CN105085530B - Ternary condenses cyclosubstituted amino hexatomic ring analog derivative and its application in medicine - Google Patents

Abstract

The present invention relates to a kind of ternarys to condense cyclosubstituted amino hexatomic ring analog derivative and its application in medicine, in particular to ternary shown in logical formula (I) condense cyclosubstituted amino hexatomic ring analog derivative or its stereoisomer, pharmaceutically acceptable salt, prodrug, the pharmaceutical composition containing the derivative and in the purposes pharmaceutically for preparing DPP IV (DPP-IV) inhibitor, formula of (I) definition of each substituent group it is identical as the definition of specification.

Description

Ternary condenses cyclosubstituted amino hexatomic ring analog derivative and its application in medicine

Technical field

The present invention relates to a kind of ternarys to condense cyclosubstituted amino hexatomic ring analog derivative and its application in medicine, tool Body, which is said, is related to that ternary shown in logical formula (I) condenses cyclosubstituted amino hexatomic ring analog derivative or medicinal salt can be used for it or it is three-dimensional Isomers and pharmaceutical composition containing the derivative as well as therapeutic agent are especially as DPP IV (DPP- IV) the purposes of inhibitor.

Background technique

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

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

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

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

Currently, the research of DPP-IV inhibitor makes great progress, including sitagliptin, saxagliptin, A Gelie DPP-IV inhibitor including spit of fland has been approved by listing.The most significant feature of DPP-IV inhibitor is, due to incretin It is secreted after body feed, DPP-IV inhibitor is not easy to increase insulin level when unsuitable, generates many antidiabetic drugs Common side effect hypoglycemia.Recent clinical data reduces blood it has been shown that DPP-IV is inhibited insulin secretion can be made to increase Sugared concentration simultaneously improves pancreas islet beta cell function (Diabetes, 1998,47:1253-1258).Common DPP-IV inhibitor Side effect has respiratory tract infection, sore throat, diarrhea, cold like symptoms, headache and dizzy etc..But it is overall have preferable safety and Tolerance, the patient used there is presently no discovery have serious weight gain or the diseases such as potential weight loss and oedema Shape.

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

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

(1) WO2008060488 discloses the compound such as flowering structure as DPP-IV inhibitor,

Wherein:

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

X is selected from O or CH₂；

V is selected fromEqual groups；It is not considered as to specifically describe in this patent It is a part of the invention.

(2) US20100120863 discloses the compound such as flowering structure as DPP IV (DPP-IV) inhibitor, Treatment, prevention type-2 diabetes mellitus purposes,

Wherein:

Ra is selected from the groups such as hydrogen, alkyl；V is selected fromDeng, and R^3a、R^3bSelected from independently selecting From hydrogen, the C replaced by 1-5 fluorine atom_1-4Alkyl；R²Selected from groups such as hydrogen, hydroxyl, halogen, carboxyls；R⁸Selected from-S (O)₂-C_1-6 Naphthenic base ,-S (O)₂-C_1-6The groups such as alkyl；It is not considered as that specifically describing in this patent is a part of the invention.

(3) CN102272136, which discloses the compound of flowering structure such as, has DPP-IV inhibitor effect, as diabetes The purposes of prevention and/or medicine,

Wherein:

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

V is selected fromEqual groups, and R²Selected from groups such as hydrogen, cyano, halogen, alkyl, carbonyls； R^3a、R^3bThe C selected from hydrogen or optionally replaced by 1-5 fluorine atom_1-4Alkyl；R⁸It is selected from ,-SO₂-C_1-6The groups such as alkyl；It is not considered as Specifically describing in this patent is a part of the invention.

(4) compound that WO2007097931 discloses DPP-IV inhibitor such as flowering structure is used to treat diabetes,

Wherein:

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

V is selected fromEqual groups, and R2 is selected from hydrogen, hydroxyl, halogen etc.；R^3a、R^3bSelected from hydrogen, The C replaced by 1-5 fluorine atom_1-4Alkyl；It is not considered as that specifically describing in this patent is a part of the invention.

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

The purpose of the present invention is introducing a kind of novel DPP-IV inhibitors, specifically there is chemical combination shown in logical formula (I) Object, research has shown that, the compound of this class formation has good DPP IV (DPP-IV) inhibitory activity and selectivity, With the prospect for treating or alleviating type-2 diabetes mellitus and similar disease.

