CN105669682A

CN105669682A - Intermediates of DPP-IV inhibitor

Info

Publication number: CN105669682A
Application number: CN201610101521.5A
Authority: CN
Inventors: 李进; 斯托克斯·迈克尔; 窦登峰; 万金桥; 冯静超; 潘飞; 宋宏梅; 胡晓; 易磊
Original assignee: Chengdu Lead Drug Development Corp Ltd
Current assignee: Chengdu Lead Drug Development Corp Ltd
Priority date: 2013-02-22
Filing date: 2014-02-24
Publication date: 2016-06-15
Anticipated expiration: 2034-02-24
Also published as: WO2014127745A1; CN105669682B; CN104003992A; CN104003992B

Abstract

The invention provides intermediates IAA, IBA, IAB, IBB, IIIAA, IIIBA, IVA and IVB of a DPP-IV inhibitor as shown in formulas IA and IB. The compounds as shown in the formulas IA and IB can effectively inhibit activity of DPP-4 and has well selectivity, and these compounds can become potential diabetes new drugs or drugs for treatment of DPP-4 related diseases, and provide a new choice for clinical medication. The intermediates can effectively synthesize the DPP-4 inhibitors as shown in the formulas IA and IB.

Description

The intermediate of a kind of DPP-IV inhibitor

The application is application number 201410061271.8, February 24 2014 applying date, point case application of denomination of invention " a kind of compound and intermediate thereof suppressing DPP-IV ".

Technical field

The present invention relates to the intermediate of a kind of DPP-IV inhibitor.

Background technology

Diabetes are a kind of metabolic disturbance diseases caused by inherited genetic factors and environmental factors acting in conjunction, serious threat human health and life security. In China, along with raising and the living-pattern preservation of quality of life, the morbidity of diabetes sharply increases. The diabetes epidemic data display that international diabetes alliance (IDF) is announced for 2013, China's maturity-onset diabetes patient's number has reached 9,840 ten thousand people, occupies the whole world the first, and the situation is tense in prevention and control. In the face of the huge market requirement, the research and development of Novel diabetes medicine enjoy the concern of domestic and international pharmaceutical manufacturer always, and dipeptidyl peptidase-IV (DPP-IV) inhibitor is then in this field an important research object.

DPP-IV, is called as again t cell surface antigen CD26, is a kind of II type transmembrane glycoprotein, is made up of 766 amino-acid residues. DPP-IV is distributed widely in multiple tissue and organ in body, it is included in (the AbbottCA such as kidney, liver, lung, small intestine, lymphocyte and vascular endothelial cell, BakerE, SutherlandGR, McCaughanGW.Genomicorganization, exactlocalization, andtissueexpressionofthehumanCD26 (dipeptidylpeptidaseIV) gene.Immunogenetics.1994; 40 (5): 331 8), part is present in blood plasma (MentleinR.Dipeptidyl peptidaseIV (CD26) roleintheinactivationofregulatorypeptides.RegulPept.1999 with soluble form; 85 (1): 9 24.). DPP-IV is the serine protease of a species specificity, and its substrate is that 2nd reciprocal of N end exists proline(Pro) (Pro) or the polypeptide of L-Ala (Ala), can from dipeptides the N end cracking of this kind of polypeptide. The pharmacological action of DPP-IV inhibitor mainly realizes by improving the concentration of activity in vivo GLP-1 (GLP-1). GLP-1 is synthesized by Intestinal L cells and secretes, and is the intestines peptide hormone that the promoting insulin secretion found is the strongest. Food digestion can promote that GLP-1 secretes and is released into blood, plays physiological function with after special GLP-1 receptor acting.Research shows, GLP-1 can play blood sugar reducing function (GautierJF from many aspects, FetitaS, SobngwiE, Sala ü n MartinC.BiologicalactionsoftheincretinsGIPandGLP 1andtherapeuticperspectivesinpatientswithtype2diabetes.D iabetesMetab.2005; 31 (3Pt1): 233 42.): the insulin secretion 1) promoting glucose dependency, increase tissue to the picked-up of glucose; 2) by promoting transcribing and strengthen mRNA stability and making its biosynthesizing increase of proinsulin gene; 3) secretion of glucagon suppression, reduces glycogen release; 4) promote beta Cell of islet proliferation and differentiation, suppress β apoptosis; 5) by suppressing stomach emptying, appetite control, reduce blood sugar, reduce the risk that body weight increases simultaneously. The treatment that the above-mentioned physiological function of GLP-1 is diabetes B provides an important target spot. But, GLP-1 is very easily hydrolyzed and then inactivation from two amino-acid residues of N end by DPP-IV in body, and its plasma half-life, less than 2 minutes, seriously limits its clinical application. DPP-IV is one of key enzyme impelling GLP-1 degraded, inactivation in body, and Selective depression DPP-IV can improve the blood plasma level of active GLP-1. Therefore, the research and development of DPP-IV inhibitor class medicine provide a new way for treating glycosuria.

2006, the Xi Gelieting (Sitagliptin) of Merck (Merck) company exploitation obtained FDA (Food and Drug Adminstration) (FDA) approval, becomes the DPP-IV inhibitor class medicine of first listing. In addition, the DPP-IV inhibitor listed at present also comprises Vildagliptin (vildagliptin), BMS-477118 (saxagliptin), Egelieting (alogliptin) and BI 1356 (linagliptin) etc. four kinds. Domestic III phase clinical study is being carried out at present by China's medicine enterprise's independent research novel DPP-IV inhibitor Rui Gelieting (retagliptin). Clinical study shows, DPP-IV inhibitor has good hypoglycemic activity (ArgyrakopoulouG, DoupisJ.DPP4inhibitors:fromsitagliptinmonotherapytothene walogliptin pioglitazonecombinationtherapy.AdvTher.2009 in diabetes B patient's body; 26 (3): 272 80.), compared with traditional diabetes medicament, have the following advantages [ScheenAJ.DPP 4inhibitorsinthemanagementoftype2diabetes:acriticalrevie wofhead to headtrials.DiabetesMetab.2012; 38 (2): 89 101.; GallwitzB.EmergingDPP 4inhibitors:focusonlinagliptinfortype2diabetes.DiabetesM etabSyndrObes.2013; 6:1 9.]: 1) oral administration; 2) the incretin secretion with blood sugar dependency, hypoglycemia risk is little; 2) can protect, improve beta Cell of islet function, stop β cell degradation, contribute to fundamentally containing the process of diabetes B; 3) do not put on weight body weight. Therefore, DPP-IV inhibitor plays more and more important effect in the treatment of diabetes B, becomes the research focus of current antidiabetic thing.

Summary of the invention

It is an object of the invention to provide a kind of compound suppressing DPP-IV and its production and use. Another object of the present invention is to provide intermediate and its preparation method of this compound.

The present invention provides the compound shown in formula IA or IB or its pharmacy acceptable salt,

R¹It is selected from substituted or unsubstituted phenyl; R²Be selected from the alkyl of C1-5 or substituted alkyl, 1-5 containing assorted alkyl or replace containing assorted alkyl or 1-5 heteroatoms or replacement heteroatoms; R³It is selected from H, CN or C1-10 alkyl or substituted alkyl; X is selected from N or CH; Y is selected from N or CR⁶, wherein, R⁶It is selected from H, CN, carboxyl or ester group.

Further, R¹In, the substituting group of described substituted-phenyl is 1-5 R⁴, wherein R⁴It is selected from the alkoxyl group that the alkoxy or halogen of CN, halogen, the alkyl of C1-6 or the alkyl of halogen substiuted or C1-6 replaces;

R²In, the substituting group of described substituted alkyl is selected from halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷, replacing heteroatoms or replacing the substituting group containing assorted alkyl is halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷;

R³In, the substituting group of described substituted alkyl is selected from 1-5 halogen;

R⁶In, described carboxyl is COOH, and described ester group is CO₂R⁷;

Wherein, heteroatoms is N, O or S; R⁵For alkyl or the substituted alkyl of C1-6, its substituting group is 1-5 halogen, COOH or CO₂R⁷; R⁷For C1-6 alkyl.

Further, described is the alkyl containing 1 heteroatomic C1-4 containing assorted alkyl.

Further, R¹It is selected from the phenyl of halogen substiuted; R²It is selected from containing assorted alkyl, 1-2 heteroatoms or C2-3 alkyl; R³It is selected from the alkyl of halogen substiuted.

Further preferably, described halogen is F or Cl.

Wherein, described compound is

Further, R¹It is selected from the phenyl of halogen substiuted; R³It is selected from the alkyl of halogen substiuted; R⁶It is selected from H, CN, carboxyl or ester group.

Further, R⁶It is selected from CO₂R⁷。

Further preferably, described compound or its pharmacy acceptable salt are:

Substituted five-membered virtue heterocycle and the selectivity of the activity of DPP4 inhibitor and other members of DPP (DPP2, DPP8, DPP9) is played main contribution by tetrahydrochysene pyrazine, and carry out tetrahydrochysene pyrazine wherein replacing and can regulate the activity and selectivity of compound. but, increase substituting group and will additionally produce multiple chiral isomer, add to the difficulties to compou nd synthesis and discriminating. the present invention finds in research process, introduces substituted radical by bridge joint mode, is possible not only to the complicacy reducing chipal compounds and increases chirality controllability, add compound rigidity simultaneously, it is possible to changes the activity and selectivity of compound. but, in early stage, building-up process finds, to replace five yuan of fragrant heterocycles and tetrahydrochysene pyrazine carries out bridging, form bridge compound in parallel, in synthesis, there is very strong challenge, need the difficult problem solved in a lot of technology, such as the bridged ring of chirality control is difficult to effective formation, bridge ring cannot directly be formed (especially that bridged ring is shorter situation) by corresponding and ring, five yuan of fragrant heterocycle building processs can be subject to the impact of bridged ring tension force and cannot complete, amino acid is with bridge and the two of ring grades of ammonia are connected difficulty by steric influence, bridge ring are in problems such as the intermediate stability differences formed in finalization compound process. contriver is through a large amount of experimental exploring and analysis, finally work out out ideal synthesis path, effectively overcome in building-up process the difficult problem existed, successfully synthesize bridge tetrahydrochysene pyrazine and substituted five-membered virtue heterocycle, and, through experimental verification, DPP4 is had good restraining effect and selectivity by these compounds.

