CN105085530A

CN105085530A - Fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine

Info

Publication number: CN105085530A
Application number: CN201510267948.8A
Authority: CN
Inventors: 范江; 冯建川; 彭飞; 陈清平
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-05-23
Filing date: 2015-05-22
Publication date: 2015-11-25
Anticipated expiration: 2035-05-22
Also published as: CN105085530B

Abstract

The invention relates to a fused tricyclic substituted amino six-membered ring derivative and application thereof in medicine, particularly a fused tricyclic substituted amino six-membered ring derivative shown in a formula (I) or stereoisomers and pharmaceutically acceptable salts or pro-drugs of the derivative, a pharmaceutical composition comprising the derivative and use of the derivative in preparing a dipeptidyl peptidase IV (DPP-IV) inhibitor in medicine, wherein the substituents in the formula (I) are defined as in the description. The formula (I) is shown in the description.

Description

Ternary condenses cyclosubstituted amino six-ring analog derivative and in application pharmaceutically

Technical field

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

Background technology

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

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

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

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

At present, the research of DPP-IV inhibitor achieves larger progress, comprise sitagliptin, BMS-477118, Egelieting DPP-IV inhibitor ratified listing.The most outstanding feature of DPP-IV inhibitor is, due to incretin only secretion after body feed, DPP-IV inhibitor not easily increases insulin level unsuitable time, produces the side effect hypoglycemia that many antidiabetic drugs are common.Recent clinical data shows, and suppresses DPP-IV that insulin secretion can be made to increase, reduces blood sugar concentration and improve pancreas islet beta cell function (Diabetes, 1998,47:1253-1258).The side effect of common DPP-IV inhibitor has respiratory tract infection, has a sore throat, suffers from diarrhoea, cold like symptoms, headache and dizzy etc.But totally there is good security and tolerance, also do not find that the patient used has serious body weight to increase or potential to lose weight and the symptom such as oedema at present.

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

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

(1) WO2008060488 discloses the compound of following structure as DPP-IV inhibitor,

Wherein:

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

X is selected from O or CH ₂;

V is selected from deng group; Do not think that specifically describing in this patent is a part of the present invention.

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

Wherein:

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

(3) compound that CN102272136 discloses following structure has DPP-IV inhibitor effect, as the purposes preventing and/or treating medicine of diabetes,

Wherein:

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

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

(4) compound that WO2007097931 discloses the following structure of DPP-IV inhibitor is used for the treatment of diabetes,

Wherein:

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

V is selected from deng group, and R2 is selected from hydrogen, hydroxyl, halogen etc.; R ^3a, R ^3bthe C be selected from hydrogen, being replaced by 1-5 fluorine atom _1-4alkyl; Do not think that specifically describing in this patent is a part of the present invention.

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

The object of the invention is to introduce a class novel DPP-IV inhibitors, specifically there is the compound shown in general formula (I), show after deliberation, the compound of this class formation has good DPP IV (DPP-IV) inhibit activities and selectivity, has the prospect being used for the treatment of or alleviating type ii diabetes and similar disease.

Summary of the invention

The present invention relates to the ternary shown in a kind of general formula (I) and condense cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug:

Wherein:

X is selected from-O-,-S-,-NH-or-CH ₂-, preferably-O-;

W is selected from

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, I, cyano group, hydroxyl, C independently of one another _1-8alkyl, C _1-8alkoxyl group, described alkyl or alkoxyl group optional further replace by the substituting group of 0 to 5 F, Cl, Br, I, cyano group, amino or hydroxyl; R ¹, R ^1a, R ^1b, R ^1cand R ^1drespective independence preferred H, F, Cl, Br, C _1-2alkyl or C _1-2alkoxyl group; R ¹, R ^1a, R ^1b, R ^1cand R ^1drespective independence is preferred H or F further;

R ²be selected from H, C _1-8alkyl ,-(CH ₂) _m-S (=O) _n-C _1-8alkyl ,-(CH ₂) _m-S (=O) _n-C _3-8cycloalkyl ,-(CH ₂) _m-S (=O) _n-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-S (=O) _n-C _6-14aryl ,-(CH ₂) _m-S (=O) _n-(6 to 14 yuan of heteroaryls) ,-(CH ₂) _m-C (=O)-OH ,-(CH ₂) _m-C (=O)-C _1-8alkyl ,-(CH ₂) _m-C (=O)-O-C _1-8alkyl ,-(CH ₂) _m-C (=O)-C _3-8cycloalkyl ,-(CH ₂) _m-C (=O)-O-C _3-8cycloalkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by 0 to 5 F, Cl, Br, I ,-CH ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-8alkyl, C _1-8alkoxyl group, C _3-8the substituting group of cycloalkyl or 3 to 8 yuan of heterocyclic radicals replaced; Described heterocyclic radical or heteroaryl contain 1 to 5 and are selected from N, O or S (=O) _natom or group; R ²preferred H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl ,-(CH ₂) _m-S (=O) _n-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-C (=O)-O-C _1-4alkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl, cycloalkyl or heterocyclyl are further by 0 to 3 F, Cl, Br, I ,-CH ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-2alkyl or C _1-2the substituting group of alkoxyl group replaced, and described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) _natom or group; R ²preferred H, C further _1-4alkyl ,-S (=O) ₂-C _1-4alkyl or-(CH ₂) _m-S (=O) ₂-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ²more preferably H, methyl, ethyl, propyl group,

R ³be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C _1-8alkyl, C _1-8alkoxyl group ,-(CH ₂) _m-C _2-8thiazolinyl-R ⁵,-(CH ₂) _m-C _2-8alkynyl-R ⁵,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-OR ⁶,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-C _6-14aryl ,-(CH ₂) _m-(6 to 14 yuan of heteroaryls) ,-(CH ₂) _m-NR ⁷r ⁸,-(CH ₂) _m-C (=O)-NR ⁷r ⁸,-(CH ₂) _m-O-C (=O)-NR ⁷r ⁸,-(CH ₂) _m-S (=O) _n-R ⁹,-(CH ₂) _m-NR ¹⁰c (=O)-NR ⁷r ⁸,-(CH ₂) _m-NR ¹⁰c (=O)-R ⁶or-(CH ₂) _m-NR ¹⁰c (=O)-OR ⁶, wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃, cyano group, nitro, isocyano-, hydroxyl, aldehyde radical, carboxyl, C _1-8alkyl or C _1-8the substituting group of alkoxyl group replaced, wherein (CH ₂) _min any CH ₂hydrogen atom optionally by 0 to 2 independently selected from F, hydroxyl ,-CH ₂f ,-CHF ₂,-CF ₃, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced; R ³preferred H, F, Cl, Br, hydroxyl, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-NR ⁷r ⁸, or-(CH ₂) _m-S (=O) _n-R ⁹, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³preferred H, F, cyano group, C further _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³more preferably R ³be selected from H, methyl, ethyl ,-CF ₃,

R ⁴be selected from H, F, Cl, Br, I, C _1-8alkyl or C _3-8cycloalkyl, wherein said alkyl or cycloalkyl is optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ⁴preferred H, F, C _1-8alkyl or C _3-8cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl or hydroxyl replace; R ⁴more preferably methyl ,-CF ₃or

R ⁵and R ⁶be selected from H, amino, hydroxyl, C independently of one another _1-8alkyl, C _1-8alkoxyl group, C _3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) _natom or group; R ⁵and R ⁶the preferred H of respective independence, amino, hydroxyl, C _1-4alkyl or C _1-4alkoxyl group;

R ⁷, R ⁸and R ¹⁰be selected from H, C independently of one another _1-8alkyl or C _3-8cycloalkyl, wherein said alkyl or cycloalkyl is optionally replaced by the substituting group of 0 to 5 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further; R ⁷, R ⁸and R ¹⁰preferred H or C of respective independence _1-4alkyl; R ⁷and R ⁸respective independence is preferred H or C further _1-2alkyl;

R ⁹be selected from H, C _1-8alkyl, C _3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) _natom or group; R ⁹preferred C _1-4alkyl; R ⁹preferred C further _1-2alkyl;

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

M is selected from 0,1,2,3 or 4; M preferably 0 or 1.

