CN105669682B

CN105669682B - A kind of intermediate of DPP-IV inhibitor

Info

Publication number: CN105669682B
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 Pioneer Drug Development Co Ltd
Current assignee: Chengdu Pioneer Drug Development Co Ltd
Priority date: 2013-02-22
Filing date: 2014-02-24
Publication date: 2019-08-30
Anticipated expiration: 2034-02-24
Also published as: CN104003992B; CN104003992A; WO2014127745A1; CN105669682A

Abstract

The present invention provides intermediate compound I AA, IBA of DPP-4 inhibitor shown in Formulas I A and IB, IAB, IBB, IIIAA, IIIBA, IV A and IV B and preparation methods.It is active that Formulas I A and IB compound represented can effectively inhibit DPP-4, and has good selectivity, these compounds can become potential Glucovance or the treatment with DPP-4 related disease, and new selection is provided for clinical application.Intermediate of the invention can be effectively synthesized DPP-4 inhibitor shown in Formulas I A and IB.

Description

A kind of intermediate of DPP-IV inhibitor

The application is application number 201410061271.8, the applying date on 2 24th, 2014, a kind of denomination of invention " inhibition The divisional application of the compound and its intermediate of DPP-IV ".

Technical field

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

Background technique

Diabetes are a kind of metabolic disturbance diseases by caused by inherent cause and environmental factor collective effect, are seriously threatened Human health and life security.In China, with the improvement of the quality of life and living-pattern preservation, the illness rate of diabetes It sharply increases.The diabetes epidemic data announced is shown within International Diabetes Federation (IDF) 2013, Chinese Adult diabetes Patient numbers up to 98,400,000 people, rank the first in the world, and the situation is tense for prevention and control.In face of the huge market demand, novel diabetes are controlled The research and development of drug are treated always by the concern of domestic and international pharmaceutical manufacturer, dipeptidyl peptidase-IV (DPP-IV) inhibitor is then the neck An important research object in domain.

DPP-IV, be otherwise known as t cell surface antigen CD26, is a kind of II type transmembrane glycoprotein, residual by 766 amino acid Base composition.DPP-IV is distributed widely in Various Tissues and organ in vivo, is included in kidney, liver, lung, small intestine, lymphocyte With (Abbott CA, Baker E, Sutherland GR, the McCaughan GW.Genomic such as vascular endothelial cell organization,exact localization,and tissue expression of the human CD26 (dipeptidyl peptidase IV)gene.Immunogenetics.1994；40 (5): 331-8), partially with soluble shape Formula is present in blood plasma (Mentlein R.Dipeptidyl-peptidase IV (CD26) -- role in the inactivation of regulatory peptides.Regul Pept.1999；85(1):9-24.).DPP-IV is a kind of The serine protease of specificity, substrate are 2nd reciprocal of N-terminal there are proline (Pro) or the polypeptide of alanine (Ala), Lower dipeptides can be cracked from the N-terminal of this kind of polypeptide.The pharmacological action of DPP-IV inhibitor, which mainly passes through, improves activity in vivo pancreas height The concentration of blood glucose sample peptide -1 (GLP-1) and realize.GLP-1 is synthesized and is secreted by Intestinal L cells, is the pancreotropic hormone having found The strongest intestines peptide hormone of secretion.Food digestion can promote GLP-1 and secrete and be released into blood, with special GLP-1 receptor Physiological function is played after effect.Studies have shown that GLP-1 can play blood sugar reducing function (Gautier JF, Fetita from many aspects S,Sobngwi E,Salaün-Martin C.Biological actions of the incretins GIP and GLP- 1and therapeutic perspectives in patients with type 2 diabetes.Diabetes Metab.2005；31 (3Pt 1): 233-42.): 1) promote the insulin secretion of glucose dependency, increases tissue to glucose Intake；2) increase its biosynthesis by the transcription and enhancing mRNA stability that promote proinsulin gene；3) inhibit pancreas The secretion of glucagons reduces glycogen release；4) promote beta Cell of islet Proliferation, Differentiation, inhibit β Apoptosis；5) pass through inhibition Gastric emptying controls appetite, reduces blood glucose, while losing weight increased risk.The above-mentioned physiological function of GLP-1 is 2 type glycosurias The treatment of disease provides an important target spot.However, GLP-1 is in vivo easily by DPP-IV from two amino acid residues of N-terminal It hydrolyzes and then inactivates, plasma half-life less than 2 minutes, seriously limits its clinical application.DPP-IV is to promote GLP-1 in vivo One of degradation, the key enzyme of inactivation, the blood plasma level of active GLP-1 can be improved in selective depression DPP-IV.Therefore, DPP-IV The research and development of inhibitor class drug provide a new way for treatment glycosuria.

2006, the Xi Gelieting (Sitagliptin) of Merck (Merck) company exploitation obtained the management of U.S.'s food and medicine Office (FDA) approval, becomes the DPP-IV inhibitor class drug of first listing.In addition, the DPP-IV inhibitor listed at present It further include vildagliptin (vildagliptin), saxagliptin (saxagliptin), Egelieting (alogliptin) and benefit Four kinds of La Lieting (linagliptin) etc..The novel DPP-IV inhibitor Rui Gelieting of independent research is looked forward to by China's medicine (retagliptin) domestic III phase clinical research is currently carried out.Clinical research shows DPP-IV inhibitor in 2 type glycosurias There is good hypoglycemic effect (Argyrakopoulou G, Doupis J.DPP4 inhibitors:from in patient's body sitagliptin monotherapy to the new alogliptin-pioglitazone combination therapy.Adv Ther.2009；26 (3): 272-80.), compared with traditional diabetes medicament, have the following advantages that [Scheen AJ.DPP-4inhibitors in the management of type 2diabetes:a critical review of head-to-head trials.Diabetes Metab.2012；38(2):89-101.；Gallwitz B.Emerging DPP-4inhibitors:focus on linagliptin for type 2diabetes.Diabetes Metab Syndr Obes.2013；6:1-9.]: 1) it is administered orally；2) incretin with blood glucose dependence, which is secreted, makees With hypoglycemia risk is small；2) it can protect, improve islet beta cell function, prevent β cell degradation, facilitate fundamentally from root Contain the process of diabetes B in sheet；3) it does not put on weight weight.Therefore, DPP-IV inhibitor is in the treatment of diabetes B Increasingly important role is played, the research hotspot of current antidiabetic object is become.

Summary of the invention

The purpose of the present invention is to provide a kind of compounds and its preparation method and application for inhibiting DPP-IV.Of the invention Another object is to provide intermediate of the compound and preparation method thereof.

The present invention provides Formulas I A or IB compound represented or its pharmaceutically acceptable salt,

R¹Selected from substituted or unsubstituted phenyl；R²Alkyl or substitution alkyl, 1-5 selected from C1-5 are a to be contained miscellaneous alkyl or takes In generation, is containing miscellaneous alkyl or 1-5 hetero atom or replaces hetero atom；R³Selected from H, CN or C1-10 alkyl or replace alkyl；X is selected from N Or CH；Y is selected from N or CR⁶, wherein R⁶Selected from H, CN, carboxyl or ester group.

Further, R¹In, the substituent group of the substituted-phenyl is 1-5 R⁴, wherein R⁴Selected from CN, halogen, C1-6 alkane The alkoxy that the alkoxy or halogen of alkyl or C1-6 that base or halogen replace replaces；

R²In, the substituent group for replacing alkyl is selected from halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷, replace hetero atom or the substituent group containing miscellaneous alkyl replaced to be halogen, CN, OH, R⁵、OR⁵、NHSO₂R⁵、SO₂R⁵, COOH or CO₂R⁷；

R³In, the substituent group for replacing alkyl is selected from 1-5 halogen；

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

Wherein, hetero atom N, O or S；R⁵For the alkyl or substitution alkyl of C1-6, substituent group is 1-5 halogen, COOH Or CO₂R⁷；R⁷For C1-6 alkyl.