Present invention also offers above-claimed cpd or its pharmacy acceptable salt, for the preparation of the purposes in dipeptidyl peptidase-iv inhibitor.

Further, described dipeptidyl peptidase-iv inhibitor be treatment or/and prevent diabetes, the medicine of hyperglycemia, insulin resistance.

Present invention also offers described formula IIA or the preparation method of formula IIB compound, it is characterised in that: reaction comprises the following steps:

Wherein, Step1: with (1S, 5R)-3,8-diazabicyclo [3.2.1] heptane-2-ketone (Tetrahedron, 1992,23,4985) it is raw material, reacts in the basic conditions with tert-Butyl dicarbonate, obtain product and stay the reactant doing next step;

Step2: product lawesson reagent obtained in the previous step carries out thio reaction, obtains product and stays the reactant doing next step;

Step3: by product obtained in the previous step, adds strong acid solution reaction, obtains product and stays the reactant doing next step;

Step4: the product that Step3 is obtained and R³-CONHNH₂At activating reagent R³The lower reaction of-COONa effect, obtains product and stays the reactant doing next step;

Step5: product that Step4 is obtained, R¹The protection β aminobutyric acid, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

Step6: product that Step3 is obtained, R¹The protection β aminobutyric acid, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

Step7: the product that Step6 is obtained and R³-CONHNH₂At activating reagent R³The lower reaction of-COONa effect, obtains product and stays the reactant doing next step;

Step8: the product getting Step5 or Step7, adds strong acid and carries out deprotection reaction, obtain formula IIA product;

Or, it is raw material with (1R, 5S)-3,8-diazabicyclo [3.2.1] heptane-2-ketone and uses identical synthetic method namely to obtain Compound I IB; Or use raceme raw material, according to the method described above after synthesis, split optical isomer, Compound I IA or IIB can be obtained.

Further, wherein, Step1 solvent for use is aprotic solvent, and described non-protonic solvent is preferably methylene dichloride, ethyl acetate or tetrahydrofuran (THF), and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 2 to 16 hours;

Step2 solvent for use is polar aprotic solvent, and described non-protonic solvent is preferably tetrahydrofuran (THF), ether, Di Iso Propyl Ether or toluene, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 0.5-3 hour; Solvent can also be made, reacting by heating with toluene.

Step3 acid used is proton strong acid, and described proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and solvent for use is preferably methylene dichloride or ethyl acetate, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 4 hours;

Step4 solvent for use is polar protic solvent, and described polar protic solvent is preferably propyl carbinol, and temperature of reaction is 110 to 130 DEG C, it is preferable to 118 DEG C, and the reaction times is 2 to 12 hours;

Step5 solvent for use is aprotic solvent, described aprotic solvent is preferably methylene dichloride, tetrahydrofuran (THF) or N, dinethylformamide, alkali used is diisopropylethylamine or other organic bases, condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole or 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, temperature of reaction used is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 2 hours;

Step6 solvent for use is aprotic solvent, described aprotic solvent is preferably methylene dichloride, tetrahydrofuran (THF) or N, dinethylformamide, alkali used is diisopropylethylamine or other organic bases, and condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole or 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, temperature of reaction used is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 2 hours.

Step7 solvent for use is polar protic solvent, and described polar protic solvent is preferably propyl carbinol, and range of reaction temperature is 110 to 130 DEG C, and the reaction times is 2 to 12 hours;

Step8 acid used is proton strong acid, and described proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and solvent for use is preferably methylene dichloride, ethyl acetate or nothing, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 4 hours.

Present invention also offers the preparation method of above-mentioned formula III A or IIIB compound, reactions steps is as follows:

Wherein, nitrobenzyloxycarbonyl-2-aziridine carboxylate methyl ester is reacted by Step1:N-Boc-3-amido-1,2-propanediol and (S)-1-when Louis acid catalysis, obtains product and stays the reactant doing next step;

Step2: previous step obtains product and carries out oxidizing reaction, obtains product and stays the reactant doing next step;

Step3: product obtained in the previous step is carried out hydrogenation, obtains product and stays the reactant doing next step;

Step4: by product obtained in the previous step, adds strong acid solution reaction deprotection, obtains product and stay the reactant doing next step;

Step5: by product obtained in the previous step, adds the reaction of strong basicity organic solvent, obtains product and stays the reactant doing next step;

Step6: product obtained in the previous step and tert-Butyl dicarbonate react in the basic conditions, obtains product and stays the reactant doing next step;

Step7: by product obtained in the previous step, adds lawesson reagent reaction, obtains product and stays the reactant doing next step;

Step8: by product obtained in the previous step, add strongly acidic solution, reaction, obtains product and stays the reactant doing next step;

Step9: by product obtained in the previous step, R¹The protection β aminobutyric acid, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

Step10: by product obtained in the previous step and R³-CONHNH₂At R³React under-COONa activation, obtain product and stay the reactant doing next step;

Step11: product obtained in the previous step is added strong acid reaction, obtains formula III A product;

Or, change starting raw material be (R)-1-to nitrobenzyloxycarbonyl-2-aziridine carboxylate methyl ester, prepare compound III B according to above-mentioned synthetic method; Or, it may also be useful to raceme N-Boc-serine methylester, according to the method described above after synthesis, splits optical isomer and namely obtains compound III A or IIIB.

Further, wherein, Step1 solvent for use is non-polar solvent, and described non-polar solvent is preferably toluene or dimethylbenzene, and Lewis acid is preferably boron trifluoride diethyl etherate, and temperature of reaction is 20 to 30 DEG C, and the reaction times is 0.5 to 2 hours;

Step2 solvent for use is polar aprotic solvent, and described polar aprotic solvent is preferably methylene dichloride or tetrahydrofuran (THF), and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 1 to 2 hours;

Step3 solvent for use is polar solvent, and described polar solvent is preferably ethyl acetate or methyl alcohol, and used catalyst is metal catalyst, and described metal catalyst is preferably palladium carbon, and temperature of reaction is 20 to 30 DEG C, and the reaction times is 2 to 4 hours;

Step4 solvent for use is polar aprotic solvent, and described polar aprotic solvent is preferably methylene dichloride or ethyl acetate, and acid used is strong acid, it is preferable to trifluoroacetic acid or hydrochloric acid, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 2 to 4 hours;

Step5 solvent for use is polar aprotic solvent, it is preferable to methyl alcohol, and highly basic used is preferably sodium methylate, and temperature of reaction is 20 to 30 DEG C, and the reaction times is 4 to 16 hours;

Solvent described in Step6 is polar aprotic solvent, it is preferable to methyl alcohol, and described alkali is preferably tertiary amine, and the reaction times is 2 to 10 hours;

Step7 solvent for use is polar aprotic solvent, and described non-protonic solvent is preferably tetrahydrofuran (THF), ether or Di Iso Propyl Ether, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 3 hours;

Step8 solvent for use is polar aprotic solvent, and described polar aprotic solvent is preferably methylene dichloride or ethyl acetate, and acid used is strong acid, it is preferable to trifluoroacetic acid, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 2 to 4 hours;

Step9 solvent for use is aprotic solvent, described aprotic solvent is preferably methylene dichloride, N, N is to dimethyl formamide or tetrahydrofuran (THF), alkali used is diisopropylethylamine or other organic bases, condensing agent is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole or 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, temperature of reaction used is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 2 hours;

Step10 solvent for use is polar protic solvent, and described polar protic solvent is preferably propyl carbinol, and temperature of reaction is 110 to 130 DEG C, it is preferable to 118 DEG C of reaction times are 2 to 12 hours;

Step11 solvent for use is polar aprotic solvent, and described polar aprotic solvent is preferably methylene dichloride or ethyl acetate, and acid used is strong acid, it is preferable to trifluoroacetic acid, and temperature of reaction is 0 DEG C to 30 DEG C, and the reaction times is 0.5 to 2 hours.

Present invention also offers above-mentioned formula IA and the intermediate of IB compound, its structural formula is as follows:

Wherein, R^2’It is selected from alkyl or the substituted alkyl of C1-5; R^2”It is selected from 1-5 containing assorted alkyl or replace containing assorted alkyl, 1-5 heteroatoms or replace heteroatoms; R³It is selected from H, CN or C1-10 alkyl or substituted alkyl; X is selected from N or CH; R⁶It is selected from H, CN, carboxyl or ester group.

Further, R^2’In, the substituting group of described substituted alkyl is selected from halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷; R^2”In, described heteroatoms is selected from N, S or O, and replacing heteroatoms or replacing the substituting group containing assorted alkyl is halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷;

Wherein, R⁵For alkyl or the substituted alkyl of C1-6, its substituting group is 1-5 halogen, COOH or CO₂R⁷; R⁷For C1-6 alkyl.

