further can be substituted by hydroxyl or amino on alkyl；
R4For C1-C10Straight or branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom can in straight or branched alkyl Further substituted by hydroxyl, sulfydryl or amino, n 1,2,3 or 4；Further, R4For C1-C10Straight or branched alkyl, wherein C1-C10Any hydrogen atom further can be substituted by hydroxyl or amino in straight or branched alkyl, n 2,3 or 4；Further, R4For C1-C10Straight or branched alkyl；N is 2 or 3；Preferably, R4For C1-C10Straight chained alkyl；N is 2.
R5For C1-C20Straight or branched alkyl or cycloalkyl, wherein C1-C20Any hydrogen atom can in straight or branched alkyl Further substituted by hydroxyl, sulfydryl or amino；Further, R5For C1-C20Straight or branched alkyl, wherein C1-C20Straight chain or Any hydrogen atom further can be substituted by hydroxyl or amino on branched alkyl；Further, R5For C1-C10Straight or branched alkane Base；Preferable R5For C1-C10Straight chained alkyl.
In addition, invention also discloses wherein described raw material R1- X is the amino acid of amido protecting, and wherein amino acid includes Natural amino acid and artificial synthesized amino acid, amino acid can be stereoisomer and raceme.Preparation method be raw material a with The intermediate that the amino acid of amido protecting is obtained by condensation reaction sloughs blocking group and can obtain target compound I.
In addition, invention also discloses the stereoisomer of compound of the present invention and its pharmaceutically available salt.
It is a further object of the present invention to provide compound shown in above-mentioned logical formula (I) to exist in preparation or stereoisomer Prepare the purposes in treatment treatment type II diabetes or impaired glucose tolerance disease medicament.
The present invention contrasts by normal mouse oral glucose tolerance experiment (OGTT) experiment and with positive drug Trelagliptin OGTT experiment display, the embodiment of the present invention prepare product show it is more existing with excellent hypoglycemic effect, hypoglycemic effect Technology significantly improves, and has and significantly improves.
Embodiment
The present invention is described in further detail with reference to embodiments, but not limitation of the present invention, it is all according to The equivalent substitution of any this area that the disclosure of invention is made, belongs to protection scope of the present invention.
The structure of compound be by mass spectrum (MS) or nuclear magnetic resonance (1HNMR) determine.
Nuclear magnetic resonance (1HNMR) displacement (δ) is provided with the unit of hundred a ten thousandths (ppm)；Nuclear magnetic resonance (1HNMR survey) Surely it is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometers, measure solvent is deuterochloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO), it is interior Tetramethylsilane (TMS) is designated as, chemical shift is with 10-6(ppm) provided as unit.
The measure of mass spectrum (MS) is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Therm, model：Finnigan LCQ advantage MAX) carry out.
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates.
Column chromatography is carrier typically using Yantai Huanghai Sea silica gel 200-300 mesh silica gel.
In the case where the present invention does not provide specified otherwise, the reaction mentioned in the present invention is carried out under nitrogen atmosphere.
Refer to the nitrogen balloon that reaction bulb is for example connected to a 1L volume in the term " blanket of nitrogen " of the present invention.
In the case where the present invention does not provide specified otherwise, the solution referred in present invention reaction is the aqueous solution.
Refer to that temperature is between 10 DEG C -25 DEG C in the term " room temperature " of the present invention.
In one embodiment, the present invention relates to the uracil derivative with structure shown in below formula (I)：
Wherein, R1It is independently selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；R2For C1-C5Straight chain Or branched alkyl, wherein C1-C5Any hydrogen atom further can be substituted by hydroxyl or amino in straight or branched alkyl；R3For C1- C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom or carbon atom can be further by hydroxyl or amino on alkyl Substitution；R4For C1-C10Straight or branched alkyl, wherein C1-C10Any hydrogen atom can be further by hydroxyl in straight or branched alkyl Base or amino substitution；N is 2,3 or 4；R5For C1-C20Straight or branched alkyl, wherein C1-C20It is any in straight or branched alkyl Hydrogen atom further can be substituted by hydroxyl or amino.
In preferred embodiment,
R1It is independently selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；R2For C1-C5Straight chain or branch Alkyl group；R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom or carbon atom can enter one on alkyl Step is substituted by hydroxyl or amino；R4For C1-C10Straight or branched alkyl；N is 2 or 3；R5For C1-C10Straight or branched alkyl.
In preferred embodiment,
R1It is independently selected from-SO2R2、-PO(OR2)2、-COR3、-CO R3、-COO(CH2)nOR4Or-COOR5；R2For C1-C3Directly Alkyl group；R3For C1-C6Straight chain, branched alkyl or cycloalkyl, wherein C1-C6Any hydrogen atom or carbon atom can be further on alkyl Substituted by hydroxyl or amino；R4For C1-C10Straight chained alkyl；N is 2；R5For C1-C10Straight chained alkyl.
Still further preferably, R1Selected from-COR3, wherein R3For C1-C6Straight chain, branched alkyl or cycloalkyl, wherein C1-- C6Any hydrogen atom or carbon atom further can be substituted by hydroxyl or amino on alkyl.Or R1Selected from-COOR5, wherein R5For C1-C10Straight chained alkyl.
In another embodiment, there is provided the uracil substitutive derivative shown in above-mentioned logical formula (I) is as dipeptidyl peptidase The purposes of enzyme IV (DPP-IV) inhibitor.
Embodiment
The preparation of the compound 1 of embodiment 1
Preparation scheme is as shown below：
Initiation material a (100mg, 0.28mmol) is dissolved in dichloromethane (5ml), addition triethylamine (57mg, 0.56mmol), methane sulfonyl chloride (35.5mg, 0.31mmol), room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, reaction After completely, reaction solution is washed twice, and liquid separation, organic phase is dried with anhydrous magnesium sulfate, filtering, with preparing thin layer after organic phase concentration Chromatogram purification, obtain compound 1 (105mg, off-white powder), yield：86.1%.
