CN105294694B

CN105294694B - Amino hexatomic ring analog derivative and its application in medicine

Info

Publication number: CN105294694B
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: 2019-01-04
Anticipated expiration: 2035-05-21
Also published as: CN105294694A

Abstract

Application the present invention relates to a kind of amino hexatomic ring analog derivative and its in medicine, in particular to amino hexatomic ring analog derivative shown in logical formula (I) or its stereoisomer, pharmaceutically acceptable salt, prodrug, the pharmaceutical composition containing the derivative and in the purposes pharmaceutically for preparing DPP IV (DPP-IV) inhibitor

Description

Amino hexatomic ring analog derivative and its application in medicine

Technical field

Application the present invention relates to a kind of amino hexatomic ring analog derivative and its in medicine in particulars relate to logical formula (I) Shown amino hexatomic ring analog derivative or its can be used medicinal salt or its stereoisomer and containing the derivative or its can medication The pharmaceutical composition as well as therapeutic agent of salt or its stereoisomer are especially as DPP IV (DPP- IV) the purposes of inhibitor.

Background technique

Diabetes are a worldwide great medical care problems, are counted according to International Diabetes Federation (IDF), 2013 Up to 3.82 hundred million, global medical is spent up to 548,000,000,000 dollars global diabetic's number, accounts for the 11% of global medical expenditure.In advance It counts by 2035, global medical cost relevant to diabetes is up to 627,300,000,000 dollars.Insulin be by sucrose, starch and its His food conversion hormone required when being energy, diabetes be often as cannot secreting from body or suitably using insulin and It is caused.It is (or non-that diabetes are typically divided into type-1 diabetes mellitus (or insulin-dependent diabetes mellitus, IDDM) and type II diabetes Insulin-dependent diabetes mellitus, NIDDM).The most common diabetes type is type II diabetes, worldwide, II type sugar Urine disease accounts for about the 90% of all diabetes.Due to modern unsound life style, such as exercise reduces and high caloric diet is former Cause, the disease incidence of type II diabetes are in the trend gradually increased.Huge market potential has attracted a large amount of drugmaker and has ground Study carefully center and develops new anti-diabetic target spot and drug.

The drug for treating type II diabetes listing of approved mainly has insulin and the like, sulfonylureas at present Class, biguanides, thiazolidinediones (TZDs), alpha-glucosidase restrainer, dextrin analog, gut incretin hormones are similar Object, depeptidyl peptidase inhibitors (DPP-IV) etc..However, patient, which takes these antidiabetic drugs for a long time, cannot still reach expected saccharification Hemoglobin (HbA1c) reduces index, and these antidiabetic drugs have side effect, such as hypoglycemia, weight gain and painstaking effort manage-style Danger etc..These side effects have aggravated the burden of diabetic.Therefore, there is an urgent need to have height for type II diabetes exploitation The novel antidiabetic drug of effect, few side effects.

DPP IV (Dipeptidyl Peptidase, DPP-IV, EC3.4.14.5) is a serine stretch protein Enzyme, from the polypeptide N-terminal penultimate hydrolyzing N end dipeptides containing L-PROLINE and l-Alanine.Although the function of DPP-IV is not Be fully elucidated, it be considered as certain adjusting polypeptides, neuropeptide, circulating hormone and chemotactic factor (CF) major physiologicals adjust because Son.Although DPP-IV has many substrates as multiple-effect enzyme, that most known is secretin, it includes glucagon Sample peptide -1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).Secretin is a few minutes endocrine in intake nutrients And promote to take in the enteron aisle hormone of the disposition of nutrients.GLP-1 and GIP is identical to the effect of β cell, can improve β cell function, Insulin secretion, inducing beta cell proliferation, enhancing Anti-G value (Diabetes and including promoting dependence on the glucose Vascular Disease Research 20063:159)。

Different from GIP, GLP-1 is still to promote insulin secretion in type II diabetes, and therefore, improving GLP-1 is one The means (Pharmacol Rev 60:470-512,2008) of the promising treatment type II diabetes of kind.Patients with NIDDM It is middle to can obviously reduce blood glucose (Lancet, 2002,359:824-830) using GLP-1, however substrate of the GLP-1 as DPP-IV It can be hydrolyzed rapidly and inactivate in vivo, therefore develop DPP-IV inhibitor and have very important significance to treatment diabetes.

Currently, the research of DPP-IV inhibitor makes great progress, including sitagliptin, saxagliptin, A Gelie DPP-IV inhibitor including spit of fland has been approved by listing, into clinical use.The most significant feature of DPP-IV inhibitor is, due to Incretin is only secreted after body feed, and DPP-IV inhibitor is not easy to increase insulin level when unsuitable, is produced The common side effect hypoglycemia of raw many antidiabetic drugs.Recent clinical data is it has been shown that inhibit DPP-IV that can make insulin point Increase is secreted, blood sugar concentration is reduced and improves pancreas islet beta cell function (Diabetes, 1998,47:1253-1258).Common The side effect of DPP-IV inhibitor has respiratory tract infection, sore throat, diarrhea, cold like symptoms, headache and dizzy etc..But it is overall to have Preferable safety and tolerance, the patient used there is presently no discovery have serious weight gain or potential weight to subtract Less and the symptoms such as oedema.In recent years, long-acting DPP-IV inhibitor was especially noticeable.Long-acting DPP-IV inhibitor use is more square Just, it is provided simultaneously with ideal hypoglycemic effect, this can make it more favourable in patients with NIDDM.II phase clinical data is aobvious Show, the weekly DPP-IV inhibitor MK-3102 developed by Merck & Co., Inc. can obviously reduce blood glucose.Trelagliptin is By another weekly DPP-IV inhibitor of Takeda Pharmaceuticals Ltd.'s exploitation, the safety of the medicine and validity are in III phase It is confirmed that in clinic, submits New Drug Application in Japan at present.

The disease incidence of diabetes (mainly type II diabetes) is in increase trend year by year in the world, is become after painstaking effort After pipe disease and tumour, the 3rd threatens the non-communicable diseases of health of people and life.The treatment of diabetes is to family and society Heavy burden can be brought.Therefore, urgent need exploitation more updates better DPP-IV inhibition drug and is faced with meeting many patients The needs of bed medication.

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

(1) US2007232676 discloses the compound such as flowering structure as DPP-IV inhibitor, in which:

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

V is selected fromEqual groups, and R^3a、R^3bReplace independently selected from hydrogen, by 1-5 fluorine atom C_1-4Alkyl；R²Selected from groups such as hydrogen, hydroxyl, halogen, carboxyls；R⁸Selected from hydrogen ,-(CH₂)_pThe groups such as phenyl, but without methyl sulphur Acyl group；It is not considered as that specifically describing in this patent is a part of the invention.

(2) US20100120863 discloses the compound such as flowering structure as DPP IV (DPP-IV) inhibitor, In treatment, the purposes of prevention type-2 diabetes mellitus, in which:

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

V is selected fromDeng, and R^3a、R^3bSelected from replacing independently selected from hydrogen, by 1-5 fluorine atom C_1-4Alkyl；R²Selected from groups such as hydrogen, hydroxyl, halogen, carboxyls；R⁸Selected from-S (O)₂-C_1-6Naphthenic base ,-S (O)₂-C_1-6Alkyl Equal groups；It is not considered as that specifically describing in this patent is a part of the invention.

(3) WO2011103256, which discloses the compound of flowering structure such as, has DPP-IV inhibitor effect, as diabetes Prevention and/or medicine purposes, in which:

Ar is the phenyl optionally replaced by 1-5 independently selected from groups such as halogen, cyano, hydroxyls；

V is selected fromEqual groups, and R²Selected from groups such as hydrogen, hydroxyl, cyano, halogen, alkyl, alkoxy, carbonyls； R^3a、R^3bThe C selected from hydrogen or optionally replaced by 1-5 fluorine atom_1-4Alkyl；R⁸Selected from hydrogen, alkyl, aryl, naphthenic base, heteroaryl Base ,-SO₂-C_1-6The groups such as alkyl；It is not considered as that specifically describing in this patent is a part of the invention.

(4) WO2007126745 discloses the compound of DPP-IV inhibitor such as flowering structure for treating diabetes, in which:

Ar is selected from substituted or unsubstituted phenyl, and when replacing, phenyl is selected from halogen, hydroxyl, C by 1-3_1-6Alkyl etc. Replace；

V is selected fromEqual groups, and R²Selected from hydrogen, hydroxyl, halogen, alkenyl, alkynes Base, aryl, heteroaryl etc.；R^3a、R^3bSelected from hydrogen, the C replaced by 1-5 fluorine atom_1-4Alkyl；R8 be selected from H, naphthenic base, phenyl, The groups such as alkyl；It is not considered as that specifically describing in this patent is a part of the invention.

There are also WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784 etc. also discloses related DPP-IV inhibitor compound for treating diabetes.

Summary of the invention

The main object of the present invention is to provide a kind of novel DPP-IV inhibitor, specifically has shown in logical formula (I) Compound or its stereoisomer, pharmaceutically acceptable salt or prodrug, research has shown that, the compound of this class formation or its Stereoisomer, pharmaceutically acceptable salt or prodrug have good DPP IV (DPP-IV) inhibitory activity and/or Selectivity and/or long-term effect have the prospect for treating or alleviating type-2 diabetes mellitus and similar disease.