Further, described intermediate is:

Present invention also offers above-mentioned formula IIAA or the preparation method of IIBA compound, reactions steps is as follows:

Wherein, comprise the following steps:

Step1: with (1S, 5R)-3,8-diazabicyclo [3.2.1] heptane-2-ketone (Tetrahedron, 1992,23,4985) for raw material and tert-Butyl dicarbonate react in basic solution, obtain product and stay the reactant doing next step;

Step2: by product obtained in the previous step, adds lawesson reagent reaction, obtains product and stays the reactant doing next step;

Step4: by product obtained in the previous step, R³-CONHNH₂With sodium acetate or R³-COONa reacts, and obtains product and stays the reactant doing next step;

Or, changing starting raw material is (1R, 5S)-3,8-diazabicyclo [3.2.1] heptane-2-ketone, prepares Compound I IBA according to the method described above; Or, it may also be useful to raceme raw material, according to the method described above after synthesis, splits optical isomer and namely obtains Compound I IAA or IIBA.

Further, reactions steps is as follows:

Wherein, reaction process comprises the following steps:

Step1: reacted in a solvent by nitrobenzyloxycarbonyl-2-aziridine carboxylate methyl ester with (S)-1-by N-Boc-3-amido-1,2-propanediol, obtains product and stays the reactant doing next step;

Step2: previous step obtains product and Dai Si-Martin's reagent react, obtains product and stays the reactant doing next step;

Step4: by product obtained in the previous step, add strong acid solution, reaction, obtains product and stays the reactant doing next step;

Step5: by product obtained in the previous step, adds sodium methylate and reacts in a solvent, obtains product and stays the reactant doing next step;

Step6: by product obtained in the previous step, adds tert-Butyl dicarbonate and tertiary amine reaction, obtains product and stay the reactant doing next step;

Step8: by product obtained in the previous step, add strong acid solution, reaction, obtains product and stays the reactant doing next step;

Or, change starting raw material be (R)-1-to nitrobenzyloxycarbonyl-2-aziridine carboxylate methyl ester, prepare compound III BA according to the method described above; Or, it may also be useful to raceme amino acid methyl ester, according to the method described above after synthesis, splits optical isomer and namely obtains compound III AA or IIIBA.

Present invention also offers a kind of compound, shown in its structural formula following IAA, IBA, IA or IAA:

Wherein, R^2’It is selected from alkyl or the substituted alkyl of C1-5; R^2”What be selected from C1-5 containing assorted alkyl, 1-5 heteroatoms or replaces heteroatoms containing assorted alkyl or replacement; R³It is selected from H, CN or C1-10 alkyl or substituted alkyl; X is selected from N or CH; R⁶It is selected from H, CN, carboxyl or ester group.

Further, described R^2’It is selected from alkyl or the substituted alkyl of C1-2.

Further, described R^2”What be selected from C1-2 contains assorted alkyl.

Further, described R³It is selected from H, CN, C1-2 alkyl or substituted alkyl; R³In, described substituted alkyl is replaced by 1-5 halogen.

Further, described compound is:

Further, described X is selected from N; R₃It is selected from-CF₃。

Present invention also offers described formula IIAA or the preparation method of IIBA compound, reactions steps is as follows:

Wherein, comprise the following steps:

Step1: be that raw material and tert-Butyl dicarbonate react in basic solution with (1S, 5R)-3,8-diazabicyclo [3.2.1] heptane-2-ketone, obtains product and stays the reactant doing next step;

Or, changing starting raw material is (1R, 5S)-3,8-diazabicyclo [3.2.1] heptane-2-ketone, prepares Compound I IBA according to the method described above;Or, it may also be useful to raceme raw material, according to the method described above after synthesis, splits optical isomer and namely obtains Compound I IAA or IIBA.

Present invention also offers and a kind of prepare the method for DPP-IV inhibitor using described formula IIAA or formula IIBA compound as raw material, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;

(1) by compound shown in formula IIAA, R¹The protection β aminobutyric acid, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

(2) add strong acid and carry out deprotection reaction, obtain formula IIA product;

Or, taking compound shown in formula IIBA as raw material and use identical synthetic method namely to obtain Compound I IB:

Or use compound shown in formula IIAA and the racemic mixture of compound shown in formula IIBA, according to the method described above after synthesis, split optical isomer, Compound I IA or IIB can be obtained.

Present invention also offers a kind of compound, shown in following IIIAA or IIIBA of its structural formula:

Further, reactions steps is as follows:

Wherein, reaction process comprises the following steps:

Step7: by product obtained in the previous step, add lawesson reagent, reaction, obtains product and stays the reactant doing next step;

Step8: by product obtained in the previous step, add strong acid, reaction, obtains product and stays the reactant doing next step;

Or, change starting raw material be (R)-1-to nitrobenzyloxycarbonyl-2-aziridine carboxylate methyl ester, prepare compound III BA according to the method described above;

Or, it may also be useful to raceme amino acid methyl ester, according to the method described above after synthesis, splits optical isomer and namely obtains compound III AA or IIIBA.

Present invention also offers a kind of method preparing DPP-IV inhibitor using described formula III AA or formula III BA compound as raw material, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;

(1) by compound, R shown in formula III AA¹The protection β aminobutyric acid replaced or R¹The protection β amino butyryl chloride, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

(2) by product obtained in the previous step and R³-CONHNH₂At sodium acetate or R³React under-COONa activation, obtain product and stay the reactant doing next step;

(3) product obtained in the previous step is added strong acid reaction, obtains formula III A product;

Or, changing starting raw material is compound shown in formula III BA, prepares compound III B according to above-mentioned synthetic method:

Or, it may also be useful to the racemic mixture of compound shown in formula III AA and compound shown in formula III BA, according to the method described above after synthesis, splits optical isomer and namely obtains compound III A or IIIB.

Present invention also offers a kind of compound, shown in its structural formula following IV A or IV B:

Present invention also offers described formula IV A or the preparation method of IV B compound, it is characterised in that: reactions steps is as follows:

Wherein, reaction process comprises the following steps:

Step1: taking L-Glutimic acid, thionyl chloride and methyl alcohol as raw material reaction, obtains product and stays the reactant doing next step;

Step2: previous step is obtained product and sodium hydride and bromine benzyl and reacts, obtain product and stay the reactant doing next step;

Step3: product obtained in the previous step and lawesson reagent are reacted, obtains product and stays the reactant doing next step;

Step4: by product obtained in the previous step and iodomethane reaction, obtains product and stays the reactant doing next step;

Step5: reacted with Nitromethane 99Min. under alkaline environment by product obtained in the previous step, obtains product and stays the reactant doing next step;

Step6: product obtained in the previous step is first led to into hydrogen hydrogenation in the mixing solutions of ethyl acetate and acetic acid by catalyzer of palladium carbon, then by its in methyl alcohol through ammonium formiate-palladium carbon system back flow reaction, obtain product and stay the reactant doing next step;

Step7: by product obtained in the previous step, adds tert-Butyl dicarbonate and tertiary amine reaction, obtains product and stay the reactant doing next step;

Step8: by product obtained in the previous step, add lawesson reagent, reaction, obtains product and stays the reactant doing next step;

Step9: by product obtained in the previous step, add strong acid, reaction, obtains IV A compound;

Or, changing starting raw material is D-Pyrrolidonecarboxylic acid, prepares compound IV B according to above-mentioned synthetic method;

Or, it may also be useful to L-Glutimic acid and D-Pyrrolidonecarboxylic acid racemic mixture, according to the method described above after synthesis, split optical isomer and namely obtain compound IV A or IV B.

Present invention also offers a kind of method preparing DPP-IV inhibitor using described formula IV A or IV B compound as raw material, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;

(1) by compound, R shown in formula IV A¹The protection β aminobutyric acid, the condensation reagent that replace react, and obtain product and stay the reactant doing next step;

(3) product obtained in the previous step is added strong acid reaction, obtains formula IIA product;

Or, changing starting raw material is compound shown in formula IV B, prepares compound III B according to above-mentioned synthetic method:

Or, it may also be useful to the racemic mixture of compound shown in formula IV A and compound shown in formula IV B, according to the method described above after synthesis, splits optical isomer and namely obtains Compound I IA or IIB.

The compound provided herein and derivative can be named according to IUPAC (International Union of Pure and Applied Chemistry(IUPAC)) or CAS (chemical abstracts service, Columbus, OH) naming system.

About the definition of the use term of the present invention. Unless otherwise explanation, the initial definition that group or term provide herein is applicable to this group or the term of entire description. For the term being not specifically defined, it should according to disclosure and context, provide the implication that those skilled in the art can give them herein.

" replacement " refers to that the hydrogen atom in molecule is replaced by other different atom or molecule.

In hydrocarbon group, the minimum value of carbon content and maximum value are represented by prefix, such as, prefix (Ca-b) alkyl show any containing " a " to alkyl of " b " individual carbon atom.Such as, (C1 4) alkyl refers to the alkyl comprising 1-4 carbon atom.

Term " pharmaceutically acceptable " refers to certain carrier, load, thinner, auxiliary material, and/or the salt formed usually chemically or physically with form certain pharmaceutical dosage form other becomes phase-splitting compatibility, and mutually compatible with acceptor on physiology.