MS m/z(ES):436.1[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.6,5.3Hz, 1H), 7.11 (td, J=8.3,2.3Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 5.39 (s, 1H), 5.24 (dd, J=30.1,16.4Hz, 2H), 4.88 (s, 1H), 3.62–3.59(m,1H),3.30–3.22(m,4H),2.94(s,3H),2.80–2.77(m,3H),1.95–1.87(m,2H), 1.69–1.58(m,2H).
The preparation of the compound 2 of embodiment 2
Preparation scheme is as shown below：
Initiation material a (100mg, 0.28mmol) is dissolved in dichloromethane (5ml), addition triethylamine (57mg, 0.56mmol), diethyl chloro-phosphate (53.5mg, 0.31mmol), room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, instead Should completely after, reaction solution wash twice, liquid separation, organic phase is dried with anhydrous magnesium sulfate, filtering, organic phase concentration after with prepare it is thin Layer Chromatography, obtain compound 2 (110mg, off-white powder), yield：79.7%.
MS m/z(ES):494.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.70 (dd, J=8.6,5.3Hz, 1H), 7.09 (td, J=8.3,2.4Hz, 1H), 6.86 (dd, J=9.0,2.3Hz, 1H), 5.39 (s, 1H), 5.30-5.18 (m, 2H), 4.07-3.97 (m, 4H), 3.31- 3.27(m,4H),3.17–3.13(m,1H),2.87–2.85(m,1H),2.65–2.55(m,3H),1.96–1.93(m,1H), 1.81-1.78 (m, 1H), 1.66-1.61 (m, 2H), 1.30 (t, J=7.0,6H)
The preparation of the compound 3 of embodiment 3
Preparation method is as shown below：
Initiation material a (100mg, 0.28mmol) is dissolved in dichloromethane (5ml), add positive enanthic acid (36.5mg, 0.28mmol), DCC (70mg, 0.34mmol), HOBT (38mg, 0.28mmol), K2CO3(58mg, 0.42mmol), room temperature reaction Overnight.Thin-layer chromatography tracks reaction process, after reaction completely, filtering, with thin layer chromatography is prepared after organic phase concentration, must change Compound 3 (112mg, off-white powder), yield：85.2%.
MS m/z(ES):470.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.6,5.3Hz, 1H), 7.10 (td, J=8.3,2.3Hz, 1H), 7.01 (d, J=9.0Hz, 1H), 5.58 (s, 1H), 5.37 (s, 1H), 5.31-5.21 (m, 2H), 4.07-4.05 (m, 1H),3.30(s,3H),3.17–3.12(m,1H),2.84–2.61(m,3H),2.13–2.08(m,2H),1.94–1.79(m, 2H), 1.71-1.54 (m, 4H), 1.26-1.33 (m, 6H), 0.87 (t, J=6.7Hz, 3H)
The preparation of the compound 4 of embodiment 4
Preparation method is as shown below:
Initiation material a (100mg, 0.28mmol) is dissolved in dichloromethane (5ml), addition n-caproic acid (32.5mg, 0.28mmol), DCC (70mg, 0.34mmol), HOBT (38mg, 0.28mmol), K2CO3(58mg, 0.42mmol), room temperature reaction Overnight.Thin-layer chromatography tracks reaction process, after reaction completely, filtering, with thin layer chromatography is prepared after organic phase concentration, must change Compound 4 (102mg, light yellow solid), yield：80%.
MS m/z(ES):456.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.5,5.3Hz, 1H), 7.10 (td, J=8.2,2.2Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 5.58 (s, 1H), 5.37 (s, 1H), 5.31-5.21 (m, 2H), 4.07-4.04 (m, 1H),3.30(s,3H),3.17–1.12(m,1H),2.88–2.60(m,3H),2.14–2.04(m,2H),1.94–1.79(m, 2H), 1.70-1.55 (m, 4H), 1.35-1.23 (m, 4H), 0.87 (t, J=6.9Hz, 3H)
The preparation of the compound 5 of embodiment 5
Preparation method is as shown below：
Initiation material a (100mg, 0.28mmol) is dissolved in dichloromethane (5ml), addition glacial acetic acid (17mg, 0.28mmol), DCC (70mg, 0.34mmol), HOBT (38mg, 0.28mmol), K2CO3(58mg, 0.42mmol), room temperature reaction Overnight.Thin-layer chromatography tracks reaction process, after reaction completely, filtering, with thin layer chromatography is prepared after organic phase concentration, must change Compound 5 (95mg, light yellow solid), yield：85%.
MS m/z(ES):400.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.70 (dd, J=8.6,5.3Hz, 1H), 7.11 (td, J=8.3,2.5Hz, 1H), 7.01 (d, J=7.7Hz, 1H), 5.77 (s, 1H), 5.37 (s, 1H), 5.32-5.21 (m, 2H), 4.07-4.05 (m, 1H),3.30(s,3H),3.15–3.12(m,1H),2.88–2.66(m,3H),1.93(s,3H),1.87–1.77(m,2H), 1.71–1.65(m,2H).
The preparation of the compound 6 of embodiment 6
Preparation method is as shown below：
First step compound 6a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), addition Boc- glycine (147mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), room temperature reaction Overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, and organic phase is concentrated into It is dry, obtain compound 6a (420mg, yellow solid), yield：97.2%.
MS m/z(ES)：515.2[M+1]
The preparation of second step compound 6
Compound 6a (420mg, 0.82mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 6 (260mg, white solid), yield：76.5%.
MS m/z(ES)：415.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71-7.67 (m, 2H), 7.09 (td, J=8.2,2.2Hz, 1H), 6.92 (dd, J=9.0,2.0Hz, 1H), 5.39 (s, 1H), 5.30-5.26 (m, 2H), 4.07-4.05 (m, 1H), 3.45-3.36 (m, 2H), 3.29(s,3H),3.22–3.11(m,1H),2.88–2.74(m,3H),1.86–1.78(m,2H),1.67–1.62(m,2H).
