CN106543188A - A kind of amino tetrahydro pyran derivant and its purposes in medicine - Google Patents

Abstract

A kind of amino tetrahydro pyran derivant and its purposes in medicine.The present invention relates to the substituted-amino Pentamethylene oxide. of the novel structure formula I of structure, which is the inhibitor of dipeptidyl peptidase-IV and can be used for the treatment or prevention of the disease related to dipeptidyl peptidase-IV, such as diabetes and particularly type ii diabetes.The invention further relates to the pharmaceutical composition of these compounds is included, and the purposes of these compounds and compositionss in the prevention or treatment of this kind of disease relevant with dipeptidyl peptidase-IV.

Description

A kind of amino tetrahydro pyran derivant and its purposes in medicine

Technical field

The present invention relates to can be used for suppressing the compound of dipeptidyl peptidase, and its preparation method and such compound are combined individually or with other drugs Using the application in the disease related to dipeptidylpeptidase activity is treated.

Background technology

Diabetes are one group of metabolic diseases being characterized with hyperglycemia.Hyperglycemia is damaged due to defect of insulin secretion or its biological agent, or Person has concurrently and causes.Long-standing hyperglycemia during diabetes, cause various tissues, particularly eye, kidney, heart, blood vessel, nerve chronic lesion, Dysfunction.

Now, with socio-economic development and the improvement of people's living standards, in clinical medicine, diabetes have become commonly encountered diseases, frequently-occurring disease.Grind Study carefully discovery, the big or middle city of China and more than the 20 years old crowd's diabetes prevalence in small towns already exceed 10%.And prediabeteses are up to 15%, Make the matter worse to the preventing and treating of diabetes.The data that diabetes alliance of the world in 2007 is announced according to China, it is contemplated that to the patient of diabetes of China in 2025 Person is up to tens of millions of people, and this numeral makes China surmount India becomes the most country of global diabetes number.Diabetes be divided into type Ⅰ diabetes mellitus and Type Ⅱdiabetes mellitus, there are about 90%～95% and belong to type Ⅱdiabetes mellitus in diabeticss.Type Ⅱdiabetes mellitus, also known as non-insulin-dependent diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM), is mainly shown as tissue to insulin insensitivity (insulin resistant) and β Cell dysfunction is so as to causing hyperglycemia.

DPP-IV is a kind of glycoprotein, is present in the surface of cell membrane of great majority tissue.Including including GLP-1, DPP-IV can degrade many dipeptides The protein of sequence, reduces or eliminates their biological activity or biological selectivity.Possible DPP-IV substrates include that growth hormone release swashs Element, the release of GIP (glucose-dependent insulinotropic peptide, glucose-dependent insulinotropic peptide), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, Kallidin I, gastrin Peptide, neuropeptide tyrosine, peptide YY, some chemotactic factors etc..As DPP-IV acts on multiple proteins, therefore DPP-IV inhibitor Biological safety becomes particularly significant.But, although DPP-IV may act on above-mentioned protein, but only have minority protein to show life in vivo Reason activity.So far, only GLP-1 and GIP are confirmed substrate for DPP-IV in vivo.People by DPP-IV extract mice and The low Fischer rats of DPP-IV inject GLP-1 and GIP respectively, it is found that GLP-1, GIP and insulin level are all increased significantly.DPP-IV Low Fischer rats show glucose tolerance enhancing, insulin secretion and increase.Although DPP-IV can adjust the activity of GLP-1, its There is on Metabolism control higher effect.Compared with normal rat, the low Fischer rats of DPP-IV can suppress the generation of the obesity that diet causes. Therefore, the long-term effect for suppressing DPP-IV have fat-reducing, but which also needs clinical trial to prove.

Dipeptidyl peptidase-IV (dipeptidyl peptidase-IV, DPP-IV) inhibitor is oral antidiabetic drug of the class based on incretin, is passed through Increase endogeneous activity glucagon-like-peptide-1 (GLP-1) and glucose sugar dependent form insulinoptropic peptides (GIP) level, improve α and β cell work( Can obstacle.Simultaneously also with effect outside the pancreas such as increase insulin sensitivity and regulation blood lipid metabolism, and there is reduction generation hypoglycemia, do not affect stomach The features such as emptying.

At present, the sitagliptin phosphate (Sitagliptin phosphate, Januvia) of Merck ＆ Co., Inc.'s production was criticized by U.S. FDA in October, 2006 Quasi- listing, third season income from sales in 2007 just reach 1.85 hundred million, 2010 and list in China.Sitagliptin has higher oral bio profit Expenditure (87%) and longer plasma half-life (8-14h), metabolic stability is also high, daily oral sitagliptin 100mg, DPP-IV in 24h Suppression ratio is mainly excreted with active compound form Jing kidney more than 80%.The new drug vildagliptin (vildagliptin, Galvus) of Novartis Co., Ltd is obtained EU Committee's approval is obtained, in 27 European Union member countries and Norway and Ireland listing.On July 31st, 2009, U.S. FDA have approved beautiful when hundred The Saxagliptin tablets (saxagliptin, Onglyza) of Shi Guibao companies exploitation, the high blood of patients with NIDDM of being grown up for oral medication once a day Sugared disease.

Additionally, the BI 1356 (linagliptin) of Boehringer Ingelheim company in the U.S. with Tradjenta^TMFor trade name list, Japan and other Then with Trazenta on market^TMList for commodity.The Egelieting (alogliptin) of Japanese Wu Tian companies exploitation was obtained on April 16th, 2010 The listing approval of Japanese MHLW (MHLW).Egelieting is good for patients with NIDDM toleration, without dose-limiting toxicity, It is especially suitable for the early treatment of type Ⅱdiabetes mellitus.

DPP-IV inhibitor is widely paid close attention in the treatment of diabetes because suppressing the activity of DPP-IV.Develop various high-efficiency low-toxicities, height Selective DPP-IV inhibitor also becomes the important research topic of pharmaceuticals industry.