The present invention relates to a kind of logical formula (I) compound represented or its stereoisomers, pharmaceutically acceptable salt or preceding Medicine:

Wherein:

V is selected from one of following group:

Ar is phenyl, optionally further by 0 to 5 R¹Replace；

R¹It is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynes Base ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 yuan miscellaneous Aryl ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、- (CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (= O)-R⁵, the alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally further by 0 to 3 It is a to be selected from F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4It is described miscellaneous replaced the substituent group of alkoxy Naphthenic base or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group；

R²And R^2aIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)- NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m- NR⁹- C (=O)-R⁵, the alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally further F, Cl, Br, I ,-CH are selected from by 0 to 3₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, The Heterocyclylalkyl or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group；

R^3aAnd R^3bIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano or C_1-8Alkyl, the alkyl is optionally into one Step is selected from F, Cl, Br, I ,-CH by 0 to 5₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4The substituent group of alkoxy is taken Generation；

R⁴Selected from H, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,- (CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)- R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、- (CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (=O)-R⁵, wherein the alkane Base, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl optionally further by 0 to 3 selected from F, Cl, Br、I、-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, the Heterocyclylalkyl or heteroaryl Base contains 1 to 5 selected from N, O or S (=O)_nAtom or group；

R⁵Selected from hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls ,-O-C_3-15 Naphthenic base ,-O-C_6-10Aryl or-O-6 are to 10 unit's heteroaryls；

R⁶、R⁷And R⁹It is independently selected from H, C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 membered heterocycloalkyls；

R⁸Selected from C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 membered heterocycloalkyls, wherein The alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl optionally further replaced 0 to 5 F, the Heterocyclylalkyl or Heteroaryl contains 1 to 5 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.

The preferred solution of the invention, compound or its stereoisomer, pharmaceutically acceptable salt described in a kind of logical formula (I) Or prodrug, in which:

R¹It is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynes Base ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 yuan miscellaneous Aryl ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、- (CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (= O)-R⁵, preferably H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy ,-(CH₂)_m-C_3-8Naphthenic base ,-(CH₂)_m- 3 to 8 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- S (=O)_n- R⁸、-(CH₂)_m- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (=O)-R⁵, further preferred H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy ,-(CH₂)_m-C_3-8Naphthenic base ,-(CH₂)_m- 3 to 8 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl or- (CH₂)_m- 6 to 10 unit's heteroaryls, more preferable H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_m-C_3-6 Naphthenic base or-(CH₂)_m- 3 to 6 membered heterocycloalkyls；The alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl Or heteroaryl is optionally further selected from F, Cl, Br, I ,-CH by 0 to 3₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Alcoxyl Replaced the substituent group of base, the Heterocyclylalkyl or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group；

R²And R^2aIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)- NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m- NR⁹- C (=O)-R⁵, preferably H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_m-C_3-8Naphthenic base ,- (CH₂)_m- 3 to 8 membered heterocycloalkyls ,-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m- C (=O)-NR⁶R⁷Or- (CH₂)_m-NR⁹- C (=O)-R⁵, further preferred H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_m- C_3-8Naphthenic base ,-(CH₂)_m- 3 to 8 membered heterocycloalkyls, more preferable H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl, C_1-6Alcoxyl Base ,-(CH₂)_m-C_3-6Naphthenic base ,-(CH₂)_m- 3 to 6 membered heterocycloalkyls；The alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally further selected from F, Cl, Br, I ,-CH by 0 to 3₂F、-CHF₂、-CF₃, hydroxyl, C_1-4 Alkyl or C_1-4Replaced the substituent group of alkoxy, the Heterocyclylalkyl or heteroaryl contain 1 to 5 selected from N, O or S (=O)_n Atom or group；

R⁴Selected from H, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,- (CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)- R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、- (CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (=O)-R⁵, preferably H, cyano, C_1-8Alkyl, C_1-8Alkoxy ,-(CH₂)_m-C_3-8Naphthenic base ,-(CH₂)_m- 3 to 8 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,- (CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁶R⁷、- (CH₂)_m- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (=O)-R⁵, further preferred H, cyano, C_1-6Alkyl, C_1-6Alkoxy ,- (CH₂)_m-C_3-6Naphthenic base ,-(CH₂)_m- 3 to 6 membered heterocycloalkyls ,-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸ Or-(CH₂)_m-NR⁶R⁷, more preferable H, cyano, C_1-6Alkyl ,-(CH₂)_m-C_3-6Naphthenic base ,-(CH₂)_m-NR⁹- S (=O)_n-R⁸Or- (CH₂)_m- S (=O)_n-R⁸；The alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl optionally into One step is selected from F, Cl, Br, I ,-CH by 0 to 3₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4The substituent group of alkoxy is taken Generation, the Heterocyclylalkyl or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group；

R⁵Selected from hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls ,-O-C_3-15 Naphthenic base ,-O-C_6-10Aryl or-O-6 are to 10 unit's heteroaryls, preferably hydroxyl, C_1-6Alkyl, C_1-6Alkoxy or C_3-8Naphthenic base, into The preferred hydroxyl of one step, C_1-4Alkyl or C_1-4Alkoxy；

R⁶、R⁷And R⁹It is independently selected from H, C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 membered heterocycloalkyls, preferably H, C_1-6Alkyl or C_3-8Naphthenic base, further preferred H, C_1-4Alkyl or C_3-6Naphthenic base；

R⁸Selected from C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 membered heterocycloalkyls, preferably C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 8 membered heterocycloalkyls, further preferred C_1-6Alkyl, C_3-6Naphthenic base or 3 to 6 membered heterocycloalkyls, more preferable C_1-4Alkyl or C_3-6Naphthenic base；The wherein alkyl, naphthenic base, heterocycle alkane Base, aryl or heteroaryl optionally further replaced 0 to 5 F, the Heterocyclylalkyl or heteroaryl contain 1 to 5 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.

R¹Selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl or C_1-6Alkoxy, preferably H, F, Cl, Br, I, hydroxyl, Cyano, C_1-4Alkyl or C_1-4Alkoxy, further preferred H, F, Cl, Br, hydroxyl or cyano；

R²And R^2aIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl ,-(CH₂)_m-C_3-6Naphthenic base or- (CH₂)_m- 3 to 8 membered heterocycloalkyls, the alkyl, naphthenic base or Heterocyclylalkyl optionally further by 0 to 3 selected from F, Cl, Br, I、-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, the Heterocyclylalkyl contains 1 to 3 It is a to be selected from N, O or S (=O)_nAtom or group；

R^3aAnd R^3bIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano or C_1-6Alkyl, the alkyl is optionally into one Step is selected from F, Cl, Br, I ,-CH by 0 to 5₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4The substituent group of alkoxy is taken Generation；

R⁴Selected from H, cyano, C_1-8Alkyl ,-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m- 3 to 10 circle heterocyclic rings Alkyl ,-(CH₂)_m- 6 to 8 unit's heteroaryls or-(CH₂)_m-NR⁹- S (=O)_n-R⁸；R⁴It preferably is selected from H, cyano, C_1-8Alkyl ,- (CH₂)_m-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸Or-(CH₂)_m-NR⁹- S (=O)_n-R⁸, more preferable H, C_1-6Alkyl ,-(CH₂)_m-S (=O)_n-R⁸Or-(CH₂)_m-NR⁹- S (=O)_n-R⁸, further preferred H, C_1-4Alkyl or-(CH₂)_m- S (=O)_n-R⁸；

R⁶Or R⁷It is independently selected from H or C_1-6Alkyl；

R⁸Selected from C_1-6Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 8 membered heterocycloalkyls, preferably C_1-6 Alkyl, C_3-6Naphthenic base or 3 to 8 membered heterocycloalkyls, further preferred C_1-4Alkyl, C_3-6Naphthenic base or 3 to 6 membered heterocycloalkyls；Its Described in alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl optionally further replaced 0 to 5 F, the Heterocyclylalkyl Or heteroaryl contains 1 to 3 selected from N, O or S (=O)_nAtom or group；

R⁹Selected from H, C_1-6Alkyl or C_3-10Naphthenic base；It is preferred that H or C_1-2Alkyl；

M is selected from 0,1 or 2；

N is selected from 0,1 or 2.

R¹It is independently selected from H or F；

R²And R^2aIt is independently selected from H, C_1-6Alkyl, C_3-6Naphthenic base or 3 to 8 membered heterocycloalkyls, preferably H, C_1-6Alkyl Or C_3-6Naphthenic base, further preferred H or C_1-4Alkyl, the alkyl, naphthenic base or Heterocyclylalkyl are optionally further by 0 to 3 Selected from F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, the heterocycle Alkyl contains 1 to 3 selected from N, O or S (=O)₂Atom or group；

R^3aAnd R^3bIt is independently selected from H or C_1-4Alkyl, wherein the alkyl optionally further by 0 to 3 selected from F, Hydroxyl or C_1-4Replaced the substituent group of alkoxy；

R⁴Selected from H or-S (=O)₂-R⁸

R⁸Selected from C_1-6Alkyl, C_3-6Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 8 membered heterocycloalkyls, preferably C_1-6 Alkyl, C_3-6Naphthenic base or 3 to 8 membered heterocycloalkyls, further preferred C_1-4Alkyl, C_3-6Naphthenic base or 3 to 6 membered heterocycloalkyls, more It is preferred that C_1-4Alkyl or C_3-6Naphthenic base；Wherein the alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally further by 0 To replaced 5 F, the Heterocyclylalkyl or heteroaryl contain 1 to 3 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；It is preferred that 2,5- difluorophenyl；

R²And R^2aIt is each independently selected from H, C_1-6Alkyl or C_3-6Naphthenic base, preferably H or C_1-4Alkyl, wherein the alkyl or Naphthenic base is optionally further selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy；

R^3aAnd R^3bIt is independently selected from H or C_1-4Alkyl, preferably H, wherein the alkyl is optionally further by 0 to 3 Selected from F, hydroxyl or C_1-4Replaced the substituent group of alkoxy；

R⁴For-S (=O)₂-R⁸；

R⁸Selected from C_1-2Alkyl, 3 to 6 membered heterocycloalkyls or C_3-6Naphthenic base, wherein the alkyl, Heterocyclylalkyl or naphthenic base Optionally further replaced 0 to 5 F, the Heterocyclylalkyl contains 1 to 3 selected from N, O or S (=O)₂Atom or group.