Preferred version of the present invention, comprises ternary shown in general formula (I) and condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug, wherein:

X is selected from-O-;

W is selected from

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, C independently of one another _1-2alkyl or C _1-2alkoxyl group; R ¹, R ^1a, R ^1b, R ^1cand R ^1dpreferred H or F of respective independence; Further preferably, R ¹and R ^1cindependently be selected from H, R separately ^1aand R ^1dindependently be selected from F, R separately ^1bbe selected from H or F;

R ²be selected from H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl ,-(CH ₂) _m-S (=O) _n-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-C (=O)-O-C _1-4alkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl, cycloalkyl or heterocyclyl are further by 0 to 3 F, Cl, Br, I ,-CH ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-2alkyl or C _1-2the substituting group of alkoxyl group replaced; Described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) _natom or group; R ²preferred H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl or-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl optional further replace by the substituting group of 0 to 3 F, Cl, Br or hydroxyl;

R ³be selected from H, F, Cl, Br, hydroxyl, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-NR ⁷r ⁸, or-(CH ₂) _m-S (=O) _n-R ⁹, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³preferred H, F, Cl, Br, hydroxyl, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace;

R ⁴be selected from H, F, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace; R ⁴preferred H, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br replace;

R ⁶independently selected from amino, hydroxyl, C _1-4alkyl or C _1-4alkoxyl group; R ⁶preferred C _1-4alkoxyl group, further preferred C _1-2alkoxyl group;

R ⁷and R ⁸be selected from H or C independently of one another _1-4alkyl; R ⁷and R ⁸preferred H or C of respective independence _1-2alkyl;

R ⁹be selected from C _1-4alkyl, C _3-6cycloalkyl or 3 to 6 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) _natom or group; R ⁹preferential C _1-4alkyl, further preferred C _1-2alkyl;

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

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

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, methyl, ethyl, methoxy or ethoxy independently of one another; R ¹and R ^1cpreferred H, R ^1aand R ^1dpreferred F, R ^1bpreferred H or F;

R ²be selected from H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl ,-(CH ₂) _m-C (=O)-O-C _1-4alkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ²preferred H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ²preferred H, C further _1-2alkyl ,-(CH ₂) _m-S (=O) _n-C _1-2alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl optional further replace by the substituting group of 0 to 3 F, Cl, Br or hydroxyl; R ²further preferably H, methyl, ethyl, propyl group, r ²more preferably H,

R ³be selected from H, F, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-NR ⁷r ⁸or-(CH ₂) _m-S (=O) _n-R ⁹, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³preferred H, C _1-4alkyl ,-C (=O)-R ⁶or-C (=O)-NR ⁷r ⁸, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³preferred H, methyl, ethyl ,-CF further ₃, r ³more preferably H ,-CF ₃,

R ⁴be selected from H, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace; R ⁴preferred H, C _1-2alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace; R ⁴more preferably methyl ,-CF ₃or

R ⁶be selected from amino, hydroxyl or C _1-4alkoxyl group; R ⁶preferred amino, hydroxyl or C _1-2alkoxyl group; R ⁶preferred C further _1-2alkoxyl group;

R ⁹be selected from C _1-4alkyl; R ⁹preferred C _1-2alkyl;

N is selected from 2;

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

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H or F independently of one another; R ¹and R ^1cpreferred H, R ^1aand R ^1dpreferred F, R ^1bpreferred H or F;

R ²be selected from H, C _1-4alkyl ,-S (=O) ₂-C _1-4alkyl or-S (=O) ₂-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ²preferred H, C _1-2alkyl ,-S (=O) ₂-C _1-2alkyl or-S (=O) ₂-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl optional further replace by the substituting group of 0 to 3 F, Cl, Br or hydroxyl;

R ³be selected from H, C _1-4alkyl ,-C (=O)-R ⁶or-C (=O)-NR ⁷r ⁸, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced; R ³preferred H, C _1-2alkyl ,-C (=O)-R ⁶or-C (=O)-NR ⁷r ⁸, wherein said alkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace; R ³preferred H, methyl, ethyl ,-CF further ₃, r ³more preferably H ,-CF ₃,

R ⁴be selected from H, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace; R ⁴preferred H, C _1-2alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace;

R ⁶be selected from C _1-4alkoxyl group; R ⁶preferred C _1-2alkoxyl group;

R ¹and R ^1cbe selected from H, R ^1aand R ^1dbe selected from F, R ^1bbe selected from H or F;

R ²be selected from H, methyl, ethyl, propyl group,

R ³be selected from H, methyl, ethyl ,-CF ₃,

R ⁴be selected from methyl ,-CF ₃or

Preferred version of the present invention, the present invention relates to compound and is selected from, but be not limited to:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

" hydroxyl " refers to-OH.

" cyano group " refers to-C ≡ N.

" isocyano-" refers to-N ≡ C.

" nitro " refers to-NO ₂.

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

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

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

" heterocyclic radical " refers to replacement or unsubstituted saturated or unsaturated and be at least selected from the heteroatomic non-aromatic ring of N, O or S containing 1 to 5, non-aromatic ring can be the monocycle of 3 to 10 yuan, the volution of 4 to 20 yuan ring or bridged ring, N, S that in heterocyclic ring, selectivity replaces can be oxidized to various oxidation state.Preferably 3 to 12 yuan of heterocycles.Non-limiting example comprises oxirane base, oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, oxacyclohexyl, oxa-ring octyl group, ethylenimine base, azelidinyl, nitrogen heterocyclic amyl group, piperidyl, aziridinyl, 1,3 dioxy cyclopentyl, 1,4-dioxy cyclopentyl, 1,3-dioxy cyclopentyl, 1,3-dioxocyclohex base, 1,3-bis-sulphur cyclohexyl, azepine base, morpholinyl, piperazinyl, pyranyl, piperidyl, thio-morpholinyl, dihydropyrane, Isosorbide-5-Nitrae-Dioxin base,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The synthetic method of the compounds of this invention

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

Scheme one:

Intermediate compound I-A and I-B obtains intermediate compound I-C by reductive amination conditioned response, and intermediate compound I-C obtains general formula (I) compound by removing amino protecting group again.

Scheme two:

Intermediate compound I-D and intermediate compound I-E obtains intermediate compound I-C by condensation reaction, and intermediate compound I-C obtains general formula (I) compound by deaminizating protecting group.

Prepared by intermediate compound I-A referenced patent WO2010056708, US2007232676 document, its method is described below:

Wherein, R ¹, R ^1a, R ^1b, R ^1c, R ^1dwith W as hereinbefore defined, R ^2abe selected from C _1-8alkyl or C _3-8cycloalkyl, P is amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl groups (Fmoc), and V is halogen, preferred chlorine, and L is selected from halogen, preferred bromine.

Embodiment

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

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

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

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

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

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

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

Without specified otherwise, methyl tertiary butyl ether, hydrazine hydrate, Tetrabutyl amonium bromide, sodium hydride, triphenyl phosphorus, N,N-dimethylacetamide, glycol dimethyl ether, trifluoroacetic acid are bought in Chengdu Ke Long chemical reagent factory; Two dimethyl dicarbonate butyl esters, N, N'-dicarbapentaborane diimidazole, DMF dimethylacetal, n-Butyl Lithium, N, O-dimethyl hydroxylamine hydrochloride are bought in Ace spy (Chengdu) medical science company limited; Cesium carbonate, N-hydroxysuccinimide, two (trimethyl silicon based) sodium amide, diphenylmethylene glycine ethyl ester are bought in the resistance to Jilin Chemical of peace; Ammonia/methyl alcohol is bought in the smooth Science and Technology Co., Ltd. of upper Haitai; 2-(TMS) ethoxymethyl chlorine, 2,5-difluoro bromobenzenes are bought in Shanghai De Mo Pharmaceutical Technology Co., Ltd; Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution is bought in lark prestige Science and Technology Ltd.; Tetrabutyl ammonium fluoride, three (acetoxyl group) sodium borohydride, propargyl bromide, tetrabutyl phosphofluoric acid amine are bought in this Reagent Company of Adama; Two (triphenylphosphine) ruthenium chloride (II) of cyclopentadienyl is bought in ACROSorgainics; Cyclopropyl sulfonyl chloride, borane dimethylsulf iotade are bought in splendid scientific and technological (Shanghai) Co., Ltd. of chemistry far away; Phenylsulfonic acid is bought in Tianjin recovery fine chemistry industry institute; Chlorine { [amino-1, the 2-diphenyl-ethyl of (1R, 2R)-(-)-2-] (penta fluoro benzene sulphonyl) is amino } (Paracymene) ruthenium (II) is bought in Stremchemical; Cobalt octacarbonyl is bought in AlfaAesar reagent; Lithium diisopropylamine is bought in Aladdin reagent.

Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 2L volume.Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.Without specified otherwise in embodiment, solution refers to the aqueous solution.Without specified otherwise in embodiment, the temperature of reaction is room temperature.Abridge in embodiment: Bn: benzyl; Et: ethyl; Ac: ethanoyl; Me: methyl; Boc: tertbutyloxycarbonyl; Ph: phenyl; COOH: carboxyl; OMe: methoxyl group; OTBS: dimethyl tertiary butyl silicon ether; SO ₃h: sulfonic group; Ms: methyl sulphonyl; SEM:2-(trimethyl silicane) ethoxyl methyl.