Further, it is described containing miscellaneous alkyl be the alkyl containing 1 heteroatomic C1-4.

Further, R¹The phenyl replaced selected from halogen；R²Selected from containing miscellaneous alkyl, 1-2 hetero atom or C2-3 alkyl； R³The alkyl replaced selected from halogen.

It is further preferred that the halogen is F or Cl.

Wherein, the compound is

Further, R¹The phenyl replaced selected from halogen；R³The alkyl replaced selected from halogen；R⁶Selected from H, CN, carboxyl or ester Base.

Further, R⁶Selected from CO₂R⁷。

It is further preferred that the compound or its pharmaceutically acceptable salt are as follows:

Substituted five-membered heteroaromatic and tetrahydro pyrazine to the activity and DPP of DPP4 inhibitor other members (DPP2, DPP8, DPP9 selectivity) plays main contributions, and to tetrahydro pyrazine therein carry out the activity for replacing adjustable compound and Selectivity.But multiple chiral isomers will additionally be generated by increasing substituent group, to compound synthesis and be identified more difficult. The present invention has found in the course of the research, introduces substituent group by bridge joint mode, can not only reduce the complexity of chipal compounds Property and increase chiral controllability, while increasing compound rigidity, thus it is possible to vary the activity and selectivity of compound.However, It is found in early period synthesis process, to five yuan of substituted heteroaromatics and tetrahydro pyrazine carries out bridging, forms bridge parallel connection compound and is closing There is very strong challenge at upper, need to solve many technical problems, for example, the bridged ring of chiral control be difficult to be effectively formed, Simultaneously ring can not be directly by corresponding and ring forms (situation especially shorter to bridged ring), five yuan of heteroaromatic building process will receive for bridge The influence of bridged ring tension and be unable to complete, the secondary amine of amino acid and bridge and ring by steric influence connection difficult, bridge and ring is in shape The problems such as poor at the intermediate stability during final compound.Inventor passes through a large amount of experimental exploring and analysis, finally Ideal synthesis path has been worked up, problem present in synthesis process is effectively overcomed, has successfully synthesized bridge four Hydrogen pyrazine and substituted five-membered heteroaromatic, moreover, experiments verify that, these compounds have good inhibiting effect and selection to DPP4 Property.

The present invention also provides above compound or its pharmaceutically acceptable salts, are being used to prepare dipeptidyl peptidase-IV Purposes in inhibitor.

Further, the dipeptidyl peptidase-iv inhibitor is that treatment or/and prevention diabetes, hyperglycemia, insulin are anti- The drug of property.

The present invention also provides the preparation methods of the upper Formula II A or Formula II B compound, it is characterised in that: reaction includes Following steps:

Wherein, 1 Step: with (1S, 5R) -3,8- diazabicyclo [3.2.1] heptane -2- ketone (Tetrahedron, 1992,23,4985) it is raw material, is reacted under alkaline condition with di-tert-butyl dicarbonate, obtain the reaction that product gives over to next step Object；

Step 2: product obtained in the previous step carries out thio reaction with lawesson reagent, obtains product and gives over to the anti-of next step Answer object；

Step 3: by product obtained in the previous step, strong acid solution reaction is added, obtains the reaction that product gives over to next step Object；

Step 4: by the obtained product of Step 3 and R³-CONHNH₂In activating reagent R³The lower reaction of-COONa effect, obtains Product gives over to the reactant of next step；

Step 5: product, the R that Step 4 is obtained¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product Give over to the reactant of next step；

Step 6: product, the R that Step 3 is obtained¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product Give over to the reactant of next step；

Step 7: by the obtained product of Step 6 and R³-CONHNH₂In activating reagent R³The lower reaction of-COONa effect, obtains Product gives over to the reactant of next step；

Step 8: taking the product of Step 5 or Step 7, and strong acid is added and carries out deprotection reaction, obtains Formula II A product；

Alternatively, being raw material with (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone and using identical synthesis side Method is up to compound IIB；Or raceme raw material is used, after synthesizing according to the method described above, optical isomer is split, can be obtained Compound IIA or IIB.

Further, wherein 1 solvent for use of Step is aprotic solvent, and the non-protonic solvent is preferably dichloromethane Alkane, ethyl acetate or tetrahydrofuran, reaction temperature are 0 DEG C to 30 DEG C, and the reaction time is 2 to 16 hours；

2 solvent for use of Step is polar non-solute, and the non-protonic solvent is preferably tetrahydrofuran, ether, two Isopropyl ether or toluene, reaction temperature are 0 DEG C to 30 DEG C, and the reaction time is 0.5-3 hours；It can also make solvent with toluene, add Thermal response.

Acid used in Step 3 is proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and solvent for use is preferred For methylene chloride or ethyl acetate, reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 4 hours；

4 solvent for use of Step is polar protic solvent, and the polar protic solvent is preferably n-butanol, reaction temperature Degree is 110 to 130 DEG C, and preferably 118 DEG C, the reaction time is 2 to 12 hours；

5 solvent for use of Step is aprotic solvent, and the aprotic solvent is preferably methylene chloride, tetrahydrofuran or N, Dinethylformamide, alkali used are 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 Base urea hexafluorophosphoric acid ester, reaction temperature used are 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 2 hours；

6 solvent for use of Step is aprotic solvent, and the aprotic solvent is preferably methylene chloride, tetrahydrofuran or N, Dinethylformamide, alkali used are 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 hexafluorophosphoric acid ester, reaction temperature used are 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 2 hours.

7 solvent for use of Step is polar protic solvent, and the polar protic solvent is preferably n-butanol, reaction temperature Spending range is 110 to 130 DEG C, and the reaction time is 2 to 12 hours；

Acid used in Step 8 is proton strong acid, and the proton strong acid is preferably trifluoroacetic acid or hydrochloric acid, and solvent for use is preferred For methylene chloride, ethyl acetate or nothing, reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 4 hours.

The present invention also provides the preparation method of above-mentioned formula III A or IIIB compound, reaction step is as follows:

Wherein, Step 1:N-Boc-3- amino -1,2-PD and (S) -1- are to nitrobenzyloxycarbonyl -2- aziridine carboxylic Sour methyl esters reacts under conditions of Louis acid catalysis, obtains the reactant that product gives over to next step；

Step 2: previous step is obtained into product and carries out oxidation reaction, obtains the reactant that product gives over to next step；

Step 3: product obtained in the previous step is subjected to hydrogenation, obtains the reactant that product gives over to next step；

Step 4: by product obtained in the previous step, strong acid solution reaction deprotection is added, obtains product and gives over to next step Reactant；

Step 5: by product obtained in the previous step, the reaction of strong basicity organic solvent is added, obtains product and gives over to next step Reactant；

Step 6: product obtained in the previous step reacts under alkaline condition with di-tert-butyl dicarbonate, obtains product and gives over to The reactant of next step；

Step 7: by product obtained in the previous step, lawesson reagent reaction is added, obtains the reaction that product gives over to next step Object；

Step 8: by product obtained in the previous step, strongly acidic solution is added, reaction obtains product and gives over to the anti-of next step Answer object；

Step 9: by product obtained in the previous step, R¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product Give over to the reactant of next step；

Step 10: by product obtained in the previous step and R³-CONHNH₂In R³It reacts, is produced under-COONa activation Object gives over to the reactant of next step；

Step 11: strong acid reaction is added in product obtained in the previous step, obtains formula III A product；

Alternatively, replacement starting material is (R) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylate methyl ester, according to above-mentioned synthesis Compound IIIB is prepared in method；Alternatively, after synthesizing according to the method described above, being torn open using raceme N-Boc- serine methylester Spectroscopy isomers is up to compound IIIA or IIIB.

