CN105294694A

CN105294694A - Amino hexatomic ring derivative and application thereof to medicine

Info

Publication number: CN105294694A
Application number: CN201510261370.5A
Authority: CN
Inventors: 张晨; 范江; 雷鸣; 魏用刚
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-06-18
Filing date: 2015-05-21
Publication date: 2016-02-03
Anticipated expiration: 2035-05-21
Also published as: CN105294694B

Abstract

The invention relates to an amino hexatomic ring derivative and application thereof to medicine, in particular to the amino hexatomic ring derivative shown in the general formula (I) (in the description), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, a drug composition comprising the derivative, and medical application to preparation of a dipeptidyl peptidase IV (DPP-IV) inhibitor. In the general formula (I), the definitions of the substituent groups are the same as those in the description.

Description

Amino six-ring analog derivative and in application pharmaceutically

Technical field

The present invention relates to a kind of amino six-ring analog derivative and in application pharmaceutically, relate to amino six-ring analog derivative shown in general formula (I) or its available medicinal salt or its steric isomer and the pharmaceutical composition containing this derivative or its available medicinal salt or its steric isomer specifically, and its as therapeutical agent particularly as the purposes of DPP IV (DPP-IV) inhibitor.

Background technology

Diabetes are worldwide great medical care problems, and according to IDF (IDF) statistics, within 2013, global diabetic subject's number has reached 3.82 hundred million, and global medical cost reaches 5,480 hundred million dollars, account for 11% of global medical expenditure.Expect 2035, the global medical cost relevant to diabetes will reach 6,273 hundred million dollars.Regular Insulin is hormone required when being energy by sucrose, starch and other food conversions, and diabetes are normally owing to can not secreting from body or suitably utilizing Regular Insulin to cause.Diabetes are divided into type i diabetes (or insulin-dependent diabetes mellitus, IDDM) and type II diabetes (or non insulin dependent diabetes, NIDDM) usually.Modal diabetes type is type II diabetes, and worldwide, type II diabetes accounts for 90% of all diabetes.Due to modern times unsound mode of life, as tempered the reasons such as minimizing and full diet, the sickness rate of type II diabetes is in the trend increased gradually.Huge market potential has attracted a large amount of drugmakers and research centre to develop new anti-diabetic target spot and medicine.

The medicine being used for the treatment of type II diabetes listing of current approved mainly contains Regular Insulin and analogue, sulfonylurea, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitor, dextrin analogue, gut incretin hormones analogue, depeptidyl peptidase inhibitors (DPP-IV) etc.But the glycolated hemoglobin (HbA1c) that these antidiabetic drugs of patient's long-term taking still can not reach expection reduces index, and these antidiabetic drugs all have side effect, as hypoglycemia, body weight increase and cardiovascular risk etc.These side effects have increased the weight of the burden of diabetic subject.Therefore, in the urgent need to there is novel antidiabetic drug that is efficient, few side effects for type II diabetes exploitation.

DPP IV (DipeptidylPeptidase, DPP-IV, EC3.4.14.5) is a serine protease, holds penultimate hydrolyzing N end dipeptides from the polypeptide N containing L-PROLINE and ALANINE.Although the function of DPP-IV is not fully elucidated, it is considered to the major physiological regulatory factor that some regulates polypeptide, neuropeptide, circulating hormone and chemokine.Although as multiple-effect enzyme, DPP-IV has many substrates, and that the most known is secretin, and it comprises glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).Secretin is taking in nutraceutical several minutes internal secretion and the enteron aisle hormone of the nutraceutical disposal of promotion absorption.The effect of GLP-1 with GIP to β cell is identical, β cell function can be improved, comprise the insulin secretion of promotion dependence on the glucose, inducing beta cell propagation, strengthen Anti-G value (DiabetesandVascularDiseaseResearch20063:159).

Different from GIP, GLP-1 is still and promotes insulin secretion in type II diabetes, therefore, improves the means (PharmacolRev60:470 – 512,2008) that GLP-1 is a kind of promising treatment type II diabetes.GLP-1 is used can obviously to reduce blood sugar (Lancet in patients with NIDDM, 2002,359:824-830), but GLP-1 can be hydrolyzed and inactivation rapidly in vivo as the substrate of DPP-IV, therefore develops DPP-IV inhibitor and has very important significance to treatment diabetes.

At present, the research of DPP-IV inhibitor achieves larger progress, comprise sitagliptin, BMS-477118, Egelieting DPP-IV inhibitor ratified listing, enter Clinical practice.The most outstanding feature of DPP-IV inhibitor is, due to incretin only secretion after body feed, DPP-IV inhibitor not easily increases insulin level unsuitable time, produces the side effect hypoglycemia that many antidiabetic drugs are common.Recent clinical data shows, and suppresses DPP-IV that insulin secretion can be made to increase, reduces blood sugar concentration and improve pancreas islet beta cell function (Diabetes, 1998,47:1253-1258).The side effect of common DPP-IV inhibitor has respiratory tract infection, has a sore throat, suffers from diarrhoea, cold like symptoms, headache and dizzy etc.But totally there is good security and tolerance, also do not find that the patient used has serious body weight to increase or potential to lose weight and the symptom such as oedema at present.In recent years, long-acting DPP-IV inhibitor was noticeable especially.Long-acting DPP-IV inhibitor uses more convenient, and possess desirable hypoglycemic effect, this can make it more welcome in patients with NIDDM simultaneously.The clinical data display of II phase, the DPP-IV inhibitor MK-3102 weekly developed by Merck & Co., Inc., obviously can reduce blood sugar.Trelagliptin is another DPP-IV inhibitor weekly developed by Takeda Pharmaceuticals Ltd., and the security of this medicine and validity obtain confirmation in III phase is clinical, submit new drug application in Japan at present.

The sickness rate of diabetes (mainly type II diabetes), in the world in increasing trend year by year, becomes after cardiovascular disorder and tumour, the Non Communicable Diseases (NCD) of the 3rd threat health of people and life.The treatment of diabetes brings white elephant to family and society.Therefore, being badly in need of the better DPP-IV of the more renewals of exploitation suppresses medicine to meet the needs of extensive patients clinical application.

At present, the document about DPP-IV inhibitor correlative study is reported in succession:

(1) US2007232676 discloses the compound of following structure as DPP-IV inhibitor, wherein:

Ar is selected from and is selected from halogen, hydroxyl, C by 1-5 _1-6the phenyl that the substituting groups such as alkyl replace;

V is selected from deng group, and R ^3a, R ^3bindependently selected from hydrogen, by the C of 1-5 fluorine atom replacement _1-4alkyl; R ²be selected from the groups such as hydrogen, hydroxyl, halogen, carboxyl; R ⁸be selected from hydrogen ,-(CH ₂) _pthe groups such as-phenyl, but without methyl sulphonyl; Do not think that specifically describing in this patent is a part of the present invention.

(2) US20100120863 discloses the compound of following structure as DPP IV (DPP-IV) inhibitor, in the purposes for the treatment of, prevention type ii diabetes, wherein:

Ar is selected from the group such as hydrogen, alkyl;

V is selected from deng, and R ^3a, R ^3bbe selected from independently selected from hydrogen, by the C of 1-5 fluorine atom replacement _1-4alkyl; R ²be selected from the groups such as hydrogen, hydroxyl, halogen, carboxyl; R ⁸be selected from-S (O) ₂-C _1-6cycloalkyl ,-S (O) ₂-C _1-6the groups such as alkyl; Do not think that specifically describing in this patent is a part of the present invention.

(3) compound that WO2011103256 discloses following structure has DPP-IV inhibitor effect, as the purposes preventing and/or treating medicine of diabetes, wherein:

Ar is optionally by the phenyl of the group replacements such as 1-5 independent selected from halo, cyano group, hydroxyl;

V is selected from deng group, and R ²be selected from the groups such as hydrogen, hydroxyl, cyano group, halogen, alkyl, alkoxyl group, carbonyl; R ^3a, R ^3bbe selected from hydrogen or optionally by C that 1-5 fluorine atom replaces _1-4alkyl; R ⁸be selected from hydrogen, alkyl, aryl, cycloalkyl, heteroaryl ,-SO ₂-C _1-6the groups such as alkyl; Do not think that specifically describing in this patent is a part of the present invention.

(4) compound that WO2007126745 discloses the following structure of DPP-IV inhibitor is used for the treatment of diabetes, wherein:

Ar is selected from substituted or unsubstituted phenyl, and when replacing, phenyl is selected from halogen, hydroxyl, C by 1-3 _1-6the replacements such as alkyl;

V is selected from deng group, and R ²be selected from hydrogen, hydroxyl, halogen, thiazolinyl, alkynyl, aryl, heteroaryl etc.; R ^3a, R ^3bthe C be selected from hydrogen, being replaced by 1-5 fluorine atom _1-4alkyl; R8 is selected from the groups such as H, cycloalkyl, phenyl, alkyl; Do not think that specifically describing in this patent is a part of the present invention.

WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784 etc. are also had also to disclose relevant DPP-IV inhibitor compound for treating diabetes.