Intermediate 1

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

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

The first step: ethyl 2-Aminopentyl-4-acetylenic acid ester (1B)

ethyl2-aminopent-4-ynoate

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

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

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

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

MSm/z(ESI):212.0[M-1]。

3rd step: the tertiary butyl (6-methoxyl group-5-carbonyl-1-in heptan alkynes-4-base) carbamate (1D)

tert-butyl(6-methoxy-5-oxohept-1-yn-4-yl)carbamate

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

MSm/z(ESI):156.9[M+1]。

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

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

Under nitrogen protection; by 2; 5-difluoro bromobenzene (15.05g; 78mmol) be dissolved in dry toluene (50mL); cryosel bath is cooled to less than-10 DEG C; dropwise add isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (66mL, 1.3mol/L), remain on about-10 DEG C and stir 1 hour.1D (10g, 39mmol) is dissolved in dry tetrahydrofuran (100mL), dropwise drops in above-mentioned reaction solution, maintain the temperature at less than-10 DEG C, finish, react 4 hours under room temperature.Cool the temperature to less than-10 DEG C, dropwise add saturated ammonium chloride solution (40mL), stir 10 minutes, with hydrochloric acid soln adjust ph to 5 ~ 6 of 3mol/L, stratification, aqueous phase methyl tertiary butyl ether (50mL × 2) extracts, merge organic phase, with saturated nacl aqueous solution (30mL × 2) washing, in organic phase, add anhydrous sodium sulfate drying, filter, concentrated, column chromatography for separation (petrol ether/ethyl acetate (v/v)=50:1-8:1), obtains faint yellow solid 1E (10.1g, productive rate 83.5%).

MSm/z(ESI):210.1[M+1]。

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

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

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

MSm/z(ESI):334.2[M+23]。

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

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

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

MSm/z(ESI):256.2[M+1]。

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

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

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

MSm/z(ESI):274.1[M+1]。

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

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

MSm/z(ESI):272.0[M+1]；

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

Intermediate 2

Tertiary butyl 3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (intermediate 2)

tert-butyl3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-5(6H)-carboxylate

The first step: tertiary butyl allyl group (support-2-alkynes-1-base) carbamate (2B)

tert-butylallyl(prop-2-yn-1-yl)carbamate

By N-tertbutyloxycarbonyl allylamine 2A (20g; 127.39mmoL) be dissolved in DMF (100mL), by sodium hydride (7.6g; 60%; 191.08mmoL) with after normal hexane process, add DMF (400mL); under nitrogen protection; be added drop-wise at 0 DEG C in reaction solution, stir 30 minutes at 0 DEG C, continue reaction under rising to room temperature 20 minutes.Under ice bath, be added dropwise to propargyl bromide (30.3g, 245.78mmoL), keep 0 DEG C to stir 30 minutes.Reaction solution is slowly added in trash ice and processes excessive sodium hydride, with ethyl acetate (100mL × 3) extraction, merge organic phase and wash with saturated aqueous common salt (100mLx3), anhydrous sodium sulfate drying, filtering, filtrate reduced in volume.Residue, with silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=100:1 ~ 50:1), obtains yellow liquid 2B (21g, productive rate 85%).

MSm/z(ESI):140.1[M+1]。

Second step: tertiary butyl 5-carbonyl six hydrogen cyclopentano [c] pyrroles-2 (1H)-manthanoate (2C)

tert-butyl5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

By compound 2B (39g, 202.2mmoL) be dissolved in glycol dimethyl ether (275mL), add cobalt octacarbonyl (83g, 242.7mmoL), water (82.4mL), stir 30 minutes, be warmed up to 84 DEG C of return stirrings 16 hours.Concentrated by reaction solution, the hydrochloric acid (240mL) adding saturated aqueous common salt (500mL), ethyl acetate (250mL) and 1mol/L dissolves residual solid.Separatory, aqueous phase ethyl acetate (250mLx3) extracts, merge organic phase, with saturated aqueous common salt (250mL × 2) washing, anhydrous sodium sulfate drying, filters, pressurization is concentrated, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3:1 ~ 2:1), obtains faint yellow solid 2C (27.6g, productive rate 61.3%).

MSm/z(ESI):170.1[M+1]；

¹HNMR(400MHz,CDCl ₃):δ3.68-3.64(m,2H),3.24-3.21(d,2H),2.97-2.88(m,2H),2.52-2.45(dd,2H),2.20-2.14(dd,2H),1.46(s,9H)。

3rd step: (E)-tertiary butyl 4-((dimethylamino) methene)-5-carbonyl six hydrogen cyclopentano [c] pyrroles-2 (1H)-manthanoate (2D)

(E)-tert-butyl4-((dimethylamino)methylene)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

2C (20g, 88.9mmoL) is dissolved in DMF dimethylacetal (13.7g, 115.6mmoL) heated and stirred to reflux 4 hours.Reaction solution is concentrated, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2:1 ~ 1:4), obtain brown oil 2D (15.8g, productive rate 63%).

MSm/z(ESI):281.2[M+1]。

4th step: tertiary butyl 7a-hydroxyl-3b, 4,6,6a, 7,7a-six hydrogen-1H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (2H)-manthanoate (2E)

tert-butyl7a-hydroxy-3b,4,6,6a,7,7a-hexahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-5(2H)-carboxylate

2D (15.8g, 56.4mmoL) is dissolved in toluene (90mL), adds hydrazine hydrate (4.2g, 67.7mmoL, 80%), stir 16 hours at 45 DEG C.By reaction solution cool to room temperature, filter, filter cake ethyl acetate drip washing, filter cake is dried, obtains white solid 2E (13.6g, productive rate 90%)

5th step: tertiary butyl 3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (intermediate 2)

tert-butyl3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-5(6H)-carb-oxylate

2E (13.6g, 50.9mmoL) is dissolved in methylene dichloride (90mL), is cooled to 0 DEG C, add tosic acid hydrate (0.97g, 5.09mmoL), stir 30 minutes.In reaction solution, add saturated sodium bicarbonate solution regulate reacting liquid pH value 7 ~ 8, separatory.Aqueous phase methylene dichloride (500mL × 3) extracts, merge organic phase, and wash with saturated aqueous common salt (500mLx2), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1:1 ~ 1:2), obtain white solid intermediate 2 (10g, productive rate 78.8%).

¹HNMR(400MHz,CD ₃OD):δ7.33(S,1H),3.76-3.71(m,1H),3.64-3.63(D,2H),3.43(m,2H),2.95-2.89(m,2H),2.57-2.53(d,1H),1.42(s,9H)。

Intermediate 2 is split by chiral high performance liquid chromatography and obtains two single configuration of compound, chiral high performance liquid chromatography separation condition:

Chiral column: CHIRALPAKAY-H; Chiral column specification: 0.46cmI.D. × 15cmL; Sample size: 2 μ L; Moving phase: normal hexane/Virahol (v/v)=90/10; Flow velocity: 1.0mL/min; Determined wavelength: UV214nm; Temperature: 35 DEG C;

Peak 1:t=3.685min is intermediate 2-1;

Peak 2:t=4.627min is intermediate 2-2;

Intermediate 3

Tertiary butyl 3-(trifluoromethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (intermediate 3)

tert-butyl3-(trifluoromethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-5(6H)-carboxylate

The first step: tertiary butyl 5-carbonyl-4-(2,2,2-trifluoroacetyl group) six hydrogen cyclopentano [c] pyrroles-2 (1H)-manthanoate (3A)

tert-butyl5-oxo-4-(2,2,2-trifluoroacetyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Under room temperature, 2C (1.13g, 5.0mmol) is dissolved in tetrahydrofuran (THF) (15mL), is cooled to-70 DEG C.Add lithium diisopropyl amido (2.5mL, 2mol/L), in-70 DEG C of reactions 0.5 hour.Trifluoroacetic Acid Ethyl Ester (0.71g, 5.0mmol) is joined in reaction solution, naturally rises to room temperature reaction 4 hours.Reaction system is cooled to-10 DEG C, drips ammonium chloride (15mL) in reaction solution.With methyl tertiary butyl ether (40mL × 3) extraction, merge organic phase, wash with the saturated common salt aqueous solution (30mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue, with silica gel column chromatography separating purification (ethyl acetate/petroleum ether (v/v)=3:1-1:1), obtains brown liquid 3A (1.36g, productive rate 84%).

MSm/z(ESI):322.1[M+1]。

Second step, the 3rd step:

Under room temperature, be dissolved in by 3A (1.36g, 4.23mmol) in toluene (20mL), add hydrazine hydrate (0.26g, 5.08mmol), 40 DEG C are reacted 2 hours.In reaction system, add water (30mL), with methylene dichloride (50mL) extraction, merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume is obtained 3B.Compound 3B is dissolved in methylene dichloride (30mL), is cooled to 0 DEG C, anhydrous methanol (10mL) solution of tosic acid (0.42g, 2.18mmol) is added drop-wise in reaction solution, in 0 DEG C of reaction 1 hour.Drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (20mL × 4).Merge organic phase, wash with the saturated common salt aqueous solution (20mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=5:1-1:1) purifying, obtains white solid intermediate 3 (0.44g, productive rate 32.8%).

MSm/z(ESI):318.3[M+1]。

Embodiment 1

2-(5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-2-base) ethanol (compound 1-1)

2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-2-yl)ethanol

2-(5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-1H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethanol (compound 1-2)

2-(5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7-hexahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-1-yl)ethanol

The first step: tertiary butyl 2-(2-oxyethyl group-2-carbonylethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (1a-1)

tert-butyl2-(2-ethoxy-2-oxoethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta

[1,2-c]pyrazole-5(6H)-carboxylate

Tertiary butyl 1-(2-oxyethyl group-2-carbonylethyl)-3b, 4,6a, 7-tetrahydro-1 H-pyrrolo is [3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (1a-2) also

tert-butyl1-(2-ethoxy-2-oxoethyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta

[1,2-c]pyrazole-5(6H)-carboxylate

Intermediate 2 (2.0g, 8.0mmoL) is dissolved in DMF (20mL), cools to 0 DEG C, add sodium hydride (385mg, 60%, 9.6mmoL), rise to stirred at ambient temperature 1 hour.Cool to 0 DEG C again, be added dropwise to ethyl bromoacetate (1.6g, 9.6mmoL), naturally rise to stirring at room temperature 16 hours.Reaction solution is poured in trash ice, stir, and add appropriate sodium-chlor, extract by ethyl acetate (80mL × 3), merge organic phase, and wash with saturated aqueous common salt (50mLx3), organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, with silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2:1), obtain the mixture (2g, productive rate 74%) of colorless oil 1a-1 and 1a-2.