The content of the invention

It is an object of the invention to provide a class 3- amido Pentamethylene oxide. class compound, its pharmaceutically acceptable salt, hydrate, solvate or vertical Body isomer is used as novel DPP-IV inhibitors.

It is a further object to provide the compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer Pharmaceutical composition.

A further object of the present invention is to provide application of the compounds of this invention in the medicine for preparing the disease related to DPP-IV enzymatic activitys.

Further aim of the present invention is to provide a kind of compound of the invention, its pharmaceutically acceptable salt, hydrate, solvate or vertical Body isomer, or the method that combinations thereof treat the disease related to DPP-IV enzymatic activitys.

The present invention provides the compound of structure Formulas I：

Or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer；Wherein

Ar be substituted or unsubstituted aryl, heteroaryl；

R₁And R₂Hydrogen is each independently selected from, (CH₂)_m- phenyl, (CH₂)_m-C_3-6Cycloalkyl, and C_1-10Alkyl, wherein alkyl are optionally selected by 1～10 Replace from the substituent group of fluorine and hydroxyl, and wherein phenyl and cycloalkyl optionally by 1～5 independently selected from halogen, hydroxyl, C_1-6Alkyl and C_1-6Alkane The substituent group of epoxide replaces, and wherein alkyl and alkoxyl are optionally replaced by 1～5 fluorine；

Or R₁And R₂Azacyclo- is formed together with the nitrogen-atoms being connected with them, wherein the heterocycle optionally by 1～3 independently selected from halogen, hydroxyl Base, C_1-6Alkyl and C_1-6The substituent group of alkoxyl replaces, and wherein alkyl and alkoxyl are optionally replaced by 1～5 fluorine；

R₃Selected from hydrogen, halogen, cyano group,

M is 0,1 or 2.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, Ar is for not necessarily By 1～3 independently selected from F, Cl, Br, I ,-CH₃,-CF₃,-OCF₃Substituted phenyl.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, Ar is 2,5- difluoros Phenyl or 2,4,5- trifluorophenyls.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂It is independent Ground is selected from hydrogen, C_1-10Alkyl, C_3-6Cycloalkyl, phenyl ,-CH₂- phenyl ,-(CH₂)₂- phenyl；

Wherein, optionally by 1～6 independently selected from halogen, hydroxyl, the substituent group of trifluoromethyl replace alkyl；

Cycloalkyl is optionally by 1～3 independently selected from halogen, hydroxyl, C_1-6Alkyl, C_1-6Alkyloxycarbonyl or C_1-6The substituent group of alkoxyl takes In generation, wherein alkyl and alkoxyl, can be replaced by 1～5 fluorine；

Phenyl is optionally by 1～5 independently selected from, halogen, hydroxyl, C_1-6Alkyl, C_1-6Alkyloxycarbonyl or C_1-6The substituent group of alkoxyl takes Generation；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, pyrroles, tetrahydric quinoline group, Tetrahydroisoquinoli- Quinoline base, hexahydroisoindoline, the heterocycle of azetidine, wherein the heterocycle optionally by 1～3 independently selected from halogen, hydroxyl, C_1-6Alkyl or C_1-6The substituent group of alkoxyl replaces, and wherein each alkyl and alkoxyl are optionally replaced by 1～5 fluorine.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂It is independent Ground be selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1,2- dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyls, 1,3- Dimethylbutyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methyl oneself Base, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3, 3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, phenyl, benzyl；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, pyrroles, tetrahydric quinoline group, Tetrahydroisoquinoli- Quinoline base, azetidine.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂It is independent Ground be selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, phenyl, Benzyl；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, pyrroles, tetrahydric quinoline group, Tetrahydroisoquinoli- Quinoline base, hexahydroisoindoline, azetidine.

Compound of the present invention, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂It is independent Ground is selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl；Phenyl, Benzyl.

Compound of the present invention, selected from following compound：

The method of the treatment disease related to DPP-IV inhibitory action, obstacle or syndrome, methods described include giving needs its individual administration basis The compound or its prodrug or the pharmaceutical composition comprising formula (I) compound or its prodrug and pharmaceutically acceptable excipient of any one of the present invention.

Foregoing Therapeutic Method, wherein described disease, obstacle or syndrome are selected from insulin resistant, hyperglycemia, the disease of type 2 diabetes mellitus, Individuality therein is the animal for including people.

The present invention includes isotope-labeled compound, and they are equal to those described by formula (I), but one or more atoms by atomic mass or Mass number is different from the common atomic mass of nature or the atom of mass number is replaced.The isotopic example bag that can be introduced in the compounds of this invention The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine is included, respectively for example²H,³H,¹³C,¹¹C,¹⁴C,¹⁵N,¹⁸O,¹⁷O,³¹P,³²P,³⁵S,¹⁸F and³⁶Cl.Other isotopic the compounds of this invention containing above-mentioned isotope and/or other atoms, its prodrug and describedization The pharmaceutically acceptable salt of compound or the prodrug belongs to the scope of the present invention.Some isotope-labeled the compounds of this invention, for example, draw Enter radiosiotope (such as³H and¹⁴C) those can be used for medicine and/or substrate tissue measure of spread.Tritium, i.e.,³H and carbon-14, i.e.,¹⁴C is same Position element is particularly preferred, because they easily prepare and detect.Further, replaced by heavier isotope, such as deuterium, i.e.,²H, due to metabolism it is steady The qualitative higher benefit that can be provided in treatment, for example, extend Half-life in vivo or reduce volume requirements, thus be probably preferred in some cases. Isotope-labeled formula (I) compound of the present invention and its prodrug can typically be prepared, and carry out following flow processs and/or embodiment and preparation Example disclosed in technique when, replace nonisotopically labelled reagent with the isotope-labeled reagent being readily obtained.

Formula (I) compound can further generate pharmaceutically acceptable preparation, the salt comprising formula (I) compound, solvate, salt include but It is not limited to acid-addition salts and/or alkali salt.