The preparation of the compound 7 of embodiment 7
Preparation method is as shown below：
First step compound 7a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds L-Boc- alanine (159mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 7a (430mg, yellow solid), yield：96.8%.
MS m/z(ES)：529.2[M+1]
The preparation of second step compound 7
Compound 7a (430mg, 0.81mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 7 (280mg, yellow solid), yield：80.7%.
MS m/z(ES)：429.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71-7.67 (m, 2H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.93 (dd, J=9.0,2.0Hz, 1H), 5.40 (s, 1H), 5.30-5.27 (m, 2H), 4.02-3.99 (m, 1H), 3.58-3.53 (m, 1H), 3.29–3.22(m,4H),2.89–2.87(m,1H),2.70–2.63(m,2H),1.87–1.78(m,2H),1.67–1.57(m, 2H), 1.30 (d, J=6.9Hz, 3H)
The preparation of the compound 8 of embodiment 8
Preparation method is as shown below：
First step compound 8a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds L-Boc- leucines (194mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 8a (450mg, yellow solid), yield：93.9%.
MS m/z(ES)：571.3[M+1]
The preparation of second step compound 8
Compound 8a (450mg, 0.79mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 8 (304mg, off-white powder), yield：81.8%.
MS m/z(ES)：471.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.70-7.67 (m, 2H), 7.08 (td, J=8.2,2.3Hz, 1H), 6.93 (dd, J=9.0,2.0Hz, 1H), 5.38 (s, 1H), 5.30-5.27 (m, 2H), 4.03-4.00 (m, 1H), 3.35-3.30 (m, 4H), 3.18–3.12(m,1H),2.87–2.61(m,3H),1.83–1.78(m,2H),1.67–1.59(m,4H),1.25–1.20(m, 1H),0.94–0.90(m,6H).
The preparation of the compound 9 of embodiment 9
Preparation method is as shown below：
First step compound 9a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds L-Boc- serines (172mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 9a (442mg, yellow solid), yield：96.7%.
MS m/z(ES)：545.2[M+1]
The preparation of second step compound 9
Compound 9a (442mg, 0.81mmol) is dissolved in ethyl acetate (10ml), instills concentrated hydrochloric acid (2.5ml), drop finishes Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, liquid separation, organic phase is washed once, merges aqueous phase, is used Wet chemical regulation pH ≈ 9, use dichloromethane:Methanol=1:1 mixed extractant solvent five times, merge organic phase, use saturation Salt washing once adds anhydrous sodium sulfate drying afterwards, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 9 (205mg, off-white powder), yield：56.9%.
MS m/z(ES)：445.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.74-7.68 (m, 2H), 7.09 (td, J=8.4,2.4Hz, 1H), 6.93 (dd, J=9.1,2.0Hz, 1H), 5.39 (s, 1H), 5.30-5.22 (m, 2H), 4.04-4.02 (m, 1H), 3.84-3.81 (m, 1H), 3.68–3.66(m,1H),3.48–3.45(m,1H),3.29(s,3H),3.20–3.18(m,1H),2.86–2.67(m,3H), 1.87–1.79(m,2H),1.66–1.61(m,2H).
The preparation of the compound 10 of embodiment 10
Preparation method is as shown below：
First step compound 10a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds L-Boc- threonines (184mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 10a (444mg, yellow solid), yield：94.7%.
MS m/z(ES)：559.3[M+1]
The preparation of second step compound 10
Compound 10a (444mg, 0.79mmol) is dissolved in ethyl acetate (10ml), instills concentrated hydrochloric acid (2.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, liquid separation, organic phase is washed once, merges aqueous phase, With wet chemical regulation pH ≈ 9, dichloromethane is used:Methanol=1:1 mixed extractant solvent five times, merge organic phase, with full Once add anhydrous sodium sulfate drying afterwards with salt washing, filtering, with thin layer chromatography is prepared after filtrate concentration, obtain compound 10 (256mg, off-white powder), yield：70.3%.
MS m/z(ES)：459.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71-7.68 (m, 2H), 7.09 (td, J=8.3,2.5Hz, 1H), 6.93 (dd, J=9.1,2.3Hz, 1H), 5.39 (s, 1H), 5.31-5.22 (m, 2H), 4.25-4.20 (m, 1H), 4.06-4.04 (m, 1H), 3.30(s,3H),3.23–3.17(m,2H),2.86–2.67(m,3H),1.88–1.80(m,2H),1.68–1.63(m,2H), 1.15 (d, J=6.4Hz, 3H)
The preparation of the compound 11 of embodiment 11
Preparation method is as shown below：
First step compound 11a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds L-Boc- proline (181mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 11a (410mg, yellow solid), yield：88%.
MS m/z(ES)：555.3[M+1]
The preparation of second step compound 11
Compound 11a (410mg, 0.74mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 11 (290mg, yellow solid), yield：86.3%.
MS m/z(ES)：455.2[M+1]
1H NMR(400MHz,CDCl3) δ 8.03 (s, 1H), 7.69 (dd, J=8.6,5.3Hz, 1H), 7.09 (td, J= 8.3,2.3Hz, 1H), 6.93 (dd, J=9.0,2.0Hz, 1H), 5.38 (s, 1H), 5.30-5.27 (m, 2H), 4.00-3.98 (m,1H),3.91–3.88(m,1H),3.30(s,3H),3.19–3.17(m,1H),3.10–3.04(m,1H),2.91–2.85 (m,2H),2.71–2.63(m,2H),2.24–2.15(m,1H),1.88–1.82(m,3H),1.77–1.66(m,3H),1.33– 1.25(m,1H).
The preparation of the compound 12 of embodiment 12
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 12a (103mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 12 (170mg, off-white color Solid), yield：64.2%.