Term " salt " and " pharmaceutically useful salt " are by compound or its steric isomer, and the acid formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry and/or subsalt, also comprise zwitter-ion salt (inner salt), also comprise quaternary ammonium salt, such as alkylammonium salt. These salt can be directly obtain in the last abstraction and purification of compound. Can also be by by compound, or its steric isomer, with the acid of some amount or alkali suitably (such as equivalent) be obtained by mixing. These salt may form precipitation in the solution and collect with filter method, or reclaim after the solvent evaporates and obtain, or it is obtained to react postlyophilization in water medium. Salt described in the present invention can be the hydrochloride of compound, vitriol, citrate, benzene sulfonate, hydrobromate, hydrofluoric acid salt, phosphoric acid salt, acetate, propionic salt, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.

In one embodiment of the present invention, present invention comprises the formula of isotopic labeling (IA) or (IB) compound, described compound isotopically labelled refers to identical with listed compound herein, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from nature common atomic mass or total mass number. Hydrogen, carbon, nitrogen, oxygen, sulphur can be comprised by isotropic substance in drawing-in system (IA) or (IB) compound, namely 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S. Containing above-mentioned isotropic substance and/or the formula (IA) of other atom isotope or the compound of (IB) and steric isomer thereof, and the pharmaceutically useful salt of this compound, steric isomer all should be included within the scope of the invention.

Key intermediate and compound in the present invention carry out abstraction and purification, and the example that the mode used is Isolation and purification method conventional in organic chemistry and described method comprises filtration, extraction, drying, is spin-dried for and various types of chromatogram. Selectively, it is possible to make intermediate not purified namely carry out next step reaction.

In some embodiments, one or more compounds of the present invention can combine with one another use. Also can select to be combined the compound of the present invention with other active agent any, for the preparation of medicine or the pharmaceutical composition of regulating cell function or disease therapy. If using one group of compound, then can by these compounds simultaneously, carry out administration respectively or in an orderly manner to study subject.

The compounds of this invention can effectively suppress DPP-IV active, and member DPP2, DPP8, DPP9 of DPP family is had rational selectivity. These compounds can be used in multiple treatments with DPP-4 relative disease such as diabetes, for clinical application provides new selection.

Embodiment

Embodiment 1 (R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base) preparation of-1-butanone trifluoroacetate (compound 1)

Step 1:L-Pyrrolidonecarboxylic acid methyl esters (compound 1b)

Thionyl chloride (65mL, 900mmol) is dropwise added in 100mL methyl alcohol by ice bath, then adds L-Glutimic acid 1a (58g, 449mmol).Reaction mixture at room temperature stirs decompressing and extracting solvent after 16h. Adding ethyl acetate (200mL), sodium carbonate (50g) and water (100mL) also stir 1 hour. Separation organic phase, is extracted with ethyl acetate aqueous phase (100mL × 3). Merge organic phase, anhydrous sodium sulfate drying, and concentrate and obtain compound 1b, colourless liquid 51g, receipts rate 79%.

MS (ESI) m/z:144 (M+1);¹HNMR(400mHz,CDCl₃):δ2.20-2.60(m,4H),3.78(s,3H),4.23-4.30(m,1H),6.23(br,1H)。

Step 2:N-benzyl-L-Glutimic acid methyl esters (compound 1c)

Compound 1b (20g, 140mmol) is dissolved in the DMF of 80mL drying, under ice bath stirs, slowly adds sodium hydride (4g, 170mmol), add after stirring 1 hour, add bromine benzyl (28.7g, 168mmol). Remove ice bath, stirred overnight at room temperature. With methylene dichloride (300mL) extraction, and wash with saturated sodium bicarbonate (100mL × 3). Organic phase concentrates to dry after anhydrous sodium sulfate drying. Crude product obtains compound 1c, white solid 18g, receipts rate 55% after column chromatography (silica gel, ethyl acetate/petroleum ether wash-out).

MS (ESI) m/z:234 (M+1);¹HNMR(400mHz,CDCl₃): δ 2.00-2.63 (m, 4H), 3.67 (s, 3H), 3.96-4.04 (m, 2H), 5.02 (d, J=14Hz, 1H), 7.18-7.36 (m, 5H).

Step 3:(S)-N-benzyl-5-thiopyrrolidone-2-methyl-formiate (compound 1d)

Compound 1c is dissolved in 80mL dry tetrahydrofuran, adds lawesson reagent (12.5g, 30mmol) with vigorous stirring. Decompressing and extracting tetrahydrofuran (THF) after 3 hours, and dissolve residuum with ethyl acetate (150mL), then wash with saturated sodium bicarbonate (50mL × 3) and saturated sodium-chloride (50mL) respectively. Organic phase is concentrated after anhydrous sodium sulfate drying. Crude product obtains compound 1d, white solid 11g, receipts rate 86% by column chromatography (silica gel, ethyl acetate/petroleum ether) purifying.

MS (ESI) m/z:250 (M+1);¹HNMR(400mHz,CDCl₃):δ2.17(m,1H),2.27(m,1H),3.15(m,2H),3.69(s,3H),4.30(dd,1H),4.37(d,1H),5.73(d,1H),7.32(m,5H)。

Step 4:(S)-1-benzyl-2-(methoxycarbonyl)-5-(methylthio group)-3,4-dihydro-2 h-pyrrole-1-iodate (compound 1e)

Compound 1d (11g, 44mmol) being dissolved in 40mL methyl iodide, stirred overnight at room temperature, concentrating under reduced pressure obtains compound 1e, yellow solid 16g, receipts rate 93%.

MS (ESI) m/z:264 (M+1);¹HNMR(400mHz,CDCl₃):δ2.24(m,1H),3.04(s,3H),3.16(m,1H),3.25(m,1H),3.63(s,3H),4.29(dd,1H),4.72(d,1H),4.89(dd,1H),5.14(d,1H),7.43(m,3H),7.51(m,2H)。

Step 5: trans-(S)-1-benzyl-(nitro methene)-tetramethyleneimine-2-methyl-formiate (compound 1f)

Compound 1e (8g, 20.5mmol) is dissolved in the dry DMF of 50mL, and adds Nitromethane 99Min. (7.5g, 123mmol) and triethylamine (4mL, 29mmol), stirred overnight at room temperature. Then react 5 hours at 60 DEG C. Decompressing and extracting solvent, then obtains compound 1f, yellow liquid 4.8g, receipts rate 85% after column chromatography (silica gel, ethyl acetate/petroleum ether wash-out).

MS (ESI) m/z:277 (M+1);¹HNMR(400mHz,CDCl₃):2.22(m,1H),2.34(m,1H),3.39(5,1H),3.74(dd,1H),3.72(s,3H),4.24(dd,1H),4.30(d,1H),4.51(d,1H),6.87(s,1H),7.16(dd,2H),7.35(m,3H)。

Step 6:(1S, 5R) assorted two rings [3.2.1] octane-2-ketone (compound 1g) of-3,8-nitrogen two

Under 10% palladium carbon katalysis, by compound 1f (2.1g, 7.6mmol) hydrogenation 4 hours in ethyl acetate and acetic acid mixing solutions (10mL+10mL). With diatomite, palladium-carbon catalyst is filtered out, then concentrate to dry. Resistates (1.8g, 7.3mmol) is dissolved in 15mL methyl alcohol, adds ammonium formiate (4.57g, 72.5mmol) and 10% palladium carbon (1.5g), and reflux 4 hours. With diatomite, palladium-carbon catalyst is filtered out, then concentrate and obtain compound 1g to dry, white solid 0.9g, receipts rate 94%.

MS (ESI) m/z:127 (M+1);¹HNMR(400mHz,CDCl₃): δ 1.75 (m, 1H), 2.05 (m, 3H), 2.45 (bs, 1H), 3.0 (dd, J=2.0,9.0Hz, 1H), 3.48 (dd, J=4.0,9.0Hz, 1H), 3.74 (m, 2H), 6.35 (s, 1H).

Step 7:(1S, 5R) assorted two rings [3.2.1] octane-2-ketone (compound 1h) of-8-tertiary butoxy carbonyl-3,8-nitrogen two

To compound 1g (2g under ice bath, 40mL dichloromethane solution 15.9mmol) adds tert-Butyl dicarbonate (5.19g, 23.8mmol) with triethylamine (0.66mL, 4.8mmol), and allow to rise to room temperature reaction and spend the night. Resistates, except after desolventizing, is carried out column chromatography (silica gel, ethyl acetate/petroleum ether wash-out) and obtains compound 1h, white solid 2.8g, receipts rate 78% by underpressure distillation.

MS (ESI) m/z:227 (M+1);¹HNMR(400mHz,CDCl₃): δ 1.45 (s, 9H) 1.77-1.84 (m, 1H), 2.10-2.16 (m, 2H), 2.18-2.26 (m, 1H), 3.03 (dd, J=2.4,10.8Hz, 1H), 4.42 (s, 1H), 4.48 (s, 1H), 5.73 (s, 1H).

Step 8:(1S, 5R) assorted two rings [3.2.1] octane-2-sulphur of-8-tertiary butoxy carbonyl-3,8-nitrogen two is for ketone (compound 1i)

Compound 1h (40mg, 0.18mmol) is dissolved in 5mL tetrahydrofuran (THF), and adds lawesson reagent (43mg, 0.1mmol) with vigorous stirring. After reaction solution stirs 3 hours, reaction solution is steamed dry and is again dissolved in 20mL ethyl acetate. Organic phase is through saturated sodium bicarbonate and saturated common salt water washing, and after anhydrous sodium sulfate drying, decompression arranges to dry. Crude product obtains compound 1i, white solid 35mg, receipts rate 86% after column chromatography (silica gel, ethyl acetate/petroleum ether wash-out). MS (ESI) m/z:243 (M+1).