The present invention also provides pharmaceutical preparation, (I) compound of the formula comprising therapeutically effective amount or its therapeutically acceptable salt and which is pharmaceutically acceptable Carrier, diluent or excipient.All these forms belong to the present invention.

Following definition used herein is applicable.

" alkyl " refers to the construction unit of the alkyl and alkoxyl of a group and other groups such as halogen substiuted in the present invention, it is possible to make straight chain Or side chain.Including straight chained alkyl such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, hendecane Base, dodecyl etc..Branched chain isomer of the term also including straight chained alkyl, including but not limited to for example following group：-CH(CH₃)₂, -CH(CH₃)(CH₂CH₃) ,-CH (CH₂CH₃)₂,-C (CH₃)₃,-CH₂CH(CH₃)₂,-CH₂CH(CH₃)(CH₂CH₃) ,-CH₂CH(CH₂CH₃)₂, -CH₂C(CH₃)₃,-CH₂C(CH₂CH₃)₃,-CH (CH₃)-CH(CH₃)(CH₂CH₃) ,-CH₂CH₂CH(CH₃)₂, -CH₂CH₂CH(CH₃)(CH₂CH₃) ,-CH₂CH₂CH(CH₂CH₃)₂,-CH₂CH₂C(CH₃)₃,-CH₂CH₂C(CH₂CH₃)₃, -CH(CH₃)CH₂CH(CH₃)₂,-CH (CH₃)CH(CH₃)CH(CH₃)₂,-CH (CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃) etc..Therefore, Term alkyl includes primary alkyl, secondary alkyl and tertiary alkyl.Preferred alkyl includes C_1-12Straight chained alkyl and C_3-10Branched alkyl.

Term " thiazolinyl " refers to that two of which adjacent carbon atom passes through doubly linked alkyl as defined above.

Term " alkynyl " is related to two of which adjacent carbon atom by three bonded alkyl.

Term " halogen " refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine.

Term " alkoxyl " refers to (alkyl)-O- groups, and wherein alkyl is as defined above.

Term " hydroxyl " refers to group-OH.

Term " amino " refers to group-NH₂.Term " imino group " refers to group-NH-.

Term " nitro " refers to group-NO₂.Term " nitroso-group " refers to group-NO.

Term " trifluoromethyl " refers to group-CF₃。

Term " carboxyl " refers to group-COOH.

Term " sulfydryl " refers to group-SH.

Term " aryl " refers to that each atom for wherein forming ring is the aromatic ring of carbon atom.Aryl rings can be by five, six, seven, eight It is individual, nine or formed more than nine carbon atoms.Aromatic yl group can be optionally substituted.The example of aromatic yl group includes but is not limited to phenyl, naphthyl, Phenanthryl, anthryl, fluorenyl and indenyl.

Term " heteroaryl " or selective " heteroaromatic base " refer to aromatic group, including the one or more of free nitrogen, oxygen and sulfur Ring hetero atom." heteroaromatic base " or " heteroaryl " containing N partly refers to aromatic group, and the skeletal atom at least one of its medium ring is nitrogen-atoms. The illustrative example of heteroaryl groups includes following components：

Deng.According to structure, heteroaryl Group can be single free radical or diradical (that is, heteroarylene groups groups).

Term " cycloalkyl " refers to monocyclic or multi-ring free radical, and which only contains carbon and hydrogen, and is optionally saturation, and part is undersaturated Or it is completely undersaturated.Group of naphthene base includes the group with 3 to 10 annular atoms.The illustrative example of group of naphthene base includes following portion Point：

Deng.According to structure, cycloalkanes Base group is single free radical or diradical (for example, ring alkylidene group), if " low-grade cycloalkyl " then has 3 to 8 carbon atoms.

Term " Heterocyclylalkyl " refers to that at least one is non-aromatic containing one or more double or triple bonds selected from the hetero atom of O, N and S and optionally Cycloalkyl.Cycloheteroalkyl can have 3～14 annular atoms and (such as have for monocyclic heterocycloalkyl containing 1～5 hetero atom as overall There are 3～6 annular atoms, there are for multi-ring Heterocyclylalkyl 7～14 annular atoms).Heterocyclylalkyl can be in any heteroatom for producing rock-steady structure Or be covalently attached with defined chemical constitution on carbon atom.One or more N or S atom on Heterocyclylalkyl can be oxidized (such as morpholine N- oxides, tetrahydro-1,4-thiazine S- oxides, tetrahydro-1,4-thiazine S, S- dioxide).Heterocyclylalkyl can also contain one or more oxo groups, such as adjacent Phthalimido, piperidone base, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidine radicals, pyridine -2 (1H) -one base etc..Heterocyclylalkyl Example also include morpholinyl, tetrahydro-1,4-thiazine base, pyranose, imidazolidinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrrole Oxazoline base, pyrrolidinyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-thiazoles base, hexahydroisoindoline base, piperidyl, azacyclo- Butane, N- methyl azetidine bases, piperazinyl, N methyl piperazine base, diazepine base etc..

Term " nitrogen heterocycle " refers to the ring system containing nitrogen-atoms, and the ring system with " a pair of horses going side by side is closed " fragrant and non-aromatic ring system, or can pass through " spiral shell carbon Atom " links other ring systems, such as following structure：

Etc..

Term " oxo " refers to double bond oxygen (that is ,=O).

Term " acyl group " represents-CO- groups, and Exemplary acyl includes acetyl group, trifluoroacetyl group, benzoyl etc..

Term " amide groups " refers to the chemical part with formula-C (O) NHR or-NHC (O) R, and wherein R is selected from alkyl, cycloalkyl, heterocycle alkane Base (is bonded by ring carbon), aryl, and heteroaryl (is bonded by ring carbon).

Term " ester group " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, and cycloalkyl, Heterocyclylalkyl (are bonded by ring carbon), Aryl, heteroaryl (are bonded by ring carbon).

