CN102757420B - Heterotactic aryl carboxylic acid compound, preparation method thereof, medicine composition comprising compound and application of compound - Google Patents

Heterotactic aryl carboxylic acid compound, preparation method thereof, medicine composition comprising compound and application of compound Download PDF

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CN102757420B
CN102757420B CN201110108003.3A CN201110108003A CN102757420B CN 102757420 B CN102757420 B CN 102757420B CN 201110108003 A CN201110108003 A CN 201110108003A CN 102757420 B CN102757420 B CN 102757420B
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reaction
carboxylic acid
yhhu
preparation
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CN102757420A (en
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胡有洪
王贺瑶
闫建伟
姬俊
盛佳
王婷
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a heterotactic aryl carboxylic acid compound as shown in a general formula I, a preparation method of the compound, a medicine composition comprising the compound and application of the compound, in particular to a novel compound synthesized by using heterotactic aryl as a framework and designing different substituent groups, a preparation method of the compound, a medicine composition comprising the compound and application of the compound to preparing medicines for treating obesity, diabetes mellitus, hyperlipidemia, hepatic steatosis and other metabolism-related diseases.

Description

Connection heteroaryl carboxylic acid compounds, its preparation method, comprise pharmaceutical composition and the purposes of this compound
Technical field
The present invention relates to a kind of heteroaryl carboxylic acid compounds, its preparation method, the pharmaceutical composition comprising this compound and purposes.Specifically, the present invention relates to a kind of to join heteroaryl for skeleton, the novel cpd, the preparation method of this compounds, the pharmaceutical composition comprising this compounds and this compounds that synthesize by the designing different substituting groups purposes in the medicine preparing treatment or adults, obesity, diabetes, hyperlipidaemia and fatty liver and other metabolic trouble relevant to DGAT.
Background technology
Along with the raising of people's material life, obesity, diabetes, cardiovascular disorder are spread unchecked day by day, become the important threat of human health.Due to one of Major Risk Factors that obesity is cardiovascular disorder, the fat very big enthusiasm causing scientist for the treatment of, has found new target spot and mechanism of action thereupon.Triglyceride level is that human body maintains normal physiological function necessary energy matter, but its in vivo excessive aggregation will cause fat, the metabolic disease such as insulin resistant, fatty liver and hyperlipidaemia.The unique rate determining step of final sum that DGAT (DG oxygen acyltransferase) catalyzing glycerol three ester generates is rapid.Two hypotype DGAT-1 and DGAT-2 of DGAT are identified out respectively, and the two has expresses widely.Research finds that these enzymes synthesize high level expression (Cases, S.et al Jr.Proc.Natl.Acad.Sci.U.S.A.1998,95,13018 in active tissue at triglyceride level such as fatty tissue, small intestine and livers; Cases, S.et al J.Biol.Chem.2001,276,38870.).The mouse of DGAT-1 gene knockout can resist the mode of generation by energy increase energy expenditure of Diet-Induced Obesity, and improves susceptibility (Smith, S.J.et al Nat.Genet.2000,25,87 to Regular Insulin and leptin; Chen, H.C.et al J.Clin.Invest.2002,109,1049; Chen, H.C.et al Diabetes 2002,51,3189.).These researchs show, suppress the expression of DGAT-1 may become one of methods for the treatment of of treatment obesity and diabetes B.
Nearest document (Gang Zhao et al J.Med.Chem., 2008,51,380; Alan M.Birch et al J.Med.Chem.2009,52,1558; Yimin Qian et al J.Med.Chem.2011,54,2433; Yimin Qian et al) disclose the pharmacological characteristic and DGAT-1 gene knockout showed after rodent takes small molecules DGAT-1 inhibitor after show similar.Bayer house journal application (US20040224997A1; WO2007016538A2) and Abbott house journal application (US2008001527A1) report the inhibit activities that biphenyl carboxylic acid's compounds has DGAT-1.The pharmacophores such as urea groups, connection heteroaryl, amido linkage, carboxyl organically combine by the present inventor, define amide carboxylic acid's structure parent nucleus that the new phenyl ring of a class is connected with heterocycle, such compound structure is novel, DGAT inhibit activities is excellent, synthesize easy, can be applicable to the medicine preparing treatment of obesity, diabetes, hyperlipidaemia and fatty liver and other metabolism related diseases.
Summary of the invention
The present inventor has found the connection heteroaryl carboxylic acid compounds that a class is new.This compounds can suppress DGAT (DG oxygen acyltransferase) effectively; after further optimizing and screening, can research and develop becomes that preparation is easy, active higher to be used for the treatment of or the medicine of adults, obesity, diabetes, hyperlipidaemia and fatty liver and other metabolic trouble relevant to DGAT.
Therefore, an object of the present invention is to provide a kind of as treatment or the connection heteroaryl carboxylic acid compounds of adults, obesity, diabetes, hyperlipidaemia and fatty liver and other metabolic trouble relevant to DGAT or its physiologically acceptable salt, and this compound has the structure shown in following general formula I.
Another object of the present invention is to provide a kind of method preparing the connection heteroaryl carboxylic acid compounds shown in general formula I or its physiologically acceptable salt.
Another object of the present invention is to provide a kind of intermediate preparing the connection heteroaryl carboxylic acid compounds shown in general formula I or its physiologically acceptable salt.
Another object of the present invention is to provide the connection heteroaryl carboxylic acid compounds shown in a kind of general formula I or its physiologically acceptable salt purposes as DGAT inhibitor.
Another object of the present invention is to provide above-mentioned heteroaryl carboxylic acid compounds or its physiologically acceptable salt purposes in the medicine of preparation as treatment or adults, obesity, diabetes, hyperlipidaemia and fatty liver and other metabolic trouble relevant to DGAT.
Another object of the present invention is to provide the pharmaceutical composition comprising connection heteroaryl carboxylic acid compounds that general formula I represents or its physiologically acceptable salt.
According to an aspect of the present invention, the invention provides the connection heteroaryl carboxylic acid compounds shown in a kind of following general formula I or its physiologically acceptable salt.
Wherein,
N is the integer of 0 ~ 3, is preferably 0 or 1;
X, Y and Z are respectively C or N, and wherein, X, Y and Z have one at least for N;
R 1for hydrogen;
R 2and R 3be hydrogen, C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phenyl C1-C4 alkyl or substituted or unsubstituted heteroaryl C1-C4 alkyl independently of one another; R 2and R 3more preferably hydrogen, C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl C1-C3 alkyl or substituted or unsubstituted indyl C1-C3 alkyl independently of one another; More preferably, R 2and R 3in at least one is H; It is one or more that the substituting group of described replacement is selected from fluorine, chlorine, bromine, iodine and hydroxyl;
Or, R 1and R 2be connected to form the alkylidene group of C2-C5;
R 4for hydrogen, hydroxyl, halogen, C 1~ C 6alkyl, C 1~ C 6alkoxyl group or trifluoromethyl; Be preferably hydrogen;
Q is R 5nHC (O)-, R 5nHC (S)-, R 5c (O)-, R 5s (O) 2-or R 5oC (O)-; Be preferably R 5nHC (O)-;
R 5for C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, the substituting group of described replacement is that it is one or more to be selected from halogen, C1-C4 alkyl, trifluoromethyl and C1-C4 alkoxyl group;
Described heteroaryl is 5-10 unit, and is selected from the heteroatoms in N, O and S containing 1-3.
Compound represented by general formula I is more preferably:
Wherein, m is 0,1,2 or 3; R 2, R 3, R 4, X, Y, Z, Q be identical with above-mentioned definition with n.
Described heteroaryl carboxylic acid compounds can be one of following compounds further:
According to a further aspect in the invention, the invention provides a kind of method preparing the connection heteroaromatic carboxylic acid compounds shown in general formula I, prepare the connection heteroaromatic carboxylic acid compounds shown in general formula I by two reaction paths such as below shown in reaction formula 1 and 2, the method comprises the steps:
[reaction path 1]
Wherein, X, Y, Z, Q, R 2, R 3, R 4identical with aforementioned definitions with n;
Step a: compound 1 and p-nitrophenyl pinacol borate obtain compound 2 through Suzuki (Suzuki) linked reaction;
Step b: in compound 2, cyan-hydrolysis obtains carboxylic acid cpd 3;
Step c: carboxylic acid cpd 3 and amino ester condensation obtain compound 4;
Steps d: compound 4 reduces to obtain aminated compounds 5;
Step e: compound 5 and acyl chlorides, SULPHURYL CHLORIDE or isocyanate reaction obtain compound 6;
Step f: compound 6 is hydrolyzed to obtain the connection heteroaryl carboxylic acid compounds shown in general formula I-1.
Wherein:
In step a, the reaction conditions that compound 1 and the suzuki of p-nitrophenyl pinacol borate react is that the routine of those skilled in the art is selected.Generally speaking, this reaction can be carried out in a heated condition under alkali and metal palladium catalyst exist, and described alkali is known in those skilled in the art, such as, can be Cs 2cO 3, Na 2cO 3, K 2cO 3, KF, K 3pO 4deng.Described metal palladium catalyst is known in those skilled in the art, such as, can be two (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium etc.Described heating condition is known in those skilled in the art, such as, can be heated to backflow.
In step b, the reaction conditions of cyan-hydrolysis reaction is the routine selection of those skilled in the art, generally with strong acid or highly basic hydrolysis, and the such as vitriol oil or concentrated sodium hydroxide or potassium hydroxide heating hydrolysis.
In step c, the reaction conditions of amino and sour condensation reaction is the routine selection of those skilled in the art.Generally speaking, can carry out under room temperature or heating condition with amino acid condensation agent.Described amino acid condensation agent is known in those skilled in the art, such as can be O-(7-nitrogen benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, 2-(7-azepine benzotriazole)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N '-DIC etc.
In steps d, the reaction conditions of nitro-reduction reaction is the routine selection of those skilled in the art.Generally speaking, can carry out under ice bath to room temperature or heating condition with reductive agent.Described reductive agent is known in those skilled in the art, such as, can be sodium borohydride, hydrazine hydrate, tindichloride, reduced iron powder or H 2deng.