Step 9:(1S, 5R) assorted two rings [3.2.1] octane-2-sulphur of-3,8-nitrogen two is for ketone (compound 1j)

Compound 1i (40mg, 0.16mmol) is dissolved in 0.2mL methyl alcohol, then adds 4N hydrochloric ethyl acetate solution (4mL), and at room temperature stir and spend the night. Compound 1j is obtained, white solid 23mg, receipts rate 98%) by after excessive hydrochloric acid and solvent pressure distillation. MS (ESI) m/z:143 (M+1).

Step 10:(6R, 9S)-3-(trifluoromethyl)-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole [4,3-a] azepines (compound 1k)

Compound 1j (37mg, 0.262mmol), 2,2,2-trifluoroacetyl hydrazine (101mg, 0.787mmol) and sodium-acetate (65mg, 0.79mmol) are dissolved in 10mL propyl carbinol, and solvent is steamed dry by backflow after spending the night. Crude product obtains compound 1k after preparative high performance liquid chromatography, yellow oil 7.4mg, receipts rate 13%. MS (ESI) m/z:219 (M+1).

Step 11:((2R)-4-oxygen-4-(6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-1-(2,4,5-trifluoro-benzene base) fourth-2-alkyl) t-butyl formate (compound 1l)

By compound 1k (35mg, 0.162mmol) with (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (53.9mg, 0.2mmol) it is dissolved in 2mL methylene dichloride, and under ice bath, add I-hydroxybenzotriazole (26mg, 0.2mmol) and 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (47mg, 0.24mmol) successively. React after 4 hours, add 15mL methylene dichloride and receive (5mL) with unsaturated carbonate hydrogen and saturated aqueous common salt (5mL) washing. Organic phase concentrates to dry after drying. Crude product obtains compound 1l after preparative high performance liquid chromatography, yellow oil 53mg, receipts rate 72%. MS (ESI) m/z:534 (M+1).

Step 12:(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base)-1-butanone (compound 1)

Trifluoroacetic acid (5mL) is added under stirring at room temperature in compound 1l (18mg, 34mmol).After 2 hours, excessive trifluoroacetic acid is depressurized to be drained. Crude product obtains compound 1 after preparative high performance liquid chromatography, the solid 10mg of white, receipts rate 68%.

MS (ESI) m/z:434 (M+1);¹HNMR(400mHz,DMSO-d₆): δ 1.92-2.35 (m, 4H), 2.74-2.76 (m, 1H), 2.84-2.97 (m, 2H), 3.71 (s, 1H), 4.13-4.22 (m, 1.4H), 4.28-4.40 (m, 0.6H), 4.80 (t, J=4.0,0.6H), 4.95 (t, J=8.0,0.4H), 5.60-5.66 (m, 2H), 7.45-7.58 (m, 2H).

(R)-3-amino-1-((6S, 9R)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base) preparation of-1-butanone trifluoroacetate (compound 1 ')

The preparation of compound 1 ' uses opposite-handed compound 1a and the preparation method completely identical with compound 1 to obtain.

Embodiment 2:(3R)-3-amino-1-(3-trifluoromethyl-6,7,9,10-tetrahydrochysene-5H-6,10-epimino [1,2,4] triazolo [3,4-d] [1,5] dislike azoles star-11-alkyl)-4-(2,4,5-trifluoro-benzene base)-1-butanone trifluoroacetate (compound 2)

Step 1:(2S)-3-(3-tert-butoxy carbonyl amino-2-propoxyl)-2-is to nitro benzyl oxygen carbonyl amido-methyl propionate (compound 2b)

Drip in toluene (80mL) solution of compound 2l (6.82g, 35.7mmol) and compound 2a (5g, 17.8mmol) under room temperature and add boron trifluoride diethyl etherate (0.3mL, 48%). Concentrate after stirred at ambient temperature 2h and obtain product 2b, yellow oil 4.8g, receipts rate 57% except after desolventizing through column chromatography (silica gel, sherwood oil: ethyl acetate=2:1).

MS (ESI) m/z:472 (M+1), 416 (M-56+1);¹HNMR(400mHz,CDCl₃): δ 8.22 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 5.08 5.13 (m, 1H), 5.19-5.26 (m, 2H), 4.42 4.58 (m, 1H), 3.91 3.94 (m, 1H), 3.78 (s, 3H), 3.73-3.83 (m, 2H), 3.54 3.62 (m, 2H), 3.42 3.50 (m, 2H), 1.44 (s, 9H).

Step 2:(3S)-3-(3-tert-butoxy carbonyl amino-2-carbonyl propoxy-)-2-is to nitro benzyl oxygen carbonyl amido-methyl propionate (compound 2c)

Add in methylene dichloride (150mL) solution of compound 2b (4.7g, 10mmol) under ice bath and add Dai Si-Ma Ting reagent (6.34g, 15.0mmol) in batches. After reaction 1h, in reaction solution, add Na2S₂O₃Solution (2N, 120mL) cancellation is reacted, and separatory, aqueous phase methylene dichloride (100mL × 2) extracts. Merge organic phase, successively with saturated sodium bicarbonate solution (350mL), saturated common salt washing (350mL). Organic phase drying, filtration, concentrated obtain product 2c, yellow oil 2.15g, receipts rate 45.9% through column chromatography (silica gel, ethyl acetate: sherwood oil=1:1) again.

MS (ESI) m/z:470 (M+1), 414 (M-56+1);¹HNMR(400mHz,CDCl₃): δ 8.22 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 5.17-5.28 (m, 3H), 4.18 (s, 2H), 4.04 (d, J=8.4Hz, 1H), 4.00 (dd, J=5.6Hz, 2.4Hz, 1H), 3.82 (s, 3H), 3.75-3.80 (m, 1H), 1.45 (s, 9H).

Step 3:(3S, 5S)-5-tert-butoxy carbonyl amino methyl-morpholine-3-methyl-formiate (compound 2d)

Palladium carbon (0.5g, 10%) join ethyl acetate (50mL) solution of compound 2c (2.0g, 4.26mmol), stir in hydrogen 2h. reaction solution after filtration, concentrated obtain product 2d through the separation of quick post again, colorless oil 0.6g, receipts rate 51.3%.

MS (ESI) m/z:275,219 (M-56+1);¹H-NMR(400mHz,CDCl₃): δ 4.97 (s, 1H), 4.11 (dd, J=11.2Hz, 3.6Hz, 1H), 3.82 (dd, J=11.2Hz, 3.6Hz, 1H), 3.75 (s, 3H), 3.71 (dd, J=10.4Hz, 3.6Hz, 1H), 3.39 (t, J=10.8Hz, 1H), 3.16-3.22 (m, 1H), 3.16 (t, J=10.8Hz, 1H), 3.00-3.11 (m, 2H), 1.45 (s, 9H).

Step 4:(3S, 5S)-5-amino methyl-morpholine-3-methyl-formiate (compound 2e)

Under ice bath, dripping in methylene dichloride (10mL) solution of compound 2d (500mg, 1.82mmol) and add trifluoroacetic acid (10mL), stirring at room temperature obtained compound 2e by concentrated for reaction solution after 2 hours, white solid 0.73g, receipts rate 100%.

MS(ESI)m/z:175(M+1)。

Step 5:3-oxo-7,9-diazabicyclo [3.3.1] nonane-6-ketone (compound 2f)

Compound 2e (317mg, 1.82mmol) and sodium methylate (491mg, 9.1mmol) are dissolved in meOH (20mL) stirring and spend the night, and filter, and filtrate (compound 2f solution) is directly used in next step reaction. MS (ESI) m/z:143 (M+1).

Step 6:6-carbonyl-3-oxo-7,9-diazabicyclo [3.3.1] nonane-9-t-butyl formate (compound 2g)

In methyl alcohol (20mL) solution of compound 2f (259mg, 1.82mmol), successively N is added, N-diisopropylethylamine (470mg, 3.64mmol) and tert-Butyl dicarbonate (476mg, 2.2mmol) under ice bath. After reacting 2h under room temperature, being removed by solvent concentration, resistates is dissolved in ethyl acetate (20mL), successively with saturated sodium bicarbonate solution (20mL), and saturated common salt washing (20mL). Organic phase drying, filtration, concentrated obtain product 2g, white solid 0.22g, receipts rate 50% through column chromatography (silica gel, ethyl acetate: sherwood oil=1:1) again.

MS (ESI) m/z:243 (M+1);¹HNMR(400mHz,CDCl₃): δ 6.00 (s, 1H), 4.42 (s, 1H), 4.28 (s, 1H), 4.03 (d, J=10.8,1H), 3.94 (d, J=11.6Hz, 1H), 3.79 (d, J=12.0Hz, 2H), 3.66 (d, J=10.8Hz, 1H), 3.41 (dd, J=12.0Hz, 2.8Hz, 1H), 1.48 (s, 9H).

Step 7:6-thiocarbonyl group-3-oxo-7,9-diazabicyclo [3.3.1] nonane-9-t-butyl formate (compound 2h)

Lawesson reagent (367mg, 0.91mmol) join compound 2g (220mg, anhydrous tetrahydro furan (10mL) 0.91mmol) stirs 3h. then concentrated except desolventizing, resistates is dissolved in ethyl acetate (20mL), successively with saturated sodium bicarbonate solution (20mL), saturated common salt washing (20mL). Organic phase drying, filtration, concentrated obtain product 2h, white solid 0.12g, receipts rate 50% through column chromatography (silica gel, ethyl acetate: sherwood oil=1:1) again.