Term " acyl group ester group " refers to the chemical part with formula-CO-COOR, and, selected from alkyl, cycloalkyl, Heterocyclylalkyl is (by ring for wherein R Bond with carbon), aryl, heteroaryl (are bonded by ring carbon).

The compounds of this invention can be with the administration in the form of pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " is referred to by pharmaceutically acceptable nontoxic The standby salt of alkali or processed with acid, the alkali or acid include inorganic or organic base and inorganic or organic acid.The alkalescence being included in term " pharmaceutically acceptable salt " Compound refers to the nontoxic salts of the usual the compounds of this invention by being prepared free alkali and suitable organic or inorganic acid reaction.

Specific embodiment

The method for preparing the compounds of this invention：

Formula (I) compound can be prepared according to flow process 1, and wherein each substituent group is as defined in summary of the invention：

Flow process 1：The preparation of intermediate II

Intermediate II can be obtained with method known to those skilled in the art.Aldehyde a in the presence of a base, obtains nitroalcohol b with nitromethane, utilizes The oxidant nitroalcohol that for example Dess-martin process is obtained, obtains nitroketone c.Nitroketone c is with 3- iodo -2- (iodo-methyl) propyl- 1- alkene in fire-bar Reaction under part obtains d.The d for obtaining is reduced agent such as sodium borohydride reduction, obtains two kinds of products of cis and trans, and cis-product therein alkali is such as DBU isomeries can easily be transformed into trans product.The trans product e1 and e2 that obtain are split by HPLC with chiral column, is obtained e2.Then, with zinc and acid such as hydrochloric acid reduction e2, amido pyrans f is obtained, g is obtained with protection group such as Boc protection amino.With oxidising agent such as Osmic acid. and N-methylmorpholine N- oxide process g obtain dihydroxyl compound h, subsequently with sodium periodate oxidation, obtain intermediate II.

Flow process 2：The preparation that intermediate III is

Intermediate III can be prepared according to general flow 2.Can be by aoxidizing, such as by the pyrrolidinol i of Boc or other protective agent protections Swern is aoxidized, and changes into ketopyrrolidine j.J in the presence of DMF-DMA, heating, there is provided k, its in suitable solvent, such as ethanol, Hydrazine, heating is added then to obtain intermediate l with acid treatment.L and q reacts, and after L leaves away, then sloughs protection group with suitable condition, there is provided in Mesosome IIIa and IIIb, and IIIa and IIIb can be by method familiar to the person skilled in the art such as column chromatography for separation.

Flow process 3：The preparation of target compound

In the presence of intermediate III (IIIa or IIIb), such as tetrahydrofuran, methanol, toluene, pyridine, DMF or DMSO in suitable solvent, Using reagent such as sodium borohydride, Decaboron tetradecahydride. or sodium triacetoxy borohydride, by the reduction amination of intermediate II, there is provided intermediate compound I a.Should Reaction is carried out in the presence of lewis acid such as titanium tetrachloride or tetra isopropyl alcohol titanium.The reaction can also be promoted by adding acid such as acetic acid. Under certain situation, intermediate III b can be salt, and such as trifluoroacetate or hydrochlorate can easily by alkali, such as N, N- diisopropyl second Amine or triethylamine, are added in reactant mixture.Then protection group is sloughed, such as trifluoroacetic acid or methanol hydrochloride solution is used in the case of Boc, Or in the case of Fmoc use triethylamine, diethylamide, piperidines or morpholine to react in DMF, NMP or acetonitrile, obtain formula (I) chemical combination Thing.

The following example purpose is the specific invention embodiment of description, is never limited in the scope of description or claims.Those skilled in the art Will recognize that, raw material can generate the compound covered by the present invention with difference using additional step, as the following example is proved. The following example only supplies purposes of illustration, is both not intended to, and also should not be interpreted in any way to limit invention.It would be recognized by those skilled in the art that , can be changed and change, and without prejudice to the spirit or scope of the present invention.(abbreviations table：DMF：DMF；DMSO： Dimethyl sulfoxide；Boc：Tertbutyloxycarbonyl；Fmoc：Fluorenes methoxy carbonyl acyl group；NMP：N-Methyl pyrrolidone；DBU：1,8- diazacyclo [5, 4,0] hendecene -7；HPLC：High performance liquid chromatography；DMF-DMA：DMF dimethylacetal；DIPEA：N, N- Diisopropylethylamine；NMO：N- methyl-N- morpholine oxides).

Embodiment 1

A. prepare intermediate

Step 1. prepares 1- (2,5- difluorophenyl) -2- nitroethyl alcohols

At 5 DEG C, to methanol (214ml) solution slowly Deca 2 of sodium hydroxide (1N, 428ml), 5- difluorobenzaldehydes (50g, 0.35mol) With the methanol solution 50ml (being more than 1h) of nitromethane (22.4ml, 0.414mol), after adding, glacial acetic acid (24ml) neutralization reaction is added Liquid, is subsequently adding ether, and organic layer is washed with saturated sodium carbonate (30ml) and saturated aqueous common salt (30ml), and anhydrous magnesium sulfate is dried organic layer simultaneously Concentration, obtains 1- (2,5- difluorophenyl) -2- nitroethyl alcohols, and which need not be further purified and can be used for step 2.

Step 2. prepares 2- nitro -1- (2,5- difluorophenyl) ethyl ketone

At 10 DEG C, dess-martin high iodine alkane (184g) was added in 30 minutes nitroethyl alcohol (68.1g) in three batches that prepare in step 1 Dichloromethane solution in.Continue stirring 24h, reactant mixture is poured over into sodium bicarbonate (441g) then and sodium thiosulfate (489g) exists In mixed liquor in water (4.2L).Using HCl (6N, 1.5L) neutralized aqueous layer, to bubble is no longer produced, dichloromethane is extracted, bicarbonate Sodium solution washed once.The organic layer for merging is dried by anhydrous magnesium sulfate, is filtered, is evaporated, by chromatography (silica gel, petroleum ether：Acetic acid second Ester 10:1 to 6:1 gradient elution) purification, the nitroketone 54g required for obtaining.¹H NMR (400MHz, CDCl₃) δ 7.74-7.70 (m, 1H), 7.43-7.37 (m, 1H), 7.28-7.22 (m, 1H), 5.82 (d, J=3.6Hz, 2H).