Summary of the invention

Cyclosubstituted amino hexatomic ring analog derivative is condensed the present invention relates to ternary shown in a kind of logical formula (I) or it is three-dimensional Isomers, pharmaceutically acceptable salt or prodrug:

Wherein:

X is selected from-O- ,-S- ,-NH- or-CH₂, preferably-O-；

W is selected from

R¹、R^1a、R^1b、R^1cAnd R^1dIt is each independently selected from H, F, Cl, Br, I, cyano, hydroxyl, C_1-8Alkyl, C_1-8Alcoxyl Base, the alkyl or alkoxy are optionally further replaced the substituent group of 0 to 5 F, Cl, Br, I, cyano, amino or hydroxyl； R¹、R^1a、R^1b、R^1cAnd R^1dRespectively independent preferably H, F, Cl, Br, C_1-2Alkyl or C_1-2Alkoxy；R¹、R^1a、R^1b、R^1cAnd R^1dRespectively Independent further preferably H or F；

R²Selected from H, C_1-8Alkyl ,-(CH₂)_m- S (=O)_n-C_1-8Alkyl ,-(CH₂)_m- S (=O)_n-C_3-8Naphthenic base ,- (CH₂)_m- S (=O)_n(3 to 8 circle heterocyclic ring base) ,-(CH₂)_m- S (=O)_n-C_6-14Aryl ,-(CH₂)_m- S (=O)_n(6 to 14 yuan Heteroaryl) ,-(CH₂)_m- C (=O)-OH ,-(CH₂)_m- C (=O)-C_1-8Alkyl ,-(CH₂)_m- C (=O)-O-C_1-8Alkyl ,- (CH₂)_m- C (=O)-C_3-8Naphthenic base ,-(CH₂)_m- C (=O)-O-C_3-8Naphthenic base or-(CH₂)_m- C (=O)-NR⁷R⁸, wherein institute Alkyl, naphthenic base, heterocycle, aryl or heteroaryl are stated optionally further by 0 to 5 F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃、 Hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_3-8Replaced the substituent group of naphthenic base or 3 to 8 circle heterocyclic ring bases；The heterocycle or miscellaneous Aryl contains 1 to 5 selected from N, O or S (=O)_nAtom or group；R²It is preferred that H, C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_1-4 Alkyl ,-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base ,-(CH₂)_m- S (=O)_n(3 to 8 circle heterocyclic ring base) ,-(CH₂)_m- C (=O)-O- C_1-4Alkyl or-(CH₂)_m- C (=O)-NR⁷R⁸, wherein the alkyl, naphthenic base or heterocycle optionally further by 0 to 3 F, Cl、Br、I、-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-2Alkyl or C_1-2Replaced the substituent group of alkoxy, the heterocycle contains There is 1 to 3 to be selected from N, O or S (=O)_nAtom or group；R²Further preferred H, C_1-4Alkyl ,-S (=O)₂-C_1-4Alkyl or- (CH₂)_m- S (=O)₂-C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is optionally further by 0 to 3 F, Cl, Br ,-CH₂F、- CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R²More preferable H, methyl, ethyl, propyl,

R³Selected from H, F, Cl, Br, I, hydroxyl, cyano, C_1-8Alkyl, C_1-8Alkoxy ,-(CH₂)_m-C_2-8Alkenyl-R⁵、- (CH₂)_m-C_2-8Alkynyl-R⁵、-(CH₂)_m- C (=O)-R⁶、-(CH₂)_m- C (=O)-OR⁶、-(CH₂)_m-C_3-8Naphthenic base ,-(CH₂)_m- (3 to 8 circle heterocyclic ring base) ,-(CH₂)_m-C_6-14Aryl ,-(CH₂)_m(6 to 14 unit's heteroaryl) ,-(CH₂)_m-NR⁷R⁸、-(CH₂)_m-C (=O)-NR⁷R⁸、-(CH₂)_m- O-C (=O)-NR⁷R⁸、-(CH₂)_m- S (=O)_n-R⁹、-(CH₂)_m-NR¹⁰C (=O)-NR⁷R⁸、- (CH₂)_m-NR¹⁰C (=O)-R⁶Or-(CH₂)_m-NR¹⁰C (=O)-OR⁶, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkanes Base, heterocycle, aryl or heteroaryl are optionally further selected from F, Cl, Br, I ,-CH by 0 to 5₂F、-CHF₂、-CF₃, cyano, nitre Base, isocyano group, hydroxyl, aldehyde radical, carboxyl, C_1-8Alkyl or C_1-8Replaced the substituent group of alkoxy, wherein (CH₂)_mIn it is any CH₂Hydrogen atom is optionally by 0 to 2 independently selected from F, hydroxyl ,-CH₂F、-CHF₂、-CF₃、C_1-4Alkyl or C_1-4Alkoxy takes Replaced Dai Ji；R³It is preferred that H, F, Cl, Br, hydroxyl, cyano, C_1-4Alkyl ,-(CH₂)_m- C (=O)-R⁶、-(CH₂)_m- C (=O)- NR⁷R⁸Or-(CH₂)_m- S (=O)_n-R⁹, wherein the alkyl is optionally further selected from F, Cl, Br ,-CH by 0 to 3₂F、- CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R³Further preferred H, F, cyano, C_1-4Alkyl ,-(CH₂)_m- C (=O)-R⁶Or- (CH₂)_m- C (=O)-NR⁷R⁸, wherein the alkyl is optionally further selected from F, Cl, Br ,-CH by 0 to 3₂F、-CHF₂、-CF₃ Or replaced the substituent group of hydroxyl；R³More preferable R³Selected from H, methyl, ethyl ,-CF₃、