V is selected from one of following group:

R²And R^2aIt is each independently selected from H, C_1-4Alkyl or C_3-6Naphthenic base, preferably H or C_1-4Alkyl, further preferred H, first Base, ethyl or isopropyl, wherein the alkyl or cycloalkyl is optionally further selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4 Replaced the substituent group of alkoxy；

R^3aAnd R^3bIt is independently selected from H, methyl, ethyl or isopropyl, preferably H；

R⁴Selected from-S (=O)₂-CH₃,-S (=O)₂-CH₂CH₃、 It is preferred that-S (=O)₂-CH₃,-S (=O)₂-CH₂CH₃、

R²And R^2aIt is each independently selected from H or C_1-4Alkyl, preferably H, methyl, ethyl or isopropyl, the alkyl is optionally into one Step is selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy.

R^2aFor C_1-4Alkyl, the alkyl are optionally further selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4Alkoxy Replaced substituent group.

V is selected from one of following group:

R²And R^2aIt is each independently selected from H or C_1-4Alkyl, preferably H, methyl, ethyl or isopropyl, the alkyl is optionally into one Step is selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy；

R^3aAnd R^3bFor H；

R⁴For-S (=O)₂-CH₃,-S (=O)₂-CH₂CH₃Or

The preferred solution of the invention, a kind of logical formula (I) compound represented or its stereoisomer, pharmaceutically acceptable salt Or prodrug, in which:

V is selected from one of following group:

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

R²Selected from H or C_1-4Alkyl, the alkyl are optionally further selected from F, hydroxyl, C by 0 to 3_1-4Alkyl or C_1-4Alkane Replaced the substituent group of oxygroup；It is preferred that H, methyl, ethyl or isopropyl；

R^2aFor C_1-4Alkyl, preferably methyl, ethyl or isopropyl, the alkyl are optionally further selected from F, hydroxyl by 0 to 3 Base, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy；

R^3aAnd R^3bFor H；

R⁴For-S (=O)₂-CH₃,-S (=O)₂-CH₂CH₃Or

The preferred solution of the invention, compound or its stereoisomer, pharmaceutically acceptable salt described in a kind of logical formula (I) Or prodrug, wherein compound is selected from logical formula (II), logical formula (III), logical formula (IV) or logical formula (V) compound represented:

Wherein:

V is selected from one of following group:

Ar is phenyl, optionally further by 0 to 5 R¹Replace；It is preferred that 2,5- difluorophenyl or 2,4,5- trifluorophenyl；

R¹It is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynes Base ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 yuan miscellaneous Aryl ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、- (CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (= O)-R⁵, preferably H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl or C_1-6Alkoxy, further preferred H or F；The alkyl, alkane Oxygroup, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl optionally further by 0 to 3 selected from F, Cl, Br, I ,- CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, the Heterocyclylalkyl or heteroaryl contain 1 to 5 is selected from N, O or S (=O)_nAtom or group；

R²And R^2aIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,-(CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)-R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (= O)-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or- (CH₂)_m-NR⁹- C (=O)-R⁵, preferably H, F, Cl, Br, I, hydroxyl, cyano, C_1-6Alkyl ,-(CH₂)_m-C_3-6Naphthenic base or- (CH₂)_m- 3 to 8 membered heterocycloalkyls, further preferred H, C_1-6Alkyl ,-(CH₂)_m-C_3-6Naphthenic base or-(CH₂)_m- 3 to 8 circle heterocyclic rings Alkyl, more preferable H, C_1-4Alkyl or-C_3-6Naphthenic base, still more preferably H or C_1-4Alkyl, further preferably C_1-4Alkyl, then into one Walk preferred methyl, ethyl or isopropyl；The alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl Base is optionally further selected from F, Cl, Br, I ,-CH by 0 to 3₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Alkoxy takes Replaced Dai Ji, F, hydroxyl, C preferably are selected from by 0 to 3_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy；The heterocycle alkane Base or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group, preferably comprise 1 to 3 selected from N, O or S (= O)_nAtom or group；

R^3aAnd R^3bIt is independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, preferably H, F, Cl, Br, I, hydroxyl Base, cyano, C_1-6Alkyl, further preferred H or C_1-4Alkyl, more preferable H, methyl, ethyl or isopropyl, still more preferably H； The alkyl is optionally further selected from F, Cl, Br, I ,-CH by 0 to 5₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Alcoxyl Replaced the substituent group of base, F, hydroxyl or C preferably are selected from by 0 to 3_1-4Replaced the substituent group of alkoxy；

R⁴Selected from H, cyano, C_1-8Alkyl, C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl ,-(CH₂)_m-C_3-15Naphthenic base ,- (CH₂)_m- 3 to 15 membered heterocycloalkyls ,-(CH₂)_m-C_6-10Aryl ,-(CH₂)_m- 6 to 10 unit's heteroaryls ,-(CH₂)_m- C (=O)- R⁵、-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- C (=O)-NR⁶R⁷、-(CH₂)_m- O-C (=O)-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸、- (CH₂)_m-NR⁹- S (=O)_n-R⁸、-(CH₂)_m-NR⁹- C (=O)-NR⁶R⁷Or-(CH₂)_m-NR⁹- C (=O)-R⁵, preferably H, cyano, C_1-8Alkyl ,-(CH₂)_m-NR⁶R⁷、-(CH₂)_m- S (=O)_n-R⁸Or-(CH₂)_m-NR⁹- S (=O)_n-R⁸, further preferred H or- (CH₂)_m- S (=O)_n-R⁸, more preferably-(CH₂)_m- S (=O)_n-R⁸, still more preferably-S (=O)₂-CH₃Or-S (=O)₂Ring Propyl；The alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally further by 0 to 3 Selected from F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-4Alkyl or C_1-4Replaced the substituent group of alkoxy, the heterocycle Alkyl or heteroaryl contain 1 to 5 selected from N, O or S (=O)_nAtom or group；

R⁵Selected from hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls ,-O-C_3-15 Naphthenic base ,-O-C_6-10Aryl or-O-6 are to 10 unit's heteroaryls, preferably hydroxyl, C_1-6Alkyl, C_1-6Alkoxy or C_3-8Naphthenic base, into The preferred hydroxyl of one step, C_1-4Alkyl or C_1-4Alkoxy, more preferable hydroxyl, methyl, ethyl, methoxy or ethoxy；

R⁶、R⁷And R⁹It is independently selected from H, C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 membered heterocycloalkyls, preferably H, C_1-6Alkyl or C_3-8Naphthenic base, further preferred H, C_1-4Alkyl, C_3-6Naphthenic base, more preferable H, Methyl, ethyl or cyclopropyl；

R⁸Selected from C_1-8Alkyl, C_3-15Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 15 Heterocyclylalkyls, preferably C_1-6 Alkyl, C_3-8Naphthenic base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 8 Heterocyclylalkyls, further preferred C_1-6Alkyl, C_3-6Cycloalkanes Base, C_6-10Aryl, 6 to 10 unit's heteroaryls or 3 to 8 membered heterocycloalkyls, more preferable C_1-2Alkyl or C_3-6Naphthenic base, it is further excellent Select methyl, ethyl, isopropyl or cyclopropyl；Wherein the alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally into one For step replaced 0 to 5 F, the Heterocyclylalkyl or heteroaryl contain 1 to 3 selected from N, O or S (=O)_nAtom or group；

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

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

The preferred solution of the invention, it is compound or its stereoisomer described in a kind of logical formula (IV), pharmaceutically acceptable Salt or prodrug, wherein the compound is selected from logical formula (VI) or logical formula (VII) compound represented:

It is preferred that

The preferred solution of the invention, compound or its stereoisomer, pharmaceutically acceptable salt described in a kind of logical formula (I) Or prodrug, the compound are selected from such as one of flowering structure:

The invention further relates to compound shown in logical formula (I) or its stereoisomer, pharmaceutically acceptable salt or prodrug, Described in salt include but is not limited to sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridiniujm, Picoline salt, 2,6- lutidines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl Ammonium salt, hydrochloride, hydrobromate, sulfate, nitrate, phosphate, formates, trifluoroacetate, acetate, maleate, Tartrate, citrate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, Oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, aspartate, glutamic acid Salt, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or it Combination, preferably hydrochloride, sulfate, phosphate, trifluoroacetate, acetate, maleate, tartrate, citric acid Salt, succinate, fumarate, malate, tosilate, benzene sulfonate, mesylate, fluoroform sulphonate or it Combination.

The invention further relates to a kind of pharmaceutical composition, the composition includes: shown in the logical formula (I) of effective dose Amino hexatomic ring analog derivative or its stereoisomer, pharmaceutically acceptable salt or prodrug, or further comprise it is a kind of or Various other therapeutic agents；And pharmaceutically acceptable carrier or excipient.

The invention further relates to a kind of pharmaceutical compositions, wherein the other therapeutic agents include:

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

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

(c) biguanides, thiazolidinediones, sulfonylurea, column how class, alpha-glucosidase restrainer or glucagon - 1 analog of sample peptide or its pharmaceutically acceptable salt or prodrug.