MSm/z(ESI):336.2[M+1]。

Second step: tertiary butyl 2-(2-hydroxyethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (1b-1)

tert-butyl2-(2-hydroxyethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta

[1,2-c]pyrazole-5(6H)-carboxylate

Tertiary butyl 1-(2-hydroxyethyl)-3b, 4,6a, 7-tetrahydro-1 H-pyrrolo is [3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (1b-2) also

tert-butyl1-(2-hydroxyethyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta

[1,2-c]pyrazole-5(6H)-carboxylate

The mixture (830mg, 2.478mmoL) of 1a-1 and 1a-2 is dissolved in methyl alcohol (15mL), under stirring, adds sodium borohydride (113mg, 2.973mmoL), stirred at ambient temperature 4 hours.Water (0.5mL) is added in reaction solution, reaction solution is concentrated, add saturated aqueous common salt (50mL), with methylene dichloride (30mLx5) extraction, merge organic phase, wash with saturated aqueous common salt (30mL × 1), anhydrous sodium sulfate drying, filters, concentrated, obtain the mixture (710mg, productive rate 97%) of pale yellow oil 1b-1 and 1b-2.

MSm/z(ESI):294.2[M+1]。

3rd step: 2-(3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-2-base) ethanol benzene sulfonate (1c-1)

2-(3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-2-yl)ethanolbenzenesulfonate

2-(3b, 4,5,6,6a, 7-six hydrogen-1H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethanol benzene sulfonate (1c-2)

2-(3b,4,5,6,6a,7-hexahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-1-yl)ethanolbenzenesulfonate

The mixture (580mg, 1.979mmoL) of 1b-1 and 1b-2, benzenesulfonic acid hydrate (476.5mg, 2.573mmoL) are dissolved in methyl alcohol (10mL), heat 60 DEG C and to stir after 4 hours and stirred overnight at room temperature.Reaction solution is concentrated, stirs by ethyl acetate (10mL), filter, dry, obtain the mixture (700mg, productive rate 100%) of colorless oil 1c-1 and 1c-2.

MSm/z(ESI):194.2[M+1]。

4th step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(2-hydroxyethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (1d-1)

tert-butyl

((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(2-hydroxyethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

The tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-(2-hydroxyethyl)-3b, 4,6a, 7-tetrahydro-1 H-pyrrolo also [3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (1d-2)

tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(2-hydroxyethyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

The mixture (1.2g, 3.522mmol) of 1c-1 and 1c-2 is added in there-necked flask, after nitrogen replacement, also adds N,N-dimethylacetamide (7mL) under nitrogen protection, stirred at ambient temperature 1 hour.Three (acetoxyl group) sodium borohydride (437.2mg, 1.994mmoL) is added, stirring at room temperature 16 hours under ice bath.Stir in downhill reaction liquid and add strong aqua (20mL), stirring at room temperature 1 hour, filter, filter cake clear water (2mL × 5) washs, dissolve with methylene dichloride and methanol mixed solvent (V/V=20:1), anhydrous sodium sulfate drying, filter, the concentrated mixture (250mg, productive rate 32.5%) obtaining white solid thing 1d-1 and 1d-2.

5th step: 2-(5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-2-base) ethanol (compound 1-1)

2-(5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-1H-pyrazoles [3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethanol (compound 1-2)

The mixture (230mg, 0.456mmoL) of 1d-1 and 1d-2 is added in methylene dichloride (1mL), under ice bath, adds trifluoroacetic acid (1mL), stir 2 hours.In reaction solution, add saturated sodium bicarbonate solution adjusts reaction solution in neutral, add saturated aqueous common salt (20mL), extract with methylene dichloride (20mL × 3), merge organic phase, saturated aqueous common salt (50mL × 2) washs, anhydrous sodium sulfate drying, filter, concentrated, residue is with tlc separation and purification (methylene chloride/methanol (v/v)=20:1), obtain compound as white solid 1-1 (62mg, productive rate 33%) and compound 1-2 (48mg, productive rate 26%).

Compound 1-1:Msm/z (ESI): 405.3 [M+1];

¹HNMR(400MHz,CD ₃OD):δ7.27(s,1H),7.18-7.08(m,3H),4.25-4.23(d,1H),4.20-4.16(m,1H),4.15-4.12(m,2H),3.85-3.82(m,2H),3.61-3.56(m,2H),3.49-3.47(m,1H),3.13-2.86(m,4H),2.63-2.48(m,4H),2.40-2.37(d,1H),1.46-1.41(m,1H)。

Compound 1-2:

¹HNMR(400MHz,CD ₃OD):δ7.20-7.04(m,4H),4.24-4.22(d,1H),4.20-4.12(m,1H),4.07-4.05(m,2H),3.88-3.79(m,2H),3.55(s,2H),3.48-3.31(m,1H),3.19-2.84(m,4H),2.74-2.45(m,4H),2.40-2.37(d,1H),1.49-1.37(m,1H)。

Embodiment 2

(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 2)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amine

The first step: (3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles benzene sulfonate (2a)

3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazolebenzenesulfonate

Under room temperature, be dissolved in methyl alcohol (6mL) by intermediate 2 (0.250g, 1.00mmol), Phenylsulfonic acid (0.250g, 1.50mmol), 68 DEG C are reacted 12 hours.By reaction solution concentrating under reduced pressure, obtain white solid 2a (0.362g, productive rate 100%).

MSm/z(ESI):150.3[M+1]。

Second step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (2b)

tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, 2a (0.350g, 1.14mmol) is dissolved in N,N-dimethylacetamide (4mL), adds intermediate 1 (0.338g, 1.04mmol), stir 1 hour at 0 DEG C.Three (acetoxyl group) sodium borohydride (0.285g, 1.34mmol) are joined in reaction solution, naturally rises to room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water successively, ammoniacal liquor regulates pH to 8, separate out white solid.By reacting liquid filtering, filter cake uses water (5mL × 3), sherwood oil (10mL × 1) to wash successively.Drain, by filtration cakes torrefaction, obtain white solid 2b (0.230g, productive rate 48.4%).

MSm/z(ESI):461.3[M+1]。

3rd step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 2)

Under room temperature, 2b (0.220g, 0.480mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (2mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1) with thin layer, obtain shallow compound as white solid 2 (0.160g, productive rate 92.9%).

MSm/z(ESI):361.3[M+1]；

¹HNMR(400MHz,CD ₃OD):δ7.27(s,1H),7.04-7.19(m,3H),4.12-4.23(m,2H),3.57-3.59(m,1H),3.48(s,1H),3.34-3.36(d,1H),3.12(s,1H),2.95-3.02(m,2H),2.79-2.84(m,1H),2.47-2.57(m,4H),2.36-2.39(d,1H),1.36-1.47(m,1H)。

2 optical isomers of embodiment 3 compound 2 and compound 3-1 and compound 3-2

With intermediate 2-1 for raw material, the synthetic method with reference to embodiment 2 obtains compound 3-1;

MSm/z(ESI):361.3[M+1]；

¹HNMR(400MHz,CDCl ₃):δ7.21(s,1H),δ7.14-6.99(m,3H),4.18-4.16(d,1H),4.14-4.09(m,1H),3.52-3.50(m,1H),3.43-3.29(d,1H),2.97-2.91(m,3H),2.78-2.53(m,1H),2.44-2.31(m,5H),1.40-1.13(m,4H)。

With intermediate 2-2 for raw material, the synthetic method with reference to embodiment 2 obtains compound 3-2;

MSm/z(ESI):361.3[M+1]；

¹HNMR(400MHz,CDCl ₃):δ7.17(s,1H),7.10-6.95(m,3H),4.14-4.12(d,1H),4.10-4.02(m,1H),3.52-3.43(m,1H),3.43(m,1H),3.43-3.29(d,1H),2.97-2.91(m,2H),2.78-2.53(m,1H),2.71-2.36(m,5H),1.40-1.13(m,4H)。

Embodiment 4

The tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(methyl sulphonyl)-3b, 4,6a; 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (compound 4-1)

tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

The tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(methyl sulphonyl)-3b, 4,6a; 7-tetrahydro-1 H-pyrrolo also [3'; 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (compound 4-2)

tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

The first step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(methyl sulphonyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrroles

And [3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (4a-1)

The tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(methyl sulphonyl)-3b, 4,6a; 7-tetrahydro-1 H-pyrrolo also [3'; 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (4a-2)