In step e, the routine that compound 5 is those skilled in the art with the reaction conditions of acyl chlorides, SULPHURYL CHLORIDE or isocyanic ester is selected, and generally speaking, carries out under room temperature or heating condition.
In step f, the reaction conditions that compound 6 is hydrolyzed is that the routine of those skilled in the art is selected.Generally speaking, can carry out under room temperature or heating condition with LiOH, NaOH or KOH.
Or
[reaction path 2]
Wherein, X, Y, Z, Q, R 4same as described above with the definition of n, m is 0,1,2 or 3;
Step g: compound 8 and amino ester condensation compound 9;
Step h: compound 9 and p-nitrophenyl pinacol borate obtain compound 10 through the debrominate of Suzuki (Suzuki) linked reaction;
Step I: compound 10 reduces to obtain aminated compounds 11;
Step j: compound 11 and acyl chlorides, SULPHURYL CHLORIDE or isocyanate reaction obtain compound 12;
Step k: compound 12 hydrolysis is obtained the compound shown in general formula I-2.
Wherein:
In step g, the reaction conditions of amino and sour condensation reaction is the routine selection of those skilled in the art.Generally speaking, can carry out under room temperature or heating condition with amino acid condensation agent.Described amino acid condensation agent is known in those skilled in the art, such as can be O-(7-nitrogen benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, 2-(7-azepine benzotriazole)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N '-DIC etc.
In step h, the reaction conditions that compound 9 and the suzuki of p-nitrophenyl pinacol borate react is that the routine of those skilled in the art is selected.Generally speaking, this reaction can be carried out in a heated condition under alkali and metal palladium catalyst exist.Described alkali is known in those skilled in the art, such as, can be Cs 2cO 3, Na 2cO 3, K 2cO 3, KF, K 3pO 4deng.Described metal palladium catalyst is known in those skilled in the art, such as, can be two (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium etc.Described heating condition is known in those skilled in the art, such as, can be heated to backflow.
In step I, the reaction conditions of nitro-reduction reaction is the routine selection of those skilled in the art.Generally speaking, can carry out under ice bath to room temperature or heating condition with reductive agent.Described reductive agent is known in those skilled in the art, such as, can be sodium borohydride, hydrazine hydrate, tindichloride, reduced iron powder or H 2deng.
In step j, the routine that compound 11 is those skilled in the art with the reaction conditions of acyl chlorides, SULPHURYL CHLORIDE or isocyanic ester is selected.Generally speaking, carry out under room temperature or heating condition.
In step k, the reaction conditions that compound 12 is hydrolyzed is that the routine of those skilled in the art is selected.Generally speaking, can carry out under room temperature or heating condition with LiOH, NaOH or KOH.
According to the present invention, the present invention is also provided for the intermediate that preparation the present invention joins heteroaryl carboxylic acid compounds, i.e. compound 4, compound 5, compound 10 or the connection heteroaryl compound shown in compound 11:
Wherein, X, Y, Z, Q, R 2, R 3, R 4, n with m definition identical with aforementioned definitions.
The physiologically acceptable salt that the present invention joins heteroaryl carboxylic acid compounds is prepared by being carried out reacting by this alkali such as compound and NaOH or KOH, such as: the present invention is joined heteroaryl carboxylic acid compounds and be dissolved in methyl alcohol, add NaOH or the KOH stirring at room temperature 2 ~ 3 hours of equivalent, by solvent evaporate to dryness, i.e. obtained corresponding sodium salt or sylvite.
In accordance with a further aspect of the present invention, present invention also offers the pharmaceutical composition of a kind of, hyperlipidemia fat as treatment or diabetes B, fatty liver and other metabolism related diseases, it contains the connection heteroaryl carboxylic acid compounds shown in general formula I for the treatment of significant quantity and pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: thinner, as water etc.; Weighting agent, as starch, sucrose etc.; Tackiness agent, as derivatived cellulose, alginate, gelatin, polyvinylpyrrolidone; Wetting agent, as glycerine; Disintegrating agent, as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer, as quaternary ammonium compound; Tensio-active agent, as cetyl alcohol; Absorption carrier, as kaolin and soap clay; Lubricant, as talcum powder, calcium stearate and Magnesium Stearate and polyoxyethylene glycol etc.In addition, other assistant agent can also be added in the composition, as flavouring agent and sweeting agent etc.
Heteroaryl carboxylic acid compounds of the present invention can be applied to by the mode of oral, rectum or intestines external administration the patient needing this treatment in the form of compositions.For time oral, conventional solid preparation can be made into, as tablet, pulvis, granula, capsule etc., or make liquid preparation, as water or oil-suspending agent, or other liquid preparation, as syrup etc.; During for intestines external administration, can be made into injection for solution, water or oleaginous suspension etc.
Connection heteroaryl carboxylic acid compounds shown in general formula I of the present invention or its physiologically acceptable salt, through showing the Bioexperiment of the inhibit activities of DGAT, there is stronger DGAT inhibit activities, can as DGAT inhibitor for the preparation of the medicine for the treatment of or obesity controlling, hyperlipidemia or diabetes B, fatty liver and other metabolism related diseases.
Embodiment
The following examples are for specifically describing the preparation of the compounds of this invention, and it is as the biologic activity of DGAT-1 inhibitor, but the present invention is not limited to these embodiments.
Proton nmr spectra Bruker AMX-400 type, Gemini-300 type or AMX-600 type nuclear magnetic resonance analyser record, the unit of chemical shift δ is ppm.Specific rotation is measured by Perkin-Elmer241 type automatic polarimeter, and microwave used is CEM-discovery microwave reactor.All reaction solvents all conventionally carry out purifying.Column chromatography silica gel (200-300 order) is the production of Qingdao Haiyang chemical industry subsidiary factory.Thin-layer chromatography uses the efficient plate of GF254, for Yantai chemical institute is produced.Preparative thin layer chromatography board is prepared by oneself; stationary phase adopts GF254 (HG/T2354-92) silica gel and Xylo-Mucine (800-1200) preparation, is respectively Qingdao Marine Chemical Co., Ltd. and China Medicine's production.All solvents are analytical reagent, and agents useful for same is all purchased from Chemical Reagent Co., Ltd., Sinopharm Group.Adopt the colour developing of the method such as iodine, Ultraluminescence.Remove organic solvent under reduced pressure to carry out in Rotary Evaporators.
The preparation of the compound of embodiment 1 general formula 4
The preparation of compound 4-1
Starting compound (5-bromo-2-cyanopyridine) 1.82g, nitrobenzene boronic acid tetramethyl ethylene ketone 2.62g (1.2 equivalent), two (triphenylphosphine) palladium chloride 0.35g (0.05 equivalent), cesium carbonate 6.52 (2 equivalent) are dissolved in DMF, reaction system is changed to inert gas environment, be heated to 70 ~ 80 DEG C of reactions spend the night, boil off DMF, be dissolved in water inorganics, filter, drain to obtain compound a (crude product); Compound a is dissolved in 50 ~ 60 volume % sulfuric acid, is heated to 130 ~ 140 DEG C of reactions 2 ~ 3 hours, reaction solution is poured into NaOH adjust pH to 2 ~ 3 in ice, filter, drain to obtain compound b (crude product);
By the tertiary bright amino ester 0.446g of compound b 0.5g, L-(1.5 equivalent), O-(IH-benzotriazole-1-the base)-N of above-mentioned reaction gained; N; N '; N '-tetramethyl-isourea tetrafluoride boron 0.723g is dissolved in 10ml DMF; 0.68ml diisopropyl ethyl amine is added under nitrogen protection; room temperature reaction spends the night; revolve and boil off DMF; add water and methylene dichloride; be separated organic layer; anhydrous sodium sulfate drying, revolves and boils off solvent, the compound 4-10.49g (64%) of pillar layer separation.
1H NMR(300MHz，CDCl 3)δ8.86(s，1H)，8.60(d，J＝9.7Hz，1H)，8.37(d，J＝8.8Hz，2H)，8.30(d，J＝8.2Hz，1H)，8.08(dd，J＝8.2，2.2Hz，1H)，7.78(d，J＝8.8Hz，2H)，4.66(d，J＝9.8Hz，1H)，3.77(s，3H)，1.09(s，9H)。
The preparation of compound 4-2
Replace except using L-phenylpropyl alcohol amino ester, except the tertiary bright amino ester of L-, preparing compound 4-2 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.81(s，1H)，8.48(d，1H)，8.37(d，J＝8.9Hz，2H)，8.28(d，J＝8.2Hz，1H)，8.07(d，J＝8.8Hz，1H)，7.78(d，J＝8.3Hz，2H)，7.37-7.05(m，5H)，5.09(d，J＝8.1Hz，1H)，3.75(s，3H)，3.27(t，J＝5.9Hz，2H).
The preparation of compound 4-3
Replace except using D-phenylpropyl alcohol amino ester, except the tertiary bright amino ester of L-, preparing compound 4-3 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.81(d，J＝2.2Hz)，8.47(d，J＝8.2Hz)，8.37(d，J＝8.7Hz)，8.28(d，J＝8.1Hz)，8.07(dd，J＝8.1，2.3Hz)，7.77(d，J＝8.7Hz)，7.36-7.13(m)，5.09(dd，J＝14.4，6.2Hz)，3.75(s)，3.37-3.15(m).
The preparation of compound 4-4
Replace except using L-look amino ester, except the tertiary bright amino ester of L-, preparing compound 4-4 with the method identical with preparing compound 4-1.