Composition of the present invention, wherein the SGLT-2 inhibitor is selected from Dapagliflozin, canagliflozin, A Gelie Only, En Palie is net, Yi Palie is net, Tuo Fulie is net, Lu Silie is net, Rui Gelie is net, Sergliflozin or support column are net；DPP-IV inhibits Agent be selected from BI 1356, sitagliptin, vildagliptin, Egelieting, saxagliptin, Na Lieting, carmegliptin, mage column Ge Lieting, gigue column spit of fland or song Ge Lieting, are replaced at dutogliptin in spit of fland；Biguanides therapeutic agent is selected from melbine or insoral；Thiophene Oxazolidinedione class therapeutic agent is selected from Ciglitazone, pioglitazone, Rosiglitazone, troglitazone, Fa Gelie ketone or Darglitazone, sulphur Ureide derivative therapeutic agent is selected from Glimepiride, orinase, Glibornuride, glibenclamide, gliquidone, Glipizide or lattice column Qi Te, how class therapeutic agent is selected from Nateglinide, Repaglinide or Mitiglinide to column, and alpha-glucosidase restrainer is selected from A Kabo Sugar, voglibose or Miglitol, glucagon-like peptide-1 analogs are selected from Exenatide or Liraglutide.

The invention further relates to compound described in logical formula (I) or its stereoisomers, pharmaceutically acceptable salt and its group It closes object or its prodrug is preparing the application in dipeptidyl peptidase-iv inhibitor, wherein the dipeptidyl peptidase-iv inhibitor is used In the drug of preparation treatment metabolic disease, wherein the metabolic disease is selected from diabetes, diabetic retinopathy, sugar Urinate the raised of characteristic of disease neuropathy, nephrosis, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol Level, hyperlipidemia, obesity, Hypertriglyceridemia, X syndrome, diabetic complication, atherosclerosis or high blood Pressure；Preferably, the diabetes are type-2 diabetes mellitus.

Unless there are opposite statement, the term used in the specification and in the claims has following meanings.

Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in group and compound of the present invention include their same position Carbon, hydrogen, oxygen, sulphur, nitrogen or halogen involved in element and group of the present invention and compound are optionally further by one or more Their a corresponding isotopes are substituted, and wherein the isotope of carbon includes¹²C、¹³C and¹⁴C, the isotope of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), the isotope of oxygen include¹⁶O、¹⁷O and¹⁸The isotope of O, sulphur includes³²S 、³³S、³⁴S and³⁶The isotope of S, nitrogen includes¹⁴N and¹⁵N, the isotope of fluorine¹⁹The isotope of F, chlorine includes³⁵Cl and³⁷Cl, bromine it is same Position element include⁷⁹Br and⁸¹Br。

" alkyl " refers to the saturated aliphatic hydrocarbons group of straight chain and branch, and main chain includes 1 to 20 carbon atom, preferably 1 To 12 carbon atoms, further preferably 1 to 8 carbon atom, more preferably 1 to 6 carbon atom, still further preferably 1 to 4 The straight chain and branched group of carbon atom, most preferably 1 to 2 carbon atom.The example of alkyl includes but is not limited to methyl, ethyl, just Propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- amyl, 3- amyl, 2- methyl -2- butyl, 3- Methyl-2- butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyl, 3- hexyl, 2- methyl-2- amyl, 3- Methyl -2- amyl, 4- methyl -2- amyl, 3- methyl -3- amyl, 2- methyl -3- amyl, 2,3- dimethyl -2- butyl, 3,3- Dimethyl -2- butyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,2- dimethyl-penten Base, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, 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- ethylpentyl, 2- methyl -3- ethyl Amyl, n-nonyl, 2- methyl -2- ethylhexyl and positive decyl etc..Alkyl can be substituted or unsubstituted, when substituted When, substituent group can be substituted on any workable tie point, and substituent group is preferably 1 to 5 selected from F, Cl, Br, I, alkane It is base, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, miscellaneous Naphthenic base, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)- R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^d Or-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^c Be independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, Trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dIt is each independently selected from Aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base and ring group.

" alkoxy " refers to-O- alkyl, wherein for example hereinbefore definition of alkyl.Alkoxy can be substituted or unsubstituted , alkoxy embodiment include but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Tert-butoxy, sec-butoxy, n-pentyloxy and positive hexyloxy etc..When substituted, substituent group be preferably 1 to 5 selected from F, Cl, It is Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, miscellaneous Aryl, Heterocyclylalkyl, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m-C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl- R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^b With R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulphonyl Base, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl R can be formed^aWith R^dRespectively independent choosing From aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkoxyalkyl " refers to the alkyl being connected with alkoxy.Alkoxyalkyl can be substituted or unsubstituted, Non-limiting embodiment includes methoxy, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy methyl, third Oxygroup ethyl, 2- propoxy methyl, butoxypropyl, t-butoxy ethyl, amoxy ethyl, hexyloxyehtyl, cyclopropyl oxygroup Methyl, ring Among, ring propoxypropyl and cyclohexyloxy methyl；When substituted, substituent group is preferably 1 to 5 choosing From F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, Aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil base, and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,- (CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、- (CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation Or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, virtue Base, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^a With R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil Base or simultaneously ring group.

" alkenyl " refer at least composition containing carbon-to-carbon double bond as hereinbefore definition alkyl, preferably comprise 2 to 20 A carbon atom, further preferred 2 to 12 carbon atoms more preferably have 2 to 8 carbon atoms on main chain, and alkenyl can be substitution Or it is unsubstituted.Non-limiting embodiment includes vinyl, allyl, 1- acrylic, 2- acrylic, 1- cyclobutenyl, 2- fourth Alkenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, 4- pentenyl, 1- methyl-1-cyclobutenyl, 2-methyl-1-butene Alkenyl, 2- methyl -3- cyclobutenyl, 1- hexenyl, 2- hexenyl, 3- hexenyl, 4- hexenyl, 5- hexenyl, 1- methyl-1-pentene Alkenyl, 2- methyl-1-pentene alkenyl, 1- heptenyl, 2- heptenyl, 3- heptenyl, 4- heptenyl, 1- octenyl, 3- octenyl, 1- Nonenyl, 3- nonenyl, 1- decene base, 4- decene base, 1,3- butadiene, 1,3- pentadiene, 1,4- pentadiene, 1,4- oneself two Alkene, 14 carbon trialkenyl of 3- hendecene base, 4- laurylene base and 4,8,12- etc..When substituted, substituent group is selected from for 1 to 5 F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, virtue Base, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil base, and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,- (CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、- (CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation Or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, virtue Base, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^a With R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil Base or simultaneously ring group.

" alkynyl " refer to comprising at least one carbon-carbon triple bond composition as hereinbefore definition alkyl, preferably comprise 2 to 20 carbon atoms, further preferred 2 to 8 carbon atoms, more preferably there is the alkynyl of 2 to 4 carbon atoms on main chain.Alkynyl can be with It is substituted or unsubstituted.Non-limiting embodiment includes acetenyl, 1- propinyl, 2-propynyl, butynyl, 2- butine Base, 3- butynyl, 1- methyl -2-propynyl, 4- pentynyl, 3- pentynyl, 1- methyl -2- butynyl, 2- hexin base, 3- hexin Base, 2- heptynyl, 3- heptynyl, 4- heptynyl, 3- octynyl, 3- n-heptylacetylene base, 4- decynyl, 3- undecyne base and 4- dodecyne Base etc.；When substituted, substituent group is preferably one or more following groups, independently selected from F, Cl, Br, I, alkyl, cycloalkanes Base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, Bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O- (CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr- (CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independent Selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifluoro Mesyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dBe each independently selected from aryl, Heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" amino " refers to-NH₂, can be substituted or unsubstituted, when substituted, substituent group be preferably 1 to 3 with Lower group, independently selected from alkyl, naphthenic base, halogenated alkyl, mercaptan, hydroxyl, sulfydryl, amino, cyano, isocyano group, aryl, miscellaneous Aryl, Heterocyclylalkyl, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m-C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl- R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^b With R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulphonyl Base, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dRespectively independent choosing From aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkylthio group " refers to that-S- alkyl or-S- (unsubstituted naphthenic base), non-limiting embodiment include methyl mercapto, second Sulfenyl, 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 " refers to-C ≡ N.

" isocyano group " refers to-N ≡ C.

" nitro " refers to-NO₂。

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

" carboxylate " refers to-C (=O)-O-R^d, R^dSelected from alkyl, naphthenic base or Heterocyclylalkyl.

" halogenated alkyl " refer to halogen replace as hereinbefore definition alkyl, non-limiting embodiment include a fluorine first Base, difluoromethyl, trifluoromethyl, a bromomethyl, two bromomethyls, trisbromomethyl, 1- fluoro ethyl -2- base, 2- fluoro ethyl -2- base, 1,1- bis-fluoro ethyls -2- base, 1,2- bis-fluoro ethyls -2- base, 1,1,1- fluoro ethyl -2- base, 1- bromoethyl -2- base, 2- bromoethyl - 2- base and 1,1,1- three bromomethyl -2- base etc..

" sulfydryl " refers to-SH.

" mercaptan " refers to the hydrocarbon that one or more hydrogen atoms in alkyl are replaced by sulfydryl, and non-limiting embodiment includes first Mercaptan, ethyl mercaptan, bis- mercaptan of 1,2-.

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

" hydroxyalkyl " refers to that alkyl is replaced by one or more hydroxyls, is preferably replaced by 1,2 or 3 hydroxyl, alkyl is excellent It is selected as low alkyl group.Non-limiting embodiment includes methylol, 2- ethoxy, 1- ethoxy, 1,2- dihydroxypropyl, 1,3- bis- Hydroxypropyl and 2,3- dihydroxypropyl etc..

" naphthenic base " refers to saturated or unsaturated monocyclic cycloalkyl, can be substituted or unsubstituted, ring carbon atom Including 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferred 3 to 8 carbon atoms, non-limiting embodiment includes Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexene Base, cycloheptenyl, 1,5- cyclo-octadiene base, 1,4- cyclohexadienyl and cycloheptatriene base etc..When substituted, substituent group 1 To 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, Isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylic Acid esters ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、- (CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation Or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, virtue Base, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^a With R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil Base or simultaneously ring group.