Summary of the invention

Main purpose of the present invention is to provide the DPP-IV inhibitor of a class novelty, specifically there is the compound shown in general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, show after deliberation, the compound of this class formation or its steric isomer, pharmacy acceptable salt or prodrug have good DPP IV (DPP-IV) inhibit activities and/or selectivity and/or long-lasting, have the prospect being used for the treatment of or alleviating type ii diabetes and similar disease.

The present invention relates to the compound shown in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug:

Wherein:

V is selected from one of following group:

Ar is phenyl, optionally further by 0 to 5 R ¹replace;

R ¹independently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ²and R ^2aindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ^3aand R ^3bindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group or C separately _1-8alkyl, described alkyl is optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ⁴be selected from H, cyano group, C _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ⁵be selected from hydroxyl, C _1-8alkyl, C _1-8alkoxyl group, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls ,-O-C _3-15cycloalkyl ,-O-C _6-10aryl or-O-6 are to 10 yuan of heteroaryls;

R ⁶, R ⁷and R ⁹independently be selected from H, C separately _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 yuan of Heterocyclylalkyls;

R ⁸be selected from C _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 yuan of Heterocyclylalkyls, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 5 and are selected from N, O or S (=O) _natom or group;

M is selected from 0,1 or 2;

N is selected from 0,1 or 2.

Preferred version of the present invention, the compound described in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

R ¹independently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-8alkyl, C _1-8alkoxyl group ,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C further _1-8alkyl, C _1-8alkoxyl group ,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl or-(CH ₂) _m-6 to 10 yuan of heteroaryls, more preferably H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl, C _1-6alkoxyl group ,-(CH ₂) _m-C _3-6cycloalkyl or-(CH ₂) _m-3 to 6 yuan of Heterocyclylalkyls; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ²and R ^2aindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl, C _1-6alkoxyl group ,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls ,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C further _1-6alkyl, C _1-6alkoxyl group ,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls, more preferably H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl, C _1-6alkoxyl group ,-(CH ₂) _m-C _3-6cycloalkyl ,-(CH ₂) _m-3 to 6 yuan of Heterocyclylalkyls; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ⁴be selected from H, cyano group, C _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, cyano group, C _1-8alkyl, C _1-8alkoxyl group ,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, cyano group, C further _1-6alkyl, C _1-6alkoxyl group ,-(CH ₂) _m-C _3-6cycloalkyl ,-(CH ₂) _m-3 to 6 yuan of Heterocyclylalkyls ,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸or-(CH ₂) _m-NR ⁶r ⁷, more preferably H, cyano group, C _1-6alkyl ,-(CH ₂) _m-C _3-6cycloalkyl ,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸or-(CH ₂) _m-S (=O) _n-R ⁸; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ⁵be selected from hydroxyl, C _1-8alkyl, C _1-8alkoxyl group, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls ,-O-C _3-15cycloalkyl ,-O-C _6-10aryl or-O-6 to 10 yuan of heteroaryls, preferred hydroxyl, C _1-6alkyl, C _1-6alkoxyl group or C _3-8cycloalkyl, further preferred hydroxyl, C _1-4alkyl or C _1-4alkoxyl group;

R ⁶, R ⁷and R ⁹independently be selected from H, C separately _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 yuan of Heterocyclylalkyls, preferred H, C _1-6alkyl or C _3-8cycloalkyl, further preferred H, C _1-4alkyl or C _3-6cycloalkyl;

R ⁸be selected from C _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 yuan of Heterocyclylalkyls, preferred C _1-6alkyl, C _3-8cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 yuan of Heterocyclylalkyls, further preferred C _1-6alkyl, C _3-6cycloalkyl or 3 to 6 yuan of Heterocyclylalkyls, more preferably C _1-4alkyl or C _3-6cycloalkyl; Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 5 and are selected from N, O or S (=O) _natom or group;

M is selected from 0,1 or 2;

N is selected from 0,1 or 2.

R ¹be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl or C _1-6alkoxyl group, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-4alkyl or C _1-4alkoxyl group, further preferred H, F, Cl, Br, hydroxyl or cyano group;

R ²and R ^2aindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-6alkyl ,-(CH ₂) _m-C _3-6cycloalkyl or-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls, described alkyl, cycloalkyl or Heterocyclylalkyl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl contains 1 to 3 and is selected from N, O or S (=O) _natom or group;

R ^3aand R ^3bindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group or C separately _1-6alkyl, described alkyl is optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ⁴be selected from H, cyano group, C _1-8alkyl ,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-3 to 10 yuan of Heterocyclylalkyls ,-(CH ₂) _m-6 to 8 yuan of heteroaryls or-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸; R ⁴preferably from H, cyano group, C _1-8alkyl ,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸or-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸, more preferably H, C _1-6alkyl ,-(CH ₂) _m-S (=O) _n-R ⁸or-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸, preferred H, C further _1-4alkyl or-(CH ₂) _m-S (=O) _n-R ⁸;

R ⁶or R ⁷independently be selected from H or C separately _1-6alkyl;

R ⁸be selected from C _1-6alkyl, C _3-8cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 yuan of Heterocyclylalkyls, preferred C _1-6alkyl, C _3-6cycloalkyl or 3 to 8 yuan of Heterocyclylalkyls, further preferred C _1-4alkyl, C _3-6cycloalkyl or 3 to 6 yuan of Heterocyclylalkyls; Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 3 and are selected from N, O or S (=O) _natom or group;

R ⁹be selected from H, C _1-6alkyl or C _3-10cycloalkyl; Preferred H or C _1-2alkyl;

M is selected from 0,1 or 2;

N is selected from 0,1 or 2.

R ¹independently be selected from H or F separately;

R ²and R ^2aindependently be selected from H, C separately _1-6alkyl, C _3-6cycloalkyl or 3 to 8 yuan of Heterocyclylalkyls, preferred H, C _1-6alkyl or C _3-6cycloalkyl, further preferred H or C _1-4alkyl, described alkyl, cycloalkyl or Heterocyclylalkyl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl contains 1 to 3 and is selected from N, O or S (=O) ₂atom or group;

R ^3aand R ^3bindependently be selected from H or C separately _1-4alkyl, wherein said alkyl is optionally selected from F, hydroxyl or C by 0 to 3 further _1-4the substituting group of alkoxyl group replaced;

R ⁴be selected from H or-S (=O) ₂-R ⁸

R ⁸be selected from C _1-6alkyl, C _3-6cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 yuan of Heterocyclylalkyls, preferred C _1-6alkyl, C _3-6cycloalkyl or 3 to 8 yuan of Heterocyclylalkyls, further preferred C _1-4alkyl, C _3-6cycloalkyl or 3 to 6 yuan of Heterocyclylalkyls, more preferably C _1-4alkyl or C _3-6cycloalkyl; Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 3 and are selected from N, O or S (=O) ₂atom or group.

V is selected from one of following group:

Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl; Preferably 2,5-difluorophenyls;

R ²and R ^2aindependently be selected from H, C separately _1-6alkyl or C _3-6cycloalkyl, preferred H or C _1-4alkyl, wherein said alkyl or cycloalkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ^3aand R ^3bindependently be selected from H or C separately _1-4alkyl, preferred H, wherein said alkyl is optionally selected from F, hydroxyl or C by 0 to 3 further _1-4the substituting group of alkoxyl group replaced;

R ⁴for-S (=O) ₂-R ⁸;

R ⁸be selected from C _1-2alkyl, 3 to 6 yuan of Heterocyclylalkyls or C _3-6cycloalkyl, wherein said alkyl, Heterocyclylalkyl or cycloalkyl optional further replace by 0 to 5 F, described Heterocyclylalkyl contains 1 to 3 and is selected from N, O or S (=O) ₂atom or group.

V is selected from one of following group:

R ²and R ^2aindependently be selected from H, C separately _1-4alkyl or C _3-6cycloalkyl, preferred H or C _1-4alkyl, further preferred H, methyl, ethyl or sec.-propyl, wherein said alkyl or cycloalkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ^3aand R ^3bindependently be selected from H, methyl, ethyl or sec.-propyl separately, be preferably H;

R ⁴be selected from-S (=O) ₂-CH ₃,-S (=O) ₂-CH ₂cH ₃, preferably-S (=O) ₂-CH ₃,-S (=O) ₂-CH ₂cH ₃,

R ²and R ^2aindependently be selected from H or C separately _1-4alkyl, preferred H, methyl, ethyl or sec.-propyl, described alkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced.

R ^2afor C _1-4alkyl, described alkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced.