1H NMR(300MHz，CDCl 3)d ppm 3.48(d，J＝5.50Hz，2H)3.72(s，3H)5.17(dd，J＝5.50，2.48Hz，1H)7.05-7.14(m，2H)7.19(t，J＝7.43Hz，1H)7.36(d，J＝7.98Hz，1H)7.60(d，J＝7.98Hz，1H)7.76(d，J＝8.53Hz，2H)8.06(dd，J＝8.11，2.34Hz，1H)8.19(br.s.，1H)8.27-8.34(m，2H)8.34-8.41(m，2H)8.58(d，J＝7.98Hz，1H)8.75(d，J＝2.20Hz，1H)。
The preparation of compound 4-5
Replace except using 2-fluorobenzene third amino ester, except the tertiary bright amino ester of L-, preparing compound 4-5 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.82(s，1H)，8.52(d，J＝8.4Hz，1H)，8.37(d，J＝8.7Hz，2H)，8.26(d，J＝8.1Hz，1H)，8.06(d，J＝8.0Hz，1H)，7.78(d，J＝8.6Hz，2H)，7.19(d，J＝6.7Hz，2H)，7.04(dd，J＝17.4，8.7Hz，2H)，5.08(dd，J＝14.8，6.5Hz，1H)，3.77(s，2H)，3.42-3.20(m，2H).
The preparation of compound 4-6
Replace except using 3-fluorobenzene third amino ester, except the tertiary bright amino ester of L-, preparing compound 4-6 with the method identical with preparing compound 4-1.
1H NMR(300MHz，CDCl 3)-d)d ppm 3.27(dd，J＝8.39，6.19Hz，2H)3.77(s，3H)5.10(d，J＝8.53Hz，1H)6.83-7.03(m，2H)7.24(s，2H)7.78(d，J＝9.08Hz，2H)8.08(dd，J＝8.25，2.20Hz，1H)8.28(d，J＝8.25Hz，1H)8.37(d，J＝8.80Hz，2H)8.50(s，1H)8.82(d，J＝1.38Hz，1H).
The preparation of compound 4-7
Replace except using 4-fluorobenzene third amino ester, except the tertiary bright amino ester of L-, preparing compound 4-7 with the method identical with preparing compound 4-1.
1H NMR(300MHz，CDCl 3)dppm 3.15-3.35(m，2H)3.76(s，3H)5.00-5.14(m，1H)6.93-7.04(m，2H)7.11-7.20(m，2H)7.78(d，J＝9.08Hz，2H)8.08(dd，J＝8.25，2.20Hz，1H)8.28(d，J＝8.80Hz，1H)8.33-8.43(m，2H)8.46(d，J＝8.53Hz，1H)8.82(d，J＝1.38Hz，1H)。
The preparation of compound 4-8
Replace, except the tertiary bright amino ester of L-, preparing compound 4-8 with the method identical with preparing compound 4-1 except using 2-hydroxyl phenylpropyl alcohol amino ester.
1H NMR(300MHz，CDCl 3))δ9.20(s，1H)，8.61(s，1H)，8.37(s，1H)，8.23(s，2H)，7.79(s，2H)，7.02(d，J＝10.0Hz，2H)，6.90-6.68(m，3H)，4.95(s，1H)，4.81(s，1H)。
The preparation of compound 4-9
Replace, except the tertiary bright amino ester of L-, preparing compound 4-9 with the method identical with preparing compound 4-1 except using 3-hydroxyl phenylpropyl alcohol amino ester.
1H NMR(300MHz，CDCl 3))δ9.19(s，1H)，8.61(s，1H)，8.37(s，1H)，8.23(s，2H)，7.79(s，2H)，7.03(d，J＝23.5Hz，2H)，6.76(d，J＝25.0Hz，3H)，4.77(d，J＝42.8Hz，2H)，3.66(s，3H)，3.10(d，J＝125.0Hz，2H).
The preparation of compound 4-10
Replace except using tyrosine ester, except the tertiary bright amino ester of L-, preparing compound 4-10 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.81(s，1H)，8.48(d，J＝8.6Hz，1H)，8.37(d，J＝8.8Hz，2H)，8.27(d，J＝8.1Hz，1H)，8.06(d，J＝8.2Hz，1H)，7.77(d，J＝8.9Hz，2H)，7.04(d，J＝8.5Hz，2H)，6.74(d，J＝8.5Hz，2H)，4.98-5.10(m，1H)，3.76(s，3H)，3.29-3.04(m，2H)。
The preparation of compound 4-11
Replace except using ring alanine methyl ester, except the tertiary bright amino methyl of L-, preparing compound 4-11 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.80(s，1H)，8.49(s，1H)，8.35(dd，J＝14.1，8.0Hz，3H)，8.09(d，J＝8.0Hz，1H)，7.78(d，J＝7.9Hz，2H)，3.71(d，J＝1.0Hz，3H)，1.71(t，J＝5.9Hz，2H)，1.35(q，J＝4.8Hz，2H)。
The preparation of compound 4-12
Replace except using glycine methyl ester, except the tertiary bright amino methyl of L-, preparing compound 4-12 with the method identical with preparing compound 4-1.
1H NMR(500MHz，CDCl 3))δ9.08(s，1H)，8.61(s，1H)，8.20(d，J＝26.3Hz，3H)，7.79(s，2H)，3.87(s，2H)，3.63(s，3H).
The preparation of compound 4-13
Replace except using beta Alanine methyl esters, except the tertiary bright amino methyl of L-, preparing compound 4-13 with the method identical with preparing compound 4-1.
1NMR(300MHz，CDCl 3)δ8.81(s)，8.48(s)，8.36(d，J＝8.8Hz)，8.30(d，J＝8.2Hz)，8.07(dd，J＝8.1，2.2Hz)，7.77(d，J＝8.8Hz)，3.78(dd，J＝12.4，6.3Hz)，3.73(s)，2.69(t，J＝6.1Hz).
The preparation of the compound of embodiment 2 general formula I-1
The preparation of compound yhhu-2407
The first step: compound 4-1 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-1;
Second step: compound 5-1 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent phenyl isocyanate, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-1a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-1a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2407.
1H NMR(300MHz，CD 3OD)δ8.93(s，1H)，8.16(t，J＝9.3Hz，2H)，7.66(dd，J＝25.3，8.5Hz，4H)，7.44(d，J＝8.1Hz，2H)，7.29(t，J＝7.6Hz，2H)，7.04(d，J＝7.6Hz，1H)，4.9-4.80(d，2H)，1.10(s，9H).
The preparation of compound yhhu-2784
Replace except using 2,3-dichlorophenyl isocyanate, beyond phenyl isocyanate, preparing compound yhhu-2784 with the method identical with preparing compound yhhu-2407.
1h NMR (300MHz, acetone) δ 9.22 (s, 1H), 8.93 (s, 1H), 8.59 (d, J=9.8Hz, 1H), 8.36 (d, J=8.3Hz, 1H), 8.20 (dt, J=14.7,7.1Hz, 3H), 7.75 (s, 4H), 7.33 (t, J=8.2Hz, 1H), 7.27-7.18 (m, 1H), 4.64-4.51 (m, 1H), 1.11 (s, 9H).
The preparation of compound yhhu-2782
Replace except using 4-trifluoromethylbenzene based isocyanate, except phenyl isocyanate, preparing compound yhhu-2782 with the method identical with preparing compound yhhu-2407.
1H NMR(300MHz，DMSO)δ9.21(s，1H)，9.07(s，1H)，9.00(s，1H)，8.45(d，J＝10.0Hz，1H)，8.27(d，J＝8.3Hz，1H)，8.08(d，J＝8.1Hz，1H)，7.77(d，J＝8.8Hz，2H)，7.65(q，J＝8.9Hz，6H)，4.35(d，J＝9.7Hz，1H)，1.00(s，9H).
The preparation of compound yhhu-2779
Replace except using 2,6-dichlorophenyl isocyanate, beyond phenyl isocyanate, preparing compound yhhu-2779 with the method identical with preparing compound yhhu-2407.
1h NMR (300MHz, acetone) δ 8.94 (s, 1H), 8.73 (s, 1H), 8.56 (d, J=9.6Hz, 1H), 8.21 (dd, J=21.1,8.2Hz, 2H), 7.76 (t, J=7.9Hz, 5H), 7.50 (d, J=8.1Hz, 2H), 7.32 (t, J=8.1Hz, 1H), 4.58 (d, J=9.7Hz, 1H), 1.11 (s, 9H).
The preparation of compound yhhu-2788
The first step, implements the step identical with preparing the compound yhhu-2407 the first step;
Second step, is dissolved in methylene dichloride by the triphosgene of chloro-for the 2-of 1.5 equivalents 4-5-trifluoromethylaniline, 0.5 equivalent, adds 3 eq of triethylamine, room temperature reaction 5 ~ 10 minutes, adds compound 5-1 room temperature reaction and spends the night, add water, be separated organic phase, pillar layer separation obtains intermediate 5-1b;
3rd step, implements the step identical with the 3rd step preparing compound yhhu-2407, prepares compound yhhu-2788.
1H NMR(300MHz，DMSO)δ13.25-12.85(m，1H)，9.96(s，1H)，9.00(s，1H)，8.74(s，1H)，8.45(t，J＝7.8Hz，2H)，8.27(d，J＝6.2Hz，1H)，8.09(d，J＝7.9Hz，1H)，7.92-7.73(m，3H)，7.66(t，J＝9.3Hz，3H)，4.36(d，J＝9.6Hz，1H)，1.01(s，9H).
The preparation of compound yhhu-2775
The first step: compound 4-2 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-2;
Second step: compound 5-2 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-2a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-2a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2775.
1H NMR(300MHz，DMSO)δ13.33-12.76(m，1H)，9.69(s，1H)，8.93(s，1H)，8.71(d，J＝7.9Hz，1H)，8.53(s，1H)，8.20(dd，J＝19.2，7.8Hz，2H)，8.02(d，J＝7.9Hz，1H)，7.77(d，J＝8.4Hz，2H)，7.61(d，J＝8.3Hz，2H)，7.44-7.08(m，7H)，4.75(d，J＝6.2Hz，1H)，3.23(s，2H).
The preparation of compound yhhu-2753
Beyond phenyl isocyanate replacement 2,3-dichlorophenyl isocyanate, prepare compound yhhu-2753 with the method identical with preparing compound yhhu-2775.