R⁴Selected from H, F, Cl, Br, I, C_1-8Alkyl or C_3-8Naphthenic base, wherein the alkyl or cycloalkyl optionally further by 0 to 5 is selected from F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R⁴It is preferred that H, F, C_1-8Alkyl or C_3-8Naphthenic base, wherein the alkyl or cycloalkyl is optionally further selected from replaced the substituent group of F, Cl or hydroxyl by 0 to 3； R⁴More preferable methyl ,-CF₃Or

R⁵And R⁶It is each independently selected from H, amino, hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_3-8Naphthenic base or 3 to 8 yuan it is miscellaneous Ring group, the heterocycle contain 1 to 5 selected from N, O or S (=O)_nAtom or group；R⁵And R⁶Respectively independent preferably H, ammonia Base, hydroxyl, C_1-4Alkyl or C_1-4Alkoxy；

R⁷、R⁸And R¹⁰It is each independently selected from H, C_1-8Alkyl or C_3-8Naphthenic base, wherein the alkyl or cycloalkyl is optional Further replaced by the substituent group of 0 to 5 F, Cl, Br, I, hydroxyl, cyano, amino or nitro；R⁷、R⁸And R¹⁰It is respectively independent excellent Select H or C_1-4Alkyl；R⁷And R⁸Respectively independent further preferably H or C_1-2Alkyl；

R⁹Selected from H, C_1-8Alkyl, C_3-8Naphthenic base or 3 to 8 circle heterocyclic ring bases, the heterocycle contain 1 to 5 selected from N, O Or S (=O)_nAtom or group；R⁹It is preferred that C_1-4Alkyl；R⁹Further preferred C_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.

The preferred solution of the invention, including ternary shown in logical formula (I) condense cyclosubstituted amino hexatomic ring analog derivative or its Stereoisomer, pharmaceutically acceptable salt or prodrug, in which:

X is selected from-O-；

W is selected from

R¹、R^1a、R^1b、R^1cAnd R^1dIt is each independently selected from H, F, Cl, Br, C_1-2Alkyl or C_1-2Alkoxy；R¹、R^1a、R^1b、 R^1cAnd R^1dRespectively independent preferably H or F；Further preferably, R¹And R^1cIt is each independently selected from H, R^1aAnd R^1dF is each independently selected from, R^1bSelected from H or F；

R²Selected from H, C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base ,- (CH₂)_m- S (=O)_n(3 to 8 circle heterocyclic ring base) ,-(CH₂)_m- C (=O)-O-C_1-4Alkyl or-(CH₂)_m- C (=O)-NR⁷R⁸, Described in alkyl, naphthenic base or heterocycle optionally further by 0 to 3 F, Cl, Br, I ,-CH₂F、-CHF₂、-CF₃, hydroxyl, C_1-2 Alkyl or C_1-2Replaced the substituent group of alkoxy；The heterocycle contains 1 to 3 selected from N, O or S (=O)_nAtom or Group；R²It is preferred that H, C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_1-4Alkyl or-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base, wherein institute Alkyl or cycloalkyl is stated optionally further replaced the substituent group of 0 to 3 F, Cl, Br or hydroxyl；

R³Selected from H, F, Cl, Br, hydroxyl, cyano, C_1-4Alkyl ,-(CH₂)_m- C (=O)-R⁶、-(CH₂)_m- C (=O)- NR⁷R⁸Or-(CH₂)_m- S (=O)_n-R⁹, wherein the alkyl is optionally further selected from F, Cl, Br ,-CH by 0 to 3₂F、- CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R³It is preferred that H, F, Cl, Br, hydroxyl, cyano, C_1-4Alkyl ,-(CH₂)_m- C (=O)- R⁶Or-(CH₂)_m- C (=O)-NR⁷R⁸, wherein the alkyl optionally further substitution by 0 to 3 selected from F, Cl, Br or hydroxyl Replaced base；