By 2b (0.240g; 0.680mmol) be dissolved in N; in dinethylformamide (20mL); nitrogen protection borehole cooling is to 0 DEG C; add sodium hydride (0.040g, 1.12mmol) and stir 30 minutes, slowly drip Methanesulfonyl chloride (0.090g; 1.08mmol), in 0 DEG C of stirring reaction 2 hours.Reaction solution is down to 0 DEG C, add water (100mL), with methylene dichloride (60mL × 3) extraction, merge organic phase, the saturated common salt aqueous solution (30mL × 1) washs, anhydrous sodium sulfate drying, filter, concentrated, thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtain the mixture (0.116g, productive rate 31.7%) of white solid 4a-1 and 4a-2

MSm/z(ESI):538.8[M+1]。

Second step: the tertiary butyl ((2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(2-(methyl sulphonyl)-3b, 4,6a; 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (compound 4-1)

(2R; 3S; 5R)-2-(2; 5-difluorophenyl)-5-(1-(methyl sulphonyl)-3b, 4,6a; 7-tetrahydro-1 H-pyrrolo also [3'; 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 4-2)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amine

The mixture (0.10g, 0.19mmol) of 4a-1 and 4a-2 is added in methylene dichloride (2mL), under ice bath, adds trifluoroacetic acid (1mL), stir 2 hours.Reacting liquid pH value to 8 is adjusted with saturated sodium bicarbonate solution, extract with methylene dichloride (20mL × 3), merge organic phase, saturated aqueous common salt (50mL × 2) washs, anhydrous sodium sulfate drying, filters, concentrated, thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains the mixture (0.040g, productive rate 45.6%) of compound as white solid 4-1 and compound 4-2.

MSm/z(ESI):438.8[M+1]；

Compound 4-1 by have following structural formula each other each other two kinds of compounds of diastereomer form, one of them is numbered compound 4-1a, another is numbered compound 4-1b;

Compound 4-2 by have following structural formula each other each other two kinds of compounds of diastereomer form, be compound 4-2a by the compound number identical with compound 4-1a all chiral centres configuration, another one is numbered compound 4-2b;

With intermediate 2-1 for raw material, the synthetic method of reference example 2 and embodiment 4 prepares the mixture of compound 4-1a and compound 4-2a.

The mixture of compound 4-1a and compound 4-2a: ¹hNMR (400MHz, CDCl ₃): δ 7.79 (s, 1H), 7.17-7.04 (m, 3H), 4.25-4.23 (d, 1H), 4.19-7.15 (m, 1H), 3.63-3.48 (m, 2H), 2.92-2.32 (m, 8H), 1.46-1.33 (q, 2H), 1.28 (s, 3H), 0.91-0.87 (t, 1H).

Embodiment 5

(2R; 3S; 5R)-5-(2-(Cyclopropylsulfonyl)-3b; 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluoromethyl) tetrahydrochysene-2H-pyrans-3-amino (compound 5-1)

(2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

(2R; 3S; 5R)-5-(1-(Cyclopropylsulfonyl)-3b; 4,6a, 7-tetrahydro-1 H-pyrrolo also [3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-amino (compound 5-2)

(2R,3S,5R)-5-(1-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

The first step: the tertiary butyl ((2R; 3S; 5R)-5-(2-(Cyclopropylsulfonyl)-3b; 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base) carbamate (5a-1)

tert-butyl((2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

The tertiary butyl ((2R; 3S; 5R)-5-(1-(Cyclopropylsulfonyl)-3b; 4,6a, 7-tetrahydro-1 H-pyrrolo also [3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base) carbamate (5a-2)

tert-butyl((2R,3S,5R)-5-(1-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-1H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, 2b (0.200g, 0.430mmol) is dissolved in tetrahydrofuran (THF) (20mL), is cooled to 0 DEG C, add triethylamine (0.06g, 0.60mmol), react 30 minutes.Slowly drip cyclopropyl sulfonyl chloride (0.080g, 0.560mmol), react 2 hours at 0 DEG C.Reaction solution is down to 0 DEG C, add water (30mL), with methylene dichloride (30mL × 3) extraction, merge organic phase, the saturated common salt aqueous solution (30mL × 1) washs, anhydrous sodium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtain the mixture (0.090g, productive rate 37.2%) of mixture white solid 5a-1 and 5a-2.

MSm/z(ESI):564.8[M+1]。

Second step: (2R; 3S; 5R)-5-(2-(Cyclopropylsulfonyl)-3b; 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-amino (compound 5-1)

Under room temperature, the mixture (0.110g, 0.200mmol) of 5a-1 and 5a-2 is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (1.5mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains the mixture (0.050g, productive rate 57.8%) of compound as white solid 5-1 and compound 5-2.

MSm/z(ESI):464.9[M+1]；

Compound 5-1 by have following structural formula each other each other two kinds of compounds of diastereomer form, one of them is numbered compound 5-1a, another is numbered compound 5-1b;

Compound 5-2 by have following structural formula each other each other two kinds of compounds of diastereomer form, be compound 5-2a by the compound number identical with compound 5-1a all chiral centres configuration, another one is numbered compound 5-2b;

With intermediate 2-1 for raw material, the synthetic method of reference example 2 and embodiment 5 prepares the mixture of compound 5-1a and compound 5-2a.

The mixture of compound 5-1a and compound 5-2a: ¹hNMR (400MHz, CDCl ₃): δ 7.78-7.77 (s, 1H), 7.55 (s, 1H), 7.19-7.04 (m, 6H), 4.24-4.22 (d, 2H), 4.19-4.15 (m, 2H), 3.64-3.58 (m, 3H), 3.51-3.46 (m, 1H), 3.36-3.33 (m, 2H), 3.24-3.17 (m, 1H), 3.12-3.03 (m, 1H), 2.97-2.80 (m, 8H), 2.78-2.77 (m, 1H), 2.75-2.71 (m, 2H), 2.67-2.63 (m, 1H), 2.61-2.57 (m, 2H), 2.53-2.48 (m, 2H), 2.39-2.34 (m, 2H), 2.45-1.28 (m, 8H), 1.24-1.11 (m, 4H), 0.90-0.84 (m, 2H).

Embodiment 6

(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3-(trifluoromethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 6)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3-(trifluoromethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amine

The first step: 3-(trifluoromethyl)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles benzene sulfonate (6a)

3-(trifluoromethyl)-3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazolebenzenesulfonate

Under room temperature, intermediate 3 (0.420g, 1.32mmol) and Phenylsulfonic acid (0.368g, 2.00mmol) are dissolved in methyl alcohol (14mL), 68 DEG C are reacted 12 hours.By reaction solution concentrating under reduced pressure, obtain yellow solid 6a (0.460g, productive rate 92.7%).

MSm/z(ESI):218.1[M+1]；

Second step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3-(trifluoromethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (6b)

tert-butyl((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(3-(trifluoromethyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, be dissolved in by 6a (0.327g, 1.10mmol) in N,N-dimethylacetamide (4mL), add intermediate 1 (0.356g, 1.10mmol), 0 DEG C is stirred 1 hour.Three (acetoxyl group) sodium borohydride (0.303g, 1.43mmol) are joined in reaction solution, naturally rises to room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water and ammoniacal liquor adjustment pH to 8 successively, separate out white solid.Filter, filter cake uses water (5mL × 3) and sherwood oil (10mL × 1) washing successively.Drain, by filtration cakes torrefaction, obtain white solid 6b (0.367g, productive rate 63.7%).

MSm/z(ESI):529.1[M+H ⁺]；

3rd step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(3-(trifluoromethyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 6)

Under room temperature, 6b (0.357g, 0.680mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (2mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate pH to 8 in reaction solution.With methylene dichloride (30mL × 3) extraction, merge organic phase, the saturated common salt aqueous solution (50mL × 1) washs.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains light yellow solid Compound 6 (0.350g, productive rate 70.7%).

MSm/z(ESI):428.1[M+1]；

¹HNMR(400MHz,CDCl ₃):δ7.12-6.94(m,3H),4.11-4.13(d,1H),4.08-4.05(m,1H),3.52-3.48(m,2H),3.27-3.24(m,1H),3.01-2.71(m,4H),2.66-2.47(m,3H),2.43-2.27(m,2H),1.38-1.24(m,2H)。

Embodiment 7

Methyl 5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-3-manthanoate (compound 7)

methyl5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate

The first step: tertiary butyl 2-((2-(trimethyl silicon based) oxyethyl group) methyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-5 (6H)-manthanoate (7a)

tert-butyl2-((2-(trimethylsilyl)ethoxy)methyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-5(6H)-carboxylate

Under room temperature, intermediate 2 (1.0g, 4.0mmol) is dissolved in DMF (10mL), is cooled to 0 DEG C, add sodium hydride (0.176g, 4.4mmol) and stir 1 hour.2-(TMS) ethoxymethyl chlorine (0.8g, 4.8mmol) is added drop-wise in reaction solution, reacts 4 hours in stirred at ambient temperature.In reaction solution, add ammonium chloride solution (25mL), extract with methyl tertiary butyl ether (40mL × 3).Merge organic phase, use water (30mL × 2), the saturated common salt aqueous solution (30mL × 1) to wash successively.Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, obtains light yellow liquid 7a (1.6g).