1H NMR(300MHz，DMSO)δ11.41(s，1H)，10.44(s，1H)，9.17(s，2H)，8.21(s，1H)，8.02(d，J＝8.2Hz，1H)，7.74(m，6H)，7.21(m，8H)，6.92(t，1H)，4.40(m，1H)，3.30-3.10(m，2H).
The preparation of compound yhhu-2770
Beyond 2,3-dichlorophenyl isocyanate, compound yhhu-2770 is prepared with the method identical with preparing compound yhhu-2775 except replacing with 2,6-dichlorophenyl isocyanate.
1H NMR(300MHz，DMSO)δ11.41(s，1H)，10.44(s，1H)，9.17(s，2H)，8.21(s，1H)，8.02(d，J＝8.2Hz，1H)，7.74(m，6H)，7.21(m，8H)，6.92(t，1H)，4.40(m，1H)，3.30-3.10(m，2H).
The preparation of compound yhhu-2776
Replace except using 4-trifluoromethylbenzene based isocyanate, beyond 2,3-dichlorophenyl isocyanate, preparing compound yhhu-2776 with the method identical with preparing compound yhhu-2775.
1H NMR(300MHz，DMSO)δ10.32-10.11(m，1H)，10.11-9.97(m，1H)，9.02(s，1H)，8.86(s，1H)，8.23(d，J＝8.4Hz，1H)，8.02(d，J＝8.2Hz，1H)，7.69(dt，J＝21.3，8.4Hz，7H)，7.20(s，4H)，4.63(s，1H)，3.24(s，2H).
The preparation of compound yhhu-2786
The first step, implements the step identical with the first step preparing compound yhhu-2775;
Second step, is dissolved in methylene dichloride by the triphosgene of chloro-for the 2-of 1.5 equivalents 4-5-trifluoromethylaniline, 0.5 equivalent, adds 3 eq of triethylamine, and room temperature reaction 5 ~ 10 minutes adds 5-2 room temperature reaction and spends the night, adds water, and be separated organic phase, pillar layer separation obtains intermediate;
3rd step, implements the step identical with the 3rd step preparing compound yhhu-2775, obtained compound yhhu-2786.
1H NMR(300MHz，DMSO)δ10.24(s，1H)，9.03(s，1H)，8.93(s，1H)，8.72(d，J＝7.0Hz，1H)，8.44(d，J＝8.7Hz，1H)，8.24(d，J＝8.0Hz，1H)，8.05(d，J＝8.1Hz，1H)，7.87(s，1H)，7.77(d，J＝8.3Hz，2H)，7.67(d，J＝8.4Hz，3H)，7.20(s，6H)，4.59(s，1H)，3.23(s，2H)。
The preparation of compound yhhu-2763
The first step: compound 4-3 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-3;
Second step: compound 5-3 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-3a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-3a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1NHCl, filtration is drained, and obtains compound yhhu-2763.
1h NMR (300MHz, acetone) δ 9.09 (s, 1H), 8.87 (s, 1H), 8.52 (d, J=8.9Hz, 1H), 8.37 (d, J=8.3Hz, 1H), 8.22 (d, J=8.1Hz, 1H), 8.16 (s, 1H), 8.12 (d, J=6.9Hz, 1H), 7.75 (s, 4H), 7.39-7.16 (m, 7H), 5.00 (s, 1H), 3.32 (dd, J=18.0,11.1Hz, 2H).
The preparation of compound yhhu-2770
Replace except using 2,6-dichlorophenyl isocyanate, beyond 2,3-dichlorophenyl isocyanate, preparing compound yhhu-2770 with the method identical with preparing compound yhhu-2763.
1h NMR (300MHz, acetone) δ 8.86 (d, J=2.1Hz, 1H), 8.72 (s, 1H), 8.52 (d, J=7.8Hz, 1H), 8.21 (dd, J=8.1,2.2Hz, 1H), 8.14 (d, J=8.1Hz, 1H), 7.76 (d, J=20.4Hz, 5H), 7.50 (d, J=7.9Hz, 2H), 7.37-7.15 (m, 7H), 5.01 (dd, J=13.4,7.0Hz, 1H), 3.35 (qd, J=13.9,6.0Hz, 2H).
The preparation of compound yhhu-2777
Replace except using 4-trifluoromethylbenzene based isocyanate, beyond 2,3-dichlorophenyl isocyanate, preparing compound yhhu-2777 with the method identical with preparing compound yhhu-2763.
1H NMR(300MHz，Acetone)δ10.83(s，1H)，8.87(s，1H)，8.66-8.40(m，3H)，8.28-8.18(m，1H)，8.15(d，J＝8.1Hz，1H)，7.84-7.70(m，6H)，7.63(d，J＝8.5Hz，2H)，7.38-7.14(m，5H)，5.01(dd，J＝13.0，7.7Hz，1H)，3.35(qd，J＝13.9，6.0Hz，2H).
The preparation of compound yhhu-2787
The first step, implements the step identical with the first step preparing compound yhhu-2763;
Second step, is dissolved in methylene dichloride by the triphosgene of chloro-for the 2-of 1.5 equivalents 4-5-trifluoromethylaniline, 0.5 equivalent, adds 3 eq of triethylamine, and room temperature reaction 5 ~ 10 minutes adds 5-3 room temperature reaction and spends the night, adds water, and be separated organic phase, pillar layer separation obtains intermediate;
3rd step, implements the step identical with the 3rd step preparing compound yhhu-2763, obtained compound yhhu-2787.
1H NMR(300MHz，DMSO)δ10.82(s，1H)，9.51(s，1H)，8.95(s，1H)，8.79(d，J＝6.6Hz，1H)，8.36(d，J＝8.8Hz，1H)，8.23(d，J＝8.2Hz，1H)，8.06(d，J＝8.1Hz，1H)，7.86(s，1H)，7.80-7.61(m，4H)，7.16(s，5H)，4.37(s，1H)，3.28-3.10(m，2H)。
The preparation of compound yhhu-2762
The first step: compound 4-4 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-4;
Second step: compound 5-4 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate;
3rd step: upper step is obtained the mixed solvent that intermediate is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1NHCl, filtration is drained, and obtains compound yhhu-2762.
1h NMR (300MHz, acetone) δ 10.85 (s, 1H), 10.11 (s, 1H), 9.08 (s, 1H), 8.80 (s, 1H), 8.63 (d, J=8.0Hz, 1H), 8.35 (dd, J=8.3, 1.5Hz, 1H), 8.22-8.13 (m, 2H), 8.10 (s, 1H), 7.71 (s, 4H), 7.66 (d, J=7.9Hz, 1H), 7.37 (d, J=8.1Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 7.28-7.18 (m, 2H), 7.07 (t, J=7.2Hz, 1H), 6.97 (t, J=7.5Hz, 1H), 5.09 (dd, J=13.7, 5.7Hz, 1H), 3.61-3.46 (m, 2H).
The preparation of compound yhhu-2797
The first step: compound 4-5 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-5;
Second step: compound 5-5 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-5a;
3rd step: upper step is obtained the mixed solvent that intermediate is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1NHCl, filtration is drained, and obtains compound yhhu-2797.
1h NMR (300MHz, acetone) δ 10.82 (s, 1H), 9.09 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=7.6Hz, 1H), 8.22 (d, J=8.3Hz, 1H), 8.12 (d, J=7.4Hz, 1H), 7.75 (s, 3H), 7.45-7.20 (m, 3H), 7.09 (m, 2H), 5.02 (s, 1H), 3.53-3.25 (m, 2H).
The preparation of compound yhhu-2801
The first step: compound 4-6 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-6;
Second step: compound 5-6 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-6a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-6a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2801.
1h NMR (300MHz, acetone) δ 9.12 (s, 1H), 8.90-8.84 (m, 1H), 8.58 (d, J=7.9Hz, 1H), 8.36 (dd, J=8.3,1.6Hz, 1H), 8.22 (dd, J=8.2,2.2Hz, 1H), 8.14 (d, J=8.8Hz, 2H), 7.74 (s, 4H), 7.41-7.20 (m, 3H), 7.12 (dd, J=13.9,9.2Hz, 2H), 6.98 (t, J=8.6Hz, 1H), 5.10-4.94 (m, 1H), 3.39 (ddd, J=21.3,14.0,6.5Hz, 2H).
The preparation of compound yhhu-2761
The first step: compound 4-7 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-7;
Second step: compound 5-7 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-7a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-7a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1NHCl, filtration is drained, and obtains compound yhhu-2761.
1H NMR(300MHz，DMSO)δ9.73(s，1H)，8.93(s，1H)，8.75(d，J＝7.7Hz，1H)，8.55(s，1H)，8.19(dd，J＝20.5，7.2Hz，2H)，8.02(d，J＝8.7Hz，1H)，7.77(d，J＝8.4Hz，2H)，7.62(d，J＝8.1Hz，2H)，7.29(dd，J＝17.0，8.1Hz，3H)，7.06(t，J＝8.7Hz，2H)，4.74(s，1H)，3.22(s，2H).
The preparation of compound yhhu-2799
The first step: compound 4-8 is dissolved in anhydrous methanol, adds the palladium charcoal of 10wt%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-8;
Second step: compound 5-8 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-8a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-8a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2799.
1h NMR (300MHz, acetone) δ 9.36 (s, 1H), 9.01 (s, 2H), 8.97-8.81 (m, 1H), 8.51 (d, J=8.3Hz, 1H), 8.34 (d, J=10.2Hz, 2H), 8.25 (d, J=8.1Hz, 1H), 7.89 (s, 4H), 7.49 (t, J=8.2Hz, 1H), 7.44-7.32 (m, 2H), 7.20 (t, J=7.6Hz, 1H), 7.02 (d, J=8.2Hz, 1H), 6.91 (t, J=7.5Hz, 1H), 5.09 (d, J=5.0Hz, 1H), 3.61-3.36 (m, 2H).
The preparation of compound yhhu-2799-2
The first step: compound 4-9 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-9;
Second step: compound 5-9 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-9a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-9a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2799-2.