R⁴Selected from H, F, C_1-4Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is optionally further selected by 0 to 3 Replaced the substituent group of F, Cl, Br or hydroxyl；R⁴It is preferred that H, C_1-4Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl Optionally further replaced 0 to 3 substituent group selected from F, Cl, Br；

R⁶Independently selected from amino, hydroxyl, C_1-4Alkyl or C_1-4Alkoxy；R⁶It is preferred that C_1-4Alkoxy, further preferred C_1-2 Alkoxy；

R⁷And R⁸It is each independently selected from H or C_1-4Alkyl；R⁷And R⁸Respectively independent preferably H or C_1-2Alkyl；

R⁹Selected from C_1-4Alkyl, C_3-6Naphthenic base or 3 to 6 circle heterocyclic ring bases, the heterocycle contain 1 to 3 selected from N, O or S (=O)_nAtom or group；R⁹Preferential 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.

The preferred solution of the invention, including ternary shown in logical formula (I) condense cyclosubstituted amino hexatomic ring analog derivative or its Stereoisomer, pharmaceutically acceptable salt or prodrug, in which:

R¹、R^1a、R^1b、R^1cAnd R^1dIt is each independently selected from H, F, Cl, Br, methyl, ethyl, methoxy or ethoxy；R¹With R^1cIt is preferred that H, R^1aAnd R^1dIt is preferred that F, R^1bIt is preferred that H or F；

R²Selected from H, C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base ,- (CH₂)_m- C (=O)-O-C_1-4Alkyl or-(CH₂)_m- C (=O)-NR⁷R⁸, wherein the alkyl or cycloalkyl is optionally further by 0 To 3 F, Cl, Br ,-CH₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R²It is preferred that H, C_1-4Alkyl ,-(CH₂)_m- S (= O)_n-C_1-4Alkyl ,-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base, wherein the alkyl or cycloalkyl optionally further by 0 to 3 F, Cl、Br、-CH₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R²Further preferred H, C_1-2Alkyl ,-(CH₂)_m- S (= O)_n-C_1-2Alkyl ,-(CH₂)_m- S (=O)_n-C_3-6Naphthenic base, wherein the alkyl or cycloalkyl optionally further by 0 to 3 F, Replaced the substituent group of Cl, Br or hydroxyl；R²Still more preferably H, methyl, ethyl, propyl,R²More preferable H,

R³Selected from H, F, cyano, C_1-4Alkyl ,-(CH₂)_m- C (=O)-R⁶、-(CH₂)_m- C (=O)-NR⁷R⁸Or-(CH₂)_m-S (=O)_n-R⁹, wherein the alkyl is optionally further selected from F, Cl, Br ,-CH by 0 to 3₂F、-CHF₂、-CF₃Or hydroxyl takes Replaced Dai Ji；R³It is preferred that H, C_1-4Alkyl ,-C (=O)-R⁶Or-C (=O)-NR⁷R⁸, wherein the alkyl is optionally further by 0 F, Cl, Br ,-CH are selected to 3₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R³Further preferred H, methyl, second Base ,-CF₃、R³More preferable H ,-CF₃、

R⁴Selected from H, C_1-4Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is optionally further selected from by 0 to 3 F, replaced the substituent group of Cl, Br or hydroxyl；R⁴It is preferred that H, C_1-2Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is appointed Choosing is further replaced 0 to 3 substituent group selected from F, Cl, Br or hydroxyl；R⁴More preferable methyl ,-CF₃Or

R⁶Selected from amino, hydroxyl or C_1-4Alkoxy；R⁶It is preferred that amino, hydroxyl or C_1-2Alkoxy；R⁶Further preferred C_1-2 Alkoxy；

R⁷And R⁸It is each independently selected from H or C_1-4Alkyl；R⁷And R⁸Respectively independent preferably H or C_1-2Alkyl；

R⁹Selected from C_1-4Alkyl；R⁹It is preferred that C_1-2Alkyl；

N is selected from 2；

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

The preferred solution of the invention, including ternary shown in logical formula (I) condense cyclosubstituted amino hexatomic ring analog derivative or its Stereoisomer, pharmaceutically acceptable salt or prodrug, in which:

R¹、R^1a、R^1b、R^1cAnd R^1dIt is each independently selected from H or F；R¹And R^1cIt is preferred that H, R^1aAnd R^1dIt is preferred that F, R^1bIt is preferred that H or F；