Step 3. prepares 3- iodo -2- (iodo-methyl)-isopropyl -1- alkene

By 3- chloro -2- (chloromethyl) propyl- 1- alkene (5.75ml, 54.7mmol) and sodium iodide (45g, 301mmol) at acetone (400ml) In reactant liquor 20h is stirred at room temperature, evaporated under reduced pressure is distributed in dichloromethane and water.By anhydrous sodium sulfate drying organic layer, mistake Filter, is evaporated and obtains 3- iodo -2- (iodo-methyl) propyl- 1- alkene, be pink oily compound.

Step 4. prepares 6- (2,5- difluorophenyl) -3- methylene -5- nitro -3,4- dihydro -2H- pyrans

3- iodo -2- (iodo-methyl)-isopropyl -1- alkene (16.8g, 54.7mmol) is dissolved in 50ml DMF, DIPEA 20ml is added, so After be slowly added dropwise 2- nitro -1- (2,5- difluorophenyl) ethyl ketone (10g, 49.7mmol), be stirred at room temperature 2h after adding, add 400ml water, acetic acid Ethyl ester is extracted three times, merges organic layer, anhydrous sodium sulfate drying, column chromatography (petroleum ether：Dichloromethane 20%-30% gradient elutions), obtain 3g Product.¹H NMR (400MHz, DMSO-d₆) δ 7.50-7.29 (m, 3H), 5.41 (brs, 1H), 5.34 (brs, 1H), 4.74 (s, 2H), 3.58 (brs, 2H).

Step 5. prepares (2R, 3S) -2- (2,5- difluorophenyl) -5- methylene -3- nitro tetrahydrochysene -2H- pyrans

To 6- (2,5- difluorophenyl) -3- methylene -5- nitro -3,4- dihydros -2H- pyrans (9.1g, 35.96mmo) in chloroform (480ml) and Silica gel (100-200 mesh) 58g and sodium borohydride (5.2g, 136.6mmol) are added in the solution of isopropanol 90ml, is stirred overnight at room temperature.Then It is slowly added to dilute hydrochloric acid (69ml, 2N) and reaction is quenched, and filters.Silica gel is washed with ethyl acetate.Organic layer is washed using sodium bicarbonate, it is anhydrous Sodium sulfate is dried.It is spin-dried for rear column chromatography (petroleum ether：Ether=16：1 to 15:1 gradient elution), obtain trans -2- (2,5- difluorophenyl) -5- sub- Methyl-3-nitro tetrahydrofuran -2H- pyrans 5.5g and cis -2- (2,5- difluorophenyl) -5- methylene -3- nitro tetrahydrofuran -2H- pyrans 2.4g.Will The product of cis-configuration, is dissolved in 50ml tetrahydrofurans, adds 120 microlitres of DBU.After 0.5h is stirred at room temperature, column chromatography (petroleum ether：Ether =16:1 to 15:1 eluting), 1.6g trans products of getting back.A part of trans product (1g) is split by HPLC (ChiralCel OD) Obtain enantiomer (2R, 3S) -5- methylene -3- nitro -2- (2,4,5- trifluorophenyl) tetrahydrochysene -2H- pyrans 440mg.¹H NMR(400 MHz, CDCl₃) δ 7.17-7.13 (m, 1H), 7.06-7.03 (m, 2H), 5.14-5.11 (m, 2H), 5.08 (d, J=9.6Hz, 1H), 4.82-4.73 (m, 1H), 4.39 (d, J=12.7Hz, 1H), 4.24 (d, J=12.8Hz, 1H), 3.13 (d, J=7.9 Hz, 2H).

Step 6. prepares (2R, 3S) -2- (2,5- difluorophenyl) -5- methylene tetrahydrochysene -2H- pyrans -3- amino

Product obtained in the previous step (440mg, 2.2mmol) is dissolved in ethanol, zinc powder (1.2g, 18.9mmol) is added, is stirred vigorously down and is added Enter 6N hydrochloric acid (6ml, 36mmol).After 3h, pH value is adjusted to 10 with 2N sodium hydroxide, extracted three times with ether, anhydrous sodium sulfate drying Afterwards, decompression boils off ether and obtains colourless transparent oil liquid 376mg, directly carries out next step reaction.

Step 7. prepares [(2R, 3S) -5- methylene -2- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- bases] t-butyl carbamate

Colourless transparent oil liquid obtained in the previous step is dissolved in dichloromethane, Bis(tert-butoxycarbonyl)oxide (507mg, 2.34mmol), room temperature is added It is stirred overnight, decompression steaming vibrating dichloromethane obtains 464mg products, directly carries out next step reaction.

Step 8. prepares [(2R, 3S) -5- hydroxyl -5- (hydroxymethyl) -2- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- bases] t-butyl carbamate

The product that step 7 is obtained is dissolved in 7ml acetone, 3.5ml water and the 14ml tert-butyl alcohols is added, is subsequently adding four oxygen of 0.258ml 2.5% Change the t-butanol solution of osmium.After 10min is stirred under room temperature, NMO 0.184ml are added, after room temperature reaction 48h, add saturation thiosulfuric acid Sodium solution, stirs half an hour, is subsequently adding ethyl acetate extraction, and after anhydrous sodium sulfate drying, evaporated under reduced pressure solvent obtains 510mg products, Next step reaction is carried out directly.