V is selected from one of following group:

R ²and R ^2aindependently be selected from H or C separately _1-4alkyl, preferred H, methyl, ethyl or sec.-propyl, described alkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ^3aand R ^3bfor H;

R ⁴for-S (=O) ₂-CH ₃,-S (=O) ₂-CH ₂cH ₃or

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

V is selected from one of following group:

Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl;

R ²be selected from H or C _1-4alkyl, described alkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced; Preferred H, methyl, ethyl or sec.-propyl;

R ^2afor C _1-4alkyl, preferable methyl, ethyl or sec.-propyl, described alkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ^3aand R ^3bfor H;

R ⁴for-S (=O) ₂-CH ₃,-S (=O) ₂-CH ₂cH ₃or

Preferred version of the present invention, compound described in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, wherein compound is selected from general formula (II), general formula (III), general formula (IV) or the compound shown in logical formula V:

Wherein:

V is selected from one of following group:

Ar is phenyl, optionally further by 0 to 5 R ¹replace; Preferably 2,5-difluorophenyls or 2,4,5-trifluorophenyl;

R ¹independently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl or C _1-6alkoxyl group, further preferred H or F; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ²and R ^2aindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl ,-(CH ₂) _m-C _3-6cycloalkyl or-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls, further preferred H, C _1-6alkyl ,-(CH ₂) _m-C _3-6cycloalkyl or-(CH ₂) _m-3 to 8 yuan of Heterocyclylalkyls, more preferably H, C _1-4alkyl or-C _3-6cycloalkyl, further preferred H or C _1-4alkyl, more preferred C _1-4alkyl, further preferable methyl, ethyl or sec.-propyl; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and is preferably selected from F, hydroxyl, C by 0 to 3 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced; Described Heterocyclylalkyl or heteroaryl contain 1 to 5 and are selected from N, O or S (=O) _natom or group, be preferably selected from N, O or S (=O) containing 1 to 3 _natom or group;

R ^3aand R ^3bindependently be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C separately _1-8alkyl, preferred H, F, Cl, Br, I, hydroxyl, cyano group, C _1-6alkyl, further preferred H or C _1-4alkyl, more preferably H, methyl, ethyl or sec.-propyl, further preferred H; Described alkyl is optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and is preferably selected from F, hydroxyl or C by 0 to 3 _1-4the substituting group of alkoxyl group replaced;

R ⁴be selected from H, cyano group, C _1-8alkyl, C _1-8alkoxyl group, C _2-8thiazolinyl, C _2-8alkynyl ,-(CH ₂) _m-C _3-15cycloalkyl ,-(CH ₂) _m-3 to 15 yuan of Heterocyclylalkyls ,-(CH ₂) _m-C _6-10aryl ,-(CH ₂) _m-6 to 10 yuan of heteroaryls ,-(CH ₂) _m-C (=O)-R ⁵,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-O-C (=O)-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸,-(CH ₂) _m-NR ⁹-C (=O)-NR ⁶r ⁷or-(CH ₂) _m-NR ⁹-C (=O)-R ⁵, preferred H, cyano group, C _1-8alkyl ,-(CH ₂) _m-NR ⁶r ⁷,-(CH ₂) _m-S (=O) _n-R ⁸or-(CH ₂) _m-NR ⁹-S (=O) _n-R ⁸, preferred H or-(CH further ₂) _m-S (=O) _n-R ⁸, more preferably-(CH ₂) _m-S (=O) _n-R ⁸, further preferred-S (=O) ₂-CH ₃or-S (=O) ₂-cyclopropyl; Described alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl or heteroaryl contain 1 to 5 and be selected from N, O or S (=O) _natom or group;

R ⁵be selected from hydroxyl, C _1-8alkyl, C _1-8alkoxyl group, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls ,-O-C _3-15cycloalkyl ,-O-C _6-10aryl or-O-6 to 10 yuan of heteroaryls, preferred hydroxyl, C _1-6alkyl, C _1-6alkoxyl group or C _3-8cycloalkyl, further preferred hydroxyl, C _1-4alkyl or C _1-4alkoxyl group, more preferably hydroxyl, methyl, ethyl, methoxy or ethoxy;

R ⁶, R ⁷and R ⁹independently be selected from H, C separately _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 yuan of Heterocyclylalkyls, preferred H, C _1-6alkyl or C _3-8cycloalkyl, further preferred H, C _1-4alkyl, C _3-6cycloalkyl, more preferably H, methyl, ethyl or cyclopropyl;

R ⁸be selected from C _1-8alkyl, C _3-15cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 15 Heterocyclylalkyls, preferred C _1-6alkyl, C _3-8cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 Heterocyclylalkyls, further preferred C _1-6alkyl, C _3-6cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 yuan of Heterocyclylalkyls, more preferably C _1-2alkyl or C _3-6cycloalkyl, further preferable methyl, ethyl, sec.-propyl or cyclopropyl; Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 3 and are selected from N, O or S (=O) _natom or group;

M is selected from 0,1 or 2, and preferably 0;

N is selected from 0,1 or 2, and preferably 2.

Preferred version of the present invention, the compound described in a kind of general formula (IV) or its steric isomer, pharmacy acceptable salt or prodrug, wherein this compound is selected from general formula (VI) or the compound shown in general formula (VII):

preferably

Preferred version of the present invention, the compound described in a kind of general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug, this compound is selected from one of following structure:

The invention still further relates to compound or its steric isomer shown in general formula (I), pharmacy acceptable salt or prodrug, wherein said salt includes but not limited to sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridinium salt, picoline salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, formate, trifluoroacetate, acetate, maleate, tartrate, Citrate trianion, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination, preferably salt hydrochlorate, vitriol, phosphoric acid salt, trifluoroacetate, acetate, maleate, tartrate, Citrate trianion, succinate, fumarate, malate, tosilate, benzene sulfonate, mesylate, fluoroform sulphonate or their combination.

The invention still further relates to a kind of pharmaceutical composition, described composition comprises: the amino six-ring analog derivative shown in the described general formula (I) of effective dose or its steric isomer, pharmacy acceptable salt or prodrug, or comprises one or more other treatment agent further; And pharmaceutically acceptable carrier or vehicle.

The invention still further relates to a kind of pharmaceutical composition, wherein said other treatment agent comprises:

(a) DPP-IV inhibitor or pharmacy acceptable salt, and/or

(b) SGLT-2 inhibitor or pharmacy acceptable salt, and/or

(c) biguanides, thiazolidinediones, sulfonylurea, arrange how class, alpha-glucosidase inhibitor or glucagon-like peptide-1 analogs, or its pharmacy acceptable salt or prodrug.

The composition that the present invention relates to, wherein said SGLT-2 inhibitor is selected from that Da Gelie is clean, Kan Gelie is clean, A Gelie is clean, En Palie is clean, Yi Palie is clean, Tuo Fulie is clean, Lu Silie is clean, Rui Gelie is clean, She Gelie is clean or relies on row clean; DPP-IV inhibitor be selected from BI 1356, sitagliptin, Vildagliptin, Egelieting, BMS-477118, Na Lieting, carmegliptin, melogliptin, dutogliptin, for Ge Lieting, gigue row spit of fland or bent Ge Lieting; Biguanides therapeutical agent is selected from N1,N1-Dimethylbiguanide or phenformin; Thiazolidinediones therapeutical agent is selected from ciglitazone, pioglitazone, rosiglitazone, troglitazone, Fa Gelie ketone or darglitazone, sulfonylurea treatment agent is selected from glimepiride, tolbutamide, glibornuride, Glyburide, gliquidone, Glipizide or gliclazide, arrange how class therapeutical agent is selected from nateglinide, repaglinide or mitiglinide, alpha-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and glucagon-like peptide-1 analogs is selected from Exenatide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].

The invention still further relates to the compound described in general formula (I) or its steric isomer, pharmacy acceptable salt and composition thereof or its prodrug are preparing the application in dipeptidyl peptidase-iv inhibitor, wherein said dipeptidyl peptidase-iv inhibitor is for the preparation of the medicine for the treatment of metabolic disease, wherein said metabolic disease is selected from diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the level of the rising of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis or hypertension, preferably, described diabetes are type ii diabetes.

Unless there are contrary statement, the term used in the specification and in the claims has following implication.

Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group of the present invention and compound include their isotropic substance, and in group of the present invention and compound involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen optional further substitute by the isotropic substance of their correspondences one or more, wherein the isotropic substance of carbon comprises ¹²c, ¹³c and ¹⁴c, the isotropic substance of hydrogen comprises protium (H), deuterium (D is also called heavy hydrogen), tritium (T is also called tritium), and the isotropic substance of oxygen comprises ¹⁶o, ¹⁷o and ¹⁸o, the isotropic substance of sulphur comprises ³²s, ³³s, ³⁴s and ³⁶s, the isotropic substance of nitrogen comprises ¹⁴n and ¹⁵n, the isotropic substance of fluorine ¹⁹f, the isotropic substance of chlorine comprises ³⁵cl and ³⁷cl, the isotropic substance of bromine comprises ⁷⁹br and ⁸¹br.

" alkyl " refers to the representative examples of saturated aliphatic hydrocarbyl group of straight chain and side chain, main chain comprises 1 to 20 carbon atom, be preferably 1 to 12 carbon atom, more preferably 1 to 8 carbon atom, be more preferably 1 to 6 carbon atom, the preferably straight chain of 1 to 4 carbon atom and branched group, most preferably 1 to 2 carbon atom further again.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl isophthalic acid-butyl, 2-methyl-1-butene base, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 3-methyl-3-amyl group, 2-methyl-3-amyl group, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,2-dimethylhexanyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl and positive decyl etc.Alkyl can be replacement or unsubstituted, when substituted, substituting group can be substituted on any spendable tie point, and substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^dindependently be selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base cyclic group separately.