R²Selected from H, C_1-4Alkyl ,-S (=O)₂-C_1-4Alkyl or-S (=O)₂-C_3-6Naphthenic base, wherein the alkyl or ring Alkyl is optionally further by 0 to 3 F, Cl, Br ,-CH₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R²It is preferred that H, C_1-2 Alkyl ,-S (=O)₂-C_1-2Alkyl or-S (=O)₂-C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is optionally further by 0 to 3 Replaced the substituent group of a F, Cl, Br or hydroxyl；

R³Selected from H, C_1-4Alkyl ,-C (=O)-R⁶Or-C (=O)-NR⁷R⁸, wherein the alkyl is optionally further by 0 to 3 It is a to be selected from F, Cl, Br ,-CH₂F、-CHF₂、-CF₃Or replaced the substituent group of hydroxyl；R³It is preferred that H, C_1-2Alkyl ,-C (=O)-R⁶ Or-C (=O)-NR⁷R⁸, wherein the alkyl is optionally further selected from replaced the substituent group of F, Cl, Br or hydroxyl by 0 to 3； R³Further preferred H, methyl, ethyl ,-CF₃、R³More preferable H ,-CF₃、

R⁴Selected from H, C_1-4Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is optionally further selected from by 0 to 3 F, replaced the substituent group of Cl, Br or hydroxyl；R⁴It is preferred that H, C_1-2Alkyl or C_3-6Naphthenic base, wherein the alkyl or cycloalkyl is appointed Choosing is further replaced 0 to 3 substituent group selected from F, Cl, Br or hydroxyl；

R⁶Selected from C_1-4Alkoxy；R⁶It is preferred that C_1-2Alkoxy；

R⁷And R⁸It is each independently selected from H or C_1-4Alkyl；R⁷And R⁸Respectively independent preferably H or C_1-2Alkyl；

The preferred solution of the invention, including ternary shown in logical formula (I) condense cyclosubstituted amino hexatomic ring analog derivative or its Stereoisomer, pharmaceutically acceptable salt or prodrug, in which:

R¹And R^1cSelected from H, R^1aAnd R^1dSelected from F, R^1bSelected from H or F；

R²Selected from H, methyl, ethyl, propyl,

R³Selected from H, methyl, ethyl ,-CF₃、

R⁴Selected from methyl ,-CF₃Or

The preferred solution of the invention, the present invention relates to compounds to be selected from, but is not limited to:

The invention further relates to compound shown in logical formula (I) or its stereoisomer, hydrate, solvate, pharmaceutically may be used Salt, eutectic or the prodrug of receiving, wherein the salt include but is not limited to sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, Front three amine salt, triethylamine salt, pyridiniujm, picoline salt, 2,6- lutidines salt, ethanolamine salt, diethanolamine salt, three second Alcohol amine salt, cyclohexylamine salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, sulfate, nitrate, phosphate, formates, trifluoro Acetate, acetate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malonate, Malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citron Hydrochlorate, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, second Sulfonate, fluoroform sulphonate or their combination.

The invention further relates to a kind of pharmaceutical composition, the composition includes ternary shown in the logical formula (I) of effective dose Condense cyclosubstituted amino hexatomic ring analog derivative or its stereoisomer, pharmaceutically acceptable salt or prodrug and/or one kind Or various other therapeutic agents and pharmaceutically acceptable carrier or excipient.

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

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

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

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

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

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

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

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

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

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

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

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

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

" isocyano group " refers to-N ≡ C.