Further, wherein 1 solvent for use of Step is nonpolar solvent, and the nonpolar solvent is preferably toluene or two Toluene, lewis acid are preferably boron trifluoride ether, and reaction temperature is 20 to 30 DEG C, and the reaction time is 0.5 to 2 hours；

2 solvent for use of Step is polar non-solute, and the polar non-solute is preferably methylene chloride or tetrahydro Furans, reaction temperature are 0 DEG C to 30 DEG C, and the reaction time is 1 to 2 hours；

3 solvent for use of Step is polar solvent, and the polar solvent is preferably ethyl acetate or methanol, used catalyst For metallic catalyst, the metallic catalyst is preferably palladium carbon, and reaction temperature is 20 to 30 DEG C, and the reaction time is 2 to 4 hours；

4 solvent for use of Step is polar non-solute, and the polar aprotic solvent is preferably methylene chloride or second Acetoacetic ester, acid used are strong acid, preferably trifluoroacetic acid or hydrochloric acid, and reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 2 to 4 small When；

5 solvent for use of Step is polar aprotic solvent, and preferably methanol, highly basic used are preferably sodium methoxide, reaction temperature It is 20 to 30 DEG C, the reaction time is 4 to 16 hours；

Solvent described in Step 6 is polar aprotic solvent, and preferably methanol, the alkali are preferably tertiary amine, and the reaction time is 2 to 10 hours；

7 solvent for use of Step be polar non-solute, the non-protonic solvent be preferably tetrahydrofuran, ether or Di Iso Propyl Ether, reaction temperature are 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 3 hours；

8 solvent for use of Step is polar non-solute, and the polar aprotic solvent is preferably methylene chloride or second Acetoacetic ester, acid used are strong acid, preferably trifluoroacetic acid, and reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 2 to 4 hours；

9 solvent for use of Step is aprotic solvent, and the aprotic solvent is preferably methylene chloride, N, N to dimethyl methyl Amide or tetrahydrofuran, alkali used are 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 Base urea hexafluorophosphoric acid ester, reaction temperature used are 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 2 hours；

10 solvent for use of Step is polar protic solvent, and the polar protic solvent is preferably n-butanol, reaction temperature Degree is 110 to 130 DEG C, and preferably 118 DEG C of reaction time are 2 to 12 hours；

11 solvent for use of Step be polar non-solute, the polar aprotic solvent be preferably methylene chloride or Ethyl acetate, acid used are strong acid, preferably trifluoroacetic acid, and reaction temperature is 0 DEG C to 30 DEG C, and the reaction time is 0.5 to 2 small When.

The present invention also provides the intermediate of above-mentioned Formulas I A and IB compound, structural formula is as follows:

Wherein, R^2’The substitution alkyl of alkyl or C1-5 selected from C1-5；R^2”Taking containing miscellaneous alkyl or C1-5 selected from C1-5 In generation, contains miscellaneous alkyl, 1 hetero atom or 1 substitution hetero atom；R³Replace alkyl selected from H, CN or C1 alkyl or C1；X be selected from N or CH；

R³In, the substitution alkyl is replaced 1-5 halogen；

R^2’In, the substituent group for replacing alkyl is selected from halogen, CN, R⁵Or OR⁵；R^2”In, the hetero atom be selected from N, S or O replaces hetero atom or the substituent group containing miscellaneous alkyl is replaced to be halogen, CN, R⁵Or OR⁵；

Wherein, R⁵Replace alkyl for the alkyl or C1 of C1, substituent group is 1 halogen.

Further, the intermediate are as follows:

The present invention also provides the preparation method of above-mentioned Formula II AA or IIBA compound, reaction step is as follows:

Wherein, comprising the following steps:

Step 1: with (1S, 5R) -3,8- diazabicyclo [3.2.1] heptane -2- ketone (Tetrahedron, 1992,23, 4985) it is reacted in alkaline solution for raw material with di-tert-butyl dicarbonate, obtains the reactant that product gives over to next step；

Step 2: by product obtained in the previous step, lawesson reagent reaction is added, obtains the reaction that product gives over to next step Object；

Step 4: by product obtained in the previous step, R³-CONHNH₂With sodium acetate or R³- COONa reaction, obtains product and stays Make the reactant of next step；

Alternatively, replacement starting material is (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone, according to above-mentioned side Compound IIBA is prepared in method；Alternatively, after synthesizing according to the method described above, splitting optical isomer is using raceme raw material Obtain compound IIAA or IIBA.

Further, reaction step is as follows:

Wherein, reaction process the following steps are included:

Step 1: by N-Boc-3- amido-1,2-propanediol and (S) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylic acid first Ester reacts in a solvent, obtains the reactant that product gives over to next step；

Step 2: previous step is obtained into product and Dai Si-Martin reagent reacts, obtains the reaction that product gives over to next step Object；

Step 4: by product obtained in the previous step, strong acid solution is added, reaction obtains the reaction that product gives over to next step Object；

Step 5: by product obtained in the previous step, sodium methoxide is added and reacts in a solvent, obtains product and gives over to next step Reactant；

Step 6: by product obtained in the previous step, di-tert-butyl dicarbonate and tertiary amine reaction is added, obtains product and gives over to The reactant of next step；

Step 8: by product obtained in the previous step, strong acid solution is added, reaction obtains the reaction that product gives over to next step Object；

Alternatively, replacement starting material is (R) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylate methyl ester, according to the method described above Compound IIIBA is prepared；Alternatively, after synthesizing according to the method described above, splitting optical siomerism using raceme amino acid methyl ester Body is up to compound IIIAA or IIIBA.

The present invention also provides a kind of compound, shown in structural formula following IAA, IBA, IAB or IBB:

R³In, the substitution alkyl is replaced 1-5 halogen；

Further, the compound are as follows:

Further, the X is selected from N；R₃Selected from-CF₃。

The present invention also provides the preparation method of the Formula II AA or IIBA compound, reaction step is as follows:

Wherein, comprising the following steps:

Step 1: with (1S, 5R) -3,8- diazabicyclo [3.2.1] heptane -2- ketone for raw material and di-tert-butyl dicarbonate It is reacted in alkaline solution, obtains the reactant that product gives over to next step；

The present invention also provides one kind to prepare DPP-IV inhibitor using the Formula II AA or Formula II BA compound as raw material Method, it the following steps are included:

Wherein, R¹The phenyl replaced selected from halogen；

(1) by compound shown in Formula II AA, R¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product and give over to The reactant of next step；

(2) strong acid is added and carries out deprotection reaction, obtain Formula II A product；

Alternatively, using compound shown in Formula II BA as raw material and using identical synthetic method up to compound IIB:

Or the racemic mixture using compound shown in compound and Formula II BA shown in Formula II AA, according to the method described above After synthesis, optical isomer is split, can be obtained compound IIA or IIB.

The present invention also provides a kind of compound, shown in structural formula following IIIAA or IIIBA:

Further, reaction step is as follows:

Wherein, reaction process the following steps are included:

Step 7: by product obtained in the previous step, lawesson reagent is added, reaction obtains the reaction that product gives over to next step Object；

Step 8: by product obtained in the previous step, strong acid is added, reaction obtains the reactant that product gives over to next step；

Alternatively, replacement starting material is (R) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylate methyl ester, according to the method described above Compound IIIBA is prepared；

Alternatively, after synthesizing according to the method described above, splitting optical isomer using raceme amino acid methyl ester up to compound IIIAA or IIIBA.