MS m/z(ES)：474.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71 (dd, J=8.6,5.3Hz, 1H), 7.09 (td, J=8.3,2.4Hz, 1H), 6.87 (dd, J=9.0,2.1Hz, 1H), 5.38 (s, 1H), 5.32-5.20 (m, 2H), 4.71 (s, 1H), 4.21-4.12 (m,2H),3.77–3.75(m,1H),3.60–3.58(m,2H),3.55–3.50(m,2H),3.31(s,3H),3.20–3.18 (m,1H),2.90–2.87(m,1H),2.77–2.74(m,1H),2.55–2.53(m,1H),1.92–1.89(m,1H),1.83– 1.80 (m, 1H), 1.70-1.62 (m, 2H), 1.21 (t, J=6.9,3H)
The preparation of the compound 13 of embodiment 13
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 13a (111mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 13 (194mg, off-white color Solid), yield：71.1%.
MS m/z(ES)：488.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71 (dd, J=8.6,5.3Hz, 1H), 7.09 (td, J=8.3,2.3Hz, 1H), 6.87 (dd, J=8.8,2.0Hz, 1H), 5.38 (s, 1H), 5.32-5.21 (m, 2H), 4.70 (s, 1H), 4.21-4.11 (m, 2H), 3.76-3.75 (m, 1H), 3.60-3.58 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 3.31 (s, 3H), 3.21- 3.18(m,1H),2.90–2.87(m,1H),2.76–2.75(m,1H),2.55–2.48(m,1H),1.91–1.89(m,1H), 1.82-1.80 (m, 1H), 1.71-1.58 (m, 4H), 0.91 (t, J=7.3,3H)
The preparation of the compound 14 of embodiment 14
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 14a (150mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 14 (235mg, off-white color Solid), yield：75.3%.
MS m/z(ES)：558.3[M+1]
1H NMR(400MHz,CDCl3) δ 7.71 (dd, J=8.5,5.3Hz, 1H), 7.09 (td, J=8.4,2.2Hz, 1H), 6.87 (dd, J=8.9,2.0Hz, 1H), 5.38 (s, 1H), 5.32-5.21 (m, 2H), 4.69 (s, 1H), 4.21-4.11 (m, 2H), 3.76-3.74 (m, 1H), 3.59-3.56 (m, 2H), 3.44 (t, J=6.8Hz, 2H), 3.31 (s, 3H), 3.21- 3.19(m,1H),2.90–2.87(m,1H),2.76–2.74(m,1H),2.55–2.53(m,1H),1.92–1.89(m,1H), 1.83-1.79 (m, 1H), 1.70-1.60 (m, 4H), 1.28-1.23 (m, 10H), 0.87 (t, J=6.8,3H)
The preparation of the compound 15 of embodiment 15
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 15a (118mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 15 (185mg, off-white color Solid), yield：66.1%.
MS m/z(ES)：500.3[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.6,5.3Hz, 1H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.90 (d, J=8.5Hz, 1H), 5.38 (s, 1H), 5.31-5.21 (m, 2H), 4.63 (s, 1H), 4.01-3.98 (m, 2H),3.77–3.74(m,1H),3.31(s,3H),3.21–3.18(m,1H),2.90–2.87(m,1H),2.76–2.74(m, 1H),2.56–2.54(m,1H),1.92–1.90(m,1H),1.84–1.80(m,1H),1.71–1.68(m,1H),1.62–1.56 (m, 3H), 1.32-1.26 (m, 8H), 0.88 (t, J=6.6Hz, 3H)
The preparation of the compound 16 of embodiment 16
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 16a (126mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Add anhydrous sodium sulfate drying, filtering, filtrate concentration after with thin layer chromatography is prepared, obtain compound 16 (192mg, it is light yellow Solid), yield：66.7%.
MS m/z(ES)：514.3[M+1]
1H NMR(400MHz,CDCl3) δ 7.68 (dd, J=8.5,5.4Hz, 1H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.90 (d, J=8.5Hz, 1H), 5.38 (s, 1H), 5.31-5.21 (m, 2H), 4.63 (s, 1H), 4.00-3.97 (m, 2H),3.77–3.75(m,1H),3.30(s,3H),3.21–3.18(m,1H),2.90–2.87(m,1H),2.76–2.74(m, 1H),2.56–2.54(m,1H),1.92–1.89(m,1H),1.83–1.78(m,1H),1.71–1.55(m,4H),1.31–1.26 (m, 10H), 0.87 (t, J=6.7Hz, 3H)
The preparation of the compound 17 of embodiment 17
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 17a (133mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 17 (213mg, off-white color Solid), yield：72.1%.
MS m/z(ES)：528.3[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.4,5.4Hz, 1H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.90 (d, J=8.5Hz, 1H), 5.38 (s, 1H), 5.31-5.21 (m, 2H), 4.62 (s, 1H), 4.01-3.98 (m, 2H),3.77–3.75(m,1H),3.30(s,3H),3.21–3.18(m,1H),2.91–2.88(m,1H),2.76–2.75(m, 1H),2.57–2.55(m,1H),1.92–1.90(m,1H),1.84–1.77(m,1H),1.71–1.56(m,4H),1.30–1.26 (m, 12H), 0.87 (t, J=6.7Hz, 3H)
The preparation of the compound 18 of embodiment 18
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 18a (110mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 18 (200mg, off-white color Solid), yield：73.5%.
MS m/z(ES)：486.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.68 (dd, J=8.5,5.3Hz, 1H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.90 (d, J=8.2Hz, 1H), 5.38 (s, 1H), 5.31-5.21 (m, 2H), 4.64 (s, 1H), 4.01-3.98 (m, 2H),3.77–3.75(m,1H),3.30(s,3H),3.21–3.18(m,1H),2.91–2.88(m,1H),2.76–2.74(m, 1H),2.56–2.54(m,1H),1.92–1.89(m,1H),1.83–1.79(m,1H),1.71–1.63(m,2H),1.57–1.54 (m, 2H), 1.32-1.28 (m, 6H), 0.88 (t, J=6.5Hz, 3H)
Embodiment 19:The preparation of compound 19
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 19a (102mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 19 (180mg, off-white color Solid), yield：68.1%.