Step 9. prepares [(2R, 3S) -5- oxo -2- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- bases] t-butyl carbamate

The product of previous step is dissolved in 10ml tetrahydrofurans, adds the aqueous solution 4ml of sodium metaperiodate (327mg, 1.53mmol), mixture to stir Mix 4h.After concentration, column chromatography (10% to 20% ethyl acetate is in chloroform), obtains 410mg white solids.¹H NMR (400MHz, CDCl₃) δ 7.23 (d, J=3.3Hz, 1H), 7.05-7.00 (m, 2H), 4.83 (d, J=8.0Hz, 1H), 4.71 (d, J=9.0Hz, 1H), 4.31 (dd, J=16.3,1.5Hz, 1H), 4.18-3.99 (m, 2H), 3.06 (dd, J=16.6,5.1Hz, 1H), 2.75-2.68 (m, 1H), 1.31 (s, 9H)；ESI-MS:272.1(M+1-56).

B. prepare intermediate

It is prepared by step 1.

3- oxo-pyrrolidines -1- carboxylic acid tert-butyl esters (40g, 216mmol) is dissolved in 300ml DMF-DMA, is heated 40 minutes at 105 DEG C. Cooling is evaporated under reduced pressure the solution, is processed using hexane, is filtrated to get orange solids 41g, is dried, and can be used for next step reaction without the need for purification.

It is prepared by step 2.

By previous step to orange solids 41g be dissolved in 200ml toluene, hydrazine hydrate 15ml (80% content) be slowly added dropwise under 40 degree, drip Afterwards, reactant liquor cooling is had white solid to separate out by room temperature reaction 2h, and the solid being filtrated to get normal heptane is washed and obtains 37.2g products.

It is prepared by step 3.

37.2g white solids obtained in the previous step are dissolved in methanol, 5N hydrochloric acid are added, is stirred 6h at room temperature, after concentration, add ammonia methanol Solution (2N), adjusts PH to alkalescence, adds dichloromethane 200ml, add triethylamine 40ml, in room temperature Deca Bis(tert-butoxycarbonyl)oxide 64g Dichloromethane (40ml) solution, reaction half an hour after, be spin-dried for, column chromatography (methanol：Ammonia：Ethyl acetate=135:15:350), obtain 20g White solid.¹H NMR (400MHz, CDCl₃) δ 8.03 (brs, 1H), 7.34 (d, J=12.8Hz, 1H), 4.50 (t, J=16.6 Hz, 4H), 1.53 (s, 9H).

C. prepare intermediate

It is prepared by step 1.

N-Boc pyrazoles pyrrolizine (1g, 4.78mmol) is dissolved in 10ml methyltetrahydrofurans, sodium hydride (230mg, 5.74mmol) is subsequently adding, Dimethylaminosulfonyl chloride (616 μ l, 5.74mmol) is added after 0.5h is stirred at room temperature, after continuing stirring reaction 2h, water is added, is extracted with ethyl acetate Take, concentrate organic faciess, column chromatography (P:E=2：1) white solid 600mg, yield 39.7% are obtained.

It is prepared by step 2.

Solid 200mg prepared by previous step is dissolved in 5ml dichloromethane, 1ml trifluoroacetic acids is subsequently adding, after reaction 3h, is removed under reduced pressure molten Agent, in the appropriate ammonia of addition with after, silica gel column chromatography (dichloromethane：Methanol=20:1) white solid 108mg, yield 79% are obtained.

D. prepare compound 1：(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [2- (dimethylaminosulfonyl) -2,6- pyrrolin simultaneously [3,4-c] pyrazoles - 5 (4H)-yls] tetrahydrochysene -2H- pyrans -3- amine

By [(2R, 3S) -5- oxo -2- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- bases] t-butyl carbamate (108mg, 0.499mmol) and Simultaneously [3,4-c] pyrazoles (163mg, 0.499mmol) is dissolved in 5ml methanol solutions 2- (dimethylaminosulfonyl) -2,6- pyrrolin, is subsequently adding Decaboron tetradecahydride. (18mg, 0.15mmol), room temperature reaction overnight after, silica gel column chromatography (dichloromethane after removal of solvent under reduced pressure：Methanol=50:1) obtain White solid 180mg, this white solid is dissolved in 5ml dichloromethane, is subsequently adding 1ml trifluoroacetic acids, and after room temperature reaction 2h, decompression is removed After removing solvent, in the appropriate ammonia of addition with after, silica gel column chromatography (dichloromethane：Methanol=20:1) 114mg white solids, yield 78% are obtained.¹H NMR(400MHz,CDCl₃) δ 7.68 (s, 1H), 7.18 (ddd, J=8.5,5.1,3.1Hz, 1H), 7.10-6.94 (m, 2H), 4.32-4.26 (m, 1H), 4.24 (d, J=9.5Hz, 1H), 3.90 (d, J=5.9Hz, 2H), 3.86 (s, 2H), 3.44 (t, J=10.7Hz, 1H), 3.05 (tt, J= 10.9,4.1Hz, 1H), 2.94 (s, 6H), 2.91-2.82 (m, 1H), 2.49 (dd, J=12.3,2.3Hz, 1H), 1.58-1.43 (m, 1H) .ESI-MS m/z:426.2(M-1)^-。

Embodiment 2

The synthetic method reference implementation example 1 of the compounds of this invention 2, changes the dimethylamino sulfonic acid chloride in embodiment 1 into two trifluoromethyl amino sulphurs Acyl chlorides, obtains white solid 2.ESI-MS m/z:536.2.

Embodiment 3

The synthetic method reference implementation example 1 of the compounds of this invention 3, changes the dimethylamino sulfonic acid chloride in embodiment 1 into diethylamino sulfonic acid chloride, Obtain white solid 3.ESI-MS m/z:456.3.

Embodiment 4

The synthetic method reference implementation example 1 of the compounds of this invention 4, changes the dimethylamino sulfonic acid chloride in embodiment 1 into diη-propyl aminosulfonyl Chlorine, obtains white solid 4.ESI-MS m/z:484.3.

Embodiment 5

The synthetic method reference implementation example 1 of the compounds of this invention 5, changes the dimethylamino sulfonic acid chloride in embodiment 1 into methylethylamine sulphonyl Chlorine, obtains white solid 5.ESI-MS m/z:442.5.