" alkoxyl group " refers to-O-alkyl, and wherein alkyl is as hereinbefore definition.Alkoxyl group can be replacement or unsubstituted, and alkoxyl group embodiment includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, sec-butoxy, n-pentyloxy and positive hexyloxy etc.When substituted, substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl R can be formed ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" alkoxyalkyl " refers to the alkyl be connected with alkoxyl group.Alkoxyalkyl can be replacement or unsubstituted, its non-limiting example comprises, methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy methyl, Among, 2-propoxy methyl, butoxypropyl, t-butoxy ethyl, pentyloxy ethyl, hexyloxyehtyl, ring propoxy methyl, ring Among, ring propoxypropyl and cyclohexyloxy methyl; When substituted, substituting group is preferably 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" thiazolinyl " refers at least containing the alkyl as hereinbefore definition of a carbon-to-carbon double bond composition, preferably containing 2 to 20 carbon atoms, preferred 2 to 12 carbon atoms further, more preferably have 2 to 8 carbon atoms on main chain, and thiazolinyl can be to replace or unsubstituted.Non-limiting example comprises vinyl, allyl group, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 3-butenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonene base, 3-nonene base, 1-decene base, 4-decene base, 1, 3-divinyl, 1, 3-pentadiene, 1, 4-pentadiene, 1, 4-hexadiene, 3-hendecene base, 4-laurylene base and 4, 8, 12-14 carbon trialkenyl etc.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" alkynyl " refers to the alkyl as hereinbefore definition comprising at least one carbon-to-carbon triple bond composition, and preferably containing 2 to 20 carbon atoms, preferred 2 to 8 carbon atoms further, more preferably have the alkynyl of 2 to 4 carbon atoms on main chain.Alkynyl can be replacement or unsubstituted.Non-limiting example comprises ethynyl, 1-proyl, 2-propynyl, butynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butyne base, 2-hexin base, 3-hexin base, 2-heptyne base, 3-heptyne base, 4-heptyne base, 3-octyne base, 3-n-heptylacetylene base, 4-decynyl, 3-undecyne base and 4-dodecyne base etc.; When substituted, substituting group is preferably one or more following group, independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" amino " refers to-NH ₂it can be replacement or unsubstituted, when substituted, substituting group is preferably less than 1 to 3 group, independently selected from alkyl, cycloalkyl, haloalkyl, mercaptan, hydroxyl, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" alkylthio " refers to-S-alkyl or-S-(not being substituted cycloalkyl), and non-limiting example comprises methylthio group, ethylmercapto group, rosickyite base and butylthio etc.

" acyl group " or " carbonyl " refers to-C (=O)-R ^agroup, wherein R ^aas defined above.

" aldehyde " refers to-C (=O)-H.

" halogen " refers to fluorine, chlorine, bromine, iodine.

" hydroxyl " refers to-OH.

" cyano group " refers to-C ≡ N.

" isocyano-" refers to-N ≡ C.

" nitro " refers to-NO ₂.

" carboxylic acid " refers to-C (=O)-OH.

" carboxylicesters " refers to-C (=O)-O-R ^d, R ^dbe selected from alkyl, cycloalkyl or Heterocyclylalkyl.

" haloalkyl " refers to the alkyl as hereinbefore definition of halogen substiuted, non-limiting example comprises a methyl fluoride, difluoromethyl, trifluoromethyl, a brooethyl, two brooethyls, trisbromomethyl, 1-fluoro ethyl-2-base, 2-fluoro ethyl-2-base, 1,1-bis-fluoro ethyl-2-base, 1,2-bis-fluoro ethyl-2-base, 1,1,1-fluoro ethyl-2-base, 1-bromotrifluoromethane-2-base, 2-bromotrifluoromethane-2-base and 1,1,1-three bromomethyl-2-base etc.

" sulfydryl " refers to-SH.

" mercaptan " refers to that the hydrocarbon that the one or more hydrogen atoms in alkyl are replaced by sulfydryl, non-limiting example comprise thiomethyl alcohol, sulfur alcohol, 1,2-bis-mercaptan.

" sulfonyl " or " thiocarbonyl " refers to-C (=S)-R ^agroup, wherein R ^aas defined above.

" hydroxyalkyl " refers to that alkyl is optionally substituted with one or more hydroxyl replacement, and preferably replaced by 1,2 or 3 hydroxyl, alkyl is preferably low alkyl group.Non-limiting example comprises methylol, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl and 2,3-dihydroxypropyl etc.

" cycloalkyl " refers to saturated or undersaturated monocyclic cycloalkyl, it can be replacement or unsubstituted, ring carbon atom comprises 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, preferred 3 to 8 carbon atoms further, non-limiting example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadiene base, 1，4-cyclohexadiene base and cycloheptatriene base etc.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" Heterocyclylalkyl " refers to replacement or unsubstituted saturated or unsaturated and be at least selected from the heteroatomic non-aromatic ring of N, O or S containing 1 to 5, non-aromatic ring can be the monocycle of 3 to 10 yuan, the volution of 4 to 20 yuan ring or bridged ring, N, S that in heterocycloalkyl ring, selectivity replaces can be oxidized to various oxidation state.Preferably 3 to 12 yuan of heterocycles.Non-limiting example comprises oxirane base, oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, oxacyclohexyl, oxa-ring octyl group, ethylenimine base, azelidinyl, nitrogen heterocyclic amyl group, piperidyl, aziridinyl, 1, 3 dioxy cyclopentyl, 1, 4-dioxy cyclopentyl, 1, 3-dioxy cyclopentyl, 1, 3-dioxocyclohex base, 1, 3-bis-sulphur cyclohexyl, azepine base, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrryl, pyranyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, thio-morpholinyl, dihydropyrane, thiadiazolyl group, oxazolyl, oxadiazolyl, pyrazolyl, 1, 4-Dioxin base, or deng.When substituted, substituting group can be 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^cdeng group, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" volution " refers to 5 to the 20 yuan of polycyclic moiety sharing a carbon atom (title spiro atom) between replacement or unsubstituted monocycle, and it can comprise 0 to 5 double bond, and can be selected from N, O or S (=O) containing 0 to 5 _nheteroatoms.Be preferably 6 to 14 yuan, more preferably 6 to 12 yuan, more select 6 to 10 yuan, its non-limiting example comprises

When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" and ring " refers to that each ring in system and other rings in system share the polycyclic moiety of a pair carbon atom adjoined, wherein one or more rings can contain 0 or multiple double bond, and can be replace or do not replace, and each ring in member ring systems can be selected from N, S (=O) containing 0 to 5 _nor the heteroatoms of O.Be preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more select 5 to 12 yuan, more preferably 5 to 10 yuan further.Non-limiting example comprises

With when substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" bridged ring " refers to the polycyclic moiety of any two carbon atoms directly do not connected, and can contain 0 or multiple double bond, and can be replacement or unsubstituted, and any ring in member ring systems can be selected from N, S (=O) containing 0 to 5 _nor O heteroatoms or group (wherein n is 1,1,2).Annular atoms comprises 5 to 20 atoms, is preferably 5 to 14 atoms, preferably 5 to 12 further, at preferably 5 to 10 further.Non-limiting example comprises

And diamantane.When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^drespective be independently selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base or and cyclic group.

" benzyl " refers to-CH ₂-phenyl, described phenyl is that replace or unsubstituted, and its non-limiting example comprises-CH ₂-phenyl ,-CH ₂-p-methylphenyl etc.

" aryl " refers to replacement or unsubstituted 6 to 14 yuan of cyclic aromatic groups, comprises mono-cyclic aromatic base and polycyclic aromatic base.Preferably 6 to 14 yuan of aromatic nucleus, further preferred 6 to 10 yuan of aromatic nucleus, its limiting examples comprises phenyl, naphthyl, anthryl and phenanthryl etc.Described aryl rings can condense on heteroaryl, Heterocyclylalkyl or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:

When substituted, substituting group is 1 to 5 and is selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxyl group, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano-, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, volution base cyclic group, hydroxyalkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylicesters ,-(CH ₂) _m-C (=O)-R ^a,-O-(CH ₂) _m-C (=O)-R ^a,-(CH ₂) _m-C (=O)-NR ^br ^c,-(CH ₂) _ms (=O) _nr ^a,-(CH ₂) _m-thiazolinyl-R ^a, OR ^dor-(CH ₂) _m-alkynyl-R ^a(wherein m, n are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR ^br ^c, wherein R ^bwith R ^cindependently be selected from and comprise H, hydroxyl, amino, carbonyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylsulfonyl, trifyl, as selection, R ^bwith R ^cfive or six-ring alkyl or Heterocyclylalkyl can be formed.R ^awith R ^dindependently be selected from aryl, heteroaryl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, volution base cyclic group separately.