MS m/z(ES)：472.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.5,5.4Hz, 1H), 7.09 (td, J=8.3,2.4Hz, 1H), 6.90 (d, J=8.7Hz, 1H), 5.39 (s, 1H), 5.31-5.22 (m, 2H), 4.63 (s, 1H), 4.03-3.98 (m, 2H),3.78–3.76(m,1H),3.31(s,3H),3.21–3.18(m,1H),2.90–2.88(m,1H),2.79–2.74(m, 1H),2.57–2.53(m,1H),1.92–1.90(m,1H),1.83–1.80(m,1H),1.71–1.57(m,4H),1.32–1.25 (m, 4H), 0.90 (t, J=6.9Hz, 3H)
The preparation of the compound 20 of embodiment 20
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 20a (86mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 20 (167mg, off-white color Solid), yield：67.3%.
MS m/z(ES)：444.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.69 (dd, J=8.5,5.4Hz, 1H), 7.08 (td, J=8.3,2.3Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 5.38 (s, 1H), 5.31-5.21 (m, 2H), 4.63 (s, 1H), 4.01-3.98 (m, 2H),3.77–3.74(m,1H),3.31(s,3H),3.21–3.18(m,1H),2.91–2.88(m,1H),2.80–2.75(m, 1H),2.64–2.54(m,1H),1.92–1.90(m,1H),1.83–1.79(m,1H),1.71–1.57(m,4H),0.91(t,J =7.4Hz, 3H)
The preparation of the compound 21 of embodiment 21
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 21a (94mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 21 (186mg, off-white color Solid), yield：72.7%.
MS m/z(ES)：458.2[M+1]
1H NMR (400MHz, DMSO) δ 7.94 (dd, J=8.6,5.5Hz, 1H), 7.33 (td, J=8.5,2.3Hz, 1H), 7.20-7.15 (m, 2H), 5.35 (s, 1H), 5.20-5.10 (m, 2H), 3.87 (t, J=6.6Hz, 2H), 3.44-3.40 (m,1H),3.32(s,1H),3.10(s,3H),3.05–3.02(m,1H),2.94–2.91(m,1H),2.72–2.66(m,1H), 1.77-1.75 (m, 2H), 1.51-1.44 (m, 2H), 1.33-1.23 (m, 4H), 0.87 (t, J=7.3Hz, 3H)
The preparation of the compound 22 of embodiment 22
Preparation method is as shown below：
First step compound 22a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds D-Boc- alanine (159mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 22a (425mg, yellow solid), yield：95.8%.
MS m/z(ES)：529.2[M+1]
The preparation of second step compound 22
Compound 22a (425mg, 0.80mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 22 (271mg, yellow solid), yield：78.7%.
MS m/z(ES)：429.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.70-7.67 (m, 2H), 7.07 (td, J=8.2,2.3Hz, 1H), 6.93 (dd, J=9.1,2.0Hz, 1H), 5.41 (s, 1H), 5.31-5.27 (m, 2H), 4.02-3.98 (m, 1H), 3.57-3.53 (m, 1H), 3.28–3.22(m,4H),2.89–2.86(m,1H),2.71–2.63(m,2H),1.87–1.78(m,2H),1.67–1.57(m, 2H), 1.31 (d, J=6.9Hz, 3H)
The preparation of the compound 23 of embodiment 23
Preparation method is as shown below：
First step compound 23a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds D-Boc- leucines (194mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 23a (458mg, yellow solid), yield：95.6%.
MS m/z(ES)：571.3[M+1]
The preparation of second step compound 23
Compound 23a (458mg, 0.80mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 23 (314mg, yellow solid), yield：83.2%.
MS m/z(ES)：471.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.70-7.66 (m, 2H), 7.09 (td, J=8.3,2.3Hz, 1H), 6.92 (dd, J=9.0,2.0Hz, 1H), 5.39 (s, 1H), 5.30-5.27 (m, 2H), 4.03-4.00 (m, 1H), 3.36-3.30 (m, 4H), 3.17–3.12(m,1H),2.87–2.62(m,3H),1.82–1.78(m,2H),1.66–1.59(m,4H),1.25–1.20(m, 1H),0.94–0.91(m,6H).
The preparation of the compound 24 of embodiment 24
Preparation method is as shown below：
First step compound 24a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds D-Boc- serines (172mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 24a (436mg, yellow solid), yield：95.4%.
MS m/z(ES)：545.2[M+1]
The preparation of second step compound 24
Compound 24a (436mg, 0.80mmol) is dissolved in ethyl acetate (10ml), instills concentrated hydrochloric acid (2.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, liquid separation, organic phase is washed once, merges aqueous phase, With wet chemical regulation pH ≈ 9, dichloromethane is used:Methanol=1:1 mixed extractant solvent five times, merge organic phase, with full Once add anhydrous sodium sulfate drying afterwards with salt washing, filtering, with thin layer chromatography is prepared after filtrate concentration, obtain compound 24 (201mg, yellow solid), yield：56.5%.
MS m/z(ES)：445.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.74-7.67 (m, 2H), 7.08 (td, J=8.4,2.4Hz, 1H), 6.92 (dd, J=9.1,2.0Hz, 1H), 5.38 (s, 1H), 5.31-5.22 (m, 2H), 4.03-4.02 (m, 1H), 3.84-3.81 (m, 1H), 3.68–3.66(m,1H),3.48–3.45(m,1H),3.30(s,3H),3.21–3.18(m,1H),2.85–2.67(m,3H), 1.86–1.79(m,2H),1.66–1.62(m,2H).