" Heterocyclylalkyl " refer to substituted or unsubstituted saturation or it is unsaturated and at least containing 1 to 5 selected from N, O or The heteroatomic non-aromatic ring of S, non-aromatic ring can be 3 to 10 yuan of monocycle, 4 to 20 yuan of loop coil and ring or bridged ring, heterocycle alkane N, the S selectively replaced in basic ring can be oxidized to various oxidation state.It is preferred that 3 to 12 circle heterocyclic rings.Non-limiting embodiment includes Oxirane base, oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, oxacyclohexyl, oxa- cyclooctyl, azacyclo- third Alkyl, azelidinyl, azepine cyclopenta, piperidyl, aziridinyl, 1,3 dioxy cyclopenta, 1,4- dioxy ring penta Base, 1,3- dioxy cyclopenta, 1,3- dioxocyclohex base, bis- sulphur cyclohexyl of 1,3-, azepine base, morpholinyl, piperazinyl, pyrrole Piperidinyl, furyl, thienyl, pyrrole radicals, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, piperazine Piperidinyl, thio-morpholinyl, dihydropyran, thiadiazolyl group, oxazolyl, oxadiazoles base, pyrazolyl, 1,4- Dioxin Base, OrDeng.When substituted, substituent group can be selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogen for 1 to 5 Substituted alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil Base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)- R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein M, n be 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^cGroups are waited, wherein R^bWith R^cIt is independently selected from including H, hydroxyl Base, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifyl, as Selection, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dBe each independently selected from aryl, heteroaryl, alkyl, Alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" loop coil ", which refers to, shares more than 5 to 20 yuan of carbon atom (claiming spiro-atom) between substituted or unsubstituted monocycle Cyclic group may include 0 to 5 double bond, and can be selected from N, O or S (=O) containing 0 to 5_nHetero atom.Preferably 6 To 14 yuan, further preferably 6 to 12 yuan, 6 to 10 yuan are more selected, non-limiting example includes

When substituted, substituent group is 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, sulphur Alcohol, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil base and ring group, Hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m-C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein m, n 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkane Base, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cIt can shape At five or hexa-atomic naphthenic base or Heterocyclylalkyl.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, miscellaneous Naphthenic base, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" and ring " refers to the polycyclic group of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system Group, wherein one or more rings can contain 0 or multiple double bonds, and can be it is substituted or unsubstituted, and in ring system Each ring can contain 0 to 5 selected from N, S (=O)_nOr the hetero atom of O.Preferably 5 to 20 yuan, further preferably 5 to 14 yuan, More select 5 to 12 yuan, still further preferably 5 to 10 yuan.Non-limiting example includes

WithWhen substituted, substituent group be 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, Halogenated alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, spiral shell Ring group and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (= O)-R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a (wherein 0,1 or 2 m, n), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl Base, amino, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifyl, as Selection, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dBe each independently selected from aryl, heteroaryl, alkyl, Alkoxy, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" bridged ring " refers to the polycyclic moiety for the carbon atom that any two are not directly connected, and can contain 0 or multiple double bonds, And it can be substituted or unsubstituted, and any ring in ring system can contain 0 to 5 selected from N, S (=O)_nOr O hetero atom Or group (wherein n is 1,1,2).Annular atom include 5 to 20 atoms, preferably 5 to 14 atoms, further preferred 5 to 12 It is a, at further preferred 5 to 10.Non-limiting example includes

And adamantane.When substituted, substituent group is 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogen Substituted alkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil Base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)- R^a、-(CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein M, n be 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, ammonia Base, carbonyl, alkyl, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic naphthenic base or Heterocyclylalkyl can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alcoxyl Base, naphthenic base, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" benzyl " refers to-CH₂Phenyl, the phenyl be it is substituted or unsubstituted, non-limiting embodiment include- CH₂Phenyl ,-CH₂P-methylphenyl etc..

" aryl " refers to substituted or unsubstituted 6 to 14 yuan of cyclic aromatic groups, including mono-cyclic aromatic base and condensed ring virtue Perfume base.It is preferred that 6 to 14 yuan of aromatic rings, further preferred 6 to 10 yuan of aromatic rings, non-limiting example include phenyl, naphthalene, anthracene Base and phenanthryl etc..The aryl rings can be condensed on heteroaryl, Heterocyclylalkyl or cycloalkyl ring, wherein connecting with precursor structure Ring together is aryl rings, and non-limiting embodiment includes:

When substituted, substituent group is 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, halogenated alkyl, sulphur Alcohol, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, Heterocyclylalkyl, bridged ring base, loop coil base and ring group, Hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、-(CH₂)_m-C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein m, n 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkane Base, alkoxy, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cIt can shape At five or hexa-atomic naphthenic base or Heterocyclylalkyl.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, miscellaneous Naphthenic base, carbonyl, ester group, bridged ring base, loop coil base and ring group.

" heteroaryl " refers to substituted or unsubstituted 5 to 14 yuan of aromatic rings, and is selected from N, O or S (=O) containing 1 to 5_n Hetero atom or group, preferably 5 to 10 yuan of miscellaneous aromatic rings, further preferred 5 to 6 yuan.The non-limiting embodiment of heteroaryl includes But be not limited to pyridyl group, furyl, thienyl, pyridyl group, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, Imidazole radicals, piperidyl, morpholine, thiomorpholine, 1,3- dithiane, benzimidazole, piperazine sting base, benzimidazole, benzo pyridine, pyrroles And pyridine etc..The heteroaryl ring can be condensed on aryl, Heterocyclylalkyl or cycloalkyl ring, wherein being connected to precursor structure Ring together is heteroaryl ring, and non-limiting embodiment includes

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

" silylation " refers to that one or more hydrogen atoms in silicomethane are replaced by alkyl and is formed by group, embodiment packet Include but be not limited to trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl and tert-butyl diphenyl silicon substrate etc..

Term " singly-bound " refers to that chemical single bond, such as " being a singly-bound between A and B " indicate that there are a changes between A and B Learn singly-bound, it may be assumed that A-B.

" optional " or " optionally " refer to event or environment described later can with but necessarily occur, which includes The occasion that the event or environment occur or do not occur.Such as: " alkyl optionally replaced by F " refer to alkyl can with but necessarily taken by F In generation, illustrates to include situation that alkyl is not replaced by the F situation replaced and alkyl by F.

" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to keeping the life of free acid or free alkali Object validity and characteristic, and the free acid by with nontoxic inorganic base or organic base or the free acid by with Those of nontoxic inorganic acid or organic acid reaction acquisition salt, including alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkaline-earth metal Salt, such as calcium salt, magnesium salts；Other metal salts, such as molysite, mantoquita, cobalt salt；Organic alkali salt, such as ammonium salt, triethylamine salt, pyridine Salt, picoline salt, 2,6- lutidines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine Salt, guanidine salt, isopropyl amine salt, trismethylamine salt, tripropyl amine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, diformazan Ethylethanolamine salt, dicyclohexyl amine salt, coffee alkali salt, procaine salt, choline salt, beet alkali salt, Benethamine Penicillin salt, grape Osamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, cocoa alkali salt, amino butanetriol salt, purine salt, piperazine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, N- ethyl Piperidinium salt, tetramethyl amine salt, dibenzyl amine salt and phenylglycine alkyl ester salt etc.；Halogen acid salt, such as hydrofluoride, hydrochloric acid Salt, hydriodate, hydrobromate etc.；Inorganic acid salt, such as nitrate, sulfate, perchlorate, phosphate；Rudimentary alkyl sulfonic acid Salt, such as mesylate, fluoroform sulphonate, esilate；Arylsulphonate, such as benzene sulfonate, tosilate；Have Machine hydrochlorate, such as formate, fumarate, formates, trifluoroacetate, furoate, gluconate, glutamate, glycolic It is salt, isethionate, lactate, maleate, malate, mandelate, mucus hydrochlorate, embonate, pantothenate, hard Resin acid salt, succinate, sulfanilate, tartrate, malonate, 2 hydroxy propanoic acid salt, citrate, salicylate, grass Hydrochlorate, oxyacetate, glucuronate salt, galacturonic hydrochlorate, citrate, lysine salt, arginine salt, L-aminobutanedioic acid Salt, cinnamate etc..

" pharmaceutical composition " indicate compound or its physiology/pharmaceutically acceptable salt described in one or more texts or The combination of pro-drug or/and clinically use for treat, prevent diabetes drug or/and SGLT-2 inhibitor or/ With the mixture of DPP-IV inhibitor and other constituents, wherein other components include physiology/pharmaceutically acceptable load Body and excipient.Clinically using includes biguanides, thiazolidinedione, sulfonylureas, column for treating, preventing the drug of diabetes How, alpha-glucosidase restrainer, GLP-1 analog or its pharmaceutically acceptable salt, such as melbine, insoral, Ciglitazone (Ciglitazone), pioglitazone (Pioglitazone), Rosiglitazone (Rosiglitazone), troglitazone (Troglitazone), Fa Gelie ketone (Farglitazar), Darglitazone (Darglitazoan), Glimepiride (Glimepiride), orinase (Tolglybutamide), Glibornuride (Glibornuride), glibenclamide (Glibenclamide), gliquidone (Gliquidone), Glipizide (glipizide), gliclazide (gliclazipe), Nateglinide (Nateglinide), Repaglinide (Repaglinide), Mitiglinide (mitiglinide), acarbose (Acarbose), voglibose (Voglibose), Miglitol (Miglitol), Chinese mugwort Fill in that peptide (Exenatide) or Liraglutide (Liraglutide), SGLT-2 inhibitor such as Dapagliflozin (Dapagliflozin), canagliflozin (Canagliflozin), En Palie net (Empagliflozin), Yi Palie are net (Ipragliflozin), Tuo Fulie net (Tofogliflozin), Lu Silie net (Luseogliflozin), Rui Gelie are net (Remogliflozin), Sergliflozin (Sergliflozin) or support arrange net (Ertugliflozin), DPP-IV inhibitor Such as BI 1356 (Linagliptin), sitagliptin (Sitagliptin), vildagliptin (Vildagliptin), A Gelie Spit of fland (Alogliptin), saxagliptin (Saxagliptin), MK-3102, Na Lieting (Denagliptin), carmegliptin (Carmegliptin), melogliptin (Melogliptin), dutogliptin (Dutogliptin), replace Ge Lieting (Teneligliptin), gigue column spit of fland (Gemigliptin) or song Ge Lieting (Trelagliptin).The mesh of pharmaceutical composition Be promote compound on organism body administration.