Embodiment 6

The synthetic method reference implementation example 1 of the compounds of this invention 6, changes the dimethylaminosulfonyl chloride in embodiment 1 into methyl-n-propylamino sulphonyl Chlorine, obtains white solid 6.ESI-MS m/z:456.2.

Embodiment 7

The synthetic method reference implementation example 1 of the compounds of this invention 7, changes the dimethylaminosulfonyl chloride in embodiment 1 into MethYlphenylamino sulfonic acid chloride, Obtain white solid 7.ESI-MS m/z:490.3.

Embodiment 8

The synthetic method reference implementation example 1 of the compounds of this invention 8, changes the dimethylamino sulfonic acid chloride in embodiment 1 into methylbenzylamide sulphonyl Chlorine, obtains white solid 8.ESI-MS m/z:504.6.

Embodiment 9

The synthetic method reference implementation example 1 of the compounds of this invention 9, changes 2,5- difluorobenzaldehydes in embodiment 1 into 2,3,5- trifluro benzaldehydes, obtains White solid 9.ESI-MS m/z:446.4.

Embodiment 10

The synthetic method reference implementation example 1 of the compounds of this invention 10, changes the dimethylamino sulfonic acid chloride in embodiment 1 into methylamino sulfonic acid chloride, Obtain white solid 10.ESI-MS m/z414.5.

Embodiment 11

The synthetic method reference implementation example 1 of the compounds of this invention 11, changes the dimethylamino sulfonic acid chloride in embodiment 1 into ethylamino sulfonic acid chloride, Obtain white solid 11.ESI-MS m/z:428.10.

Embodiment 12

The synthetic method reference implementation example 1 of the compounds of this invention 12, changes the dimethylamino sulfonic acid chloride in embodiment 1 into n-propyl amino sulfonic acid chloride, Obtain white solid 12.ESI-MS m/z:442.1.

Embodiment 13

Step 1：Prepare tetrahydroisoquinoline -1- sulfonic acid chlorides

20ml acetonitriles are added in 100ml single-necked flasks, sulfonic acid chloride (1.78ml, 22mmol) is subsequently adding, is cooled to 0 DEG C, then by four During hydrogen isoquinoline (1.38ml, 11mmol) and triethylamine (1.7ml, 12mmol) add 30ml acetonitriles, then it is slowly added dropwise in flask, After reaction 5h, reaction is complete, after removal of solvent under reduced pressure, adds water and ethyl acetate, isolated organic layer, then has with saturated common salt water washing Machine layer, sodium sulfate be dried after, be spin-dried for white solid be tetrahydroisoquinoline -1- sulfonic acid chlorides.

Step 2：

The synthetic method reference implementation example 1 of compound 13, changes the dimethylaminosulfonyl chloride in embodiment 1 into tetrahydroisoquinoline -1- sulfonic acid chlorides, obtains To white solid.¹H NMR (400MHz, MeOD) δ 7.94 (s, 1H), 7.32-7.02 (m, 7H), 4.49-4.44 (m, 2H), 4.17 (t, J=8.7 Hz, 1H), 4.11-4.08 (m, 1H), 4.05 (brs, 1H), 3.73-3.69 (m, 3H), 3.58-3.56 (m, 2H), 3.25 (dd, J=21.7,10.9Hz, 1H), 2.99-2.88 (m, 2H), 2.85-2.82 (m, 2H), 2.31 (d, J=11.7Hz, 1H), 1.46-1.35 (m, 1H) .ESI-MS:516.2(M+1)⁺。

Embodiment 14

The synthetic method reference implementation example 1 of the compounds of this invention 14, changes the dimethylaminosulfonyl chloride in embodiment 1 into tetrahydroquinoline -1- sulfonic acid chlorides Obtain white solid 14, ESI-MS:516.1(M+1)⁺。

Embodiment 15

The synthetic method reference implementation example 1 of the compounds of this invention 15, specific solution is as follows：

15A (1g, 4.78mmol) is dissolved in 10ml methyltetrahydrofurans, sodium hydride (230mg, 5.74mmol) is subsequently adding, is stirred at room temperature Dimethylaminosulfonyl chloride (616 μ l, 5.74mmol) is added after 0.5h, after continuing stirring reaction 2h, water is added, is extracted with ethyl acetate, concentrate Organic faciess, column chromatography (P:E=2：1) white solid 15B600mg, yield 39.7% are obtained.

15B (300mg, 0.95mmol) is dissolved in 5ml anhydrous tetrahydro furans, after being cooled to -78 DEG C, 0.95ml n-BuLis are slowly added to, After stirring 0.5h, the tetrahydrofuran solution of NIS (449mg, 1.995mmol) is slowly added to, after reaction 6h, saturated sodium bicarbonate solution is added Reaction is quenched, after tetrahydrofuran is removed under reduced pressure, ethyl acetate extractive reaction concentrates ethyl acetate layer, and column chromatography obtains 178mg solid 15C, produces Rate 42%.

Solid 15C obtained in the previous step is dissolved in 5ml dichloromethane solutions, 1mlTFA is subsequently adding, after 2h is stirred at room temperature, is removed under reduced pressure molten After agent, with a small amount of ammonia and after, column chromatography (C:M=20：1) 15D solid 78mg, yield 56.6% are obtained.

15E (89mg, 0.274mmol) and 15D (78mg, 0.228mmol) are dissolved in 5mlDMA, are placed under condition of ice bath, are subsequently adding three Acetoxyl group sodium borohydride (72.5mg, 0.342mmol), adds water after stirring 2h, is extracted with ethyl acetate, after removal of solvent under reduced pressure, post layer Analysis (P:E=2：1) 15F solid 73mg, yield 49% are obtained.