The preparation of the compound 25 of embodiment 25
Preparation method is as shown below：
First step compound 25a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds D-Boc- threonines (184mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 25a (440mg, yellow solid), yield：93.8%.
MS m/z(ES)：559.3[M+1]
The preparation of second step compound 25
Compound 25a (440mg, 0.79mmol) is dissolved in ethyl acetate (10ml), instills concentrated hydrochloric acid (2.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, liquid separation, organic phase is washed once, merges aqueous phase, With wet chemical regulation pH ≈ 9, dichloromethane is used:Methanol=1:1 mixed extractant solvent five times, merge organic phase, with full Once add anhydrous sodium sulfate drying afterwards with salt washing, filtering, with thin layer chromatography is prepared after filtrate concentration, obtain compound 25 (254mg, yellow solid), yield：70.4%.
MS m/z(ES)：459.2[M+1]
1H NMR(400MHz,CDCl3) δ 7.71-7.67 (m, 2H), 7.08 (td, J=8.3,2.4Hz, 1H), 6.92 (dd, J=9.0,2.3Hz, 1H), 5.40 (s, 1H), 5.30-5.22 (m, 2H), 4.24-4.20 (m, 1H), 4.06-4.04 (m, 1H), 3.31(s,3H),3.22–3.17(m,2H),2.85–2.67(m,3H),1.87–1.80(m,2H),1.68–1.64(m,2H), 1.14 (d, J=6.5Hz, 3H)
The preparation of the compound 26 of embodiment 26
Preparation method is as shown below：
First step compound 26a preparation
Initiation material a (300mg, 0.84mmol) is dissolved in dichloromethane (5ml), adds D-Boc- proline (181mg, 0.84mmol), DCC (208mg, 1mmol), HOBT (113mg, 0.84mmol), K2CO3(174mg, 1.26mmol), Room temperature reaction is overnight.Thin-layer chromatography tracks reaction process, and after reaction completely, filtering, filter cake is washed with a small amount of dichloromethane, organic Mutually it is concentrated to dryness, obtains compound 26a (418mg, yellow solid), yield：89.8%.
MS m/z(ES)：555.3[M+1]
The preparation of second step compound 26
Compound 26a (418mg, 0.75mmol) is dissolved in dichloromethane (5ml), instills trifluoro formic acid (1.5ml), drop Finish room temperature reaction overnight.Thin-layer chromatography tracks reaction process, after reaction completely, reaction solution is concentrated under reduced pressure into dry, residue is molten In dichloromethane (10ml), 0~10 DEG C is cooled to, pH ≈ 8, liquid separation, aqueous phase dichloromethane are adjusted with sodium bicarbonate aqueous solution Alkane is extracted twice, and merges organic phase, washing twice afterwards plus anhydrous sodium sulfate drying, filtering, with preparing thin layer color after filtrate concentration Spectrum purifying, obtains compound 26 (297mg, yellow solid), yield：86.7%.
MS m/z(ES)：455.2[M+1]
1H NMR(400MHz,CDCl3) δ 8.02 (s, 1H), 7.69 (dd, J=8.5,5.4Hz, 1H), 7.09 (td, J= 8.4,2.3Hz, 1H), 6.92 (dd, J=9.0,2.0Hz, 1H), 5.39 (s, 1H), 5.30-5.27 (m, 2H), 4.01-3.98 (m,1H),3.90–3.88(m,1H),3.30(s,3H),3.19–3.17(m,1H),3.11–3.04(m,1H),2.90–2.85 (m,2H),2.71–2.64(m,2H),2.24–2.16(m,1H),1.88–1.82(m,3H),1.76–1.66(m,3H),1.32– 1.25(m,1H).
The preparation of the compound 27 of embodiment 27
Preparation method is as shown below：
Initiation material a (200mg, 0.56mmol) is dissolved in anhydrous tetrahydro furan (4ml), addition 27a (78mg, 0.56mmol), 0~10 DEG C is cooled to, Methyl triflate is instilled and (92mg, 0.56mmol, is dissolved in 1ml anhydrous tetrahydro furans In), drop, which finishes, is warmed to room temperature reaction overnight.Thin-layer chromatography tracks reaction process.After reaction completely, reaction solution is concentrated under reduced pressure into Dry, residue is dissolved in dichloromethane (10ml), and pH ≈ 8, liquid separation, after organic phase washing twice are adjusted with sodium bicarbonate aqueous solution Anhydrous sodium sulfate drying is added, filtering, with thin layer chromatography is prepared after filtrate concentration, obtains compound 27 (154mg, off-white color Solid), yield：64.4%.
MS m/z(ES)：430.2[M+1]
1H NMR (400MHz, CDCl3) δ 7.69 (dd, J=8.6,5.3Hz, 1H), 7.09 (td, J=8.3,2.3Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 5.39 (s, 1H), 5.31-5.21 (m, 2H), 4.65 (s, 1H), 4.06-4.03 (m, 2H),3.78–3.76(m,1H),3.31(s,3H),3.21–3.18(m,1H),2.89–2.88(m,1H),2.76–2.75(m, 1H),2.56–2.53(m,1H),1.91–1.88(m,1H),1.84–1.80(m,1H),1.71–1.62(m,2H),1.21(t,J =7.6Hz, 3H)
Test example 1：Influence (OGTT experiment) of the embodiment compound to normal Mouse oral sugar tolerance
1. test material：
1.1 medicine：
Instrument medicine：Glucose, GC≤99.5%, provided by sigma companies, lot number SZBC3390V, specification 100g/ bottles；
Solvent：A little (a few drops) Tween 80 is added to be fully ground, then plus distilled water fully mixes；
By reagent：
The compound of embodiment 1:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140221；
The compound of embodiment 2:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140310；
The compound of embodiment 3:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140107；
The compound of embodiment 6:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, white solid, lot number： 20140214；
The compound of embodiment 8:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140219；
The compound of embodiment 9:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140220；
The compound of embodiment 10:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140306。
1.2 test equipment：
FA2204B electronic balances, provided by Shanghai precision instrument scientific instrument Co., Ltd；
METTLER-toledo assay balances, XS-105 types, provided by Mettler Toledo Inc. of Switzerland；
Blood sugar test paper：The full vigor type blood sugar test papers of Luo Kang, specification：50 dresses, lot number 23435532, by Roche Diagnistics' product (Shanghai) Co., Ltd. provides；
Operating scissors, syringe etc..