The present invention also provides one kind to inhibit using the formula III AA or formula III BA compound as raw material preparation DPP-IV The method of agent, it the following steps are included:

Wherein, R¹The phenyl replaced selected from halogen；

(1) by compound shown in formula III AA, R¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product and stay Make the reactant of next step；

(2) by product obtained in the previous step and R³-CONHNH₂In sodium acetate or R³It reacts, obtains under-COONa activation Product gives over to the reactant of next step；

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

Alternatively, replacement starting material is compound shown in formula III BA, compound is prepared according to above-mentioned synthetic method IIIB:

Alternatively, using the racemic mixture of compound shown in compound shown in formula III AA and formula III BA, according to above-mentioned After method synthesis, optical isomer is split up to compound IIIA or IIIB.

The present invention also provides a kind of compound, shown in structural formula following IV A or IV B:

The present invention provides the preparation method of IV A of previously described formula or IV B compound, reaction step is as follows:

Wherein, comprising the following steps:

Step 3: by product obtained in the previous step, strong acid solution reaction is added, obtains IV A of product；

Alternatively, replacement starting material is (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone, according to above-mentioned side Compounds Ⅳ B is prepared in method；Alternatively, after synthesizing according to the method described above, splitting optical isomer using raceme raw material to obtain the final product Compounds Ⅳ A or IV B.

The present invention provides a kind of using IV A of previously described formula or IV B compound as the method for raw material preparation DPP-IV inhibitor, It the following steps are included:

Step 1: protection β aminobutyric acid, the condensation reagent that formula IV A, R1 are replaced react, and obtain product and give over in next step Reactant；

Step 2: replace formylhydrazine anti-in the case where activating reagent R3 replaces sodium formate to act on product and R3 that Step 1 is obtained It answers, obtains the reactant that product gives over to next step；

Step 3: the product for taking Step 2 to obtain is added strong acid and carries out deprotection reaction, obtains Formula II A product；

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

About the definition of the invention using term.Unless otherwise indicated, what group or term herein provided is initial Definition is suitable for group or term of entire description.For the term being not specifically defined herein, it should according to open Content and context, their meaning can be given by providing those skilled in the art.

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

The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix (Ca-b) alkyl Show any alkyl containing " a " to " b " a carbon atom.For example, (C1-4) alkyl refers to the alkyl comprising 1-4 carbon atom.

Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.

Term " salt " and " pharmaceutical salt " are by compound or its stereoisomer, with inorganic and/or organic bronsted lowry acids and bases bronsted lowry The acid and/or basic salt of formation also include amphoteric ion salt (inner salt), further include quaternary ammonium salt, such as alkylammonium salt.These salt It can be and directly obtained in being finally separating and purify of compound.It is also possible to by by compound or its stereoisomer, It is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be formed in the solution precipitating and It is collected with filter method, or recycles obtain after the solvent evaporates, or be freeze-dried and be made after reacting in an aqueous medium.The present invention Described in salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, the phosphoric acid of compound Salt, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartrate Or trifluoroacetate.

In one embodiment of the present invention, present invention comprises the formula of isotope labelling (IA) or (IB) compound, The compound isotopically labelled refers to identical as listed compound herein, but one or more of atoms are another A atom replaces, and the atomic mass or mass number of the atom are different from atomic mass or mass number common in nature.It can be with Isotope in introduction-type (IA) or (IB) compound includes hydrogen, carbon, nitrogen, oxygen, sulphur, i.e. 2H, 3H, 13C, 14C, 15N, 17O, 18O,35S.The compound and its alloisomerism of formula (IA) or (IB) containing above-mentioned isotope and/or other atom isotopes The pharmaceutical salt of body and the compound, stereoisomer should be included within the scope of the invention.

Key intermediate and compound in the present invention are separated and are purified, and used mode is normal in organic chemistry The example of Isolation and purification method and the method includes filtering, extraction, drying, is spin-dried for and various types of chromatographies.It can Selectively, intermediate can be made to carry out next step reaction without further purification.

In some embodiments, one or more compounds of the invention can be used in conjunction with one another.Also may be selected will The compound of the present invention is used in combination with any other active agent, is used to prepare regulating cell function or treats the medicine of disease Object or pharmaceutical composition.If using one group of compound, can by these compounds simultaneously, respectively or in an orderly manner to tested Object is administered.

It is active that the compounds of this invention can effectively inhibit DPP-IV, and to member DPP2, DPP8, DPP9 of DPP family With reasonable selectivity.These compounds can be used in and treatment of DPP-4 related disease a variety of to diabetes etc., for clinic Medication provides new selection.

Specific embodiment

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

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

Thionyl chloride (65mL, 900mmol) is added dropwise in 100mL methanol in ice bath, L- coke paddy ammonia is then added Sour 1a (58g, 449mmol).Decompressing and extracting solvent after 16h is stirred at room temperature in reaction mixture.Ethyl acetate is added (200mL), sodium carbonate (50g) and water (100mL) simultaneously stir 1 hour.Organic phase is separated, water phase (100mL is extracted with ethyl acetate ×3).Merge organic phase, anhydrous sodium sulfate is dry, and is concentrated to get compound 1b, colourless liquid 51g, yield 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 dry DMF of 80mL, is slowly added to sodium hydride under ice bath stirring (4g, 170mmol) after adding stirring 1 hour, is added bromobenzyl (28.7g, 168mmol).Ice bath is removed, is stirred overnight at room temperature.With Methylene chloride (300mL) extraction, and washed with saturated sodium bicarbonate (100mL × 3).Organic phase is dried over anhydrous sodium sulfate rear dense It is reduced to dry.Crude product obtains compound 1c, white solid 18g after column chromatography (silica gel, ethyl acetate/petroleum ether elution), receives Rate 55%.

MS(ESI)m/z:234(M+1)；¹HNMR(400mHz,CDCl₃):δ2.00-2.63(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 formate (compound 1d)

Compound 1c is dissolved in 80mL dry tetrahydrofuran, with vigorous stirring be added lawesson reagent (12.5g, 30mmol).Decompressing and extracting tetrahydrofuran after 3 hours, and residue is dissolved with ethyl acetate (150mL), then use saturated carbon respectively Sour hydrogen sodium (50mL × 3) and saturated sodium-chloride (50mL) washing.Organic phase is concentrated after being dried over anhydrous sodium sulfate.Crude product passes through column Chromatography (silica gel, ethyl acetate/petroleum ether) purifying obtains compound 1d, white solid 11g, yield 86%.

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 group) -5- (methyl mercapto) -3,4- dihydro-2 h-pyrrole -1- iodate (change Close object 1e)

Compound 1d (11g, 44mmol) is dissolved in 40mL iodomethane, is stirred overnight at room temperature, is concentrated under reduced pressure to give compound 1e, yellow solid 16g, yield 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)-pyrrolidines -2- methyl formate (compound 1f)

Compound 1e (8g, 20.5mmol) is dissolved in the dry DMF of 50mL, and nitromethane (7.5g, 123mmol) and three are added Ethamine (4mL, 29mmol), is stirred overnight at room temperature.Then it is reacted 5 hours at 60 DEG C.Decompressing and extracting solvent, then chromatographs through column Compound 1f, yellow liquid 4.8g, yield 85% are obtained after (silica gel, ethyl acetate/petroleum ether elution).