" heteroaryl " refers to substituted or unsubstituted 5 to 14 yuan of aromatic nucleus, and is selected from N, O or S (=O) containing 1 to 5 _nheteroatoms or group, preferably 5 to 10 yuan of assorted aromatic nucleus, preferably 5 to 6 yuan further.The non-limiting example of heteroaryl includes but not limited to that pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholine, thiomorpholine, 1,3-dithiane, benzoglyoxaline, piperazine sting base, benzoglyoxaline, benzo pyridine, pyrrolopyridine etc.Described heteroaryl ring can condense on aryl, Heterocyclylalkyl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises

" artyl sulfo " refers to-S-aryl as defined herein or-S-heteroaryl.Artyl sulfo example includes but not limited to thiophenyl, pyridinylthio, furyl sulfenyl, thienyl sulfenyl, pyrimidine-based sulfur-base etc.

" silylation " refer to one or more hydrogen atoms in silicomethane by alkyl replace the group that formed, embodiment include but not limited to trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl and tert-butyl diphenyl silica-based etc.

Term " singly-bound " refers to chemical single bond, and such as " being a singly-bound between A and B " represents to there is chemical single bond, that is: an A-B between A and B.

" optionally " or " optionally " refer to subsequently described event or environment can but need not beard and hair raw, this explanation comprises the occasion that this event or environment occur or do not occur.As: " optionally by alkyl that F replaces " refer to alkyl can but must do not replaced by F, illustrate and comprise situation that alkyl replaced by F and alkyl not by situation that F replaces.

" pharmacy acceptable salt " or " its pharmacy acceptable salt " refers to the biological effectiveness and characteristic that keep free acid or free alkali, and described free acid by with nontoxic mineral alkali or organic bases, or described free acid those salt by obtaining with nontoxic mineral acid or organic acid reaction, comprise an alkali metal salt, as sodium salt, sylvite, lithium salts etc., alkaline earth salt, as calcium salt, magnesium salts etc., other metal-salts, as molysite, mantoquita, cobalt salt etc., organic alkali salt, as ammonium salt, triethylamine salt, pyridinium salt, picoline salt, 2, 6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidinesalt, sec.-propyl amine salt, trismethylamine salt, tripropyl amine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethyl ethanol amine salt, dicyclohexyl amine salt, coffee alkali salt, procaine salt, choline salt, beet alkali salt, Penicillin G benethamine salt, glucose amine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, cocoa alkali salt, tromethamine salt, purine salt, piperazine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, N-ethylpiperidine salt, tetramethyl-amine salt, dibenzyl amine salt and phenylglycine alkyl ester salt etc., halogen acid salt, as hydrofluoride, hydrochloride, hydriodate, hydrobromate etc., inorganic acid salt, as nitrate, vitriol, perchlorate, phosphoric acid salt etc., lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc., arylsulphonate, as benzene sulfonate, tosilate etc., organic acid salt, as formate, fumarate, formate, trifluoroacetate, furoate, gluconate, glutaminate, glycollate, isethionate, lactic acid salt, maleate, malate, mandelate, mucus hydrochlorate, embonate, pantothenate, stearate, succinate, sulfanilate, tartrate, malonate, 2 hydroxy propanoic acid salt, Citrate trianion, salicylate, oxalate, oxyacetate, glucuronate, galacturonic hydrochlorate, citrate, lysine salt, arginic acid salt, aspartate, cinnamate etc.

" pharmaceutical composition " represent compound described in one or more texts or its physiology/pharmacy acceptable salt or prodrug combination or/and use clinically be used for the treatment of, the medicine of prevent diabetes or/and SGLT-2 inhibitor is or/and the mixture of DPP-IV inhibitor and other moietys, wherein other component comprises physiology/pharmaceutically acceptable carrier and vehicle.What use clinically is used for the treatment of, the medicine of prevent diabetes comprises biguanides, thiazolidinedione, sulfonylurea, row how, alpha-glucosidase inhibitor, GLP-1 analogue or its pharmacy acceptable salt, such as N1,N1-Dimethylbiguanide, phenformin, ciglitazone (Ciglitazone), pioglitazone (Pioglitazone), rosiglitazone (Rosiglitazone), troglitazone (Troglitazone), Fa Gelie ketone (Farglitazar), darglitazone (Darglitazoan), glimepiride (Glimepiride), tolbutamide (Tolglybutamide), glibornuride (Glibornuride), Glyburide (Glibenclamide), gliquidone (Gliquidone), Glipizide (glipizide), gliclazide (gliclazipe), nateglinide (Nateglinide), repaglinide (Repaglinide), mitiglinide (mitiglinide), acarbose (Acarbose), voglibose (Voglibose), miglitol (Miglitol), Exenatide (Exenatide) or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (Liraglutide), SGLT-2 inhibitor is Da Gelie clean (Dapagliflozin) such as, Kan Gelie clean (Canagliflozin), En Palie clean (Empagliflozin), Yi Palie clean (Ipragliflozin), Tuo Fulie clean (Tofogliflozin), Lu Silie clean (Luseogliflozin), Rui Gelie clean (Remogliflozin), She Gelie clean (Sergliflozin) or support row clean (Ertugliflozin), DPP-IV inhibitor is BI 1356 (Linagliptin) such as, sitagliptin (Sitagliptin), Vildagliptin (Vildagliptin), Egelieting (Alogliptin), BMS-477118 (Saxagliptin), MK-3102, ground Na Lieting (Denagliptin), carmegliptin (Carmegliptin), melogliptin (Melogliptin), dutogliptin (Dutogliptin), for Ge Lieting (Teneligliptin), gigue row spit of fland (Gemigliptin) or bent Ge Lieting (Trelagliptin).The object of pharmaceutical composition is the administration promoting compound on organism body.

" carrier " refers to and can not produce obvious stimulation to organism and can not eliminate the biological activity of given compound and the carrier of characteristic or thinner.

" vehicle " refers to and joins in pharmaceutical composition to depend on the inert substance of compound administration further.The example of vehicle includes but not limited to calcium carbonate, calcium phosphate, various sugar and dissimilar starch, derivatived cellulose (comprising Microcrystalline Cellulose), gelatin, vegetables oil, polyethylene glycols, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc.

" prodrug " is referred to and in physiological conditions or can be converted into the compound with bioactive the compounds of this invention by solvolysis.Prodrug of the present invention is prepared by the phenolic group group be modified in this compound, and this modification can operation routinely or be removed in vivo, and obtains parent compound.When prodrug of the present invention is bestowed mammalian subject, prodrug is formed free hydroxyl respectively by isolating.The phenolic hydroxyl group that the example of prodrug includes, but are not limited to the compounds of this invention becomes sodium salt derivative with phosphoric acid.

Some compound as herein described can exist as tautomer, along with the transfer of one or more double bond, has different hydrogen tie points.Such as keto-enol tautomerism body.Single tautomer and composition thereof is all included in the scope of the compounds of this invention.Tautomer within the scope of the compounds of this invention includes but not limited to:

Compound described herein can contain one or more asymmetric center, and can exist with racemoid, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer thus.

Some compound described herein contains double bond, except as otherwise noted, comprises E and Z geometry structure body.

" X syndromes " refers to the illness of metabolic syndrome, disease and illness.Detailed description is shown in JohannssonJ.Clin.Endocrinol.Metab., 1997,82,727-734.

" effective dose " has guided the amount of the compound of tissue, system or subject physiologic or medical science translation, this amount is sought, is included in and is enough to prevent one or more symptoms of subject illness or illness to occur with it when curee uses or makes it alleviate amount to compound to a certain degree.

" solvate " refers to the compounds of this invention or its salt, and they also comprise with the stoichiometry of non-covalent intermolecular forces combination or non-stoichiometric solvent.When solvent is water, then it is hydrate.

" IC ₅₀" refer to half-inhibition concentration, refer to the concentration reaching maximum suppression effect one half.

The synthetic method of the compounds of this invention

In order to complete object of the present invention, the compounds of this invention can be prepared by following scheme and obtain:

General formula (I-1) compound and fluoro reagent are obtained by reacting general formula (I-2) compound, general formula (I-2) compound and intermediate (H-V) compound are obtained by reacting general formula (I-3) compound, obtain general formula (I) compound after general formula (I-3) compound goes protecting group; The definition of Ar with V defines consistent with general formula (I);

R ¹¹and R ¹²independently be selected from H or amino protecting group, preferred R separately ¹¹and R ¹²be asynchronously H; wherein said amino protecting group includes but not limited to tert-butoxycarbonyl, benzyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl, allyloxy carbonyl, tri-chloroethoxy base carbonyl, trimethyl silicon based ethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-xenyl-2-third oxygen carbonyl, tert.-butoxy, phthaloyl, p-toluenesulfonyl, ortho-nitrophenyl alkylsulfonyl, p-nitrophenyl alkylsulfonyl, pivaloyl group, formyl radical, trifluoroacetyl group, benzoyl, benzyl, trityl, to methoxy-benzyl or 2; 4-dimethoxy-benzyl, preferred H or tert-butoxycarbonyl.

Accompanying drawing explanation

Fig. 1 is compound 1 ¹h- ¹hCOSY collection of illustrative plates.

Fig. 2 is compound 1 ¹h- ¹hNOESY collection of illustrative plates.

Embodiment

Describe the beneficial effect of implementation process of the present invention and generation below by way of specific embodiment in detail, be intended to help reader to understand essence of the present invention and feature better, not as can the restriction of practical range to this case.

The structure of compound is determined by nucleus magnetic resonance (NMR) and/or mass spectrum (MS).