1.3 experimental animal
KM mouse, 6 week old, 18~22g of body weight, male and female half and half, 80, carried by Chengdu up to large bio tech ltd For production facility licensing：SCXK (river) 2013-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection It is used to test after epidemic disease is qualified.
2. test method：
2.1 packets and administration：After animal fasting 12 hours, it is grouped at random according to table 1 according to the fasting blood sugar of measure, so Corresponding tested material is given to each group animal gavage (i.g) afterwards, blank group gives solvent；
Influence dosage regimen of the embodiment compound of table 1 to normal Mouse oral sugar tolerance
2.2 blood-sugar level measuring：
Be administered 0.5h after gavage gives glucose respectively again, respectively measure give glucose (glucose load) afterwards 30min, 60min blood glucose value.
3 statistical methods：
Counted using Excel, experimental data is represented using mean+SD, is used between multigroup experimental data The bilateral T methods of inspection carry out statistics comparison.
4. experimental result：
Influence of the embodiment compound of table 2 to normal Mouse oral sugar tolerance
Note：Compared with blank group,*P ＜ 0.05,*P ＜ 0.01；
5. conclusion：
(1) from Table 2, it can be seen that compared with blank group, after glucose load 30min, 60min, embodiment 1,2,3,6 groups The reduction of blood glucose value conspicuousness (*P ＜ 0.05), and embodiment 8,9,10 groups of blood glucose value pole conspicuousness reduce (*P ＜ 0.01)；
(2) in summary, under 10mg/kg dosage, the embodiment of the present invention 1,2,3,6,8,9,10 be administered 1 hour after drop Sugared significant effect, the wherein effect of embodiment 8,9,10 are relatively more preferable.
Test example 2：Influence (OGTT experiment) of the embodiment compound to normal Mouse oral sugar tolerance
1. test material：
1.1 medicine：
Instrument medicine：Glucose, GC≤99.5%, provided by sigma companies, lot number SZBC3390V, specification 100g/ bottles；
Solvent：A little (a few drops) Tween 80 is added to be fully ground, then plus distilled water fully mixes；
By reagent：
The compound of embodiment 12:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20131231；
The compound of embodiment 15 is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140113；
The compound of embodiment 16:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, light yellow solid, lot number： 20140114；
The compound of embodiment 17:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140115；
The compound of embodiment 19:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140312；
The compound of embodiment 20:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140314；
The compound of embodiment 27：There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140327。
1.2 test equipment：
FA2204B electronic balances, provided by Shanghai precision instrument scientific instrument Co., Ltd；
METTLER-toledo assay balances, XS-105 types, provided by Mettler Toledo Inc. of Switzerland；
Blood sugar test paper：The full vigor type blood sugar test papers of Luo Kang, specification：50 dresses, lot number 23435532, by Roche Diagnistics' product (Shanghai) Co., Ltd. provides；
Operating scissors, syringe etc..
1.3 experimental animal
KM mouse, 6 week old, 18~22g of body weight, male and female half and half, 80, carried by Chengdu up to large bio tech ltd For production facility licensing：SCXK (river) 2013-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection It is used to test after epidemic disease is qualified.
2. test method：
2.1 packets and administration：
After animal fasting 12 hours, it is grouped at random according to table 3 according to the fasting blood sugar of measure, it is poor without statistics between group It is different, corresponding tested material then is given to each group animal gavage (i.g), blank group gives solvent；
Influence dosage regimen of the embodiment compound of table 3 to normal Mouse oral sugar tolerance
2.2 blood-sugar level measuring：
Be administered 0.5h after gavage gives glucose respectively again, respectively measure give glucose (glucose load) afterwards 30min, 60min blood glucose value.
3 statistical methods：
Counted using Excel, experimental data is represented using mean+SD, is used between multigroup experimental data The bilateral T methods of inspection carry out statistics comparison.
4. experimental result：
Influence of the embodiment compound of table 4 to normal Mouse oral sugar tolerance
Note：Compared with blank group,*P ＜ 0.05,*P ＜ 0.01；
5. conclusion：
(1) as can be seen from Table 4, compared with blank group, after glucose load 30min, 60min, the blood glucose that 12 group of embodiment The reduction of value conspicuousness (*P ＜ 0.05), and embodiment 15,16,17,19,20,27 groups of blood glucose value pole conspicuousness reduce (*P ＜ 0.01)；
(2) in summary, under 10mg/kg dosage, the embodiment of the present invention 12,15,16,17,19,20,27 is administered 1 hour Hypoglycemic effect afterwards is notable, and the wherein effect of embodiment 15,16,17,19,20,27 is relatively more preferable.
Test example 3：Tested with the OGTT of positive drug Trelagliptin contrasts
1. test material：
1.1 medicine：
Instrument medicine：Glucose, GC≤99.5%, provided by sigma companies, lot number SZBC3390V, specification 100g/ bottles；
By reagent：
The compound of embodiment 8:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140219；
The compound of embodiment 10:There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140306；
The compound of embodiment 27：There is provided by Chengdu Yuan Dong Pharma Inc.s study on the synthesis room, off-white powder, lot number： 20140327；
Positive controls：Trelagliptin, Chengdu Yuan Dong Pharma Inc.s study on the synthesis room are provided (according to document J.Med.Chem.2011,54,510-524, Design and Synthesis of Pyrimidinone and It is prepared by Pyrimidinedione Inhibitor s of Dipeptidyl Peptidase IV disclosures), white is solid Body, lot number：20140213.1.2 test equipment：
The multi-functional microwell plate detecting systems of EnVision, are provided by PerkinElmer companies；
FA2204B electronic balances, provided by Shanghai precision instrument scientific instrument Co., Ltd；
METTLER-toledo assay balances, XS-105 types, provided by Mettler Toledo Inc. of Switzerland；
Operating scissors, syringe etc..