" nitro " refers to-NO₂。

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

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

" naphthenic base " refers to substituted or unsubstituted saturated or unsaturated cyclic hydrocarbon radical, can be 3 to 10 yuan of monocycle, 4 to 20 yuan of loop coil and ring or bridged ring.Ring carbon atom includes 3 to 20 carbon atoms, and preferably 3 to 10 carbon atoms are further excellent 3 to 8 carbon atoms are selected, non-limiting embodiment includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, ring Acrylic, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, 1,5- cyclo-octadiene base, 1,4- cyclohexadienyl and ring Heptantriene base etc..When substituted, substituent group is 1 to 5 selected from F, Cl, Br, I, alkyl, naphthenic base, alkoxy, alkyl halide Base, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano, isocyano group, aryl, heteroaryl, heterocycle, bridged ring base, loop coil base and ring Base, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_m- C (=O)-R^a、-O-(CH₂)_m- C (=O)-R^a、- (CH₂)_m- C (=O)-NR^bR^c、-(CH₂)_mS (=O)_nR^a、-(CH₂)_mAlkenyl-R^a、OR^dOr-(CH₂)_mAlkynyl-R^a(wherein m, n For 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cBe independently selected from including H, hydroxyl, amino, Carbonyl, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^c Five or hexa-atomic naphthenic base or heterocycle can be formed.R^aWith R^dBe each independently selected from aryl, heteroaryl, alkyl, alkoxy, naphthenic base, Heterocycle, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" heterocycle " refers to substituted or unsubstituted saturation or unsaturation and at least containing 1 to 5 selected from N, O or S Heteroatomic non-aromatic ring, non-aromatic ring can be 3 to 10 yuan of monocycle, 4 to 20 yuan of loop coil and ring or bridged ring, heterocycle N, the S selectively replaced in ring can be oxidized to various oxidation state.It is preferred that 3 to 12 circle heterocyclic rings.Non-limiting embodiment includes oxygen Heterocycle propyl, oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, oxacyclohexyl, oxa- cyclooctyl, aziridine Base, azelidinyl, azepine cyclopenta, piperidyl, aziridinyl, 1,3 dioxy cyclopenta, 1,4- dioxy ring penta Base, 1,3- dioxy cyclopenta, 1,3- dioxocyclohex base, bis- sulphur cyclohexyl of 1,3-, azepine base, morpholinyl, piperazinyl, pyrrole Mutter base, piperidyl, thio-morpholinyl, dihydropyran, 1,4- Dioxin base,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The synthetic method of the compounds of this invention

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

Scheme one:

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

Scheme two:

Intermediate compound I-D and intermediate compound I-E obtains intermediate compound I-C by condensation reaction, and intermediate compound I-C is protected by deamination Base obtains logical formula (I) compound.

The preparation of intermediate compound I-A referenced patent WO2010056708, US2007232676 document, method are described as follows:

Wherein, R¹、R^1a、R^1b、R^1c、R^1dIt is as hereinbefore defined with W, R^2aSelected from C_1-8Alkyl or C_3-8Naphthenic base, P are amino Protecting group, for example tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9- fluorenylmethoxycarbonyl groups (Fmoc), V are halogen, It is preferred that chlorine, L is selected from halogen, preferably bromine.

Specific embodiment

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

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

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

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

The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18100x 4.6mm).

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

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

Without specified otherwise, methyl tertiary butyl ether(MTBE), hydrazine hydrate, tetrabutylammonium bromide, sodium hydride, triphenyl phosphorus, N, N- bis- Methylacetamide, glycol dimethyl ether, trifluoroacetic acid purchase are in Chengdu Ke Long chemical reagent factory；Two dimethyl dicarbonate butyl esters, N, N'- dicarbapentaborane diimidazole, N,N-dimethylformamide dimethylacetal, n-BuLi, N, the purchase of O- dimethyl hydroxylamine hydrochloride It buys in special (Chengdu) the medical science Co., Ltd of Ace；Cesium carbonate, N- hydroxysuccinimide, two (trimethyl silicon substrate) amino Sodium, the purchase of diphenyl methylene glycine ethyl ester are in the resistance to Jilin Chemical of peace；Ammonia/methanol purchase is in the limited public affairs of the smooth scientific and technological share of upper Haitai Department；2- (trimethylsilyl) ethoxymethyl chlorine, the purchase of 2,5- difluoro bromobenzene are in Shanghai De Mo Pharmaceutical Technology Co., Ltd；Isopropyl Base magnesium chloride/lithium chloride tetrahydrofuran solution purchase is in lark prestige Science and Technology Ltd.；Tetrabutyl ammonium fluoride, three (acetoxyl groups) Sodium borohydride, propargyl bromide, the purchase of tetrabutyl hexafluorophosphoric acid amine are in this Reagent Company of Adama；Cyclopentadienyl group is bis- (triphenylphosphine) Ruthenic chloride (II) is bought in ACROS orgainics；Cyclopropyl sulfonyl chloride, borane dimethylsulf iotade purchase are in splendid remote chemistry science and technology (Shanghai) Co., Ltd.；Benzene sulfonic acid purchase recovers fine chemistry industry research institute in Tianjin；Chlorine { [(1R, 2R)-(-) -2- amino -1,2- Diphenyl-ethyl] (phenyl-pentafluoride sulphonyl) amino (p-cymene) ruthenium (II) purchase in Strem chemical；Cobalt octacarbonyl purchase It buys 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 one about The hydrogen balloon of 2L volume.Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.Without specified otherwise in embodiment, Solution refers to aqueous solution.Without specified otherwise in embodiment, the temperature of reaction is room temperature.It abridges in embodiment: Bn: benzyl；Et: second Base；Ac: acetyl group；Me: methyl；Boc: tertbutyloxycarbonyl；Ph: phenyl；COOH: carboxyl；OMe: methoxyl group；OTBS: dimethyl Tert-butyl silicon ether；SO₃H: sulfonic group；Ms: methyl sulphonyl；SEM:2- (trimethyl silicane) ethoxyl methyl.