The mensuration of NMR is with (BrukerADVANCEIII400) nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆), deuterochloroform (CDCl ₃), deuterated methanol (CD ₃oD), tetramethylsilane (TMS) is inside designated as.

The mensuration of MS uses (Agilent6120B (ESI)).

The mensuration of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (ZorbaxSB-C18100x4.6mm).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.20mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.

Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.

Without specified otherwise, triethylamine, methyl tertiary butyl ether, hydrazine hydrate, Tetrabutyl amonium bromide, thionyl chloride, imidazoles, sodium hydride, triphenyl phosphorus, trifluoroacetic acid are bought in Chengdu Ke Long chemical reagent factory; Two dimethyl dicarbonate butyl esters, N, N'-dicarbapentaborane diimidazole, DMF dimethylacetal, N, O-dimethyl hydroxylamine hydrochloride, cis-4-hydroxy-d-proline hydrochloride are bought in Ace spy (Chengdu) medical science company limited; Cesium carbonate, lithium borohydride, TERT-BUTYL DIMETHYL CHLORO SILANE, N-hydroxysuccinimide, two (trimethyl silicon based) sodium amide, diphenylmethylene glycine ethyl ester, trans-L-1,2-oxyproline are bought in the resistance to Jilin Chemical of peace; Wearing this Martin buys in the smooth Science and Technology Co., Ltd. of upper Haitai; Methyl triflate, 2,5-difluoro bromobenzenes are bought in Shanghai De Mo Pharmaceutical Technology Co., Ltd; 2-iodopropane is bought in Shanghai Bepharm Science & Technology Co., Ltd.; Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution is bought in lark prestige Science and Technology Ltd.; Propargyl benzene sulfonate, tetrabutyl ammonium fluoride, three (acetoxyl group) sodium borohydride, tetrabutyl phosphofluoric acid amine are bought in this Reagent Company of Adama; Two (triphenylphosphine) ruthenium chloride (II) of cyclopentadienyl is bought in ACROSorgainics; Borane dimethylsulf iotade is bought in splendid scientific and technological (Shanghai) Co., Ltd. of chemistry far away; Tetrahydrofuran (THF)-3-alkylsulfonyl chlorine is bought in Nanjing Kang Manlin chemical industry Industrial Co., Ltd.; Sodium peroxoborate is bought in Tianjin recovery fine chemistry industry institute; [(R, R)-N-(amino-1, the 2-Diphenethyl of 2-) pentafluorobenzenesulfonamide] chlorination (Paracymene) ruthenium (II) is bought in Stremchemical; Methyl iodide, Methanesulfonyl chloride are bought in medicine company limited-liability company of traditional Chinese medicines group.

Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 2L volume.

Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

Ambient temperature is 20 DEG C ~ 30 DEG C.

Abridge in embodiment:

Bn: benzyl; Et: ethyl; Ac: ethanoyl; Me: methyl; Boc: tertbutyloxycarbonyl; Ph: phenyl; COOH: carboxyl; OMe: methoxyl group; OTBS: dimethyl tertiary butyl silicon ether; SO ₃h: sulfonic group; Ms: methyl sulphonyl.

Intermediate 1: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-carbonyl tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 1)

tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate

The first step: 2-amino-4-alkynes Valeric acid ethylester (1B)

ethyl2-aminopent-4-ynoate

Under room temperature, by diphenylmethylene glycine ethyl ester 1A (50g, 0.187mol) be dissolved in methyl tertiary butyl ether (300mL), add propargyl benzene sulfonate (44g, 0.224mol) and Tetrabutyl amonium bromide (6.1g, 0.019mol), be warming up to 50 DEG C, add cesium carbonate (121.8g, 0.374mol), react at 50 DEG C of temperature and spend the night.By reacting liquid filtering, filter cake methyl tertiary butyl ether (40mL × 2) washs, merge organic phase, concentrated by rotary evaporation, to half volume, adds hydrochloric acid soln (3mol/L, 100mL), stirred at ambient temperature 1 hour, leave standstill separatory, aqueous phase methyl tertiary butyl ether (70mL × 2) extracts, collect aqueous phase, concentrate and obtain 1B.

Second step: 2-((tertbutyloxycarbonyl) is amino)-4-alkynes valeric acid (1C)

2-((tert-butoxycarbonyl)amino)pent-4-ynoicacid

By sodium hydroxide (33.7g, 0.842mol) water-soluble (100mL), dropwise drop to 1B (26.4g, in reaction solution 0.187mol), stirred at ambient temperature 2 hours, drip methyl tertiary butyl ether (125mL) solution of two dimethyl dicarbonate butyl esters (45g, 0.206mol), stirred at ambient temperature 4 hours.Leave standstill separatory, aqueous phase methyl tertiary butyl ether (80mL × 2) washs, the hydrochloric acid soln of aqueous phase 3mol/L regulates pH to 3, with methyl tertiary butyl ether (100mL × 2) extraction, merges organic phase, organic phase saturated sodium-chloride water solution (30mL × 2) washs, anhydrous magnesium sulfate drying, filters, is spin-dried for, obtain yellow oily liquid 1C (33g, productive rate 83%).

MSm/z(ESI):212.0[M-1]。

3rd step: the tertiary butyl (1-(methoxyl group (methyl) is amino)-1-carbonyl amyl group-4-alkynes-2-base) carbamate (1D)

tert-butyl(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate

By 1C (33g, 0.155mol) be dissolved in DMF (200mL), control temperature is less than 10 DEG C, add N, N'-carbonyl dimidazoles (32.58g, 0.201mol), reacts 1 hour at 0 DEG C, add N, O-dimethyl hydroxylamine hydrochloride (19.6g, 0.186mol), stirred overnight at room temperature.Water (150mL) is dropwise added in reaction solution, stir 1 hour, extract by ethyl acetate (100mL × 2), merge organic phase, organic phase uses saturated sodium bicarbonate solution (60mL × 3), saturated nacl aqueous solution (60mL × 3) to wash successively, anhydrous magnesium sulfate drying, filter, concentrated, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10:1), obtain white solid 1D (35g, productive rate 88.2%).

MSm/z(ESI):156.9[M+1]。

4th step: the tertiary butyl (1-(2,5-difluorophenyl)-1-carbonyl amyl group-4-alkynes-2-base) carbamate (1E)

tert-butyl(1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate

Under nitrogen protection, by 2, 5-difluoro bromobenzene (15.05g, 78mmol) be dissolved in dry toluene (50mL), cryosel bath is cooled to less than-10 DEG C, dropwise add isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (66mL, 1.3mol/L), remain on about-10 DEG C to stir 1 hour, drip 1D (10g, dry tetrahydrofuran (100mL) solution 39mmol), keep temperature-10 DEG C, finish, react 4 hours under room temperature, cool the temperature to about-10 DEG C, dropwise add saturated ammonium chloride solution (40mL), stir 10 minutes, pH to 5 ~ 6 are regulated with the hydrochloric acid soln of 3mol/L, leave standstill separatory, aqueous phase methyl tertiary butyl ether (50mL × 2) extracts, merge organic phase, organic phase saturated nacl aqueous solution (30mL × 2) washs, anhydrous sodium sulfate drying, filter, concentrated, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=50:1 ~ 8:1), obtain faint yellow solid 1E (10.1g, productive rate 83.5%).

MSm/z(ESI):210.1[M+1]。

5th step: the tertiary butyl ((1R, 2S)-1-(2,5-difluorophenyl)-1-Hydroxy pentyl-4-alkynes-2-base) carbamate (1F)

tert-butyl((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypent-4-yn-2-yl)carbamate

By 1E (16.07g, 52mmol) be dissolved in tetrahydrofuran (THF) (100mL), add triethylene diamine (17.39g, 155mmol) with [(R, R)-N-(2-amino-1,2-Diphenethyl) pentafluorobenzenesulfonamide] chlorination (Paracymene) ruthenium (II) (i.e. RuCl (p-cymene) (R, R)-FSDPEN) (0.37g, 0.52mmol), dropwise drip formic acid (14.27g, 310mmol), finish, spend the night in 40 DEG C of reactions.By reaction solution concentrated removing tetrahydrofuran (THF) and formic acid, water (60mL) and hydrochloric acid (3mol/L is added in residue, 10mL), extract with methyl tertiary butyl ether (90mL × 3), merge organic phase, organic phase saturated sodium bicarbonate solution (35mL × 2) washs, anhydrous magnesium sulfate drying, filter, concentrated, residue, with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=60:1 ~ 10:1), obtains faint yellow jelly 1F (15.37g, productive rate 95%).