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) -3,8- nitrogen di (hetero) two ring [3.2.1] octane -2- ketone (compound 1g)

Under 10% palladium carbon catalytic action, by compound 1f (2.1g, 7.6mmol) in ethyl acetate and acetic acid mixed solution Hydrogenation 4 hours in (10mL+10mL).Palladium-carbon catalyst is filtered out with diatomite, is then concentrated to dryness.By residue (1.8g, It 7.3mmol) is dissolved in 15mL methanol, ammonium formate (4.57g, 72.5mmol) and 10% palladium carbon (1.5g) is added, and flow back 4 hours. Palladium-carbon catalyst is filtered out with diatomite, is then concentrated to dryness to obtain compound 1g, white solid 0.9g, yield 94%.

MS(ESI)m/z:127(M+1)；¹HNMR(400mHz,CDCl₃):δ1.75(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) two ring [3.2.1] octane -2- ketone (compound 1h) of -8- tertbutyloxycarbonyl -3,8- nitrogen di (hetero)

Di-tert-butyl dicarbonate is added into the 40mL dichloromethane solution of compound 1g (2g, 15.9mmol) under ice bath (5.19g, 23.8mmol) and triethylamine (0.66mL, 4.8mmol), and allow to be warmed to room temperature reaction overnight.Vacuum distillation removes After solvent, residue is subjected to column chromatography (silica gel, ethyl acetate/petroleum ether elution) and obtains compound 1h, white solid 2.8g, Yield 78%.

MS(ESI)m/z:227(M+1)；¹HNMR(400mHz,CDCl₃):δ1.45(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) two thio ketone (compound of ring [3.2.1] octane -2- of -8- tertbutyloxycarbonyl -3,8- nitrogen di (hetero) 1i)

Compound 1h (40mg, 0.18mmol) is dissolved in 5mL tetrahydrofuran, and lawesson reagent is added with vigorous stirring (43mg, 0.1mmol).After reaction solution stirs 3 hours, reaction solution is evaporated and is re-dissolved into 20mL ethyl acetate.It is organic Mutually through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate is dry, decompression is arranged to dry.Crude product is chromatographed by column Compound 1i, white solid 35mg, yield 86% are obtained after (silica gel, ethyl acetate/petroleum ether elution).MS(ESI)m/z:243 (M+1)。

Step 9:(1S, 5R) two thio ketone (compound 1j) of ring [3.2.1] octane -2- of -3,8- nitrogen di (hetero)

Compound 1i (40mg, 0.16mmol) is dissolved in 0.2mL methanol, 4N hydrochloric ethyl acetate solution is then added (4mL), and be stirred at room temperature overnight.Compound 1j, white solid will be obtained after excessive hydrochloric acid and solvent distillation under pressure 23mg, yield 98%).MS(ESI)m/z:143(M+1).

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

By compound 1j (37mg, 0.262mmol), 2,2,2- trifluoroacetyl hydrazines (101mg, 0.787mmol) and sodium acetate (65mg, 0.79mmol) is dissolved in 10mL n-butanol, and is evaporated solvent after being refluxed overnight.Crude product passes through preparative high-efficient liquid phase color Compound 1k, yellow oil 7.4mg, yield 13% are obtained after spectrum.MS(ESI)m/z:219(M+1).

Step 11:((2R) -4- oxygen -4- (6R, 9S) -3- trifluoromethyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -1- (2,4,5- trifluorophenyl) butyl- 2- alkyl) t-butyl formate (changes Close object 1l)

By compound 1k (35mg, 0.162mmol) and (R) -3- tert-butoxycarbonylamino -4- (2,4,5- trifluorophenyl) butyric acid (53.9mg, 0.2mmol) is dissolved in 2mL methylene chloride, and sequentially add under ice bath I-hydroxybenzotriazole (26mg, 0.2mmol) and 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride (47mg, 0.24mmol).After reaction 4 hours, add Enter 15mL methylene chloride and is received (5mL) with unsaturated carbonate hydrogen and saturated salt solution (5mL) washs.Organic phase is concentrated after drying It is extremely dry.Crude product obtains compound 1l, yellow oil 53mg, yield 72% after preparative high performance liquid chromatography.MS(ESI) m/z:534(M+1)。

Step 12:(R) -3- amino -1- ((6R, 9S) -3- trifluoromethyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone (compound 1)

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

MS(ESI)m/z:434(M+1)；¹HNMR(400mHz,DMSO-d₆):δ1.92-2.35(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- tetrahydro -5H-6,9- epimino [1,2,4] three Nitrogen azoles simultaneously [4,3-a] azepines -10- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone trifluoroacetate (compound 1 ') Preparation

The preparation of compound 1 ' is obtained using opposite-handed compound 1a and with the identical preparation method of compound 1 Obtain

Embodiment 2:(3R) -3- amino -1- (3- trifluoromethyl -6,7,9,10- tetrahydro -5H-6,10- epimino [1,2,4] Triazol [3,4-d] [1,5] oxazole star -11- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone trifluoroacetate (compound 2)

Step 1:(2S) -3- (3- tertiary butyloxycarbonyl acylamino- -2- propoxyl) -2- is to nitro benzyloxy carbonyl acylamino--propionic acid Methyl esters (compound 2b)

It is molten to the toluene (80mL) of compound 2l (6.82g, 35.7mmol) and compound 2a (5g, 17.8mmol) at room temperature Boron trifluoride ether (0.3mL, 48%) is added dropwise in liquid.It is concentrated after removing solvent after stirring 2h at room temperature through column chromatography (silica gel, stone Oily ether: ethyl acetate=2:1) obtain product 2b, yellow oil 4.8g, yield 57%.

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- tertiary butyloxycarbonyl acylamino- -2- carbonyl propoxyl group) -2- is to nitro benzyloxy carbonyl acylamino--the third Sour methyl esters (compound 2c)

It is added under ice bath into methylene chloride (150mL) solution of compound 2b (4.7g, 10mmol) and Dai Si-is added portionwise Horse spit of fland reagent (6.34g, 15.0mmol).After reacting 1h, Na is added into reaction solution₂S₂O₃Solution (2N, 120mL) quenching reaction, Liquid separation, water phase are extracted with methylene chloride (100mL × 2).Merge organic phase, successively use saturated sodium bicarbonate solution (350mL), satisfies (350mL) is washed with salt.Organic phase chromatographs (silica gel, ethyl acetate: petroleum ether=1:1) through column again through drying, filtering, concentration Obtain product 2c, yellow oil 2.15g, yield 45.9%.

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 Aminomethyl-morpholine -3- methyl formate (compound 2d)

Palladium carbon (0.5g, 10%) is added to ethyl acetate (50mL) solution of compound 2c (2.0g, 4.26mmol), in hydrogen 2h. reaction solution is stirred in gas to be filtered, be concentrated and obtain product 2d, colorless oil 0.6g, yield through quick post separation again 51.3%.

MS(ESI)m/z:275,219(M-56+1)；¹H-NMR(400mHz,CDCl₃):δ4.97(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- Aminomethyl-morpholine -3- methyl formate (compound 2e)

Under ice bath, trifluoroacetic acid is added dropwise into methylene chloride (10mL) solution of compound 2d (500mg, 1.82mmol) Reaction solution is concentrated to get compound 2e, white solid 0.73g, yield 100% after being stirred at room temperature 2 hours by (10mL).

MS(ESI)m/z:175(M+1)。

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

It is stirred that compound 2e (317mg, 1.82mmol) and sodium methoxide (491mg, 9.1mmol) are dissolved in meOH (20mL) At night, filtering, filtrate (compound 2f solution) is directly used in be reacted in next step.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)

N, N- diisopropyl is successively added into methanol (20mL) solution of compound 2f (259mg, 1.82mmol) under ice bath Base ethamine (470mg, 3.64mmol) and di-tert-butyl dicarbonate (476mg, 2.2mmol).It is after reacting 2h at room temperature, solvent is dense Contracting removes, and residue is dissolved in ethyl acetate (20mL), successively uses saturated sodium bicarbonate solution (20mL), saturated common salt washing (20mL).Organic phase obtains product 2g through column chromatography (silica gel, ethyl acetate: petroleum ether=1:1) again through drying, filtering, concentration, White solid 0.22g, yield 50%.