1H NMR(500MHz，CDCl 3)δ9.20(d，J＝7.9Hz，2H)，9.20(d，J＝7.9Hz，2H)，8.61(s，1H)，8.61(s，1H)，8.37(d，J＝9.4Hz，2H)，8.37(d，J＝9.4Hz，2H)，7.74-7.50(m，6H)，7.31(d，J＝25.0Hz，2H)，7.05(s，1H)，6.77(d，J＝25.0Hz，3H)，4.73(d，J＝7.4Hz，2H)，3.18-2.80(m，J＝125.0Hz，2H).
The preparation of compound yhhu-2799-3
The first step: compound 4-10 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-10;
Second step: compound 5-10 is dissolved in dry tetrahydrofuran (THF), adds 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, add methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-10a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-10a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2799-3.
1H NMR(500MHz，CDCl 3)δ9.18(d，J＝3.2Hz，2H)，8.60(s，1H)，8.36(d，J＝7.8Hz，2H)，7.65(d，J＝15.0Hz，3H)，7.54(s，2H)，7.30(d，J＝25.0Hz，2H)，7.00(s，2H)，6.71(d，J＝27.1Hz，3H)，4.71(s，1H)，4.57(s，1H)，3.16-2.82(m，2H).
The preparation of compound yhhu-2752
The first step: compound 4-11 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-11;
Second step: compound 5-11 is dissolved in dry tetrahydrofuran (THF), adds 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, add methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-11a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-11a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2752.
1H NMR(300MHz，DMSO)δ9.20(s，1H)，8.99(s，1H)，8.91(s，1H)，8.82(s，1H)，8.23(d，J＝10.7Hz，1H)，8.04(d，J＝8.2Hz，1H)，7.75(d，J＝8.9Hz，2H)，7.61(d，J＝8.7Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.27(t，J＝7.9Hz，2H)，6.96(t，J＝7.3Hz，1H)，1.40(s，2H)，1.19(s，2H).
The preparation of compound yhhu-2764
The first step: compound 4-12 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-12;
Second step: compound 5-12 is dissolved in dry tetrahydrofuran (THF), adds 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, add methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-12a;
3rd step: upper step is obtained the mixed solvent that middle 5-12a body is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2764.
1H NMR(300MHz，DMSO)δ12.70(s，1H)，9.07-8.85(m，3H)，8.77(s，1H)，8.26(d，J＝8.2Hz，1H)，8.08(d，J＝8.2Hz，1H)，7.78(d，J＝8.6Hz，2H)，7.63(d，J＝8.6Hz，2H)，7.47(d，J＝8.0Hz，2H)，7.29(t，J＝7.8Hz，2H)，6.98(t，J＝7.2Hz，1H)，4.00(d，J＝5.9Hz，2H).
The preparation of compound yhhu-2751
The first step: compound 4-13 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 5-13;
Second step: compound 5-13 is dissolved in dry tetrahydrofuran (THF), adds 1.5 equivalent 2,3-dichlorophenyl isocyanates, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, add methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 5-13a;
3rd step: upper step is obtained the mixed solvent that intermediate 5-13a is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2751.
1H NMR(300MHz，DMSO)δ12.43-12.20(m，1H)，8.93(s，2H)，8.79(s，2H)，8.24(d，J＝7.4Hz，1H)，8.07(d，J＝8.1Hz，1H)，7.76(d，J＝8.2Hz，2H)，7.62(d，J＝8.1Hz，2H)，7.47(d，J＝7.7Hz，2H)，7.29(t，J＝7.4Hz，2H)，6.98(s，1H)，3.54(d，J＝6.4Hz，2H)，2.53(d，J＝11.8Hz，2H).
The preparation of the compound of embodiment 3 general formula 10
The preparation of compound 10-1
The first step: starting compound 5-bromo-2-pyridyl carboxylic acid 1.82g, L-PROLINE methyl esters (1.5 equivalent), TBTU are dissolved in 10ml DMF; diisopropyl ethyl amine (2 equivalent) is added under nitrogen protection; room temperature reaction spends the night; revolve and boil off DMF; add water and methylene dichloride, be separated organic layer, anhydrous sodium sulfate drying; revolve and boil off solvent, the compound 10-1a of pillar layer separation.
Second step: compound 10-1a, 4-nitrobenzene boronic acid tetramethyl ethylene ketone (1.2 equivalent), tetraphenyl phosphine palladium (0.05 equivalent), salt of wormwood (2 equivalent) are dissolved in the mixed solvent of toluene-ethano-water, reaction system is changed to inert gas environment, be heated to 70 ~ 80 DEG C of reactions spend the night, boil off solvent, add methylene chloride and water, be separated organic phase, pillar layer separation obtains compound 10-1.
1H NMR(300MHz，CDCl 3)δ8.79(d，J＝39.7Hz，1H)，8.35(dd，J＝8.8，3.2Hz，2H)，8.25-7.98(m，2H)，7.77(dd，J＝8.0，5.8Hz，2H)，5.24-4.67(m，1H)，4.07(s，1H)，4.00-3.81(m，1H)，3.73(d，J＝32.8Hz，3H)，2.40-1.89(m，4H).
The preparation of compound 10-2
Replace, except L-PROLINE methyl esters, preparing compound 10-2 with the method identical with preparing compound 10-1 except using the tertiary bright amino ester of D-.
1H NMR(300MHz，CDCl 3)δ8.79(d，J＝39.7Hz，1H)，8.35(dd，J＝8.8，3.2Hz，2H)，8.25-7.98(m，2H)，7.77(dd，J＝8.0，5.8Hz，2H)，5.24-4.67(m，1H)，4.07(s，1H)，4.00-3.81(m，1H)，3.73(d，J＝32.8Hz，3H)，2.40-1.89(m，4H).
The preparation of compound 10-3
Replace except using 2 piperidine carboxylic acid methyl esters, except L-PROLINE methyl esters, preparing compound 10-3 with the method identical with preparing compound 10-1.
1H NMR(300MHz，CDCl 3)δ8.44(s，1H)，8.23(s，2H)，7.80(d，J＝8.1Hz，3H)，7.42(s，1H)，3.95(s，1H)，3.70(d，J＝13.7Hz，4H)，3.40(d，J＝59.0Hz，2H)，2.78(s，1H)，2.30(s，1H)，1.81-1.18(m，3H).
The preparation of compound 10-4
Replace except using 3-piperidine carboxylic acid methyl esters, except L-PROLINE methyl esters, preparing compound 10-4 with the method identical with preparing compound 10-1.
1H NMR(300MHz，CDCl 3)δ8.84(s)，8.36(d，J＝8.3Hz)，8.03(d，J＝7.6Hz)，7.78(t，J＝7.5Hz)，4.44(d，J＝30.0Hz)，4.07(d，J＝15.0Hz)，3.68(d，J＝27.8Hz)，3.49-3.03(m)，2.68(s)，2.13(s)，1.92-1.67(m).
The preparation of compound 10-5
Replace except using the bromo-2-pyrimidine carboxylic of 5-, except 5-bromo-2-pyridyl carboxylic acid, preparing compound 10-5 with the method identical with preparing compound 10-1.
1H NMR(300MHz，CDCl 3)δ9.07(d，J＝12.1Hz，2H)，8.41(dd，J＝8.9，2.3Hz，2H)，7.79(dd，J＝8.9，2.6Hz，2H)，4.99-4.71(m，1H)，4.06-3.61(m，5H)，2.40-1.87(m，4H).
The preparation of compound 10-6
Replace except using the bromo-5-pyrimidine carboxylic of 2-, except 5-bromo-2-pyridyl carboxylic acid, preparing compound 10-6 with the method identical with preparing compound 10-1.
1H NMR(300MHz，CDCl 3)δ8.96(s，1H)，8.35(d，J＝8.5Hz，2H)，8.21(d，J＝8.5Hz，2H)，8.06(d，J＝8.2Hz，1H)，7.88(d，J＝8.1Hz，1H)，4.71(s)，3.82-3.70(m，4H)，3.61(s，1H)，2.36(s，1)，2.20-1.90(m，3H).
The preparation of the compound of embodiment 4 general formula I-2
The preparation of compound yhhu-2027
The first step: compound 10-1 is dissolved in anhydrous methanol, adds the palladium charcoal of 10%, adds 3 ~ 4 equivalent of sodium borohydride under ice bath in nitrogen atmosphere, react 5 ~ 6 hours, react completely, add 1N hydrochloric acid and emerge to there is no bubble, elimination palladium charcoal, revolve and boil off solvent, add water and methylene dichloride, be separated organic phase, anhydrous sodium sulfate drying, revolve and boil off organic solvent, pillar layer separation obtains compound 11-1;
Second step: compound 11-1 is dissolved in dry tetrahydrofuran (THF), add 1.5 equivalent phenyl isocyanate, add two eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, be separated organic phase, pillar layer separation obtains intermediate 11-2;
3rd step: upper step is obtained the mixed solvent that intermediate 11-2 is dissolved in first alcohol and water, add 5 Equivalent Hydrogen Lithium Oxide 98mins, room temperature reaction spends the night, and boils off methyl alcohol, and adjust pH value of solution to 3 ~ 4 with 1N HCl, filtration is drained, and obtains compound yhhu-2027.
1H NMR(300MHz，DMSO)δ9.08(s，1H)，8.84(d，J＝41.8Hz，2H)，8.18(s，1H)，7.85(dd，J＝26.1，8.2Hz，1H)，7.73(t，J＝8.0Hz，2H)，7.60(d，J＝6.8Hz，2H)，7.45(d，J＝8.5Hz，2H)，7.27(t，J＝7.9Hz，2H)，6.96(t，J＝7.2Hz，1H)，4.40-5.18(m，1H)，3.84(s，1H)，3.64(s，1H)，2.39-2.11(m，1H)，1.88(m，3H).
The preparation of compound yhhu-2420
Except phenyl isocyanate, compound yhhu-2420 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 2-chlorophenyl isocyanate.