" carrier " refers to that obvious stimulation will not be generated to organism and will not eliminate the bioactivity of given compound With the carrier or diluent of characteristic.

" excipient " refers to being added to the inert substance that compound administration is further relied in pharmaceutical composition.It assigns The example of shape agent include but is not limited to calcium carbonate, calcium phosphate, various sugar and different types of starch, cellulose derivative (including Microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycols, diluent, granulating agent, lubricant, adhesive, disintegrating agent etc..

" prodrug ", which refers to, to be converted into biologically active chemical combination of the present invention in physiological conditions or by solvolysis The compound of object.Prodrug of the invention prepared by the phenolic group group modified in the compound, which can routinely Operation is removed in vivo, and obtains parent compound.It is preceding when pro-drug of the invention is delivered to mammalian subject Body drug is isolated and is respectively formed free hydroxyl.The example of prodrug includes, but are not limited to the phenolic hydroxyl group of the compounds of this invention With phosphoric acid at sodium salt derivative.

Certain compounds as described herein can be used as tautomer presence, along with turning for one or more double bonds It moves, there is different hydrogen tie points.Such as ketone-enol tautomers.Single tautomer and its mixture are included in The range of the compounds of this invention.Tautomer within the scope of the compounds of this invention includes but is not limited to:

Compound described herein can be containing one or more asymmetric centers, and it is possible thereby to racemate, outer Racemic mixture, single enantiomter, non-enantiomer mixture and single diastereoisomer exist.

Certain compounds described herein contain double bond, include E and Z geometry structure body unless otherwise indicated.

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

The amount for the compound that " effective dose " has guided tissue, system or subject physiologic or medicine to translate, this amount is institute Seek, the one or more of symptoms for being enough to prevent treated illness or illness with subject when including applying occur Or mitigate it to the amount of compound to a certain degree.

" solvate " refers to the compounds of this invention or its salt, they further include in terms of the chemistry that non-covalent intermolecular forces combine Amount or non-stoichiometric solvent.It is then hydrate when solvent is water.

“IC₅₀" refer to half-inhibitory concentration, refer to concentration when reaching maximum suppression effect half.

The synthetic method of the compounds of this invention

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

General formula (I-1) compound reacts to obtain general formula (I-2) compound with fluoro reagent, and general formula (I-2) compound is in Mesosome (H-V) compound reacts to obtain general formula (I-3) compound, obtains logical formula (I) after general formula (I-3) compound deprotection base Close object；The definition of Ar and V and the definition of logical formula (I) are consistent；

R¹¹And R¹²It is independently selected from H or amino protecting group, preferably R¹¹And R¹²It is not simultaneously H, wherein the amino is protected Protecting base includes but is not limited to tert-butoxycarbonyl, benzyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, allyloxy carbonyl, tri-chloroethoxy base carbonyl Base, trimethyl silicon substrate carbethoxyl group, methoxycarbonyl group, carbethoxyl group, 2- xenyl -2- propylene carbonyl oxygen, tert-butoxy, O-phthalic Acyl group, p-toluenesulfonyl, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, formoxyl, trifluoroacetyl group, benzene Formoxyl, benzyl, trityl, to methoxy-benzyl or 2,4- dimethoxy-benzyl, preferably H or tert-butoxycarbonyl.

Detailed description of the invention

Fig. 1 is compound 1¹H-¹H COSY map.

Fig. 2 is compound 1¹H-¹H NOESY map.

Specific embodiment

Below by way of the beneficial effect of the specific embodiment implementation process that the present invention will be described in detail and generation, it is intended to which help is read Reader more fully understands essence and feature of the invention, does not limit the scope of the present invention.

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

The measurement of NMR is to use (Bruker ADVANCE III 400) nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

(Agilent 6120B (ESI)) is used in the measurement of MS.

The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (100 x of Zorba x SB-C18 4.6mm)。

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.20mm, thin-layer chromatography isolate and purify product use specification be 0.4mm~ 0.5mm。

Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.

Without specified otherwise, triethylamine, methyl tertiary butyl ether(MTBE), hydrazine hydrate, tetrabutylammonium bromide, thionyl chloride, imidazoles, hydrogen Change sodium, triphenyl phosphorus, trifluoroacetic acid purchase in Chengdu Ke Long chemical reagent factory；Two dimethyl dicarbonate butyl esters, N, N'- dicarbapentaborane Diimidazole, N,N-dimethylformamide dimethylacetal, N, O- dimethyl hydroxylamine hydrochloride, cis -4-hydroxy-d-proline salt Hydrochlorate purchase is in special (Chengdu) the medical science Co., Ltd of Ace；Cesium carbonate, lithium borohydride, tert-butyl chloro-silicane, N- Hydroxysuccinimide, two (trimethyl silicon substrate) Sodamides, diphenyl methylene glycine ethyl ester, trans-L-1,2-hydroxy-proline purchase It buys in the resistance to Jilin Chemical of peace；This Martin purchase is worn in the smooth Science and Technology Co., Ltd. of upper Haitai；Methyl triflate, 2,5- difluoro Bromobenzene is bought in Shanghai De Mo Pharmaceutical Technology Co., Ltd；2- iodopropane is bought in Shanghai Bepharm Science & Technology Co., Ltd.；It is different Propyl magnesium chloride/lithium chloride tetrahydrofuran solution purchase is in lark prestige Science and Technology Ltd.；Propargyl benzene sulfonate, tetrabutyl fluorine Change ammonium, three (acetoxyl group) sodium borohydrides, the purchase of tetrabutyl hexafluorophosphoric acid amine in this Reagent Company of Adama；Cyclopentadienyl group is double (triphenylphosphine) ruthenic chloride (II) is bought in ACROS orgainics；Borane dimethylsulf iotade purchase in it is splendid it is remote chemistry science and technology (on Sea) Co., Ltd；Tetrahydrofuran -3- sulfonyl chlorine is bought in Nanjing Kang Manlin chemical industry Industrial Co., Ltd.；Sodium perborate purchase Fine chemistry industry research institute is recovered in Tianjin；[(R, R)-N- (2- amino -1,2- Diphenethyl) pentafluorobenzenesulfonamide] chlorination is (to umbrella Flower hydrocarbon) ruthenium (II) purchase in Strem chemical；Iodomethane, methylsufonyl chloride purchase are in the limited public affairs of Chinese medicines group medicine company share Department.

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 usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.Without specified otherwise in embodiment, solution refers to water Solution.

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

Ambient temperature is 20 DEG C~30 DEG C.

It abridges in embodiment:

Bn: benzyl；Et: ethyl；Ac: acetyl group；Me: methyl；Boc: tertbutyloxycarbonyl；Ph: phenyl；COOH: carboxyl； OMe: methoxyl group；OTBS: dimethyl tertiary butyl silicon ether；SO₃H: sulfonic group；Ms: methyl sulphonyl.

Intermediate 1: tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -5- carbonyl tetrahydro -2H- pyrans -3- base) amino Formic acid esters (intermediate 1)

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

Step 1: 2- amino -4- alkynes ethyl valerate (1B)

ethyl 2-aminopent-4-ynoate

At room temperature, diphenyl methylene glycine ethyl ester 1A (50g, 0.187mol) is dissolved in methyl tertiary butyl ether(MTBE) (300mL) In, propargyl benzene sulfonate (44g, 0.224mol) and tetrabutylammonium bromide (6.1g, 0.019mol) is added, is warming up to 50 DEG C, It is added cesium carbonate (121.8g, 0.374mol), is reacted overnight at a temperature of 50 DEG C.Reaction solution is filtered, filter cake methyl- tert fourth Base ether (40mL × 2) washing, merges organic phase, and concentrated by rotary evaporation to half volume is added hydrochloric acid solution (3mol/L, 100mL), room Temperature lower stirring 1 hour, liquid separation is stood, water phase is extracted with methyl tertiary butyl ether(MTBE) (70mL × 2), is collected water phase, is concentrated to get 1B.

Step 2: 2- ((tertbutyloxycarbonyl) amino) -4- alkynes valeric acid (1C)

2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid

Sodium hydroxide (33.7g, 0.842mol) is dissolved in water (100mL), is added dropwise to 1B (26.4g, 0.187mol) dropwise Reaction solution in, at room temperature stir 2 hours, be added dropwise two dimethyl dicarbonate butyl esters (45g, 0.206mol) methyl tertiary butyl ether(MTBE) (125mL) solution stirs 4 hours at room temperature.Liquid separation is stood, water phase is washed with methyl tertiary butyl ether(MTBE) (80mL × 2), and water phase is used The hydrochloric acid solution of 3mol/L adjusts pH to 3, is extracted with methyl tertiary butyl ether(MTBE) (100mL × 2), merges organic phase, and organic phase is used full Washed with sodium-chloride water solution (30mL × 2), anhydrous magnesium sulfate dries, filters, is spin-dried for, obtain yellow oily liquid 1C (33g, Yield 83%).