MS(ESI)m/z:243(M+1)；¹HNMR(400mHz,CDCl₃):δ6.00(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) is added to the anhydrous tetrahydro furan of compound 2g (220mg, 0.91mmol) In (10mL) then stirring 3h., which is concentrated, removes solvent, and residue is dissolved in ethyl acetate (20mL), successively molten with saturated sodium bicarbonate Liquid (20mL), saturated common salt wash (20mL).Organic phase chromatographs (silica gel, ethyl acetate: stone through column again through drying, filtering, concentration Oily ether=1:1) obtain product 2h, white solid 0.12g, yield 50%.

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, trifluoroacetic acid is added dropwise into methylene chloride (3mL) solution of compound 2h (117mg, 0.45mmol) Reaction solution is concentrated to get compound 9, white solid 123mg, yield 100% after being stirred at room temperature 2 hours by (3mL).

MS(ESI)m/z:159(M+1)。

Step 9:((2R) -4- carbonyl -4- (6- thiocarbonyl group -3- oxo -7,9- diazabicyclo [3.3.1] nonyl- 9- alkane Base) -1- (2,4,5- trifluorophenyl) butyl- 2- alkyl) benzyq carbamate (compound 2j)

N is sequentially added into methylene chloride (10mL) solution of compound 2i (71mg, 0.45mmol) under ice bath, N- bis- is different Propylethylamine (117mg, 0.91mmol), 2m (209mg, 0.54mmol).After reaction two hours, reaction solution successively uses unsaturated carbonate Hydrogen sodium (8mL), saturated salt solution (8mL) are washed.Organic phase chromatographs (silica gel, ethyl acetate: stone through column again through drying, filtering, concentration Oily ether=1:1) obtain product 2j, white solid 0.132g, yield 57.4%.

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- tetrahydro -5H-6,10- epimino [1,2,4] Triazol [3,4-d] [1,5] oxazole star -11- alkyl) -1- (2,4,5- trifluorophenyl) -2- butyl) benzyq carbamate (chemical combination Object 2k)

Compound 2j (132mg, 0.26mmol), trifluoroacetyl hydrazine (100mg, 0.78mmol) and sodium acetate (64mg, After 0.78mmol) being dissolved in n-butanol (5mL), heated overnight at reflux.(silica gel, acetic acid second are chromatographed through column after reaction mixture concentration Ester: petroleum ether=2:1) obtain product 2k, white solid 60mg, yield 39%.

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- tetrahydro -5H-6,10- epimino [1,2,4] Triazol [3,4-d] [1,5] oxazole star -11- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone trifluoroacetate (compound 2)

Palladium carbon (32mg, 10%) is added to ethyl acetate (5mL) solution of compound 2k (30mg, 0.089mmol), It is stirred in hydrogen and product 2, white solid 15mg, yield 24% is prepared through HPLC after 2h. reaction solution is filtered, is concentrated.

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- tetrahydro -5H-6,9- epimino [1,2,4] Triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone trifluoroacetate (compound 3) Preparation

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

Successively to the 10mL of (R) -3- tert-butoxycarbonylamino -4- (2,4,5- trifluorophenyl) butyric acid (347mg, 1.04mmol) Diisopropylethylamine (593mg, 4.6mmol) is added in methylene chloride, 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride Salt (265mg, 1.38mmol), I-hydroxybenzotriazole (186mg, 1.38mmol) stir 1 hour at room temperature.Then by chemical combination Reaction system is added in object 1j (150mg), is stirred overnight at room temperature.After reaction solution saturated common salt water washing, dry, concentration.Slightly Product obtain compound 3a, white solid 170mg, yield 42% after silica gel column purification (methylene chloride: methanol=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- tetrahydro -5H-6,9- epimino [1,2,4] triazol [4,3-a] azepines -10-yl) -4- carbonyl -1- (2,4,5- trifluorophenyl) -2- butyl) t-butyl carbamate (compound 3b)

In the 15mL butanol solution of compound 3a (120mg, 0.372mmol), sequentially add acethydrazide (82mg, 1.11mmol) with sodium acetate (152mg, 1.86mmol), it is then refluxed for 18 hours.After n-butanol decompression is divided exactly, residue is molten In 10mL methylene chloride, and with saturated common salt water washing.After organic phase is dry, it is concentrated to get crude product, with silica gel column purification (dichloro Methane: methanol=80:1) after obtain compound 3b, white solid 80mg, yield 60%.

MSm/z(ESI):480(M+H)⁺,380[(M+H)⁺-Boc]。

Step 3 (R) -3- amino -1- ((6R, 9S) -3- methyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1,2,4] Triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2,4,5- trifluorophenyl) -1- butanone trifluoroacetate (compound 3)

Under ice bath, to 3mL trifluoroacetic acid is added in compound 3b (80mg, 0.15mmol), it is then warmed to room temperature stirring 30 Minute.After vacuum distillation removes trifluoroacetic acid, residue obtains compound 3, white solid with liquid chromatography purification, and 30mg is received 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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2- aminomethyl phenyl) -1- butanone trifluoroacetate (compound 4) Preparation

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- trifluorophenyl) butyric acid (74.22mg, 0.25mmol) Diisopropylethylamine (89mg, 0.69mmol) is added in 5mL methylene chloride, 1- ethyl -3- (3- dimethylamine propyl) carbodiimide Hydrochloride (65.90mg, 0.35mmol), I-hydroxybenzotriazole (37.26mg, 0.28mmol) stir 0.5 hour at room temperature. Then reaction system is added in compound 1j (32.71mg, 0.23mmol), be stirred overnight at room temperature.10mL will be added in reaction solution Saturated salt solution is extracted with methylene chloride (15mL × 3), is merged drying, is concentrated to give crude product.Crude product is through silica gel column purification (dichloro Methane: methanol=100:1) after obtain compound 4a, white solid 60mg, yield 62.%).

MS(ESI)M/Z:418(M+H),362(M-tBu)。

Step 2:((R) -4- ((6R, 9S) -3- trifluoromethyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1,2,4] three Azoles simultaneously [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), 2,2,2- trifluoroacetyl hydrazines are sequentially added (55.20mg, 0.43mmol) and sodium acetate (35mg, 0.43mol) is then refluxed for overnight.It is remaining after n-butanol decompression is divided exactly 5mL water is added in object, is extracted with methylene chloride (15mL × 3), and by the saturated common salt water washing of the organic phase after merging.Organic phase After drying, it is concentrated to get crude product, with obtaining compound 4b, white solid after silica gel column purification (methylene chloride: methanol=100:1) 23mg, yield 30%).MS(ESI)M/Z:494(M+H),438(M-tBu).