MSm/z(ESI):334.2[M+23]。

6th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrans-3-base) carbamate (1G)

tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate

By 1F (15.37g, 49.4mmol) be dissolved in N under heating condition, dinethylformamide (75mL), add tetrabutyl phosphofluoric acid amine (2.49g, 6.42mmol), N-hydroxysuccinimide (2.84g, 24.75mmol), triphenylphosphine (0.86g, 3.26mmol) with sodium bicarbonate (2.16g, 25.69mmol), nitrogen replacement three times, vacuumize 15 minutes, add two (triphenylphosphine) ruthenium chloride (the II) (i.e. CpRuCl (PPh of cyclopentadienyl ₃) ₂) (1.79g, 2.47mmol), nitrogen replacement three times, and vacuumize 15 minutes, under nitrogen protection, be warming up to 85 DEG C of reactions and spend the night.Water (300mL) and methyl tertiary butyl ether (200mL) is added in reaction solution, by filtered through silica gel, separatory after filtrate leaves standstill, aqueous phase methyl tertiary butyl ether (90mL × 2) extracts, merge organic phase, organic phase saturated sodium bicarbonate solution (60mL × 2) washs, anhydrous sodium sulfate drying, filtering and concentrating, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=80:1 ~ 30:1), obtain pale yellow powder solid 1G (8.9g, productive rate 57.9%).

MSm/z(ESI):256.2[M+1]。

7th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-hydroxy tetrahydro-2H-pyrans-3-base) carbamate (1H)

tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate

By 1G (8.9g, 28.6mmol) be dissolved in dry methyl tertiary butyl ether (90mL), add dry toluene (9mL), temperature is down to-10 DEG C, dropwise add borane dimethylsulf iotade tetrahydrofuran solution (2mol/L, 35.9mL), react 3.5 hours at 0 DEG C.Slowly add water (4mL), dropwise add sodium hydroxide solution (1mol/L, 89mL), stir 15 minutes, add Sodium peroxoborate (13.2g, 85.8mmol), stirred overnight at room temperature in batches.Leave standstill separatory, aqueous phase methyl tertiary butyl ether (50mL × 2) extracts, merge organic phase, organic phase saturated nacl aqueous solution (20mL × 2) washs, anhydrous sodium sulfate drying, filter, concentrated, in residue, add toluene (50mL), be heated to 90 DEG C of dissolvings, normal hexane (200mL) is dropped in reaction solution, separates out white solid, filter, normal hexane (30mL × 2) washing leaching cake, concentrated except desolventizing, obtain white solid powder 1H (7.9g, productive rate 84%).

MSm/z(ESI):274.1[M+1]。

8th step: the tertiary butyl ((2R, 3S)-2-(2,5-difluorophenyl)-5-carbonyl-tetrahydrochysene-2H-pyrans-3-base) carbamate (intermediate 1)

tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-tetrahydro-2H-pyran-3-yl)carbamate

1H (11.53g, 35.03mmol) is dissolved in methylene dichloride (130mL), is cooled to 0 DEG C, this Martin's oxygenant (29.72g, 70.06mmol) will be worn and add in reaction solution in batches, and naturally rise to room temperature reaction 4 hours.Be cooled to 0 DEG C, saturated sodium bicarbonate solution (60mL) is dropped in reaction solution, stir 20 minutes, filter, filtrate leaves standstill separatory, aqueous phase methyl tertiary butyl ether (60mL × 3) extracts, merge organic phase, organic phase saturated sodium bicarbonate solution (30mL × 2) washs, anhydrous sodium sulfate drying, filtering and concentrating, residue is with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10:1-4:1), obtain White crystal powder intermediate 1 (10.85g, productive rate 94.7%).

MSm/z(ESI):272.0[M+1]；

¹HNMR(400MHz,DMSO-d ₆):δ7.29-7.13(m,4H),4.77–4.75(d,2H),4.22-4.12(d,2H),4.08-4.02(m,1H),2.75-2.70(m,2H),1.23(s,9H)。

Intermediate 2:2-methylsulphonic acid base-5,6-dihydro-4H-pyrrolo-[3,4-c] pyrazoles (intermediate 2)

2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole

The first step: the tertiary butyl (3Z)-3-(dimethylamino methene)-4-carbonyl-Pyrrolidine-1-manthanoate (2B)

tert-butyl(3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrolidine-1-carboxylate

By 1-tertbutyloxycarbonyl-3-pyrrolidone 2A (100g, 0.54mol) be dissolved in N, in N-N,N-DIMETHYLACETAMIDE (600mL), add DMF dimethylacetal (83.6g, 0.70mmol), be warming up to 105 DEG C of reactions 40 minutes, (500mL) cancellation that adds water is reacted, and with ethyl acetate (500mL × 2) extraction, merges organic phase.Organic phase washed with water (500mL × 2) washs, anhydrous sodium sulfate drying, concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=4:1 ~ 1:1) obtains the 2B (50g, productive rate 47%) of weak yellow liquid shape.

Second step: tertiary butyl 6a-hydroxyl-1,3a, 4,6-Pyrrolidine also [3,4-c] pyrazoles-5-manthanoate (2C)

tert-butyl6a-hydroxy-1,3a,4,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxylate

2B (50g, 0.21mol) is dissolved in methyl alcohol (200mL), adds hydrazine hydrate (7.8g, 0.16mmol, wt=80%), room temperature reaction 4 hours.Obtain 2C by concentrated for reaction solution, be directly used in next step.

3rd step: the tertiary butyl 4,6-dihydro-2 h-pyrrole is [3,4-c] pyrazoles-5-manthanoate (2D) also

tert-butyl4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate

Be dissolved in by 2C (47.5g, 0.21mol) in the mixed solvent of methylene dichloride (300mL) and methyl alcohol (180mL), be cooled to 0 DEG C, add tosic acid (5.64g, 0.029mmol), reaction is spent the night.Concentrated by reaction solution, residue silica gel column chromatography separating-purifying (methylene dichloride) obtains the 2D (20g, productive rate 44%) of faint yellow solid.

4th step: tertiary butyl 2-methylsulphonic acid base-4,6-pyrrolin also [3,4-c] pyrazoles-5-manthanoate (2E)

tert-butyl2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate

2D (3.5g, 16.7mmol) is dissolved in tetrahydrofuran (THF) (35mL), is cooled to 0 DEG C, add the sodium hydride (1.0g, 25.4mmol) of 60%, react 30 minutes, add Methanesulfonyl chloride (2.9g, 25.4mmol), react 1 hour.(10mL) cancellation that adds water in reaction solution is reacted, extract by ethyl acetate (50mL × 2), merge organic layer, organic over anhydrous dried over sodium sulfate, concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:1) obtains the 2E (2.1g, productive rate 44%) of white solid.

5th step: 2-methylsulphonic acid base-5,6-dihydro-4H-pyrrolo-[3,4-c] pyrazoles (intermediate 2)

2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole

2E (2.1g, 7.3mmol) is dissolved in methylene dichloride (25mL), is cooled to 0 DEG C, add trifluoroacetic acid (5mL), react 2 hours.Reaction solution is concentrated, adds ammoniacal liquor (2mL) cancellation reaction, obtain the intermediate 2 of white solid with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1).

¹HNMR(400MHz,MeOD)δ8.09(s,1H),4.52(m,4H),3.45(s,3H)。

Embodiment 1

(2R, 3R, 4R; 5S) the fluoro-5-of-2-(2,5-difluorophenyl)-4-(2-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 1)

(2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine

The first step: the tertiary butyl ((2R, 3R, 4R)-2-(2,5-difluorophenyl)-4-fluoro-5-carbonyl tetrahydrochysene-2H-pyrans-3-base) carbamate (1b)

tert-butyl((2R,3R,4R)-2-(2,5-difluorophenyl)-4-fluoro-5-oxotetrahydro-2H-pyran-3-yl)carbamate

Under nitrogen protection; by intermediate 1 (1.5g; 4.58mmol), trans 4-hydroxyl-D-PROLINE hydrochloride (77mg; 0.46mmol) with anhydrous sodium carbonate (728mg; 6.78mmol) join in tetrahydrofuran (THF) (20mL), stirred at ambient temperature 10 minutes, at this temperature, add the two benzsulfamide (1.44g of N-fluoro; 4.58mmol), reaction 48 hours is continued.Ethyl acetate (40mL) is added in reaction solution, stir 10 minutes, wash with water (20mL × 2), organic phase is dry by anhydrous sodium sulphate (2g), concentrated, residue, with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=2:1), obtains 1b (380mg, productive rate 24%).

MSm/z(ESI):368.3[M+23]。

Second step: ((2R, 3R, 4R, 5S)-2-(2,5-difluorophenyl) the fluoro-5-of-4-(2-(methylsulphonic acid base) pyrrolo-[3,4-c] pyrazoles-5 (2H, 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) t-butyl carbamate (1c)

tert-butyl((2R,3R,4R,5S)-2-(2,5-difluorophenyl)-4-fluoro-5-(2-(methylsulfonyl)

pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

Under nitrogen protection; by 1b (345mg, 1mmol) and intermediate 2 (206mg, 1.1mmol); be dissolved in N; in N-N,N-DIMETHYLACETAMIDE (6mL), add hydration Phenylsulfonic acid (222mg, 1.2mmol); stirred at ambient temperature 1 hour; add sodium triacetoxy borohydride (276mg, 1.3mmol), stirred at ambient temperature reacts 24 hours.Water (60mL) and ammoniacal liquor (6mL) is added in reaction system, separate out solid, filter to obtain crude product, by crude product with silica gel chromatographic column separating-purifying (petrol ether/ethyl acetate (v/v)=2:1), obtain 1c (220mg, productive rate 42.6%).