MS m/z(ESI):212.0[M-1]。

Step 3: tert-butyl (1- (methoxyl group (methyl) amino) -1- carbonyl amyl -4- alkynes -2- base) carbamate (1D)

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

1C (33g, 0.155mol) is dissolved in n,N-Dimethylformamide (200mL), temperature is controlled less than 10 DEG C, is added N, N'- carbonyl dimidazoles (32.58g, 0.201mol) react 1 hour at 0 DEG C, and N, O- dimethyl hydroxylamine hydrochloride is added (19.6g, 0.186mol), is stirred overnight at room temperature.It is added dropwise water (150mL), stirs 1 hour, with acetic acid second into reaction solution Ester (100mL × 2) extraction, merges organic phase, and organic phase successively uses saturated sodium bicarbonate solution (60mL × 3), saturated sodium-chloride Solution (60mL × 3) washing, anhydrous magnesium sulfate dries, filters, and is concentrated, residue with silica gel column chromatography separating-purifying (petroleum ether/ Ethyl acetate (v/v)=10:1), obtain white solid 1D (35g, yield 88.2%).

MS m/z(ESI):156.9[M+1]。

Step 4: tert-butyl (1- (2,5- difluorophenyl) -1- carbonyl amyl -4- alkynes -2- base) carbamate (1E)

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

Under nitrogen protection, 2,5- difluoro bromobenzene (15.05g, 78mmol) is dissolved in dry toluene (50mL), ice salt bath drop Temperature to -10 DEG C hereinafter, isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (66mL, 1.3mol/L) is added dropwise, be maintained at - 10 DEG C or so are stirred 1 hour, and dry tetrahydrofuran (100mL) solution of 1D (10g, 39mmol) is added dropwise, and are kept for -10 DEG C of temperature, It finishes, reacts 4 hours at room temperature, cool the temperature to -10 DEG C or so, be added dropwise saturated ammonium chloride solution (40mL), stir 10 minutes, pH to 5~6 is adjusted with the hydrochloric acid solution of 3mol/L, stands liquid separation, water phase is extracted with methyl tertiary butyl ether(MTBE) (50mL × 2) It takes, merges organic phase, organic phase is washed with saturated sodium chloride solution (30mL × 2), and anhydrous sodium sulfate dries, filters, concentration, residual Object silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=50:1~8:1) is stayed, faint yellow solid 1E is obtained (10.1g, yield 83.5%).

MS m/z(ESI):210.1[M+1]。

Step 5: tert-butyl ((1R, 2S) -1- (2,5- difluorophenyl) -1- Hydroxy pentyl -4- alkynes -2- base) carbamic acid Ester (1F)

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

1E (16.07g, 52mmol) is dissolved in tetrahydrofuran (100mL), is added triethylene diamine (17.39g, 155mmol) With [(R, R)-N- (2- amino -1,2- Diphenethyl) pentafluorobenzenesulfonamide] chlorination (p-cymene) ruthenium (II) (i.e. RuCl (p- Cymene) (R, R)-FSDPEN) (0.37g, 0.52mmol), formic acid (14.27g, 310mmol) is added dropwise dropwise, finishes, in 40 DEG C Reaction is overnight.Reaction solution is concentrated and removes tetrahydrofuran and formic acid, be added into residue water (60mL) and hydrochloric acid (3mol/L, 10mL), with methyl tertiary butyl ether(MTBE) (90mL × 3) extract, merge organic phase, organic phase with saturated sodium bicarbonate solution (35mL × 2) it washs, anhydrous magnesium sulfate dries, filters, and is concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/ V)=60:1~10:1), obtain faint yellow jelly 1F (15.37g, yield 95%).

MS m/z(ESI):334.2[M+23]。

Step 6: tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -3,4- dihydro -2H- pyrans -3- base) carbamic acid Ester (1G)

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

It will be dissolved in n,N-Dimethylformamide (75mL) under 1F (15.37g, 49.4mmol) heating condition, the tetrabutyl be added Hexafluorophosphoric acid amine (2.49g, 6.42mmol), N- hydroxysuccinimide (2.84g, 24.75mmol), triphenylphosphine (0.86g, It 3.26mmol) replaces three times, vacuumizes 15 minutes with sodium bicarbonate (2.16g, 25.69mmol), nitrogen, cyclopentadienyl group is added Bis- (triphenylphosphine) ruthenic chloride (II) (i.e. CpRuCl (PPh₃)₂) (1.79g, 2.47mmol), nitrogen is replaced three times, and is vacuumized 15 minutes, under nitrogen protection, it is warming up to 85 DEG C of reactions overnight.Water (300mL) and methyl tertiary butyl ether(MTBE) are added into reaction solution (200mL), is filtered with silica gel, and liquid separation after filtrate stands, water phase is extracted with methyl tertiary butyl ether(MTBE) (90mL × 2), merges organic phase, Organic phase is washed with saturated sodium bicarbonate solution (60mL × 2), and anhydrous sodium sulfate dries, filters concentration, residue silicagel column Chromatographic purification (petrol ether/ethyl acetate (v/v)=80:1~30:1), obtains pale yellow powder solid 1G (8.9g, yield 57.9%).

MSm/z(ESI):256.2[M+1]。

Step 7: tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -5- hydroxy tetrahydro -2H- pyrans -3- base) amino first Acid esters (1H)

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

1G (8.9g, 28.6mmol) is dissolved in dry methyl tertiary butyl ether(MTBE) (90mL), is added dry toluene (9mL), Temperature is down to -10 DEG C, and borane dimethylsulf iotade tetrahydrofuran solution (2mol/L, 35.9mL) is added dropwise, reacts 3.5 at 0 DEG C Hour.It is slowly added to water (4mL), is added dropwise sodium hydroxide solution (1mol/L, 89mL), stirs 15 minutes, was added portionwise Boratex (13.2g, 85.8mmol), is stirred overnight at room temperature.Liquid separation is stood, water phase is extracted with methyl tertiary butyl ether(MTBE) (50mL × 2), Merge organic phase, organic phase wash with saturated sodium chloride solution (20mL × 2), and anhydrous sodium sulfate dries, filters, and is concentrated, to residual Addition toluene (50mL) in object is stayed, 90 DEG C of dissolutions is heated to, n-hexane (200mL) is added dropwise in reaction solution, it is solid that white is precipitated Body, filtering, n-hexane (30mL × 2) wash filter cake, and concentration removes solvent, obtains white solid powder 1H (7.9g, yield 84%).

MS m/z(ESI):274.1[M+1]。

Step 8: tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -5- carbonyl-tetrahydro -2H- pyrans -3- base) amino Formic acid esters (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 chloride (130mL), is cooled to 0 DEG C, this Martin oxidation will be worn Agent (29.72g, 70.06mmol) adds in reaction solution in batches, is warmed to room temperature reaction 4 hours naturally.It is cooled to 0 DEG C, by saturated carbon Sour hydrogen sodium solution (60mL) is added dropwise in reaction solution, stirs 20 minutes, and filtering, filtrate stands liquid separation, water phase methyl tertbutyl Ether (60mL × 3) extraction, merges organic phase, and organic phase is washed with saturated sodium bicarbonate solution (30mL × 2), and anhydrous sodium sulfate is dry Dry, filtering and concentrating, residue is obtained white with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10:1-4:1) Color crystalline powder intermediate 1 (10.85g, yield 94.7%).

MS m/z(ESI):272.0[M+1]；

¹H NMR(400MHz,DMSO-d₆):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- methane sulfonic acid base -5,6- dihydro -4H- pyrrolo- [3,4-c] pyrazoles (intermediate 2)

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

Step 1: tert-butyl (3Z) -3- (dimethylamino methene) -4- carbonyl-nafoxidine -1- formic acid esters (2B)

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

1- tertbutyloxycarbonyl -3- pyrrolidones 2A (100g, 0.54mol) is dissolved in DMAC N,N' dimethyl acetamide (600mL) In, it is added n,N-Dimethylformamide dimethylacetal (83.6g, 0.70mmol), is warming up to 105 DEG C and reacts 40 minutes, add water (500mL) quenching reaction is extracted with ethyl acetate (500mL × 2), merges organic phase.Organic phase is washed with water (500mL × 2), Anhydrous sodium sulfate is dry, concentration, residue with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=4:1~1: 1) 2B (50g, yield 47%) of weak yellow liquid shape is obtained.

Step 2: tert-butyl 6a- hydroxyl -1,3a, 4,6- nafoxidine simultaneously [3,4-c] pyrazoles -5- formic acid esters (2C)

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

2B (50g, 0.21mol) is dissolved in methanol (200mL), hydrazine hydrate (7.8g, 0.16mmol, wt=is added 80%) it, reacts at room temperature 4 hours.Reaction solution is concentrated to get 2C, is directly used in next step.

Step 3: tert-butyl 4,6- dihydro-2 h-pyrrole simultaneously [3,4-c] pyrazoles -5- formic acid esters (2D)

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

2C (47.5g, 0.21mol) is dissolved in the in the mixed solvent of methylene chloride (300mL) and methanol (180mL), it is cooling It to 0 DEG C, is added p-methyl benzenesulfonic acid (5.64g, 0.029mmol), reaction is overnight.Reaction solution is concentrated, residue silicagel column color Spectrum separating-purifying (methylene chloride) obtains the 2D (20g, yield 44%) of faint yellow solid.

Step 4: tert-butyl 2- methane sulfonic acid base -4,6- pyrrolin simultaneously [3,4-c] pyrazoles -5- formic acid esters (2E)

tert-butyl 2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5- carboxylate

2D (3.5g, 16.7mmol) is dissolved in tetrahydrofuran (35mL), is cooled to 0 DEG C, 60% sodium hydride is added (1.0g, 25.4mmol) is reacted 30 minutes, is added methylsufonyl chloride (2.9g, 25.4mmol), is reacted 1 hour.Into reaction solution Adding water (10mL) quenching reaction, extracted with ethyl acetate (50mL × 2), merges organic layer, organic layer is dry with anhydrous sodium sulfate, Concentration, residue obtain the 2E of white solid with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:1) (2.1g, yield 44%).