1.3 experimental animal
KM mouse, 6 week old, 18~22g of body weight, male and female half and half, 50, carried by Chengdu up to large bio tech ltd For production facility licensing：SCXK (river) 2013-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection It is used to test after epidemic disease is qualified.
2. test method：
2.1 packets and administration：
After animal fasting 12 hours, it is grouped at random according to table 5 according to the fasting blood sugar of measure, it is poor without statistics between group It is different, corresponding tested material then is given to each group animal gavage (i.g), blank group gives solvent；
The embodiment compound of table 5 and the OGTT experiment dosage regimens of positive drug Trelagliptin contrasts
2.2 blood-sugar level measuring：
Be administered 71.5h after gavage gives glucose respectively again, respectively measure give glucose (glucose load) afterwards 30min, 60min blood glucose value.
3 statistical methods：
Counted using Excel, experimental data is represented using mean+SD, is used between multigroup experimental data The bilateral T methods of inspection carry out statistics comparison.
4. experimental result：
The embodiment compound of table 6 and the OGTT of positive drug Trelagliptin contrasts are tested
Note：Compared with blank group,*P ＜ 0.05,*P ＜ 0.01；
Compared with positive controls,▲P ＜ 0.05,▲▲P ＜ 0.01.
4. conclusion：
(1) as can be seen from Table 6, compared with blank group, after glucose load 30min, 60min, embodiment 8,10,27 groups and The blood glucose value pole conspicuousness of positive controls reduce (*P ＜ 0.01)；
(2) compared with positive controls (Trelagliptin), after glucose load 30min, embodiment 8,10,27 groups of blood glucose values Substantially less than positive controls (▲P ＜ 0.05), illustrate that the hypoglycemic effect of the embodiment of the present invention 8,10,27 is relatively preferable.
(3) in summary, under 10mg/kg dosage, the embodiment of the present invention 8,10,27 be administered 72 hours after hypoglycemic effect Significantly, there is necessarily long-acting.
Show that compound of the embodiment of the present invention shows certain long-acting blood sugar reducing function according to the above results, for ability , can be to the compounds of this invention, group for the those of ordinary skill in domain it is apparent that in the spirit or scope without departing from the present invention A variety of modification and transformations that compound and method are carried out, therefore, the present invention includes the modification and transformation to the present invention, as long as weighing In profit requirement and its equivalent scope.

Claims (9)

1. the compound shown in formula I：
Wherein, R1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；
R2For hydrogen atom, metal ion or C1-C5Straight or branched alkyl, wherein C1-C5Any hydrogen is former in straight or branched alkyl Son further can be substituted by hydroxyl, sulfydryl or amino；
R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10On alkyl any hydrogen atom or carbon atom can further by Hydroxyl, sulfydryl or amino substitution；
R4For C1-C10Straight or branched alkyl or cycloalkyl, wherein C1-C10Any hydrogen atom can enter in straight or branched alkyl One step is substituted by hydroxyl, sulfydryl or amino；
N is 1,2,3 or 4；
R5For C1-C20Straight or branched alkyl or cycloalkyl, wherein C1-C20Any hydrogen atom can enter in straight or branched alkyl One step is substituted by hydroxyl, sulfydryl or amino.
2. compound according to claim 1, it is characterised in that wherein：
R1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；
R2For C1-C5Straight or branched alkyl, wherein C1-C5In straight or branched alkyl any hydrogen atom can further by hydroxyl or Amino substitutes；
R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10On alkyl any hydrogen atom or carbon atom can further by Hydroxyl or amino substitution；
R4For C1-C10Straight or branched alkyl, wherein C1-C10Any hydrogen atom can be further by hydroxyl in straight or branched alkyl Or amino substitution；
N is 2,3 or 4；
R5For C1-C20Straight or branched alkyl, wherein C1-C20Any hydrogen atom can be further by hydroxyl in straight or branched alkyl Or amino substitution.
3. compound according to claim 1, it is characterised in that wherein：
R1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；
R2For C1-C5Straight or branched alkyl；
R3For C1-C10Straight chain, branched alkyl or cycloalkyl, wherein C1-C10On alkyl any hydrogen atom or carbon atom can further by Hydroxyl or amino substitution；
R4For C1-C10Straight or branched alkyl；
N is 2 or 3；
R5For C1-C10Straight or branched alkyl.
4. compound according to claim 1, it is characterised in that wherein：
R1Selected from-SO2R2、-PO(OR2)2、-COR3、-COO(CH2)nOR4Or-COOR5；
R2For C1-C3Straight chained alkyl；
R3For C1-C6Straight chain, branched alkyl or cycloalkyl, wherein C1-C6On alkyl any hydrogen atom or carbon atom can further by Hydroxyl or amino substitution；
R4For C1-C10Straight chained alkyl；
N is 2；
R5For C1-C10Straight chained alkyl.
5. compound according to claim 1, it is characterised in that wherein：
R1Selected from-COR3, wherein R3For C1-C6Straight chain, branched alkyl or cycloalkyl, wherein C1-C6Any hydrogen atom or carbon on alkyl Atom further can be substituted by hydroxyl or amino.
6. compound according to claim 1, it is characterised in that wherein：
R1Selected from-COOR5, wherein R5For C1-C10Straight chained alkyl.
7. compound according to claim 1, it is characterised in that the compound is selected from：
8. the compound according to claim 1 or 7, it is characterised in that the compound is selected from：
9. the compound according to any one of claim 1~8 is preparing treatment type II diabetes or impaired glucose tolerance Purposes in disease medicament.
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