1H NMR(300MHz，DMSO)δ9.78(s，1H)，8.99-8.72(m，1H)，8.44(s，1H)，8.25-8.09(m，2H)，7.86(dd，J＝25.9，8.3Hz，1H)，7.78-7.67(m，2H)，7.62(dd，J＝8.7，2.1Hz，2H)，7.45(d，J＝8.1Hz，1H)，7.30(t，J＝8.0Hz，1H)，7.03(t，J＝7.7Hz，1H)，5.21-4.40(m，1H)，3.85(s，1H)，3.59(t，J＝12.6Hz，2H)，2.26(s，1H)，2.07-1.67(m，4H).
The preparation of compound yhhu-2402
Except phenyl isocyanate, compound yhhu-2402 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 3-chlorophenyl isocyanate.
1H NMR(300MHz，CD 3OD)δ8.83(d，J＝27.1Hz，1H)，8.22-8.08(m，1H)，7.93(dd，J＝34.8，8.5Hz，1H)，7.74-7.52(m，5H)，7.34-7.20(m，2H)，7.01(d，J＝6.5Hz，1H)，4.60-5.27(m，1H)，3.84(dd，J＝23.0，16.0Hz，2H)，2.37(s，1H)，2.27-1.88(m，3H).
The preparation of compound yhhu-2409
Except phenyl isocyanate, compound yhhu-2409 is prepared with the method identical with preparing compound yhhu-2027 except replacing with 4-chlorophenyl isocyanate.
1H NMR(300MHz，DMSO)δ8.97-8.75(m，3H)，8.17(d，J＝8.1Hz，1H)，7.85(dd，J＝27.3，8.4Hz，1H)，7.77-7.67(m，2H)，7.59(d，J＝6.7Hz，2H)，7.49(d，J＝8.9Hz，2H)，7.32(d，J＝8.8Hz，2H)，5.22-4.40(m，2H)，3.85(s，1H)，3.64(s，1H)，2.25(s，1H)，1.73-2.08(m，4H).
The preparation of compound yhhu-2403
Replace, except phenyl isocyanate, preparing compound yhhu-2403 by the method identical with preparing compound yhhu-2027 except with 2-trifluoromethylbenzene based isocyanate.
1H NMR(300MHz，DMSO)δ12.61-12.27(m，1H)，9.58(s，1H)，8.87(d，J＝42.0Hz，1H)，8.16(s，2H)，7.94(t，J＝9.4Hz，2H)，7.87-7.45(m，8H)，7.30(t，J＝7.7Hz，1H)，525-4.45(m，1H)，3.86(s，1H)，3.66(s，1H)，2.27(s，1H)，2.10-1.73(m，4H).
The preparation of compound yhhu-2405
Replace, except phenyl isocyanate, preparing compound yhhu-2405 by the method identical with preparing compound yhhu-2027 except with 4-trifluoromethylbenzene based isocyanate.
1H NMR(300MHz，CD 3OD)δ8.83(d，J＝29.8Hz，1H)，8.16(dd，J＝22.2，7.1Hz，1H)，8.04-7.84(m，1H)，7.61(dd，J＝23.9，10.1Hz，9H)，460-5.26(m，2H)，4.01-3.67(m，2H)，2.36(s，1H)，1.90-2.46(m，3H).
The preparation of compound yhhu-2400
Replace, except phenyl isocyanate, preparing compound yhhu-2400 by the method identical with preparing compound yhhu-2027 except with 3-trifluoromethylbenzene based isocyanate.
1H NMR(300MHz，CD 3OD)δ8.97(d，J＝25.5Hz，1H)，8.27(t，J＝7.9Hz，1H)，8.19-7.97(m，2H)，7.87-7.69(m，5H)，7.62(t，J＝8.0Hz，1H)，7.45(d，J＝7.6Hz，1H)，5.41-4.75(m，1H)，4.17-3.87(m，2H)，2.51(d，J＝8.9Hz，1H)，2.42-1.99(m，3H).
The preparation of compound yhhu-2421
Except phenyl isocyanate, compound yhhu-2421 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 2-methoxyphenyl isocyanate.
1H NMR(300MHz，DMSO)δ9.65(s，1H)，8.85(d，J＝42.7Hz，1H)，8.32(s，1H)，8.23-8.07(m，2H)，7.86(dd，J＝24.8，8.3Hz，1H)，7.78-7.68(m，2H)，7.60(dd，J＝8.8，2.2Hz，2H)，7.05-6.82(m，3H)，5.22-4.40(m，1H)，3.86(s，3H)，3.68-3.55(m，2H)，2.26(s，2H)，2.08-1.67(m，4H).
The preparation of compound yhhu-2416
Except phenyl isocyanate, compound yhhu-2416 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 4-methoxyphenyl isocyanate.
1H NMR(300MHz，DMSO)δ12.63-12.38(m，1H)，8.85(t，J＝21.1Hz，2H)，8.55(s，1H)，8.18(s，1H)，7.87(dd，J＝27.2，8.1Hz，1H)，7.74(t，J＝7.3Hz，2H)，7.60(d，J＝8.6Hz，2H)，7.37(d，J＝8.5Hz，2H)，6.88(d，J＝8.7Hz，2H)，4.45-5.20(m，1H)，3.87(s，1H)，3.76-3.69(m，3H)，3.66(s，1H)，2.39-2.14(m，1H)，2.12-1.80(m，3H).
The preparation of compound yhhu-2401
Except phenyl isocyanate, compound yhhu-2401 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 3-methoxyphenyl isocyanate.
1H NMR(300MHz，CD 3OD)δ8.95(d，J＝27.6Hz，1H)，8.22(dd，J＝23.5，8.2Hz，1H)，8.03(dd，J＝14.3，8.3Hz，1H)，7.75(dd，J＝20.4，13.2Hz，4H)，7.41-7.26(m，2H)，7.10(d，J＝7.9Hz，1H)，6.75(d，J＝8.3Hz，1H)，5.36-4.73(m，1H)，4.19-3.82(m，5H)，2.60-2.08(m，5H).
The preparation of compound yhhu-2404
Beyond phenyl isocyanate, compound yhhu-2404 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 3,5-difluorophenyl isocyanate.
1H NMR(300MHz，CD 3OD)δ8.83(d，J＝25.9Hz，1H)，8.14(dd，J＝16.0，8.8Hz，1H)，8.07-7.86(m，1H)，7.64(t，J＝6.0Hz，4H)，7.12(d，J＝8.0Hz，2H)，6.52(t，J＝9.0Hz，1H)，4.64-5.29(m，1H)，4.05-3.71(m，2H)，2.53-1.88(m，4H).
The preparation of compound yhhu-2749
Except phenyl isocyanate, compound yhhu-2749 is prepared by the method identical with preparing compound yhhu-2027 except replacing with PITC.
1H NMR(300MHz，DMSO)δ12.45(s，1H)，8.94-8.72(m，3H)，8.17(s，1H)，7.93-7.78(m，1H)，7.73(s，2H)，7.61(s，2H)，7.45(d，J＝7.5Hz，2H)，7.27(s，2H)，6.96(s，1H)，4.43(s，3H)，3.85(s，1H)，3.64(s，1H)，2.35-2.17(m，2H)，1.93(d，J＝25.0Hz，4H).
The preparation of compound yhhu-2773
Beyond phenyl isocyanate, compound yhhu-2773 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 3,4-dichlorophenyl isocyanate.
1H NMR(300MHz，DMSO)δ12.50(s，1H)，9.06(s，1H)，9.02(s，1H)，8.92(s，1H)，8.78(s，1H)，8.17(s，1H)，7.93-7.78(m，2H)，7.78-7.69(m，2H)，7.60(d，J＝6.8Hz，2H)，7.51(d，J＝8.8Hz，1H)，7.34(d，J＝9.1Hz，1H)，5.16(s，0.5H)，4.50-4.39(m，0.5H)，3.85(s，1H)，3.61(d，J＝18.4Hz，2H)，2.40-1.97(m，2H)，1.89(s，2H).
The preparation of compound yhhu-2774
Beyond phenyl isocyanate, compound yhhu-2774 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 2,3-dichlorophenyl isocyanate.
1H NMR(300MHz，CD 3OD)δ8.84(s，1H)，8.75(s，1H)，8.12(dd，J＝21.6，8.0Hz，1H)，7.90(dd，J＝39.9，8.3Hz，1H)，7.63(d，J＝7.1Hz，3H)，7.18(qd，J＝15.8，8.2Hz，3H)，5.22(d，J＝5.2Hz，0.5H)，4.61(s，0.5H)，3.91(s，1H)，3.86-3.68(m，1H)，2.32(s，1H)，2.20(s，1H)，2.00(d，J＝12.2Hz，2H).
The preparation of compound yhhu-2790
Beyond phenyl isocyanate, compound yhhu-2790 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 2,6-dichlorophenyl isocyanate.
1H NMR(300MHz，DMSO)δ12.59-12.37(m，1H)，9.17(s，1H)，8.84(d，J＝41.7Hz，1H)，8.29(s，1H)，8.16(s，1H)，7.85(dd，J＝27.5，8.3Hz，1H)，7.72(t，J＝7.6Hz，2H)，7.56(dd，J＝20.2，7.7Hz，4H)，7.31(t，J＝8.1Hz，1H)，4.4～5.2(d，J＝9.8Hz，2H)，3.85(s，1H)，3.64(s，1H)，2.36-2.13(m，1H)，1.88(s，3H).
The preparation of compound yhhu-2415
Except phenyl isocyanate, compound yhhu-2415 is prepared by the method identical with preparing compound yhhu-2027 except replacing with 3-bromophenyl isocyanate.
1HNMR(300MHz，DMSO)δ9.14(s，2H)，8.85(d，J＝41.6Hz，1H)，8.18(s，1H)，7.94-7.79(m，2H)，7.74(t，J＝7.5Hz，2H)，7.60(d，J＝6.8Hz，2H)，7.32(d，J＝8.0Hz，1H)，7.23(t，J＝7.9Hz，1H)，7.14(d，J＝7.7Hz，1H)，5.20-4.40(d，J＝213.6Hz，1H)，3.85(s，1H)，3.64(s，2H)，2.36-1.72(m，4H).