Step 5: 2- methane sulfonic 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 chloride (25mL), is cooled to 0 DEG C, is added trifluoroacetic acid (5mL), instead It answers 2 hours.Reaction solution is concentrated, ammonium hydroxide (2mL) quenching reaction is added, with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1) obtain the intermediate 2 of white solid.

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

Embodiment 1

The fluoro- 5- of (2R, 3R, 4R, 5S) -2- (2,5- difluorophenyl) -4- (2- (methyl sulphonyl) pyrrolo- [3,4-c] pyrrole Azoles -5 (2H, 4H, 6H)-yl) tetrahydro -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

Step 1: tert-butyl (the fluoro- 5- carbonyl tetrahydro -2H- pyrans -3- of (2R, 3R, 4R) -2- (2,5- difluorophenyl) -4- Base) carbamate (1b)

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

Under nitrogen protection, by intermediate 1 (1.5g, 4.58mmol), trans- 4- hydroxyl-D-PROLINE hydrochloride (77mg, It 0.46mmol) is added in tetrahydrofuran (20mL) with natrium carbonicum calcinatum (728mg, 6.78mmol), stirs 10 minutes at room temperature, In N- fluoro bis benzene sulfonamide (1.44g, 4.58mmol) is added at this temperature, the reaction was continued 48 hours.It is added into reaction solution Ethyl acetate (40mL) is stirred 10 minutes, is washed with water (20mL × 2), and organic phase is dry with anhydrous sodium sulfate (2g), concentration, Residue obtains 1b (380mg, yield 24%) with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=2:1).

MS m/z(ESI):368.3[M+23]。

Step 2: (the fluoro- 5- of (2R, 3R, 4R, 5S) -2- (2,5- difluorophenyl) -4- (2- (methane sulfonic acid base) pyrrolo- [3,4-c] pyrazoles -5 (2H, 4H, 6H)-yl) tetrahydro -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), it is dissolved in N, N- dimethyl second In amide (6mL), hydration benzene sulfonic acid (222mg, 1.2mmol) is added, stirs 1 hour at room temperature, triacetoxy borohydride hydrogen is added Change sodium (276mg, 1.3mmol), is stirred to react at room temperature 24 hours.Water (60mL) and ammonium hydroxide (6mL) are added into reaction system, Solid is precipitated, filters to obtain crude product, by crude product with silica gel chromatographic column separating-purifying (petrol ether/ethyl acetate (v/v)=2:1), obtains 1c (220mg, yield 42.6%).

MS m/z(ESI):517.3[M+1]。

Step 3: the fluoro- 5- of (2R, 3R, 4R, 5S) -2- (2,5- difluorophenyl) -4- (2- (methyl sulphonyl) pyrrolo- [3, 4-c] pyrazoles -5 (2H, 4H, 6H)-yl) tetrahydro -2H- pyrans -3- amine (compound 1)

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

Under nitrogen protection, by 1c (220mg, 0.426mmol), be dissolved in methylene chloride (1.5mL), be cooled to 0 DEG C, slowly in Trifluoracetic acid (1.5mL) is instilled at this temperature, reaction 2 hours is warmed to room temperature after dripping off.Reaction solution is concentrated, is added into residue Enter methylene chloride (10mL), washs anhydrous sodium sulfate drying, concentration, residue preparation thin layer with 5% ammonium hydroxide (5mL × 2) Analysis purifying (methylene chloride/methanol (v/v)=20:1), obtains compound 1 (80mg, yield 45.2%).

MS m/z(ESI):417.3[M+1]；

¹H NMR(400MHz,DMSO-d₆):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 1¹H-¹H COSY and¹H-¹For H NOESY as shown in FIG. 1 to FIG. 2, data are as shown in table 1,1 structure of compound Type is shown below:

1 compound 1 of table¹HNMR、¹H-¹H COSY and¹H-¹H NOESY data (DMSO-d₆,400MHz)

Biological test

1, rat plasma DPP-IV zymetology screening experiment

Experimental animal is SD rat, 8 week old, male, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., animal Produce quality certification number: SCXK (capital) 2012-0001.Rat after fasting is grouped by weight.Rat takes blood using eye socket, The anticoagulant tested group of oral test compound of EDTA-2Na, dosage 10mg/kg；Control group takes orally blank reagent.Respectively at administration Blood is taken at different time points afterwards.Blood sample is centrifuged 15min in 2500rpm, blood plasma is taken out, is saved in -20 DEG C.Enzyme activity is surveyed Examination, each test sample take 40 μ l blood plasma, and 10 μ l H-Ala-Pro-AFC substrates (0.2mM) are added, and use microplate reader after reacting 15min Measured value (excitation wavelength Excitation=405nM；Launch wavelength Emission=535nM), it is united using Origin 7.5 Meter analysis calculates test compound to blood plasma DPP-IV enzyme activity inhibiting rate >=70% duration, the results are shown in Table 2.

2 rat plasma DPP-IV zymetology screening experiment result of table

Serial number	Compound number	>=70% inhibiting rate duration (h)
			1	Compound 1	50.8

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

2, pharmacokinetics in rats is evaluated

Male SD rat (is purchased from Vital River Laboratory Animal Technology Co.LTD, licensing Number: 11400700005540) 200-240g, overnight fasting.3 SD rats of experimental day distinguish stomach-filling 5mgkg^-1, respectively at 15min, 30min, 45min, 1h, 2h, 4h, 8h, 12h and for 24 hours before administration and after administration, by jugular vein blood collection 0.20mL, are placed in In EDTA test tube.Containing the internal standard (Verapamil, 5.00ng/mL and glibenclamide, 50.0ng/mL) is added after blood sample acquisition Acetonitrile, 13000rpm is centrifuged 10min after being acutely vortexed.Supernatant is taken to carry out LC-MS/MS detection.Using Pharsight Phoenix Non- compartment model in 6.3 calculates pharmacokinetic parameter, and experimental result is as shown in table 3.

3 pharmacokinetics in rats evaluation result of table

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

Claims

1. a kind of logical formula (I) compound represented or its pharmaceutically acceptable salt:

Wherein:

V is selected from one of following group:

Ar is 2,5- difluorophenyl or 2,4,5- trifluorophenyl；R^2aSelected from H；

R^3aAnd R^3bIt is independently selected from H；

R⁴Selected from-(CH₂)_m- S (=O)_n-R⁸；

R⁸Selected from methyl, ethyl or cyclopropyl；

M is selected from 0；

N is selected from 2.

2. compound or its pharmaceutically acceptable salt described in any one of according to claim 1, wherein compound is selected from logical Formula (II), logical formula (III), logical formula (IV) or logical formula (V) compound represented:

3. compound according to claim 1 or its pharmaceutically acceptable salt, which is selected from such as one of flowering structure:

4. compound as follows or its pharmaceutically acceptable salt:

5. compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, wherein the salt choosing From sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine salt, pyridiniujm, picoline salt, 2,6- diformazan Yl pyridines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromic acid Salt, sulfate, nitrate, phosphate, formates, trifluoroacetate, acetate, maleate, tartrate, citrate, Succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, water Poplar hydrochlorate, glucuronate salt, galacturonic hydrochlorate, citrate, aspartate, glutamate, benzoate, cinnamic acid Salt, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

6. a kind of pharmaceutical composition, the composition includes the chemical combination according to any one of claims 1 to 4 of effective dose Object or its pharmaceutically acceptable salt, or further comprise one or more other therapeutic agents and pharmaceutically acceptable carrier Or excipient.

7. pharmaceutical composition according to claim 6, wherein the other therapeutic agents include:

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

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

(c) biguanides, thiazolidinediones, sulfonylurea, column how class, alpha-glucosidase restrainer or glucagon - 1 analog of peptide or its pharmaceutically acceptable salt.

8. pharmaceutical composition according to claim 7, wherein the SGLT-2 inhibitor is selected from Dapagliflozin, Kan Ge Column are net, A Gelie is net, En Palie is net, Yi Palie is net, Tuo Fulie is net, Lu Silie is net, Rui Gelie is net, Sergliflozin or support arrange Only；The DPP-IV inhibitor be selected from BI 1356, sitagliptin, vildagliptin, Egelieting, saxagliptin, that column Ge Lieting, gigue column spit of fland or song Ge Lieting, melogliptin, dutogliptin, are replaced at carmegliptin in spit of fland；The biguanides therapeutic agent Selected from melbine or insoral；The thiazolidinediones therapeutic agent is selected from Ciglitazone, pioglitazone, Luo Gelie Ketone, troglitazone, Fa Gelie ketone or Darglitazone, sulfonylurea treatment agent are selected from Glimepiride, orinase, lattice train wave Urea, glibenclamide, gliquidone, Glipizide or gliclazide, how class therapeutic agent is selected from Nateglinide, Repaglinide or rice to column Ge Lienai, alpha-glucosidase restrainer are selected from acarbose, voglibose or Miglitol, glucagon-like-peptide-1 class Exenatide or Liraglutide are selected from like object.

9. in compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt or claim 6~8 Described in any item compositions are preparing the application in dipeptidyl peptidase-iv inhibitor.

10. application according to claim 9, the dipeptidyl peptidase-iv inhibitor is used to prepare treatment metabolic disease Drug, wherein the metabolic disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic keratopathy kidney Disease, insulin resistance, hyperglycemia, hyperinsulinemia, raised level, hyperlipidemia, the obesity, height of fatty acid or glycerol Triglyceride mass formed by blood stasis, X syndrome, diabetic complication, atherosclerosis or hypertension.

11. application according to claim 10, the diabetes are type-2 diabetes mellitus.