MSm/z(ESI):380.0[M+1]。

Second step: 5-tertiary butyl 3-methyl 2-((2-(trimethyl silicon based) oxyethyl group) methyl)-3b, 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-3,5 (6H)-dicarboxylic acid esters (7b)

5-tert-butyl3-methyl2-((2-(trimethylsilyl)ethoxy)methyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-3,5(6H)-dicarboxylate

Under room temperature, light yellow liquid 7a (1.14g, 3.0mmol) is dissolved in tetrahydrofuran (THF) (8mL).Be cooled to-70 DEG C, drip n-butyllithium solution (1.8mL, 4.5mmol, 2.5mol/L), in-70 DEG C of reactions 0.5 hour.Below-70 DEG C, methyl-chloroformate (0.37g, 3.9mmol) is added drop-wise in reaction solution, keeps-70 DEG C to react 4 hours.Less than-70 DEG C add ammonium chloride solution (10mL).With methyl tertiary butyl ether (25mL × 2) extraction, merge organic phase, with the saturated common salt aqueous solution (20mL × 1) washing, anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue uses column chromatography purifying (ethyl acetate/petroleum ether (v/v)=20:1 ~ 5:1), obtains light yellow liquid 7b (0.52g, productive rate 30.6%).

MSm/z(ESI):338.1[M+1]。

3rd step: methyl 3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-3 manthanoate benzene sulfonate (7c)

methyl3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-3-carbo-xylatebenzenesulfonate

Under room temperature, 7b (0.52g, 1.19mmol) is dissolved in anhydrous methanol (10mL), adds Phenylsulfonic acid (0.33g, 1.79mmol), heating reflux reaction 16 hours.By reaction solution concentrating under reduced pressure, obtain light yellow solid 7c (1.22g, productive rate 100%).

MSm/z(ESI):208.0[M+1]。

4th step: methyl 5-((3R, 5S, 6R)-5-((tertbutyloxycarbonyl) is amino)-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-3-manthanoate (7d)

methyl5-((3R,5S,6R)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate

Under room temperature, 7c (0.44g, 1.19mmol) is dissolved in N,N-dimethylacetamide (5mL), adds intermediate 1 (0.37g, 1.13mmol), in stirring at room temperature 1 hour.Join in reaction solution by three (acetoxyl group) sodium borohydride (0.31g, 1.47mmol), stirred at ambient temperature reacts 16 hours.Reaction solution is cooled to 0 DEG C, adds water (30mL) and ammoniacal liquor (5mL) successively, separate out white solid.By reacting liquid filtering, filter cake uses water (10mL × 2) and sherwood oil (15mL × 2) washing successively.Drain, filter cake methylene dichloride (50mL) dissolves, and anhydrous magnesium sulfate drying filters, by filtrate reduced in volume.Residue, with silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100:1 ~ 80:1), obtains light yellow solid 7d (0.28g, productive rate 47%).

5th step: methyl 5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazoles-3-manthanoate (compound 7)

Under room temperature, be dissolved in by 7d (0.08g, 0.154mmol) in methylene dichloride (2mL), be cooled to 0 DEG C, add trifluoroacetic acid (2mL), 0 DEG C is reacted 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (25mL × 2).Merge organic phase, wash with the saturated common salt aqueous solution (20mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 7 (0.02g, productive rate 34%).

¹HNMR(400MHz,CD ₃OD):δ7.21-7.09(m,3H),4.28-4.21(d,1H),4.21-4.18(d,1H),3.89(s,1H),3.71(m,1H),3.55(m,1H),3.04-2.98(m,4H),2.56-2.41(m,6H),1.37(q,1H)；

MSm/z(ESI):418.9[M+1]。

Embodiment 8

5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazole-3-formamide (compound 8)

5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c]pyrazole-3-carboxamide

The first step: the tertiary butyl ((2R; 3S; 5R)-5-(3-formamyl-3b; 4,6a, 7-tetrahydrochysene-2H-pyrrolo-[3'; 4':3; 4] cyclopentano [1,2-c] pyrazoles-5 (6H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base) carbamate (8a)

tert-butyl((2R,3S,5R)-5-(3-carbamoyl-3b,4,6a,7-tetrahydro-2H-pyrrolo[3',4':3,4]cyclo-penta[1,2-c]pyrazol-5(6H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, be dissolved in by 7d (0.1g, 0.19mmol) in ammonia/methyl alcohol (5mL, 7mol/L), 100 DEG C of sealed cans react 16 hours.Reaction solution is concentrated, obtains light yellow solid 8a (0.08g, productive rate 82.3%).

MSm/z(ESI):503.9[M+1]。

Second step: 5-((3R, 5S, 6R)-5-amino-6-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base)-3b, 4,5,6,6a, 7-six hydrogen-2H-pyrrolo-[3', 4':3,4] cyclopentano [1,2-c] pyrazole-3-formamide (compound 8)

Under room temperature, 8a (0.14g, 0.27mmol) is dissolved in methylene dichloride (4mL), is cooled to 0 DEG C, add trifluoroacetic acid (4mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume.Residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains off-white color solid chemical compound 8 (0.01g, productive rate 11%).

¹HNMR(400MHz,CD ₃OD):δ7.63(s,1H),7.407-7.404(d,2H),7.002-6.915(m,3H),5.022-4.796(m,1H),4.22-4.208(d,1H),4.104-4.052(m,4H),3.946-3.925(d,1H),3.685-3.645(m,1H),3.580-3.541(t,2H),1.417-1.382(m,3H),1.352-1.308(m,3H)。

Embodiment 9

(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 9)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine

The first step: tertiary butyl 2-methyl-4b, 5,7a, 8-Pyrrolidine is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-manthanoate (9a) also

tert-butyl2-methyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidine-6(7H)-carboxylate

Under room temperature, methylrnethwirnidamide hydrochloride (0.298g, 3.00mmol) and sodium ethylate (0.450g, 5.00mmol) are dissolved in ethanol (10mL), stir 15 minutes.Drop in reaction solution by the 2D (0.28g, 1.00mmol) be dissolved in ethanol, 85 DEG C are reacted 12 hours.Reaction solution is concentrated, with ethyl acetate (30mL × 3) extraction, merges organic phase, the saturated common salt aqueous solution (50mL × 1) washs, anhydrous magnesium sulfate drying, filters, concentrated, obtain brown oil liquid 9a (0.280g, productive rate 100%).

MSm/z(ESI):276.0[M+1]。

Second step: 2-methyl-4b, 5,6,7,7a, 8-hexahydropyrrolo is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine benzene sulfonate (9b) also

2-methyl-4b,5,6,7,7a,8-hexahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidinebenzenesulfonate

Under room temperature, 9a (0.26g, 0.95mmol) and Phenylsulfonic acid (0.262g, 1.40mmol) are dissolved in methyl alcohol (8mL), 68 DEG C are reacted 12 hours.Reaction solution concentrating under reduced pressure is obtained brown solid 9b (0.386g, productive rate 100%).

MSm/z(ESI):176.1[M+1]。

3rd step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (9c)

tert-butyl

((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, 9b (0.30g, 0.90mmol) is dissolved in N,N-dimethylacetamide (4mL), adds intermediate 1 (0.294g, 0.900mmol), stirred at ambient temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.248g, 1.20mmol) are joined in reaction solution, in room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water and ammoniacal liquor adjustment pH to 8 successively, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate is concentrated, residue, with silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=40:1), obtains white solid 9c (0.203g, productive rate 49.0%).

MSm/z(ESI):486.9[M+1]。

4th step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (compound 9)

Under room temperature, 9c (0.140g, 0.280mmol) is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (1.5mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, residue thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains compound as white solid 9 (0.030g, productive rate 28.8%).

MSm/z(ESI):386.9[M+1]；

¹HNMR(400MHz,CDCl ₃):δ8.48-8.48(dd,1H),7.18-7.03(m,3H),4.19-4.17(d,1H),4.15-4.11(m,1H),3.88-3.83(m,1H),3.36-3.32(m,1H),3.28-3.21(m,1H),3.14-3.12(m,1H),2.98-2.13(m,6H),2.68-2.64(m,3H),2.51-2.44(m,1H),2.38-2.33(m,1H),1.43-1.33(m,1H)。

Embodiment 10

(2R, 3S, 5R)-5-(2-cyclopropyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-amino (compound 10)

(2R,3S,5R)-5-(2-cyclopropyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

The first step: tertiary butyl 2-cyclopropyl-4b, 5,7a, 8-Pyrrolidine is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-manthanoate (10a) also

tert-butyl

2-cyclopropyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidine-6(7H)-carboxylate

Under room temperature, by cyclopropyl amitraz hydrochloride (0.480g, 3.00mmol) with sodium ethylate (0.45g, 5.00mmol) be dissolved in ethanol (10mL), stir 15 minutes, the 2D (0.280g, 1.00mmol) be dissolved in ethanol is dropped to reaction solution, in 85 DEG C of reactions 12 hours.Reaction solution is concentrated, add water (30mL), extract by ethyl acetate (30mL × 3), merge organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filter, filtrate is concentrated, obtains brown oil liquid 10a (0.308g, productive rate 100%).