The preparation of compound yhhu-2754
Except phenyl isocyanate, compound yhhu-2754 is prepared by the method identical with preparing compound yhhu-2027 except replacing with n-butyl isocyanate.
1H NMR(300MHz，CD 3OD)δ8.80(d，J＝26.8Hz，1H)，8.18-8.06(m，1H)，7.91(dd，J＝38.9，8.3Hz，1H)，7.62(t，J＝7.9Hz，2H)，7.51(dd，J＝8.4，3.7Hz，2H)，5.25-4.56(m，1H)，3.92(d，J＝5.8Hz，1H)，3.81(dd，J＝13.2，6.9Hz，2H)，3.21(t，J＝6.9Hz，2H)，2.37(t，J＝7.5Hz，1H)，2.27-1.85(m，4H)，1.51(dd，J＝14.3，7.1Hz，2H)，1.39(dt，J＝14.5，7.3Hz，2H)，0.96(t，J＝7.2Hz，3H).
The preparation of compound yhhu-2755
Except phenyl isocyanate, compound yhhu-2755 is prepared by the method identical with preparing compound yhhu-2027 except replacing with cyclohexyl isocyanate.
1H NMR(300MHz，DMSO)δ8.82(d，J＝41.7Hz，1H)，8.54(s，1H)，8.13(s，1H)，7.92-7.72(m，1H)，7.65(d，J＝7.1Hz，2H)，7.50(d，J＝7.3Hz，2H)，5.20-4.38(m，1H)，3.84(s，1H)，3.63(s，1H)，2.35-1.41(m，10H)，1.39-0.94(m，6H).
The preparation of compound yhhu-2789
The first step, implements the step identical with the first step preparing compound yhhu-2027;
Second step, is dissolved in methylene dichloride by the triphosgene of chloro-for the 2-of 1.5 equivalents 4-5-trifluoromethylaniline, 0.5 equivalent, adds 3 eq of triethylamine, and room temperature reaction 5 ~ 10 minutes adds 5-10 room temperature reaction and spends the night, adds water, and be separated organic phase, pillar layer separation obtains intermediate;
3rd step, implements the step identical with the 3rd step preparing compound yhhu-2027, obtained compound yhhu-2789.
1h NMR (300MHz, acetone) δ 9.46 (s, 1H), 9.00 (d, J=40.0Hz, 1H), 8.76 (d, J=8.9Hz, 1H), 8.45 (s, 1H), 8.40-8.26 (m, 1H), 8.13 (dd, J=17.8, 8.1Hz, 1H), 7.86 (d, J=6.3Hz, 5H), 7.78 (d, J=9.6Hz, 1H), 5.42 (d, J=8.1Hz, 1H), 4.79 (s, 1H), 4.17 (s, 1H), 3.87 (t, J=7.0Hz, 1H), 2.28-2.53 (m, 2H), 2.20-1.96 (m, 4H).
The preparation of compound yhhu-2406
Except compound 10-1, compound yhhu-2406 is prepared by the method identical with preparing compound yhhu-2027 except replacing with compound 10-2.
1H NMR(300MHz，DMSO)δ9.08(s，1H)，8.84(d，J＝41.8Hz，2H)，8.18(s，1H)，7.85(dd，J＝26.1，8.2Hz，1H)，7.73(t，J＝8.0Hz，2H)，7.60(d，J＝6.8Hz，2H)，7.45(d，J＝8.5Hz，2H)，7.27(t，J＝7.9Hz，2H)，6.96(t，J＝7.2Hz，1H)，4.40-5.18(m，1H)，3.84(s，1H)，3.64(s，1H)，2.39-2.11(m，1H)，1.88(m，3H).
The preparation of compound yhhu-2417
Except compound 10-1, compound yhhu-2417. is prepared by the method identical with preparing compound yhhu-2027 except replacing with compound 10-3
1H NMR(300MHz，DMSO)δ12.94(s，1H)，8.87(t，J＝6.6Hz，2H)，8.73(s，1H)，8.16(dd，J＝8.1，2.2Hz，1H)，7.72(d，J＝8.5Hz，2H)，7.59(q，J＝7.9Hz，3H)，7.46(d，J＝8.1Hz，2H)，7.27(t，J＝7.8Hz，2H)，6.96(t，J＝7.4Hz，1H)，4.90-5.23(m，1H)，3.72-4.48(m，1H)，3.58(s，1H)，3.16(s，1H)，2.86(s，1H)，2.30-2.01(m，1H)，1.60-1.78(m，3H)，1.12-1.60(m，3H).
The preparation of compound yhhu-2418
Except compound 10-1, compound yhhu-2418 is prepared by the method identical with preparing compound yhhu-2027 except replacing with compound 10-4.
1H NMR(300MHz，DMSO)δ12.62-12.24(m，1H)，8.93(d，J＝39.0Hz，2H)，8.73(s，1H)，8.11(d，J＝16.5Hz，1H)，7.73(d，J＝9.7Hz，2H)，7.59(d，J＝7.7Hz，3H)，7.45(d，J＝8.0Hz，2H)，7.27(t，J＝7.6Hz，2H)，6.97(s，1H)，4.57-4.39(m，1H)，4.24-4.07(m，1H)，3.92-3.76(m，1H)，3.76-3.59(m，1H)，2.93-3.15(m，2H)，1.92-2.05(m，1H)，1.38-1.79(m，3H).
The preparation of compound yhhu-2757
Except compound 10-1, compound yhhu-2757 is prepared by the method identical with preparing compound yhhu-2027 except replacing with compound 10-5.
1H NMR(300MHz，DMSO)δ9.19(t，J＝13.7Hz，2H)，9.01(s，1H)，8.83(s，1H)，7.80(d，J＝7.2Hz，2H)，7.63(d，J＝7.9Hz，2H)，7.46(d，J＝8.0Hz，2H)，7.28(t，J＝7.6Hz，2H)，6.97(t，J＝7.1Hz，1H)，4.46(s，1H)，3.64(s，1H)，3.51(s，1H)，2.26(s，1H)，1.89(s，3H).
The preparation of compound yhhu-2757-2
Except compound 10-1, compound yhhu-2757-2 is prepared by the method identical with preparing compound yhhu-2027 except replacing with compound 10-6.
1H NMR(300MHz，DMSO)δ9.45(s，1H)，9.21(s，1H)，8.71(d，J＝38.2Hz，1H)，8.15-7.93(m，4H)，7.62(d，J＝8.3Hz，2H)，7.46(d，J＝8.2Hz，2H)，7.27(t，J＝7.7Hz，2H)，6.96(t，J＝7.4Hz，1H)，4.42(s，1H)，3.61(s，2H)，2.26(s，1H)，1.90(s，3H).
The preparation of compound yhhu-2419
The first step: implement the step identical with the first step preparing compound yhhu-2027;
Second step: compound 11-1 is dissolved in methylene dichloride, add 1.5 equivalent Benzoyl chlorides, add 2 eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, and be separated organic phase, pillar layer separation obtains intermediate 11-1b;
3rd step: implement the step identical with the 3rd step preparing compound yhhu-2027 and obtain compound yhhu-2419.
1H NMR(300MHz，DMSO)δ12.37-12.16(m，1H)，10.21(s，1H)，8.69(d，J＝41.6Hz，1H)，8.02(d，J＝8.2Hz，1H)，7.74(dd，J＝13.6，7.2Hz，4H)，7.61(t，J＝7.5Hz，2H)，7.36(dt，J＝14.6，7.1Hz，3H)，5.01-4.19(m，1H)，3.61-3.69(m，1H)，3.35-3.49(m，1H)，2.18-1.90(m，1H)，1.90-1.48(m，3H).
The preparation of compound yhhu-2414
The first step: implement the step identical with the first step preparing compound yhhu-2027;
Second step: compound 11-1 is dissolved in methylene dichloride, add 1.1 equivalent benzene sulfonyl chlorides, add 2 eq of triethylamine, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, and be separated organic phase, pillar layer separation obtains intermediate 11-1c;
3rd step: implement the step identical with the 3rd step preparing compound yhhu-2027 and obtain compound yhhu-2414.
1H NMR(300MHz，DMSO)δ12.55-12.32(m，1H)，10.57(s，1H)，8.78(d，J＝43.6Hz，1H)，8.11(d，J＝8.3Hz，1H)，7.90-7.73(m，3H)，7.74-7.42(m，5H)，7.27-7.17(m，2H)，5.16-4.38(m，1H)，3.81(s，1H)，3.62(s，1H)，2.24(s，1H)，1.98(s，1H)，2.06-1.70(m，3H).
The preparation of compound yhhu-2742
The first step: implement the step identical with the first step preparing compound yhhu-2027;
Second step: compound 11-1 is dissolved in methylene dichloride, adds 1.1 equivalent tert-Butyl dicarbonates, adds 1 equivalent Na 2cO 3, room temperature reaction spends the night, and boils off organic solvent, adds methylene chloride and water, and be separated organic phase, pillar layer separation obtains intermediate 11-1d;
3rd step: implement the step identical with the 3rd step preparing compound yhhu-2027 and obtain compound yhhu-2742.
1H NMR(300MHz，DMSO)δ12.46(s，1H)，9.55(s，1H)，8.83(dd，J＝41.9，1.9Hz，1H)，8.22-8.10(m，1H)，7.84(dd，J＝27.7，8.4Hz，1H)，7.76-7.64(m，1H)，7.59(d，J＝6.9Hz，1H)，5.20-4.39(m，1H)，3.84(s，1H)，3.64(s，1H)，2.35-1.70(s，4H)，1.48(s，9H).
Embodiment 5 compound is to DGAT inhibitor activity testing method
DGAT obtains by extracting rat hepatic microsome preparation: get Zucker rat liver, add STE damping fluid (250mM sucrose, 10mM Tris-HCl, 10mM EDTA, pH 7.4), homogenate cracking.Slurries, with 14000g, after centrifugal 20 minutes, get supernatant again with 100,000g, 4 DEG C, centrifugal 1 hour for 4 DEG C.Abandon supernatant, precipitation adds not containing the STE damping fluid of EDTA, mixing packing ,-80 DEG C of preservations.