Solid obtained in the previous step is dissolved in 2.5ml dichloromethane, 0.5ml trifluoroacetic acids are subsequently adding, after 2h is stirred at room temperature, is removed under reduced pressure molten Agent, in the appropriate ammonia of addition with after, column chromatography (C:M=20：1) 15 solid 38mg of compound, yield 61.4% are obtained.¹H NMR(400MHz, MeOD)δ7.27–7.21(m,1H),7.15(m,2H),4.67(s,2H),4.35–4.24(m,2H),3.95(s,2H),3.87–3.74(m,2H), 3.42 (t, J=10.7Hz, 1H), 3.08 (ddd, J=10.0,7.2,3.8Hz, 1H), 3.00 (s, 6H), 2.96-2.89 (m, 1H), 2.48 (d, J=12.2 Hz,1H),1.56–1.47(m,1H).ESI-MS：553.9(M+1)⁺。

Biological assessment

Test 1

The compounds of this invention is tested to DPP-IV enzyme inhibition activities：

Add in reaction system appropriate DPP-IV enzymes (SIGMA), the dilution of 3 times of Concentraton gradient sample box HEPES buffer solution (25mM HEPES, 140mM NaCl, 1%BSA, 80mM MgCl₂), while setting up blank (without enzyme and sample box), negative control (without sample) and the positive Control (positive control is MK-3102), room temperature reaction 10min add substrate Gly-Pro-7-amido-4-methylcoumarin (SIGMA), Room temperature lucifuge reacts 30min, detects fluorescence, excitation wavelength 355nm, launch wavelength 460nm.

Suppression ratio, suppression ratio=[1- (sample-blank)/(negative-blank)] * 100%, using in Xlfit softwares are calculated according to fluorescence measurement value 4ParameteriLogistic Model calculate IC₅₀Value.Experimental result is shown in Table 1.

Table 1：Compound DPP-IV external activity test results

Compound number	DPP-IV activity IC50 (nM)
		1	0.4
2	0.5
		3	0.4
5	1.3
		6	2.2
7	1.3
		8	0.9
9	0.1
		10	0.3
11	0.2
		13	0.7
14	1.1
		15	0.3
MK-3102	2.2

Conclusion：Part of compounds of the present invention has significant inhibitory action to DPP-IV enzymes.

Claims (10)

1. the compound of structure Formulas I：

Or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer；Wherein

Ar be substituted or unsubstituted aryl, heteroaryl；

R₁And R₂Hydrogen is each independently selected from, (CH₂)_m- phenyl, (CH₂)_m-C_3-6Cycloalkyl, and C_1-10Alkyl, wherein alkyl are optionally selected by 1～10 Replace from the substituent group of fluorine and hydroxyl, and wherein phenyl and cycloalkyl optionally by 1～5 independently selected from halogen, hydroxyl, C_1-6Alkyl and C_1-6Alkane The substituent group of epoxide replaces, and wherein alkyl and alkoxyl are optionally replaced by 1～5 fluorine；

Or R₁And R₂Azacyclo- is formed together with the nitrogen-atoms being connected with them, wherein the heterocycle optionally by 1～3 independently selected from halogen, hydroxyl Base, C_1-6Alkyl and C_1-6The substituent group of alkoxyl replaces, and wherein alkyl and alkoxyl are optionally replaced by 1～5 fluorine；

R₃Selected from hydrogen, halogen, cyano group；

M is 0,1 or 2.

2. compound according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, Ar is not necessarily by 1～3 independently selected from F, Cl, Br, I ,-CH₃,-CF₃,-OCF₃Substituted phenyl.

3. compound according to claim 2, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, Ar is 2,5- difluorophenyls or 2,4,5- trifluorophenyls.

4. compound according to claim 1, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂Independently selected from hydrogen, C_1-10Alkyl, C_3-6Cycloalkyl, phenyl ,-CH₂- phenyl ,-(CH₂)₂- phenyl；

Wherein, optionally by 1～6 independently selected from halogen, hydroxyl, the substituent group of trifluoromethyl replace alkyl；

Cycloalkyl is optionally by 1～3 independently selected from halogen, hydroxyl, C_1-6Alkyl, C_1-6Alkyloxycarbonyl or C_1-6The substituent group of alkoxyl takes In generation, wherein alkyl and alkoxyl, can be replaced by 1～5 fluorine；

Phenyl is optionally by 1～5 independently selected from, halogen, hydroxyl, C_1-6Alkyl, C_1-6Alkyloxycarbonyl or C_1-6Alkoxy substituent replaces；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, nafoxidine, tetrahydric quinoline group, tetrahydrochysene Isoquinolyl, hexahydroisoindoline, the heterocycle of azetidine, wherein the heterocycle optionally by 1～3 independently selected from halogen, hydroxyl, C_1-6Alkane Base or C_1-6The substituent group of alkoxyl replaces, and wherein each alkyl and alkoxyl are optionally replaced by 1～5 fluorine.

5. compound according to claim 4, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂Independently selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, N-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, N-hexyl, 1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethyl butyrates Base, 1,3- dimethylbutyl, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl-pentens Base, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, phenyl, benzyl；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, pyrroles, tetrahydric quinoline group, Tetrahydroisoquinoli- Quinoline base, hexahydroisoindoline, azetidine.

6. compound according to claim 5, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂Independently selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, N-pentyl, phenyl, benzyl；

Or R₁And R₂Formed together with the nitrogen-atoms being connected with them selected from piperidines, piperazine, morpholine, pyrroles, tetrahydric quinoline group, Tetrahydroisoquinoli- Quinoline base, hexahydroisoindoline, azetidine.

7. compound according to claim 6, its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein, R₁And R₂Independently selected from hydrogen, methyl, trifluoromethyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, N-pentyl, phenyl, benzyl.

8. compound according to claims 1 to 7, selected from following compound：

9. the method for treating the disease related to DPP-4 inhibitory action, obstacle or syndrome, methods described include giving needs its individual administration root According to the compound or its prodrug of any one of claim 1～8, or the medicine comprising formula (I) compound or its prodrug and pharmaceutically acceptable excipient Compositions.

10. Therapeutic Method as described in claim 9, wherein described disease, obstacle or syndrome are selected from insulin resistant, hyperglycemia, 2 The disease of patients with type Ⅰ DM, individuality therein are the animals for including people.