MS (ESI) m/z:259 (M+1);¹HNMR(400mHz,CDCl₃): δ 4.87 (s, 1H), 4.18 (d, J=10.8Hz, 1H), 3.94 (d, J=11.6Hz, 1H), 3.79 (d, J=11.6Hz, 2H), 3.70-3.75 (m, 3H), 3.42 (dd, J=13.6Hz, 2.8Hz, 1H), 1.48 (s, 9H).

Step 8:3-oxo-7,9-diazabicyclo [3.3.1] nonane-6-thioketones (compound 2i)

Under ice bath, dripping in methylene dichloride (3mL) solution of compound 2h (117mg, 0.45mmol) and add trifluoroacetic acid (3mL), stirring at room temperature obtained compound 9 by concentrated for reaction solution after 2 hours, white solid 123mg, receipts rate 100%.

MS(ESI)m/z:159(M+1)。

Step 9:((2R)-4-carbonyl-4-(6-thiocarbonyl group-3-oxo-7,9-diazabicyclo [3.3.1]-9-in ninth of the ten Heavenly Stems alkyl)-1-(2,4,5-trifluoro-benzene base) fourth-2-alkyl) benzyl carbamate (compound 2j)

In methylene dichloride (10mL) solution of compound 2i (71mg, 0.45mmol), N, N-diisopropylethylamine (117mg, 0.91mmol) is added successively, 2m (209mg, 0.54mmol) under ice bath.Reacting after two hours, reaction solution is successively with saturated sodium bicarbonate (8mL), and saturated aqueous common salt (8mL) is washed. Organic phase drying, filtration, concentrated obtain product 2j, white solid 0.132g, receipts rate 57.4% through column chromatography (silica gel, ethyl acetate: sherwood oil=1:1) again.

MS (ESI) m/z:508 (M+1);¹HNMR(400mHz,CDCl₃): δ 7.29-7.35 (m, 5H), 7.06 (dd, J=17.6Hz, 9.2Hz, 1H), 6.86 (dd, J=14.4Hz, 8.4Hz, 1H), 5.46-5.54 (m, 1H), 3.85-3.94 (m, 1H), 4.51 (d, J=12.0,1H), 4.16-4.25 (m, 1H), 3.85-3.94 (m, 1H), 3.74-3.77 (m, 1H), 3.60-3.64 (m, 1H), 3.37-3.49 (m, 2H), 3.13-3.20 (m, 1H), 2.87-2.95 (m, 1H), 2.78-2.83 (m, 1H), (2.53-2.59 m, 1H).

Step 10:((2R)-4-carbonyl-4-(3-trifluoromethyl-6,7,9,10-tetrahydrochysene-5H-6,10-epimino [1,2,4] triazolo [3,4-d] [1,5] dislike azoles star-11-alkyl)-1-(2,4,5-trifluoro-benzene base)-2-butyl) benzyl carbamate (compound 2k)

After compound 2j (132mg, 0.26mmol), trifluoroacetyl hydrazine (100mg, 0.78mmol) and sodium-acetate (64mg, 0.78mmol) are dissolved in propyl carbinol (5mL), reflux is spent the night. Product 2k is obtained, white solid 60mg, receipts rate 39% through column chromatography (silica gel, ethyl acetate: sherwood oil=2:1) after reaction mixture is concentrated.

MS (ESI) m/z:584 (M+1);¹HNMR(400mHz,CDCl₃): δ 7.29-7.35 (m, 5H), 7.01 (dd, J=17.2Hz, 9.6Hz, 1H), 6.71 (dd, J=12.0Hz, 7.6Hz, 1H), 5.78 (d, J=9.2Hz, 1H), 5.35 (s, 1H), 5.01 (d, J=4.0Hz, 1H), 4.34-4.44 (m, 1H), 4.25-4.30 (m, 1H), 4.17-4.19 (m, 1H), 3.97-4.01 (m, 1H), (3.87 d, J=10.8Hz, 1H), (3.80 d, J=12.6Hz, 1H), 2.87-3.05 (m, 2H), 2.77-2.82 (m, 1H), 2.54-2.63 (m, 1H).

Step 11:(3R)-3-amino-1-(3-trifluoromethyl-6,7,9,10-tetrahydrochysene-5H-6,10-epimino [1,2,4] triazolo [3,4-d] [1,5] dislike azoles star-11-alkyl)-4-(2,4,5-trifluoro-benzene base)-1-butanone trifluoroacetate (compound 2)

By palladium carbon (32mg, 10%) join ethyl acetate (5mL) solution of compound 2k (30mg, 0.089mmol), stir in hydrogen 2h. reaction solution after filtration, concentrated after prepare product 2 through HPLC, white solid 15mg, receipts rate 24%.

MS (ESI) m/z:450 (M+1);¹H-NMR(400mHz,CDCl₃): δ 7.20 (dd, J=16.8Hz, 8.8Hz, 1H), 6.97-7.08 (m, 1H), 5.91 (s, 0.51H), 5.40 (s, 0.46H), 4.92 (s, 0.55H), 4.44 (s, 1H), 4.40 (s, 0.48H), 4.33-4.36 (m, 1H), 4.04 (t, J=9.2Hz, 1H), 3.72-3.84 (m, 4H), 2.94 (t, J=7.6,1H), 2.87 (dd, J=17.6,3.2Hz, 0.51H), 2.77 (d, J=10.0Hz, 1H), 2.51 (dd, J=17.2Hz, 8.0Hz, 0.46H).

Embodiment 3 (R)-3-amino-1-((6R, 9S)-3-methyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base) preparation of-1-butanone trifluoroacetate (compound 3)

Step 1:((R)-4-carbonyl-4-((1S, 5R)-2-thiocarbonyl group-3,8-diazabicyclo [3.2.1]-8-octane base)-1-(2,4,5-trifluoro-benzene base)-2-butyl) t-butyl carbamate (compound 3a)

Successively to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (347mg, 10mL methylene dichloride 1.04mmol) adds diisopropylethylamine (593mg, 4.6mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (265mg, 1.38mmol), I-hydroxybenzotriazole (186mg, 1.38mmol), stirred at ambient temperature 1 hour.Then compound 1j (150mg) is added reaction system, stirred overnight at room temperature. By reaction solution with after saturated common salt water washing, dry, concentrated. Crude product obtains compound 3a, white solid 170mg, receipts rate 42% after silicagel column purifying (methylene dichloride: methyl alcohol=80:1). MS (ESI) M/Z:458 (M+H), 358 [(M+H)-Boc].

Step 2:((R)-4-((6R, 9S)-3-methyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazolo [4,3-a] azepines-10-yl)-4-carbonyl-1-(2,4,5-trifluoro-benzene base)-2-butyl) t-butyl carbamate (compound 3b)

In the 15mL butanol solution of compound 3a (120mg, 0.372mmol), add acethydrazide (82mg, 1.11mmol) and sodium acetate (152mg, 1.86mmol) successively, then reflux 18 hours. After propyl carbinol decompression being divided exactly, resistates is dissolved in 10mL methylene dichloride, and uses saturated common salt water washing. After organic phase drying, concentrated obtain crude product, purify with silicagel column and obtain compound 3b, white solid 80mg, receipts rate 60% after (methylene dichloride: methyl alcohol=80:1).

MSm/z(ESI):480(M+H)⁺,380[(M+H)⁺-Boc]。

Step3 (R)-3-amino-1-((6R, 9S)-3-methyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base)-1-butanone trifluoroacetate (compound 3)

Under ice bath, in compound 3b (80mg, 0.15mmol), add 3mL trifluoroacetic acid, then rise to stirring at room temperature 30 minutes. After trifluoroacetic acid is removed by underpressure distillation, resistates liquid chromatography purification obtains compound 3, white solid, 30mg receipts rate 40%.

MS (ESI) m/z:380 (M+H);¹HNMR(400m,CD3OD):δ7.36-7.29(m,1H),7.25-7.16(m,1H),5.82(d,0.5H),5.52(d,0.5H),5.16-5.14(m,0.5H),4.32-4.27(m,1H),4.14-4.07(m,1H),3.91-3.86(m,1H),3.09-3.02(m,2H),2.91-2.89(m,1H),2.69-2.56(m,4H),2.52-2.50(m,0.5H),2.47-2.26(m,1.5H),2.17-1.95(m,2H)。

Embodiment 4 (R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl) preparation of-4-(2-aminomethyl phenyl)-1-butanone trifluoroacetate (compound 4)

Step 1:((R)-4-carbonyl-4-((1S, 5R)-2-thiocarbonyl group-3,8-diazabicyclo [3.2.1]-8-octane base)-1-(2-aminomethyl phenyl)-2-butyl) t-butyl carbamate (compound 4a)

Successively to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (74.22mg, 5mL methylene dichloride 0.25mmol) adds diisopropylethylamine (89mg, 0.69mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (65.90mg, 0.35mmol), I-hydroxybenzotriazole (37.26mg, 0.28mmol), stirred at ambient temperature 0.5 hour. Then compound 1j (32.71mg, 0.23mmol) is added reaction system, stirred overnight at room temperature. To add 10mL saturated aqueous common salt in reaction solution, with methylene dichloride (15mL × 3) extraction, merging is dry, concentrated to obtain crude product. Crude product obtains compound 4a, white solid 60mg, receipts rate 62.% after silicagel column purifying (methylene dichloride: methyl alcohol=100:1)).