The inhibit activities test of DGAT is as follows: with A922500 (reference literature Gang Zhao et al J.Med.Chem., the method synthesis of 2008,51,380) as positive drug, by certain herbaceous plants with big flowers acyl CoA (Decanoyl coenzyme A, Sigma), 1,2-bis-certain herbaceous plants with big flowers acyl-sm-glycerine (1,2-Didecanoyl-sn-glycerol, Cayman), appropriate enzyme and test-compound are dissolved in analysis buffer (20mM HEPES-NaOH, 20mM MgCl respectively 2) in, 100 μ l systems (certain herbaceous plants with big flowers acyl CoA final concentration: 20 μMs, 1,2-bis-certain herbaceous plants with big flowers acyl-sn-final glycerol concentration: 50 μMs) 37 DEG C of reactions 30 minutes, add 20 μMs of CPM (7-diethylamino-3-(4 '-maleimidylphenyl)-4-methylcoumarin), by the multi-functional microplate reader of Flexstation3 at exciting light 400nm, under utilizing emitted light 485nm, survey fluorescent value.Calculate test-compound to the inhibiting rate (%) of DGAT according to measured fluorescent value, inhibiting rate (%) calculates according to following formula:
Inhibiting rate (%)=[(A-B)-(C-B)]/(A-B) × 100%
In above formula, A represents reaction blank well (containing certain herbaceous plants with big flowers acyl CoA and two certain herbaceous plants with big flowers acyl-sm-glycerine) fluorescent value under specified wavelength after 30 minutes; B represents reaction this bottom outlet (containing certain herbaceous plants with big flowers acyl CoA) hole fluorescent value under specified wavelength after 30 minutes; C represents reaction test-compound hole (containing certain herbaceous plants with big flowers acyl CoA, two certain herbaceous plants with big flowers acyl-sm-glycerine and test-compounds) fluorescent value under specified wavelength after 30 minutes.
The results are shown in Table 1.
Heteroaryl carboxylic acid compounds of the present invention to the test result row of the inhibit activities of DGAT in Table 1.
The inhibit activities result of table 1:DGAT
Test-results shows, compound of the present invention has stronger DGAT inhibit activities.
Compound according to the present invention has excellent DGAT inhibitor activity.Compound according to the present invention may be used for the purposes for the treatment of or adults, obesity, diabetes, hyperlipidaemia and fatty liver and other metabolic trouble relevant to DGAT.

Claims (10)

1. the connection heteroaryl carboxylic acid compounds shown in following general formula I, or its physiologically acceptable salt,
Wherein,
N is the integer of 0 ~ 3;
X is that N, Y and Z are respectively C;
R 1for hydrogen;
R 2and R 3be hydrogen, C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phenyl C1-C4 alkyl or substituted or unsubstituted heteroaryl C1-C4 alkyl independently of one another; It is one or more that the substituting group of described replacement is selected from fluorine, chlorine, bromine, iodine and hydroxyl;
Or, R 1and R 2be connected to form the alkylidene group of C2-C5;
R 4for hydrogen, hydroxyl, halogen, C 1~ C 6alkyl, C 1~ C 6alkoxyl group or trifluoromethyl;
Q is R 5nHC (O)-;
R 5for substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl, the substituting group of described replacement is that it is one or more to be selected from halogen and trifluoromethyl;
Described heteroaryl is 5-10 unit, and is selected from the heteroatoms in N, O and S containing 1-3.
2. heteroaryl carboxylic acid compounds according to claim 1 or its physiologically acceptable salt, wherein,
N is 0 or 1;
R 2and R 3be hydrogen, C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl C1-C3 alkyl or substituted or unsubstituted indyl C1-C3 alkyl independently of one another; It is one or more that the substituting group of described replacement is selected from fluorine, chlorine, bromine, iodine and hydroxyl;
Or, R 1and R 2be connected to form the alkylidene group of C2-C5;
R 4for hydrogen.
3. heteroaryl carboxylic acid compounds according to claim 1 or its physiologically acceptable salt, wherein, described heteroaryl carboxylic acid compounds has following structure:
Wherein, m is 0,1,2 or 3;
R 2, R 3, R 4, X, Y, Z, Q be identical with the definition in claim 1 with n.
4. join heteroaryl carboxylic acid compounds or its physiologically acceptable salt, wherein, described heteroaryl carboxylic acid compounds has following structure:
5. prepare a method for heteroaryl carboxylic acid compounds according to claim 1 or its physiologically acceptable salt, it comprises the steps:
[reaction path 1]
Wherein, X, Y, Z, Q, R 2, R 3, R 4identical with the definition of claim 1 with n;
Step a: compound 1 and p-nitrophenyl pinacol borate obtain compound 2 through Suzuki linked reaction;
Step b: in compound 2, cyan-hydrolysis obtains carboxylic acid cpd 3;
Step c: carboxylic acid cpd 3 and amino ester condensation obtain compound 4;
Steps d: compound 4 reduces to obtain aminated compounds 5;
Step e: compound 5 and isocyanate reaction obtain compound 6;
Step f: compound 6 is hydrolyzed to obtain the connection heteroaryl carboxylic acid compounds shown in general formula I-1;
Or
[reaction path 2]
Wherein, X, Y, Z, Q, R 4identical with the definition in the claim 1 of n, m is 0,1,2 or 3;
Step g: compound 8 and amino ester condensation compound 9;
Step h: compound 9 and p-nitrophenyl pinacol borate obtain compound 10 through the debrominate of Suzuki linked reaction;
Step I: compound 10 reduces to obtain aminated compounds 11;
Step j: compound 11 and isocyanate reaction obtain compound 12;
Step k: compound 12 hydrolysis is obtained the compound shown in general formula I-2.
6. the method for heteroaryl carboxylic acid compounds according to claim 5 or its physiologically acceptable salt, wherein,
In step a, this reaction is carried out in a heated condition under alkali and metal palladium catalyst exist, and described alkali is Cs 2cO 3, Na 2cO 3, K 2cO 3, KF, K 3pO 4; Described metal palladium catalyst is two (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium; Described heating condition is for being heated to backflow;
In step b, the reaction conditions of cyan-hydrolysis reaction is with strong acid or highly basic hydrolysis;
In step c, the reaction conditions of amino and sour condensation reaction is for carry out under room temperature or heating condition with amino acid condensation agent; Described amino acid condensation agent is O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate, 2-(7-azepine benzotriazole)-N, N, N', N'-tetramethyl-urea a tetrafluoro borate, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N'-DIC;
In steps d, the reaction reductive agent of nitro-reduction reaction carries out under ice bath to room temperature or heating condition, and described reductive agent is sodium borohydride, hydrazine hydrate, tindichloride, reduced iron powder or H 2;
In step e, compound 5 carries out under room temperature or heating condition with the reaction of isocyanic ester;
In step f, the reaction that compound 6 is hydrolyzed is carried out under room temperature or heating at LiOH, NaOH or KOH;
In step g, the reaction amino acid condensation agent of amino and sour condensation reaction is carried out under room temperature or heating condition, described amino acid condensation agent is O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate, 2-(7-azepine benzotriazole)-N, N, N', N'-tetramethyl-urea a tetrafluoro borate, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N, N'-DIC;
In step h, this reaction is carried out in a heated condition under alkali and metal palladium catalyst exist, and described alkali is Cs 2cO 3, Na 2cO 3, K 2cO 3, KF, K 3pO 4, described metal palladium catalyst is two (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium; Described heating condition is for being heated to backflow;
In step I, the reaction reductive agent of nitro-reduction reaction carries out under ice bath to room temperature or heating condition, and described reductive agent is sodium borohydride, hydrazine hydrate, tindichloride, reduced iron powder or H 2;
In step j, compound 11 carries out under room temperature or heating condition with the reaction of isocyanic ester;
In step k, reaction LiOH, NaOH or KOH that compound 12 is hydrolyzed carry out under room temperature or heating condition.
7., for the preparation of an intermediate for heteroaryl carboxylic acid compounds according to claim 1 or its physiologically acceptable salt, it has following structure:
Wherein, X, Y, Z, Q, R 2, R 3, R 4, n with m definition identical with claim 5.
8. heteroaryl carboxylic acid compounds according to claim 1 or its physiologically acceptable salt are as the purposes of DGAT inhibitor in the medicine of the metabolic trouble that preparation is treated or control DGAT is correlated with.
9. purposes according to claim 8, the metabolic trouble that wherein said DGAT is relevant comprises obesity, diabetes B, hyperlipidaemia and fatty liver.
10. a pharmaceutical composition, it comprises according to the connection heteroaryl carboxylic acid compounds in Claims 1 to 4 described in any one or its physiologically acceptable salt.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1816531A (en) * 2003-05-09 2006-08-09 拜尔药品公司 Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
WO2007137107A2 (en) * 2006-05-19 2007-11-29 Abbott Laboratories Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
CN101198333A (en) * 2005-04-19 2008-06-11 拜尔药品公司 Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
CN101583352A (en) * 2005-07-29 2009-11-18 拜尔健康护理有限责任公司 Preparation and use of biphenyl amino acid derivatives for the treatment of obesity
WO2010023609A1 (en) * 2008-08-25 2010-03-04 Piramal Life Sciences Limited Oxazole, oxadiazole and thiazole derivatives as diacylglycerol acyltranferase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1816531A (en) * 2003-05-09 2006-08-09 拜尔药品公司 Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
CN101198333A (en) * 2005-04-19 2008-06-11 拜尔药品公司 Preparation and use of aryl alkyl acid derivatives for the treatment of obesity
CN101583352A (en) * 2005-07-29 2009-11-18 拜尔健康护理有限责任公司 Preparation and use of biphenyl amino acid derivatives for the treatment of obesity
WO2007137107A2 (en) * 2006-05-19 2007-11-29 Abbott Laboratories Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme
WO2010023609A1 (en) * 2008-08-25 2010-03-04 Piramal Life Sciences Limited Oxazole, oxadiazole and thiazole derivatives as diacylglycerol acyltranferase inhibitors

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