MSm/z(ESI):302.1[M+1]。

Second step: 2-cyclopropyl-4b, 5,6,7,7a, 8-hexahydropyrrolo is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine benzene sulfonate (10b) also

2-cyclopropyl-4b,5,6,7,7a,8-hexahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidinebenzenesulfonate

Under room temperature, 10a (0.29g, 0.96mmol) and Phenylsulfonic acid (0.268g, 1.40mmol) are dissolved in methyl alcohol (8mL), 68 DEG C are reacted 12 hours.By reaction solution concentrating under reduced pressure, obtain brown solid 10b (0.440g, productive rate 100%).

MSm/z(ESI):202.1[M+1]。

3rd step: the tertiary butyl ((2R, 3S, 5R)-5-(2-cyclopropyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-base) carbamate (10c)

tert-butyl

((2R,3S,5R)-5-(2-cyclopropyl-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, 10b (0.33g, 0.92mmol) is dissolved in N,N-dimethylacetamide (4mL), adds intermediate 1 (0.301g, 0.92mmol), in stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.253g, 1.21mmol) are joined in reaction solution, in room temperature reaction 16 hours.Be cooled to 0 DEG C, add water (20mL) and ammoniacal liquor adjustment pH to 8 successively, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate is concentrated, residue, with silica gel column chromatography (methylene chloride/methanol (v/v)=30:1), obtains white solid 10c (0.114g, productive rate 24.2%).

MSm/z(ESI):512.9[M+1]。

4th step: (2R, 3S, 5R)-5-(2-cyclopropyl-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji)-2-(2,5-difluorophenyl) tetrahydrochysene-2H-pyrans-3-amino (compound 10)

Under room temperature, 10c (0.10g, 0.20mmol) is dissolved in methylene dichloride (3mL), is cooled to 0 DEG C, add trifluoroacetic acid (1.5mL), in 0 DEG C of reaction 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution to reaction solution pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filters, by filtrate reduced in volume, prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1) with thin layer, obtain compound as white solid 10 (0.060g, productive rate 74%).

MSm/z(ESI):412.9[M+1]；

¹HNMR(400MHz,CDCl ₃):δ8.39-8.38(dd,1H),7.18-7.03(m,3H),4.22-4.19(d,1H),4.17-4.10(m,1H),3.85-3.79(m,1H),3.28-3.22(m,1H),3.15-3.07(m,1H),2.97-2.63(m,6H),2.50-2.44(m,1H),2.38-2.34(m,1H),2.22-2.14(m,1H),1.45-1.31(m,2H),1.09-1.01(m,4H)。

Embodiment 11

(2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) the amino trifluoroacetate (compound 11) of tetrahydrochysene-2H-pyrans-3-

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine2,2,2-trifluoroacetate

The first step: tertiary butyl 2-(trifluoromethyl)-4b, 5,7a, 8-Pyrrolidine is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-manthanoate (11a) also

tert-butyl

2-(trifluoromethyl)-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidine-6(7H)-carboxylate

Under room temperature, by trifluoromethyl amitraz hydrochloride (0.654g, 5.80mmol) with sodium ethylate (0.646g, 9.50mmol) be dissolved in ethanol (36mL), stirring minute, the 2D (0.54g, 1.90mmol) being dissolved in ethanol is dropped to reaction solution, and 85 DEG C are reacted 12 hours.Reaction solution is concentrated, with ethyl acetate (30mL × 3) extraction, merges organic phase, with the saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate drying, filters, filtrate is concentrated, obtains brown oil liquid 11a (0.398g, productive rate 63%).

MSm/z(ESI):330.1[M+1]。

Second step: 2-(trifluoromethyl)-4b, 5,6,7,7a, 8-hexahydropyrrolo is [3', 4':3,4] cyclopentano [1,2-d] pyrimidine benzene sulfonate (11b) also

2-(trifluoromethyl)-4b,5,6,7,7a,8-hexahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidinebenzenesulfonate

Under room temperature, 11a (0.39g, 1.2mmol) and Phenylsulfonic acid (0.333g, 1.80mmol) are dissolved in methyl alcohol (16mL), 68 DEG C are reacted 12 hours.By reaction solution concentrating under reduced pressure, obtain brown solid 11b (0.440g, productive rate 100%).

MSm/z(ESI):202.1[M+1]。

3rd step: the tertiary butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-base) carbamate (11c)

tert-butyl

((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carbamate

Under room temperature, 11b (0.637g, 0.90mmol) is dissolved in N,N-dimethylacetamide (5mL), adds intermediate 1 (0.295g, 0.90mmol), stirring at room temperature 1 hour.Three (acetoxyl group) sodium borohydride (0.318g, 1.20mmol) are joined in reaction solution, in room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, adds water and ammoniacal liquor adjustment pH to 8 successively, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate is concentrated, with silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30:1), obtain light yellow solid 11c (0.130g, productive rate 26%).

MSm/z(ESI):541.2[M+1]。

4th step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-amino (11d)

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b,5,7a,8-tetrahydropyrrolo[3',4':3,4]cyclopenta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine

Under room temperature, be dissolved in by 11c (0.13g, 0.24mmol) in methylene dichloride (3mL), be cooled to 0 DEG C, add trifluoroacetic acid (1.5mL), 0 DEG C is reacted 2 hours.By reaction solution concentrating under reduced pressure, drip sodium hydrogen carbonate solution and regulate reaction solution pH to 8, extract with methylene dichloride (30mL × 3).Merge organic phase, wash with the saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate drying, filter, by filtrate reduced in volume, thin layer prepares plate separation and purification (methylene chloride/methanol (v/v)=10:1), obtains white solid 11d (0.070g, productive rate 69.8%).

MSm/z(ESI):441.2[M+1]。

5th step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(trifluoromethyl)-4b, 5,7a, 8-Pyrrolidine also [3', 4':3,4] cyclopentano [1,2-d] pyrimidine-6 (7H)-Ji) tetrahydrochysene-2H-pyrans-3-amino 2,2,2-trifluoroacetate (compound 11)

Under room temperature, 11d (0.07g, 0.16mmol) is dissolved in methylene dichloride (10mL), drips trifluoroacetic acid (1mL) and stir 10 minutes.Reaction solution is concentrated, obtains compound as white solid 11 (88mg).

MSm/z(ESI):441.2[M+1]；

¹HNMR(400MHz,CDCl ₃):δ8.74-8.73(dd,1H),7.18-7.04(m,3H),4.22-4.13(d,1H),4.16-4.13(m,1H),3.95(m,1H),3.48-3.41(m,1H),3.31-3.23(m,2H),3.01-2.92(m,3H),2.84-2.75(m,3H),2.55-2.49(m,1H),2.36-2.34(m,1H),1.44-1.28(m,1H)。

Bioassay

1, the external enzyme activity determination of DPP-IV

The DPP-IV vitro enzyme of the zymetology reaction assay the compounds of this invention of recombinant human DPP-IV and H-Ala-Pro-AFC is utilized to live.Damping fluid, testing sample working fluid, DPP-IV enzyme diluent and AFC substrate dilution is prepared according to DPP-IVFluorescentActivityAssayKit (BPSBioscience).

Prepare 96 orifice plates, every hole first adds 80 μ L damping fluids, adds 5 μ LDPP-AFC-substrates afterwards.Add different concns again and treat test sample working fluid, every hole 5 μ L, blank group adds 5 μ L damping fluids.Finally in test group contrast, add 10 μ LDPP-IV enzymes, in blank group, add 10 μ L damping fluids.With Origin7.5 software, statistical analysis is carried out to data, obtain the IC of each test compounds ₅₀value, the results are shown in Table 1.

Table 1DPP-IV vitro enzyme measurement result alive

Sequence number	Compound number	IC ₅₀(μM)
			1	Compound 1-1	0.0595
2	Compound 1-2	0.103
			3	Compound 3-1	0.0332
4	Compound 3-2	0.0188
			5	Compound 4-1a and compound 4-2a mixture	0.0040
6	Compound 5-1a and compound 5-2a mixture	0.0127
			7	Compound 6	0.0452
8	Compound 7	0.0447
			9	Compound 9	0.0114
10	Compound 10	0.0210

Conclusion: the compounds of this invention has the inhibit activities of obvious DPP-IV enzyme.

2, oral glucose tolerance test

Oral glucose tolerance test (OGTT) is utilized to evaluate the hypoglycemic effect of the compounds of this invention in mouse.The animal used is SPF level ICR mouse, surrounding age, male and female half and half, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., and animal productiong conformity certification number: SCXK (capital) 2012-001.First feeding high lipid food one week, then continuous abdominal injection STZ solution (50mg/kg) 4 days.According to the basal plasma glucose value grouping after fasting, often organize 10.Test-compound becomes the suspension of 1mg/mL with 5%DMSO-5%solutol-90% normal saline.Gastric infusion, dosage is 10mg/kg.Blank group gives 5%DMSO-5%solutol-90% physiological saline.The D/W (1g/kg) of 10% is given after administration 15min, and 0,15,30,45,60,120min time use the steady bold and unconstrained Instrument for Measuring Blood Sugar of Johnson & Johnson to measure the blood glucose value of each mouse, under calculating drug-time curve, area (AUC) reduces ratio.Experimental result is in table 2.