MS(ESI)M/Z:418(M+H),362(M-tBu)。

Step 2:((R)-4-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazolo [4,3-a] azepines-10-yl)-4-carbonyl-1-(2-aminomethyl phenyl)-2-butyl) t-butyl carbamate (compound 4b)

In the 3mL butanol solution of compound 4a (60mg, 0.14mmol), adding 2,2,2-trifluoroacetyl hydrazine (55.20mg, 0.43mmol) and sodium acetate (35mg, 0.43mol) successively, then backflow is spent the night. After propyl carbinol decompression being divided exactly, resistates adds 5mL water, with methylene dichloride (15mL × 3) extraction, and by the organic phase saturated common salt water washing after merging.After organic phase drying, concentrated obtain crude product, purify with silicagel column and obtain compound 4b, white solid 23mg, receipts rate 30% after (methylene dichloride: methyl alcohol=100:1)). MS (ESI) M/Z:494 (M+H), 438 (M-tBu).

Step 3:(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2-aminomethyl phenyl)-1-butanone trifluoroacetate (compound 4)

Under ice bath, in compound 4b (23mg, 0.046mmol), add 3mL trifluoroacetic acid, then rise to stirring at room temperature 30 minutes. After trifluoroacetic acid is removed by underpressure distillation, resistates liquid chromatography purification obtains compound 4, colorless oil 10mg, receipts rate 55%).

MS (ESI) M/Z:394 (M+H);¹HNMR(400Hz,CD₃OD):δ7.21-7.10(m,4H),5.86-5.84(d,0.5H),5.50-5.48(d,0.5H),5.11(s,0.5H),4.80(s,0.5H),4.40-4.22(d,1H),4.22-4.16(t,1H),3.87(s,1H),3.33-3.31(m,3.6H),2.82-2.76(m,1H),2.53-2.51(d,4H),2.39-2.34(m,0.5H),2.12(s,3H),2.07-2.05(m,1H)。

Embodiment 5 (R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl) preparation of-4-(2-fluorophenyl)-1-butanone trifluoroacetate (compound 5)

Step 1:((R)-4-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazolo [4,3-a] azepines-10-yl)-4-carbonyl-1-(2-fluorophenyl)-2-butyl) t-butyl carbamate (compound 5a)

Successively to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (50.97mg, 5mL methylene dichloride 0.17mmol) adds diisopropylethylamine (60.31mg, 0.47mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (44.65mg, 0.23mmol), I-hydroxybenzotriazole (25.25mg, 0.18mmol), stirred at ambient temperature 0.5 hour. Then compound 1k (34.00mg, 0.15mmol) is added reaction system, stirred overnight at room temperature. To add 10mL saturated aqueous common salt in reaction solution, with methylene dichloride (15mL × 3) extraction, merging is dry, concentrated to obtain crude product. Crude product obtains compound 5a, white solid 32mg, receipts rate 41.28% after silicagel column purifying (methylene dichloride: methyl alcohol=100:1).

MS(ESI)M/Z:498(M+H),442(M-tBu)。

Step 2:(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2-fluorophenyl)-1-butanone trifluoroacetate (compound 5)

Under ice bath, in compound 5a (32.00mg, 0.064mmol), add 3mL trifluoroacetic acid, then rise to stirring at room temperature 30 minutes. After trifluoroacetic acid is removed by underpressure distillation, resistates liquid chromatography purification obtains compound 5, colorless oil 10mg, receipts rate 40%.

MS (ESI) m/z:398 (M+H);¹HNMR(400Hz,CD₃OD):δ7.38-7.24(m,2H),7.20-7.11(m,1H),7.04-6.95(t,1H),5.84-5.82(d,0.5H),5.51-5.48(d,0.5H),4.42-4.36(t,1H),4.22-4.16(t,1H),3.90-3.80(d,1H),3.16-2.98(m,2H),2.97-2.78(m,1.5H),2.50-2.34(m,2.5H),2.18-2.10(m,1H),2.07-1.92(m,1H)。

Embodiment 6 (R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl) preparation of-4-(3-chloro-phenyl-)-1-butanone trifluoroacetate (compound 6)

Step 1:((R)-4-carbonyl-4-((1S, 5R)-2-thiocarbonyl group-3,8-diazabicyclo [3.2.1]-8-octane base)-1-(3-chloro-phenyl-)-2-butyl) t-butyl carbamate (compound 6a)

Successively to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (69.03mg, 5mL methylene dichloride 0.22mmol) adds diisopropylethylamine (85.14mg, 0.66mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (63.03mg, 0.33mmol), I-hydroxybenzotriazole (44.55mg, 0.33mmol), stirred at ambient temperature 0.5 hour.Then compound 1j (31.29mg, 0.22mmol) is added reaction system, stirred overnight at room temperature. To add 10mL saturated aqueous common salt in reaction solution, with methylene dichloride (15mL × 3) extraction, merging is dry, concentrated to obtain crude product. Crude product obtains compound 6a, white solid 50mg, receipts rate 52% after silicagel column purifying (methylene dichloride: methyl alcohol=100:1).

MS(ESI)M/Z:438(M+H),382(M-tBu)。

Step 2:((R)-4-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazolo [4,3-a] azepines-10-yl)-4-carbonyl-1-(3-chloro-phenyl-)-2-butyl) t-butyl carbamate (compound 6b)

In the 5mL butanol solution of compound 6a (50mg, 0.11mmol), adding 2,2,2-trifluoroacetyl hydrazine (55.20mg, 0.43mmol) and sodium acetate (28mg, 0.34mol) successively, then backflow is spent the night. After propyl carbinol decompression being divided exactly, resistates adds 5mL water, with methylene dichloride (15mL × 3) extraction, and by the organic phase saturated common salt water washing after merging. After organic phase drying, concentrated obtain crude product, purify with silicagel column and obtain compound 6b, white solid 12mg, receipts rate 25% after (methylene dichloride: methyl alcohol=100:1)). MS (ESI) M/Z:514 (M+H), 458 (M-tBu+1).

Step 3:(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(3-chloro-phenyl-)-1-butanone trifluoroacetate (compound 6)

Under ice bath, in compound 6b (12mg, 0.023mmol), add 3mL trifluoroacetic acid, then rise to stirring at room temperature 30 minutes. After trifluoroacetic acid is removed by underpressure distillation, resistates liquid chromatography purification obtains compound 6, colorless oil 8mg, receipts rate 83%.

MS (ESI) m/z:414 (M+H); NMR (400Hz, CD₃OD)δ7.37-7.19(d,4H),5.88-5.86(d,0.5H),5.55-5.54(d,0.5H),5.13(s,0.5H),4.82(s,0.5H),4.44-4.36(t,1H),4.22-4.19(m,1H),3.90(s,1H),3.14-2.98(m,3.5H),2.56-2.18(m,1.5H),2.14-2.0(m,2.5H),1.96-1.94(m,1H)。

Embodiment 7 (R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl) preparation of-4-(2,5-difluorophenyl)-1-butanone trifluoroacetate (compound 7)

Step 1:((R)-4-carbonyl-4-((1S, 5R)-2-thiocarbonyl group-3,8-diazabicyclo [3.2.1]-8-octane base)-1-(2,5-difluorophenyl)-2-butyl) t-butyl carbamate (compound 7a)

Successively to (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-benzene base) butyric acid (290mg, 10mL methylene dichloride 0.92mmol) adds diisopropylethylamine (593mg, 4.6mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (265mg, 1.38mmol), I-hydroxybenzotriazole (186mg, 1.38mmol), stirred at ambient temperature 1 hour. Then compound 1j (150mg, 1.06mmol) is added reaction system, stirred overnight at room temperature. To add 20mL saturated aqueous common salt in reaction solution, with methylene dichloride (15mL × 3) extraction, merging is dry, concentrated to obtain crude product. Crude product obtains compound 7a, colorless oil 170mg, receipts rate 36.4% after silicagel column purifying (methylene dichloride: methyl alcohol=80:1).

MS(ESI)m/z:440(M+H)⁺,340[(M+H)⁺-Boc]。

Step 2:((R)-4-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazolo [4,3-a] azepines-10-yl)-4-carbonyl-1-(2,5-difluorophenyl)-2-butyl) t-butyl carbamate (compound 7b)

In the 15mL butanol solution of compound 7a (170mg, 0.387mmol), add the 2 of 1M successively, 2,2-trifluoroacetyl hydrazine (1.16mL, 1.16mmol) and sodium acetate (159mg, 1.94mmol)), then reflux 18 hours.After propyl carbinol decompression is divided exactly, resistates adds 10mL methylene dichloride, and after saturated common salt water washing, organic phase is dry, concentrated obtains crude product, purify with silicagel column and obtain compound 7b white solid 80mg, receipts rate 40% after (methylene dichloride: methyl alcohol=120:1). MS (ESI) m/z:516 (M+H), 416 [(M+H)-BOC].

Step 3:(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,5-difluorophenyl)-1-butanone trifluoroacetate (compound 7)

Under ice bath, in compound 7b (80mg, 0.15mmol), add 3mL trifluoroacetic acid, then rise to stirring at room temperature 30 minutes. After trifluoroacetic acid is removed by underpressure distillation, resistates liquid chromatography purification obtains compound 7, white solid 30mg, receipts rate 48%.