MSm/z(ESI):517.3[M+1]。

3rd step: (2R, 3R, 4R; 5S) the fluoro-5-of-2-(2,5-difluorophenyl)-4-(2-(methyl sulphonyl) pyrrolo-[3,4-c] pyrazoles-5 (2H; 4H, 6H)-Ji) tetrahydrochysene-2H-pyrans-3-amine (compound 1)

Under nitrogen protection, by 1c (220mg, 0.426mmol), be dissolved in methylene dichloride (1.5mL), be chilled to 0 DEG C, slowly at this temperature, instill trifluoracetic acid (1.5mL), rise to room temperature reaction after dripping off 2 hours.Reaction solution is concentrated, methylene dichloride (10mL) is added in residue, with 5% ammoniacal liquor (5mL × 2) washing anhydrous sodium sulfate drying, concentrated, residue is with Preparative TLC chromatography purification (methylene chloride/methanol (v/v)=20:1), obtain compound 1 (80mg, productive rate 45.2%).

MSm/z(ESI):417.3[M+1]；

¹HNMR(400MHz,DMSO-d ₆):δ7.72(s,1H),7.16(m,1H),7.04(m,2H),5.17(m,1H,),4.70(d,1H),4.13(m,1H),4.02(m,4H),3.93(m,1H),3.28(s,3H),3.10(m,1H),2.82(ddd,1H)。

Compound 1 ¹h- ¹hCOSY and ¹h- ¹hNOESY is as shown in Fig. 1 ~ Fig. 2, and data are as shown in table 1, and compound 1 configuration is shown below:

Table 1 compound 1 ¹hNMR, ¹h- ¹hCOSY and ¹h- ¹hNOESY data (DMSO-d ₆, 400MHz)

Bioassay

1, rat plasma DPP-IV zymetology screening experiment

Laboratory animal is SD rat, 8 week age, male, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., and animal productiong conformity certification number: SCXK (capital) 2012-0001.By the rat after fasting by body weight grouping.Rat adopts eye socket to get blood, EDTA-2Na anti-freezing tested group of oral test compound, and dosage is 10mg/kg; The oral blank reagent of control group.Blood is got respectively at different time points place after administration.By blood sample in the centrifugal 15min of 2500rpm, take out blood plasma, in-20 DEG C of preservations.Enzyme is lived and is tested, and each test sample gets 40 μ l blood plasma, adds 10 μ lH-Ala-Pro-AFC substrates (0.2mM), with microplate reader measured value (excitation wavelength Excitation=405nM after reaction 15min; Emission wavelength Emission=535nM), use Origin7.5 to carry out statistical study, calculate test compounds and plasma D PP-IV enzyme is lived inhibiting rate >=70% duration, the results are shown in Table 2.

Table 2 rat plasma DPP-IV zymetology screening experiment result

Sequence number	Compound number	>=70% inhibiting rate time length (h)
			1	Compound 1	50.8

Conclusion: the compounds of this invention significantly can suppress rat plasma DPP-IV enzymic activity.

2, pharmacokinetics in rats evaluation

Male SD rat (purchased from VitalRiverLaboratoryAnimalTechnologyCo.LTD, credit number: 11400700005540) 200-240g, overnight fasting.Experimental day 3 SD rats gavage 5mgkg respectively ^-1, respectively at 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h and 24h before administration and after administration, by jugular vein blood collection 0.20mL, be placed in EDTA test tube.The acetonitrile containing interior mark (verapamil, 5.00ng/mL and Glyburide, 50.0ng/mL) is added, the centrifugal 10min of 13000rpm after violent vortex after blood sample collection.Get supernatant and carry out LC-MS/MS detection.Adopt the non-compartment model in PharsightPhoenix6.3 to calculate pharmacokinetic parameter, experimental result is as shown in table 3.

Table 3 pharmacokinetics in rats evaluation result

Conclusion: the compounds of this invention, compared with positive control (WO2010056708 embodiment 1), rat has higher peak concentration and exposed amount, and the longer transformation period, possesses the potential quality of long-acting hypoglycemic.

Claims

1. the compound shown in a general formula (I) or its steric isomer, pharmacy acceptable salt or prodrug:

Wherein:

V is selected from one of following group:

Ar is phenyl, optionally further by 0 to 5 R ¹replace;

M is selected from 0,1 or 2;

N is selected from 0,1 or 2.

2. compound according to claim 1 or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

R ¹independently be selected from H or F separately;

R ²and R ^2aindependently be selected from H, C separately _1-6alkyl, C _3-6cycloalkyl or 3 to 8 yuan of Heterocyclylalkyls, described alkyl, cycloalkyl or Heterocyclylalkyl are optionally selected from F, Cl, Br, I ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced, and described Heterocyclylalkyl contains 1 to 3 and is selected from N, O or S (=O) ₂atom or group;

R ⁴be selected from H or-S (=O) ₂-R ⁸;

R ⁸be selected from C _1-6alkyl, C _3-6cycloalkyl, C _6-10aryl, 6 to 10 yuan of heteroaryls or 3 to 8 yuan of Heterocyclylalkyls, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl optional further replace by 0 to 5 F, described Heterocyclylalkyl or heteroaryl contain 1 to 3 and are selected from N, O or S (=O) ₂atom or group.

3. compound according to claim 2 or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

V is selected from one of following group:

Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl;

R ²and R ^2aindependently be selected from H, C separately _1-6alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ⁴for-S (=O) ₂-R ⁸;

R ⁸be selected from C _1-2alkyl, 3 to 6 yuan of Heterocyclylalkyls or C _3-6cycloalkyl, wherein said alkyl, Heterocyclylalkyl or cycloalkyl optional further replace by 0 to 5 F, described Heterocyclylalkyl has 1 to 3 to be selected from N, O or S (=O) ₂atom or group.

4. compound according to claim 3 or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

R ²and R ^2aindependently be selected from H, C separately _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optionally selected from F, hydroxyl, C by 0 to 3 further _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ^3aand R ^3bfor H;

R ⁴for-S (=O) ₂-CH ₃,-S (=O) ₂-CH ₂cH ₃,

5. the compound according to any one of Claims 1 to 4 or its steric isomer, pharmacy acceptable salt or prodrug, wherein compound is selected from general formula (II), general formula (III), general formula (IV) or the compound shown in logical formula V:

6. compound according to claim 1 or its steric isomer, pharmacy acceptable salt or prodrug, this compound is selected from one of following structure:

7. compound according to claim 6 or its steric isomer, pharmacy acceptable salt or prodrug, this compound is selected from one of following structure:

8. the compound according to any one of claim 1 ~ 7 or its steric isomer, pharmacy acceptable salt or prodrug, wherein said salt is selected from sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridinium salt, picoline salt, 2, 6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, formate, trifluoroacetate, acetate, maleate, tartrate, Citrate trianion, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

9. a pharmaceutical composition, described composition comprises compound according to any one of the claim 1 ~ 8 of effective dose or its steric isomer, pharmacy acceptable salt or prodrug, or comprises one or more other treatment agent and pharmaceutically acceptable carrier or vehicle further; Preferably, wherein said other treatment agent comprises:

(a) DPP-IV inhibitor or pharmacy acceptable salt, and/or

(b) SGLT-2 inhibitor or pharmacy acceptable salt, and/or

(c) biguanides, thiazolidinediones, sulfonylurea, arrange how class, alpha-glucosidase inhibitor or glucagon-like peptide-1 analogs, or its pharmacy acceptable salt or prodrug;

More preferably, described SGLT-2 inhibitor is selected from that Da Gelie is clean, Kan Gelie is clean, A Gelie is clean, En Palie is clean, Yi Palie is clean, Tuo Fulie is clean, Lu Silie is clean, Rui Gelie is clean, She Gelie is clean or relies on row clean; Described DPP-IV inhibitor be selected from BI 1356, sitagliptin, Vildagliptin, Egelieting, BMS-477118, Na Lieting, carmegliptin, melogliptin, dutogliptin, for Ge Lieting, gigue row spit of fland or bent Ge Lieting; Described biguanides therapeutical agent is selected from N1,N1-Dimethylbiguanide or phenformin; Described thiazolidinediones therapeutical agent is selected from ciglitazone, pioglitazone, rosiglitazone, troglitazone, Fa Gelie ketone or darglitazone, sulfonylurea treatment agent is selected from glimepiride, tolbutamide, glibornuride, Glyburide, gliquidone, Glipizide or gliclazide, arrange how class therapeutical agent is selected from nateglinide, repaglinide or mitiglinide, alpha-glucosidase inhibitor is selected from acarbose, voglibose or miglitol, and glucagon-like peptide-1 analogs is selected from Exenatide or Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37].

10. the compound according to any one of claim 1 ~ 8 or its steric isomer, pharmacy acceptable salt or prodrug or composition according to claim 9 are preparing the application in dipeptidyl peptidase-iv inhibitor; Preferably, described dipeptidyl peptidase-iv inhibitor is for the preparation of the medicine for the treatment of metabolic disease, and wherein said metabolic disease comprises the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis or hypertension; More preferably, described diabetes are type ii diabetes.