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

Under ice bath, to 3mL trifluoroacetic acid is added in compound 4b (23mg, 0.046mmol), it is then warmed to room temperature stirring 30 Minute.After vacuum distillation removes trifluoroacetic acid, residue obtains compound 4 with liquid chromatography purification, colorless oil 10mg, Yield 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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2- fluorophenyl) -1- butanone trifluoroacetate (compound 5) system It is standby

Step 1:((R) -4- ((6R, 9S) -3- trifluoromethyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1,2,4] three Azoles simultaneously [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- trifluorophenyl) butyric acid (50.97mg, 0.17mmol) Diisopropylethylamine (60.31mg, 0.47mmol) is added in 5mL methylene chloride, 1- ethyl -3- (3- dimethylamine propyl) carbon two is sub- It is small to stir 0.5 at room temperature for amine hydrochlorate (44.65mg, 0.23mmol), I-hydroxybenzotriazole (25.25mg, 0.18mmol) When.Then reaction system is added in compound 1k (34.00mg, 0.15mmol), be stirred overnight at room temperature.It will be added in reaction solution 10mL saturated salt solution is extracted with methylene chloride (15mL × 3), is merged drying, is concentrated to give crude product.Crude product is through silica gel column purification Compound 5a, white solid 32mg, yield 41.28% are obtained after (methylene chloride: methanol=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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2- fluorophenyl) -1- butanone trifluoroacetate (compound 5)

Under ice bath, to 3mL trifluoroacetic acid is added in compound 5a (32.00mg, 0.064mmol), then it is warmed to room temperature and stirs It mixes 30 minutes.After vacuum distillation removes trifluoroacetic acid, residue obtains compound 5, colorless oil with liquid chromatography purification 10mg, yield 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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (3- chlorphenyl) -1- butanone trifluoroacetate (compound 6) system It is standby

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

Successively to (R) -3- tert-butoxycarbonylamino -4- (2,4,5- trifluorophenyl) butyric acid (69.03mg, 0.22mmol) Diisopropylethylamine (85.14mg, 0.66mmol) is added in 5mL methylene chloride, 1- ethyl -3- (3- dimethylamine propyl) carbon two is sub- It is small to stir 0.5 at room temperature for amine hydrochlorate (63.03mg, 0.33mmol), I-hydroxybenzotriazole (44.55mg, 0.33mmol) When.Then reaction system is added in compound 1j (31.29mg, 0.22mmol), be stirred overnight at room temperature.It will be added in reaction solution 10mL saturated salt solution is extracted with methylene chloride (15mL × 3), is merged drying, is concentrated to give crude product.Crude product is through silica gel column purification Compound 6a, white solid 50mg, yield 52% are obtained after (methylene chloride: methanol=100:1).

MS(ESI)M/Z:438(M+H),382(M-tBu)。

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

In the 5mL butanol solution of compound 6a (50mg, 0.11mmol), 2,2,2- trifluoroacetyl hydrazines are sequentially added (55.20mg, 0.43mmol) and sodium acetate (28mg, 0.34mol) is then refluxed for overnight.It is remaining after n-butanol decompression is divided exactly 5mL water is added in object, is extracted with methylene chloride (15mL × 3), and by the saturated common salt water washing of the organic phase after merging.Organic phase After drying, it is concentrated to get crude product, with obtaining compound 6b, white solid after silica gel column purification (methylene chloride: methanol=100:1) 12mg, yield 25%).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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (3- chlorphenyl) -1- butanone trifluoroacetate (compound 6)

Under ice bath, to 3mL trifluoroacetic acid is added in compound 6b (12mg, 0.023mmol), it is then warmed to room temperature stirring 30 Minute.After vacuum distillation removes trifluoroacetic acid, residue obtains compound 6 with liquid chromatography purification, colorless oil 8mg, Yield 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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2,5- difluorophenyl) -1- butanone trifluoroacetate (compound 7) Preparation

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 the 10mL of (R) -3- tert-butoxycarbonylamino -4- (2,4,5- trifluorophenyl) butyric acid (290mg, 0.92mmol) Diisopropylethylamine (593mg, 4.6mmol) is added in methylene chloride, 1- ethyl -3- (3- dimethylamine propyl) carbodiimide hydrochloride Salt (265mg, 1.38mmol), I-hydroxybenzotriazole (186mg, 1.38mmol) stir 1 hour at room temperature.Then by chemical combination Reaction system is added in object 1j (150mg, 1.06mmol), is stirred overnight at room temperature.20mL saturated salt solution will be added in reaction solution, uses Methylene chloride (15mL × 3) extraction merges drying, is concentrated to give crude product.Crude product through silica gel column purification (methylene chloride: methanol=80: 1) compound 7a, colorless oil 170mg, yield 36.4% are obtained after.

MS(ESI)m/z:440(M+H)⁺,340[(M+H)⁺-Boc]。

Step 2:((R) -4- ((6R, 9S) -3- trifluoromethyl -6,7,8,9- tetrahydro -5H-6,9- epimino [1,2,4] three Azoles simultaneously [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), the 2 of 1M, 2,2- trifluoros are sequentially added Acethydrazide (1.16mL, 1.16mmol) and sodium acetate (159mg, 1.94mmol)), it is then refluxed for 18 hours.N-butanol is depressurized After dividing exactly, 10mL methylene chloride is added in residue, and after saturated common salt water washing, organic phase is dry, is concentrated to get crude product, uses silicon Compound 7b white solid 80mg, yield 40% are obtained after rubber column gel column purifying (methylene chloride: methanol=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- tetrahydro -5H-6,9- epimino [1, 2,4] triazole simultaneously [4,3-a] azepines -10- alkyl) -4- (2,5- difluorophenyl) -1- butanone trifluoroacetate (compound 7)

Under ice bath, to 3mL trifluoroacetic acid is added in compound 7b (80mg, 0.15mmol), it is then warmed to room temperature stirring 30 Minute.After vacuum distillation removes trifluoroacetic acid, residue obtains compound 7 with liquid chromatography purification, and white solid 30mg is received 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- tetrahydro -5H-6,9- epimino [1,2,4] three Nitrogen azoles simultaneously [4,3-a] azepines -10- alkyl) the various salt (compound 8a-f) of -4- (2,4,5- trifluorophenyl) -1- butanone system It is standby

Compound 8a

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino, the hydrobromic acid of 0.11M is added (0.209ml) water and methanol solution (methanol: water=4:1) stir 30 minutes, are concentrated to dryness to obtain compound 8a, white solid 11.8mg, yield 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

In the 1mL methanol solution of the compound 1 (10mg, 0.023mmol) of free amino, the acetic acid of 0.11M is added (0.209ml) water and methanol solution (methanol: water=4:1) stir 30 minutes, are concentrated to dryness to obtain compound 8b, white solid 11.3mg, yield 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, be added (2.67mg, 0.023mmol) maleic acid stirs 30 minutes, is concentrated to dryness to obtain compound 8c, white solid 13mg, yield 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, be added (2.67mg, 0.023mmol) succinic acid stirs 30 minutes, is concentrated to dryness to obtain compound 8d, white solid 12.6mg, yield 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, be added (3.08mg, 0.023mmol) malic acid stirs 30 minutes, is concentrated to dryness to obtain compound 8e, white solid 13mg, yield 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, be added (3.45mg, 0.023mmol) tartaric acid stirs 30 minutes, is concentrated to dryness to obtain compound 8f, white solid 14mg, yield 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)。

Beneficial effects of the present invention are illustrated below by way of test example.

Test example 1

DPP-4, DPP-2, DPP-8, DPP-9 are the members of DPP family, the study found that if inhibiting its in addition to DPP-4 He will cause suspend mode T cell dead, stomach poison by enzyme when can then generate side effect, such as inhibition DPP-8, DPP-9 enzyme activity to body A series of toxic side effects such as property and body's immunity, therefore, at present in the exploitation of DPP-4 (i.e. DPP-IV) enzyme inhibitor, It is required that improving inhibitor to the selectivity of DPP-4, while the selectivity to other families of DPP is reduced, to reduce inhibitor Toxic side effect.