Table 2 Mouse oral glucose tolerance test evaluation result

Sequence number	Compound number	AUC reduces ratio (%)
			1	Compound 9	29.01
2	Compound 10	26.08

Conclusion: the compounds of this invention has good hypoglycemic effect, obviously can reduce blood sugar after the administration of mouse single oral.

Claims

1. the ternary shown in general formula (I) condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug:

Wherein:

X is selected from-O-,-S-,-NH-or-CH ₂-;

W is selected from or

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, I, cyano group, hydroxyl, C independently of one another _1-8alkyl or C _1-8alkoxyl group, described alkyl or alkoxyl group optional further replace by the substituting group of 0 to 5 F, Cl, Br, I, cyano group, amino or hydroxyl;

R ²be selected from H, C _1-8alkyl ,-(CH ₂) _m-S (=O) _n-C _1-8alkyl ,-(CH ₂) _m-S (=O) _n-C _3-8cycloalkyl ,-(CH ₂) _m-S (=O) _n-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-S (=O) _n-C _6-14aryl ,-(CH ₂) _m-S (=O) _n-(6 to 14 yuan of heteroaryls) ,-(CH ₂) _m-C (=O)-OH ,-(CH ₂) _m-C (=O)-C _1-8alkyl ,-(CH ₂) _m-C (=O)-O-C _1-8alkyl ,-(CH ₂) _m-C (=O)-C _3-8cycloalkyl ,-(CH ₂) _m-C (=O)-O-C _3-8cycloalkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by 0 to 5 F, Cl, Br, I ,-CH ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-8alkyl, C _1-8alkoxyl group, C _3-8the substituting group of cycloalkyl or 3 to 8 yuan of heterocyclic radicals replaced; Described heterocyclic radical or heteroaryl contain 1 to 5 and are selected from N, O or S (=O) _natom or group;

R ³be selected from H, F, Cl, Br, I, hydroxyl, cyano group, C _1-8alkyl, C _1-8alkoxyl group ,-(CH ₂) _m-C _2-8thiazolinyl-R ⁵,-(CH ₂) _m-C _2-8alkynyl-R ⁵,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-OR ⁶,-(CH ₂) _m-C _3-8cycloalkyl ,-(CH ₂) _m-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-C _6-14aryl ,-(CH ₂) _m-(6 to 14 yuan of heteroaryls) ,-(CH ₂) _m-NR ⁷r ⁸,-(CH ₂) _m-C (=O)-NR ⁷r ⁸,-(CH ₂) _m-O-C (=O)-NR ⁷r ⁸,-(CH ₂) _m-S (=O) _n-R ⁹,-(CH ₂) _m-NR ¹⁰c (=O)-NR ⁷r ⁸,-(CH ₂) _m-NR ¹⁰c (=O)-R ⁶or-(CH ₂) _m-NR ¹⁰c (=O)-OR ⁶, wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃, cyano group, nitro, isocyano-, hydroxyl, aldehyde radical, carboxyl, C _1-8alkyl or C _1-8the substituting group of alkoxyl group replaced, wherein (CH ₂) _min any CH ₂hydrogen atom is optionally selected from F, hydroxyl ,-CH by 0 to 2 independently ₂f ,-CHF ₂,-CF ₃, C _1-4alkyl or C _1-4the substituting group of alkoxyl group replaced;

R ⁴be selected from H, F, Cl, Br, I, C _1-8alkyl or C _3-8cycloalkyl, wherein said alkyl or cycloalkyl is optionally selected from F, Cl, Br, I ,-CH by 0 to 5 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ⁵and R ⁶be selected from H, amino, hydroxyl, C independently of one another _1-8alkyl, C _1-8alkoxyl group, C _3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) _natom or group;

R ⁷, R ⁸and R ¹⁰be selected from H, C independently of one another _1-8alkyl or C _3-8cycloalkyl, wherein said alkyl or cycloalkyl is optionally replaced by the substituting group of 0 to 5 F, Cl, Br, I, hydroxyl, cyano group, amino or nitro further;

R ⁹be selected from H, C _1-8alkyl, C _3-8cycloalkyl or 3 to 8 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 5 and is selected from N, O or S (=O) _natom or group;

N is selected from 0,1 or 2;

M is selected from 0,1,2,3 or 4.

2. shown in general formula (I), ternary condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug according to claim 1, wherein:

X is selected from-O-;

W is selected from or

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, C independently of one another _1-2alkyl or C _1-2alkoxyl group;

R ²be selected from H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl ,-(CH ₂) _m-S (=O) _n-(3 to 8 yuan of heterocyclic radicals) ,-(CH ₂) _m-C (=O)-O-C _1-4alkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl, cycloalkyl or heterocyclyl are further by 0 to 3 F, Cl, Br, I ,-CH ₂f ,-CHF ₂,-CF ₃, hydroxyl, C _1-2alkyl or C _1-2the substituting group of alkoxyl group replaced; Described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) _natom or group;

R ³be selected from H, F, Cl, Br, hydroxyl, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-NR ⁷r ⁸or-(CH ₂) _m-S (=O) _n-R ⁹, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ⁴be selected from H, F, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace;

R ⁶be selected from amino, hydroxyl, C _1-4alkyl or C _1-4alkoxyl group;

R ⁷and R ⁸be selected from H or C independently of one another _1-4alkyl;

R ⁹be selected from C _1-4alkyl, C _3-6cycloalkyl or 3 to 6 yuan of heterocyclic radicals, described heterocyclic radical contains 1 to 3 and is selected from N, O or S (=O) _natom or group;

N is selected from 0,1 or 2;

M is selected from 0,1 or 2.

3. shown in general formula (I), ternary condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug according to claim 2, wherein:

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H, F, Cl, Br, methyl, ethyl, methoxy or ethoxy independently of one another;

R ²be selected from H, C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _1-4alkyl ,-(CH ₂) _m-S (=O) _n-C _3-6cycloalkyl ,-(CH ₂) _m-C (=O)-O-C _1-4alkyl or-(CH ₂) _m-C (=O)-NR ⁷r ⁸, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ³be selected from H, F, cyano group, C _1-4alkyl ,-(CH ₂) _m-C (=O)-R ⁶,-(CH ₂) _m-C (=O)-NR ⁷r ⁸or-(CH ₂) _m-S (=O) _n-R ⁹, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ⁴be selected from H, C _1-4alkyl or C _3-6cycloalkyl, wherein said alkyl or cycloalkyl be optionally selected from by 0 to 3 further the substituting group of F, Cl, Br or hydroxyl replace;

R ⁶be selected from amino, hydroxyl or C _1-4alkoxyl group;

R ⁷and R ⁸be selected from H or C independently of one another _1-4alkyl;

R ⁹be selected from C _1-4alkyl;

N is selected from 2;

M is selected from 0,1 or 2.

4. shown in general formula (I), ternary condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug according to claim 3, wherein:

R ¹, R ^1a, R ^1b, R ^1cand R ^1dbe selected from H or F independently of one another;

R ²be selected from H, C _1-4alkyl ,-S (=O) ₂-C _1-4alkyl or-S (=O) ₂-C _3-6cycloalkyl, wherein said alkyl or cycloalkyl is optional further by 0 to 3 F, Cl, Br ,-CH ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ³be selected from H, C _1-4alkyl ,-C (=O)-R ⁶or-C (=O)-NR ⁷r ⁸, wherein said alkyl is optionally selected from F, Cl, Br ,-CH by 0 to 3 further ₂f ,-CHF ₂,-CF ₃or the substituting group of hydroxyl replaced;

R ⁶be selected from C _1-4alkoxyl group;

R ⁷and R ⁸be selected from H or C independently of one another _1-4alkyl.

5. shown in general formula (I), ternary condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug according to claim 4, wherein:

R ²be selected from H, methyl, ethyl, propyl group, or

R ³be selected from H, methyl, ethyl ,-CF ₃, or

R ⁴be selected from methyl ,-CF ₃or

6. ternary shown in any one general formula (I) according to claims 1 to 5 condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug are selected from:

or

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

8. a pharmaceutical composition, described composition comprises: the ternary shown in general formula according to any one of claim 1 ~ 7 (I) of effective dose condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug, or comprises one or more other treatment agent and pharmaceutically acceptable carrier or vehicle further;

Preferably, wherein said other treatment agent comprises:

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

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

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

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

9. the ternary shown in general formula according to any one of claim 1 ~ 7 (I) condenses cyclosubstituted amino six-ring analog derivative or its steric isomer, pharmacy acceptable salt or prodrug or composition according to claim 8 and is preparing the application in dipeptidyl peptidase-iv inhibitor.

10. according to the application described in claim 9, wherein said dipeptidyl peptidase-iv inhibitor is for the preparation of the medicine for the treatment of metabolic disease, and wherein said metabolic disease is selected from the level of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis or hypertension; Preferably, described diabetes are type ii diabetes.