Intermediate 1

Tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -5- carbonyl tetrahydro -2H- pyrans -3- base) carbamate (in Mesosome 1)

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

Step 1: ethyl 2- Aminopentyl -4- acetylenic acid ester (1B)

ethyl 2-aminopent-4-ynoate

At room temperature, diphenyl methylene glycine ethyl ester 1A (50g, 0.187mol) is dissolved in methyl tertiary butyl ether(MTBE) (300mL) In, propargyl benzene sulfonate (44g, 0.224mol), tetrabutylammonium bromide (6.1g, 0.019mol) are added in reaction solution, risen Temperature is added cesium carbonate (121.8g, 0.374mol) to 50 DEG C, reacts overnight at a temperature of 50 DEG C.Reaction solution is filtered, methyl is used Tertbutyl ether (40mL × 2) washs filter cake, merges organic phase, and after the solvent of the more than half volumes of concentrated by rotary evaporation, hydrochloric acid solution is added (3mol/L, 100mL) is stirred 1 hour, stratification at room temperature, and water phase is extracted with methyl tertiary butyl ether(MTBE) (70mL × 2), is collected Water phase obtains 1B.

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

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

Sodium hydroxide (33.7g, 0.842mol) is dissolved in water (100mL), is added dropwise to 1B (26.4g, 0.187mol) dropwise Reaction solution in, at room temperature stir 2 hours.Two dimethyl dicarbonate butyl esters (45g, 0.206mol) are dissolved in methyl tertiary butyl ether(MTBE) (125mL), is added dropwise in reaction solution, stirs 4 hours at room temperature.Stratification, water phase are washed with methyl tertiary butyl ether(MTBE) (80mL × 2) It washs, the water phase hydrochloric acid solution of 3mol/L adjusts pH value to 3, and it is extracted with methyl tertiary butyl ether(MTBE) (100mL × 2), merges organic phase, Saturated sodium-chloride water solution (30mL × 2) washs, and anhydrous magnesium sulfate is added in organic phase and dries, filters, is spin-dried for, obtains yellow oil Shape liquid 1C (33g, yield 83%).

MS m/z(ESI):212.0[M-1]。

Step 3: tert-butyl (6- methoxyl group -5- carbonyl hept- 1- alkynes -4- base) carbamate (1D)

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

1C (33g, 0.155mol) is dissolved in n,N-Dimethylformamide (200mL), controls temperature less than 10 DEG C, by N, N'- carbonyl dimidazoles (32.58g, 0.201mol) add in reaction solution, react 1 hour at 0 DEG C.By N, O- dimethyl oxyammonia salt Hydrochlorate (19.6g, 0.186mol) adds in reaction solution, is stirred overnight at room temperature.It is added dropwise water (150mL), stirs 1 hour, use Ethyl acetate (100mL × 2) extraction, merges organic phase, with saturated sodium bicarbonate solution (60mL × 3), saturated sodium chloride solution (60mL × 3) wash organic phase, and it is dry that anhydrous magnesium sulfate is added in organic phase.Filtering, filtrate is concentrated, is used column chromatography (petrol ether/ethyl acetate (v/v)=10:1) obtains white solid 1D (35g, yield 88.2%).

MS m/z(ESI):156.9[M+1]。

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

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

Under nitrogen protection, 2,5- difluoro bromobenzene (15.05g, 78mmol) is dissolved in dry toluene (50mL), ice salt bath cooling To -10 DEG C hereinafter, isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (66mL, 1.3mol/L) is added dropwise, it is maintained at -10 DEG C or so stirring 1 hour.1D (10g, 39mmol) is dissolved in dry tetrahydrofuran (100mL), is added dropwise to above-mentioned reaction dropwise In liquid, -10 DEG C are maintained the temperature at hereinafter, finish, is reacted 4 hours at room temperature.- 10 DEG C are cooled the temperature to hereinafter, being added dropwise Saturated ammonium chloride solution (40mL) stirs 10 minutes, adjusts pH value to 5~6 with the hydrochloric acid solution of 3mol/L, stratification, water It is mutually extracted with methyl tertiary butyl ether(MTBE) (50mL × 2), merges organic phase, washed with saturated sodium chloride solution (30mL × 2), organic phase Middle addition anhydrous sodium sulfate dries, filters, and concentration, column chromatography for separation (petrol ether/ethyl acetate (v/v)=50:1-8:1) obtains To faint yellow solid 1E (10.1g, yield 83.5%).