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

The detection of DPP-4, DPP-2, DPP-8, DPP-9 external activity

Untested compound is dissolved in dimethyl sulfoxide, then with buffer solution (DPP4:100mM HEPES, pH 7.5, 0.1mg/mL BSA；DPP2:100mM HEPES, pH 5.5,0.1mg/mL BSA；DPP8:50mM Tris-HCl, pH7.5, 0.1mg/mL BSA；DPP9:25mM Tris-HCl, pH 7.5,0.1mg/mL BSA) to be diluted to a series of work molten Liquid.By recombined human DPP-4 (ultimate density is about 180ng/mL) or DPP-2 (ultimate density is about 100ng/mL) or DPP-8 is (most Final concentration is about 200ng/mL) or DPP-9 (ultimate density is about 50ng/mL) and above-mentioned a series of compound working solution it is mixed It closes, Gly-Pro-AMC (ultimate density DPP4 is 50 μM, and DPP2/8/9 is 20 μM) (total reaction volume is 100 μ L) is then added, AMC (excitation wavelength 360nm, launch wavelength 460nm) 15 minutes of continuous detection release at once.It is calculated with SigmaPlot software Half-inhibitory concentration IC50, as a result referring to following table.

1 compound of table is to DPP-4 inhibition

Inhibitory activity of 2 compound of table to DPP family

It is active that the above results show that the compounds of this invention can effectively inhibit DPP-IV, and to the member of DPP family DPP-2, DPP-8, DPP-9 have selectivity well.These compounds can be used in a variety of to diabetes etc. related to DPP-4 The treatment of disease provides new selection for clinical application.

Claims

1. a kind of compound, shown in structural formula following IAA, IBA, IAB or IBB:

Wherein, R^2’The substitution alkyl of alkyl or C1-5 selected from C1-5；R^2”The substitution containing miscellaneous alkyl or C1-5 selected from C1-5 contains Miscellaneous alkyl, 1 hetero atom or 1 substitution hetero atom；R³Replace alkyl selected from H, CN or C1 alkyl or C1；X is selected from N or CH；

R³In, the substitution alkyl is replaced 1-5 halogen；

R^2’In, the substituent group for replacing alkyl is selected from halogen, CN, R⁵Or OR⁵；R^2”In, the hetero atom is selected from N, S or O, takes For hetero atom or the substituent group containing miscellaneous alkyl is replaced to be halogen, CN, R⁵Or OR⁵；

Wherein, R⁵Replace alkyl for C1 alkyl or C1, substituent group is 1 halogen.

2. compound according to claim 1, it is characterised in that: the compound are as follows:

3. compound according to claim 2, feature exist: the X is selected from N；R₃Selected from CF₃。

4. the preparation method of Formula II AA or IIBA compound described in claim 2, it is characterised in that: reaction step is as follows:

Wherein, comprising the following steps:

S1: being that raw material and di-tert-butyl dicarbonate are molten in alkalinity with (1S, 5R) -3,8- diazabicyclo [3.2.1] heptane -2- ketone It is reacted in liquid, obtains the reactant that product gives over to next step；

S2: by product obtained in the previous step, lawesson reagent reaction is added, obtains the reactant that product gives over to next step；

S3: by product obtained in the previous step, strong acid solution reaction is added, obtains the reactant that product gives over to next step；

S4: by product obtained in the previous step, R³-CONHNH₂With sodium acetate or R³- COONa reaction obtains product and gives over in next step Reactant；

Alternatively, replacement starting material is (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone, make according to the method described above It is standby to obtain compound IIBA；Alternatively, after synthesizing according to the method described above, splitting optical isomer using raceme raw material up to changing Close object IIAA or IIBA.

5. a kind of side for preparing DPP-IV inhibitor using Formula II AA described in Claims 2 or 3 or Formula II BA compound as raw material Method, it the following steps are included:

Wherein, R¹The phenyl replaced selected from halogen；

(1) by compound shown in Formula II AA, R¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product give over to it is next The reactant of step；

Or the racemic mixture using compound shown in compound and Formula II BA shown in Formula II AA, it synthesizes according to the method described above Afterwards, optical isomer is split, can be obtained compound IIA or IIB.

6. a kind of compound, shown in structural formula following IIIAA or IIIBA:

7. the preparation method of formula III AA or IIIBA compound described in claim 6, it is characterised in that: reaction step is as follows:

Wherein, reaction process the following steps are included:

S1: by N-Boc-3- amido-1,2-propanediol and (S) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylate methyl ester in solvent Middle reaction obtains the reactant that product gives over to next step；

S2: previous step is obtained into product and Dai Si-Martin reagent reacts, obtains the reactant that product gives over to next step；

S3: product obtained in the previous step is subjected to hydrogenation, obtains the reactant that product gives over to next step；

S4: by product obtained in the previous step, strong acid solution is added, reaction obtains the reactant that product gives over to next step；

S5: by product obtained in the previous step, sodium methoxide is added and reacts in a solvent, obtains the reactant that product gives over to next step；

S6: by product obtained in the previous step, di-tert-butyl dicarbonate and tertiary amine reaction is added, obtains product and gives over to next step Reactant；

S7: by product obtained in the previous step, lawesson reagent is added, reaction obtains the reactant that product gives over to next step；

S8: by product obtained in the previous step, strong acid is added, reaction obtains the reactant that product gives over to next step；

Alternatively, replacement starting material is (R) -1- to nitrobenzyloxycarbonyl -2- aziridine carboxylate methyl ester, prepare according to the method described above Obtain compound IIIBA；

8. a kind of side for preparing DPP-IV inhibitor using formula III AA described in claim 6 or formula III BA compound as raw material Method, it the following steps are included:

Wherein, R¹The phenyl replaced selected from halogen；

(1) by compound shown in formula III AA, R¹Substituted protection β aminobutyric acid, condensation reagent reaction, obtain product give over to it is next The reactant of step；

(2) by product obtained in the previous step and R³-CONHNH₂In sodium acetate or R³It is reacted under-COONa activation, obtains product Give over to the reactant of next step；

Alternatively, replacement starting material is compound shown in formula III BA, compound IIIB is prepared according to above-mentioned synthetic method:

Alternatively, using the racemic mixture of compound shown in compound shown in formula III AA and formula III BA, according to the method described above After synthesis, optical isomer is split up to compound IIIA or IIIB.

9. a kind of compound, shown in structural formula following IV A or IV B:

10. the preparation method of IV A of formula or IV B compound described in claim 9, it is characterised in that: reaction step is as follows:

Wherein, comprising the following steps:

S3: by product obtained in the previous step, strong acid solution reaction is added, obtains IV A of product；

Alternatively, replacement starting material is (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone, make according to the method described above It is standby to obtain compounds Ⅳ B；Alternatively, after synthesizing according to the method described above, splitting optical isomer using raceme raw material up to chemical combination Object IV A or IV B.

11. a kind of using IV A of formula described in claim 9 or IV B compound as the method for raw material preparation DPP-IV inhibitor, it is wrapped Include following steps:

S1: protection β aminobutyric acid, the condensation reagent that formula IV A, R1 are replaced react, and obtain the reactant that product gives over to next step；

S2: replace formylhydrazine to react in the case where activating reagent R3 replaces sodium formate to act on R3 the product that S1 is obtained, obtain product Give over to the reactant of next step；

S3: the product for taking S2 to obtain is added strong acid and carries out deprotection reaction, obtains Formula II A product；

Alternatively, being with (1R, 5S) -3,8- diazabicyclo [3.2.1] heptane -2- ketone for raw material and using identical synthetic method Obtain compound IIB；Or raceme raw material is used, after synthesizing according to the method described above, optical isomer is split, can be obtained chemical combination Object IIA or IIB.