MS(ESI)m/z:416(M+H)⁺;¹H-NMR(400m,CD3OD):δ3.16-7.06(m,3H),5.87-5.84(m,0.5H),5.53-5.51(d,0.5H),5.14-5.11(m,0.5H),4.85-4.83(m,0.5H),4.43-4.30(m,1H),4.26-4.17(m,1H),3.95-3.82(m,1H),3.14-3.07(m,1.5H),3.04-2.99(m,1H),2.89-2.81(m,0.5H),2.79-2.65(m,0.5H),2.54-2.35( m,2H),2.28-2.15(m,1H),2.12-1.95(m,0.5H)。

(R)-3-amino-1-((6R, 9S)-3-trifluoromethyl-6,7,8,9-tetrahydrochysene-5H-6,9-epimino [1,2,4] triazole also [4,3-a] azepines-10-alkyl)-4-(2,4,5-trifluoro-benzene base) preparation of the various salt of-1-butanone (compound 8a-f)

Compound 8a

At the compound 1 (10mg of free amino group, in 1mL methanol solution 0.023mmol), add Hydrogen bromide (0.209ml) water and the methanol solution (methyl alcohol: water=4:1) of 0.11M, stir 30 minutes, concentrate and obtain compound 8a to dry, white solid 11.8mg, receipts rate 100%.

MS (ESI) m/z:434.13 (M+H);¹HNMR(400Hz,CD₃OD)δ7.39-7.09(m,2H),5.87(d,0.5H),5.59(d,0.5H),5.12-4.98(s,0.5H),4.51-4.40(m,1H),4.25-4.20(m,1H),3.09-2.92(m,4H),2.60-2.54(m,1H),2.54(m,1.5H),2.17-2.12(m,2H)。

Compound 8b

At the compound 1 (10mg of free amino group, in 1mL methanol solution 0.023mmol), add acetic acid (0.209ml) water and the methanol solution (methyl alcohol: water=4:1) of 0.11M, stir 30 minutes, concentrate and obtain compound 8b to dry, white solid 11.3mg, receipts rate 100%.

MS (ESI) m/z:434.13 (M+H);¹HNMR(400Hz,CD3OD)δ7.30-7.06(m,2H),5.83(d,0.5H),5.54(d,0.5H),5.09(s,0.5H),4.40-4.36(m,1H),4.22-4.16(t,1H),3.61-3.60(m,1H),2.93-2.70(m,4H),2.47-2.36(m,2.5H),2.14-2.04(m,2H),1.91(s,3H)。

Compound 8c

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino group, add (2.67mg, 0.023mmol) toxilic acid, stir 30 minutes, concentrate and obtain compound 8c to dry, white solid 13mg, receipts rate 100%.

MS (ESI) m/z:434.13 (M+H);¹HNMR(400Hz,CD₃OD):δ7.23-7.00(m,2H),6.17(s,2H),5.75(s,0.5H),5.43(s,0.5H),5.00(s,0.5H),4.76(m,0.5H),4.35-4.20(m,1H),4.12-4.09(m,1H),3.75-3.71(m,1H),2.97-2.78(m,3H),2.44-2.27(m,2.5H),2.12-2.04(m,1H),2.00-1.82(m,1.5H)。

Compound 8d

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino group, add (2.67mg, 0.023mmol) succinic acid, stirs 30 minutes, concentrates and obtain compound 8d to dry, white solid 12.6mg, receipts rate 100%).

MS(ESI)m/z:434.13(M+H)⁺;¹HNMR(400Hz,CD₃OD):δ7.35-7.10(m,2H),5.86(s,0.5H),5.55(s,0.5H),5.12-5.05(m,1H),4.46-4.39(m,1H),4.24-4.20(m,1H),3.84-3.78(m,1H),3.04-2.92(m,2.5H),2.84-2.81(m,1H),2.53-2.48(m,6H),2.43-2.39(m,1H),2.28-2.22(m,1H),2.19-2.02(m,1H),1.95-1.91(m,0.5H)。

Compound 8e

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino group, add (3.08mg, 0.023mmol) oxysuccinic acid, stir 30 minutes, concentrate and obtain compound 8e to dry, white solid 13mg, receipts rate 100%.

MS (ESI) m/z:434.13 (M+H);¹HNMR(400Hz,CD₃OD):δ7.25-7.21(m,1H),7.11-7.09(m,0.5H),7.01-6.98(m,0.5H),5.74(d,0.5H),5.43(d,0.5H),5.01-4.99(m,0.5H),4.32-4.24(m,1H),4.22-4.19(m,1H),4.11-4.08(m,1H),3.75-3.72(m,1H),3.25(s,0.5H),2.96-2.85(m,2.5H),2.76-2.66(m,2H),2.48-2.38(m,2H),2.31-2.24(m,1H),2.15-2..03(m,1.5H),1.96-1.85(m,1.5H)。

Compound 8f

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino group, add (3.45mg,

0.023mmol) tartrate, stirs 30 minutes, concentrates and obtain compound 8f to dry, white solid 14mg, receipts rate 100%.

MS (ESI) m/z:434.13 (M+H);¹HNMR(400Hz,CD3OD)δ7.15-7.05(m,2H),5.82(d,0.5H),5.53(d,0.5H),5.09(s,0.5H),4.45-4.37(m,2.5H),4.21-4.17(m,1H),3.82(s,1H),3.34(m,1H),3.07-2.85(m,4H),2.58-2.52(m,1H),2.41-2.36(m,1H),2.35-1.92(m,3H)。

The useful effect of the present invention is specifically described below by way of test example.

Test example 1

The member of DPP-4, DPP-2, DPP-8, DPP-9 Jun Shi DPP family, research finds, if suppressing other enzymes except DPP-4, then health can be produced side effect, during as suppressed DPP-8, DPP-9 enzyme to live, dormancy T cell will be caused dead, a series of toxic side effect such as stomach toxicity and body's immunity, therefore, in the current exploitation to DPP-4 (i.e. DPP-IV) enzyme inhibitors, require to improve inhibitor to the selectivity of DPP-4, reduce the selectivity to other families of DPP simultaneously, thus reduce the toxic side effect of inhibitor.

The present invention measures the compounds of this invention to the inhibition of DPP family by testing as follows.

DPP-4, DPP-2, DPP-8, DPP-9 external activity detects

Testing compound is dissolved in methyl-sulphoxide, then with buffered soln (DPP4:100mMHEPES, pH7.5,0.1mg/mLBSA; DPP2:100mMHEPES, pH5.5,0.1mg/mLBSA; DPP8:50mMTris-HCl, pH7.5,0.1mg/mLBSA; DPP9:25mMTris-HCl, pH7.5,0.1mg/mLBSA) it is diluted to a series of working solutions. Recombinant human DPP-4 (final concentration is about 180ng/mL) or DPP-2 (final concentration is about 100ng/mL) or DPP-8 (final concentration is about 200ng/mL) or DPP-9 (final concentration is about 50ng/mL) is mixed with above-mentioned a series of compound working solution, then (final concentration DPP4 is 50 μMs to add Gly-Pro-AMC, DPP2/8/9 is 20 μMs) (total reaction volume is 100 μ L), the AMC (excitation wavelength 360nm, emission wavelength 460nm) of continuous detecting release at once 15 minutes. With SigmaPlot computed in software half-inhibition concentration IC50, result sees table.

Table 1 compound is to DPP-4 suppression property

Table 2 compound is to the inhibit activities of DPP family

The above results shows, the compounds of this invention can effectively suppress DPP-IV active, and member DPP-2, DPP-8, DPP-9 of DPP family is had good selectivity. These compounds can be used in multiple treatments with DPP-4 relative disease such as diabetes, for clinical application provides new selection.

Claims

1. a compound, shown in its structural formula following IAA, IBA, IA or IAA:

2. compound according to claim 1, it is characterised in that: described R^2’It is selected from alkyl or the substituted alkyl of C1-2.

3. compound according to claim 1, it is characterised in that: described R^2”What be selected from C1-2 contains assorted alkyl.

4. intermediate according to the arbitrary item of claim 1-3, it is characterised in that: described R³It is selected from H, CN, C1-2 alkyl or substituted alkyl; R³In, described substituted alkyl is replaced by 1-5 halogen.

5. compound according to the arbitrary item of claim 1-3, it is characterised in that: R^2’In, the substituting group of described substituted alkyl is selected from halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷; R^2”In, described heteroatoms is selected from N, S or O, and replacing heteroatoms or replacing the substituting group containing assorted alkyl is halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷;

6. compound according to the arbitrary item of claim 1-5, it is characterised in that: described compound is:

7. compound according to claim 6, its feature exists: described X is selected from N; R₃It is selected from CF₃。

8. the preparation method of formula IIAA described in claim 6 or IIBA compound, it is characterised in that: reactions steps is as follows:

Wherein, comprise the following steps:

9. preparing a method for DPP-IV inhibitor using formula IIAA described in claim 6 or 7 or formula IIBA compound as raw material, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;

10. a compound, shown in following IIIAA or IIIBA of its structural formula:

The preparation method of formula III AA or IIIBA compound described in 11. claims 10, it is characterised in that: reactions steps is as follows:

Wherein, reaction process comprises the following steps:

Preparing the method for DPP-IV inhibitor using formula III AA described in claim 10 or formula III BA compound as raw material for 12. 1 kinds, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;

13. 1 kinds of compounds, shown in its structural formula following IV A or IV B:

The preparation method of formula IV A described in 14. claims 13 or IV B compound, it is characterised in that: reactions steps is as follows:

Wherein, reaction process comprises the following steps:

Preparing the method for DPP-IV inhibitor using formula described in claim 13 IV A or IV B compound as raw material for 15. 1 kinds, it comprises the following steps:

Wherein, R¹It is selected from the phenyl of halogen substiuted;