MS m/z(ESI):210.1[M+1]。

Step 5: tert-butyl (the amyl- 4- alkynes -2- base of (1R, 2S) -1- (2,5- difluorophenyl) -1- hydroxyl) carbamate (1F)

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

1E (16.07g, 52mmol) is dissolved in tetrahydrofuran (100mL), is added triethylene diamine (17.39g, 155mmol) With [(R, R)-N- (2- amino -1,2- Diphenethyl) pentafluorobenzenesulfonamide] chlorination (p-cymene) ruthenium (II) (i.e. RuCl (p- Cymene) (R, R)-FSDPEN) (0.37g, 0.52mmol), formic acid (14.27g, 310mmol) is added dropwise, finishes, in 40 DEG C Reaction is overnight.The tetrahydrofuran and formic acid in reaction solution are rotated, water (60mL), hydrochloric acid (3mol/L, 10mL) is added, uses methyl Tertbutyl ether (90mL × 3) extraction merges organic phase, and saturated sodium bicarbonate solution (35mL × 2) washs, and nothing is added in organic phase Water magnesium sulfate dries, filters, and concentration, column chromatography for separation (petrol ether/ethyl acetate (v/v)=60:1-10:1) obtains faint yellow Jelly 1F (15.37g, yield 95%).

MS m/z(ESI):334.2[M+23]。

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

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

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

MS m/z(ESI):256.2[M+1]。

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

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

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

MS m/z(ESI):274.1[M+1]。

Step 8: tert-butyl ((2R, 3S) -2- (2,5- difluorophenyl) -5- carbonyl tetrahydro -2H- pyrans -3- base) amino first Acid esters (intermediate 1)

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

1H (11.53g, 35.03mmol) is dissolved in methylene chloride (130mL), is cooled to 0 DEG C, this Martin oxidation will be worn Agent (Dess-Martin periodinane) (29.72g, 70.06mmol) adds in reaction solution in batches, is warmed to room temperature naturally anti- It answers 4 hours.It is cooled to 0 DEG C, saturated sodium bicarbonate solution (60mL) is added dropwise in reaction solution, is stirred 20 minutes, filtering, filtrate Stratification, water phase with methyl tertiary butyl ether(MTBE) (60mL × 3) extract, merge organic phase, with saturated sodium bicarbonate solution (30mL × 2) it washs, anhydrous sodium sulfate is added in organic phase and dries, filters concentration, column chromatography for separation (petrol ether/ethyl acetate (v/v)= 10:1-4:1), White crystal powder intermediate 1 (10.85g, yield 94.7%) is obtained.

MS m/z(ESI):272.0[M+1]；

¹H NMR(400MHz,DMSO-d₆):δ7.29-7.13(m,4H),4.77-4.75(d,2H),4.22-4.12(d, 2H),4.08-4.02(m,1H),2.75-2.70(m,2H),1.23(s,9H)。

Intermediate 2

Tert-butyl 3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-formic acid Ester (intermediate 2)

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

Step 1: tert-butyl allyl (support -2- alkynes -1- base) carbamate (2B)

tert-butyl allyl(prop-2-yn-1-yl)carbamate

N- tertbutyloxycarbonyl allylamine 2A (20g, 127.39mmoL) is dissolved in n,N-Dimethylformamide (100mL), it will After sodium hydride (7.6g, 60%, 191.08mmoL) is handled with n-hexane, it is added n,N-Dimethylformamide (400mL), in nitrogen It under protection, is added drop-wise in reaction solution at 0 DEG C, is stirred 30 minutes at 0 DEG C, be warmed to room temperature down that the reaction was continued 20 minutes.Under ice bath It is added dropwise to propargyl bromide (30.3g, 245.78mmoL), is kept for 0 DEG C stir 30 minutes.Reaction solution is slowly added to process in trash ice The sodium hydride of amount is extracted with ethyl acetate (100mL × 3), is merged organic phase and is washed with saturated salt solution (100mL x 3), Anhydrous sodium sulfate dries, filters, filtrate decompression concentration.Residue silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=100:1~50:1), obtain yellow liquid 2B (21g, yield 85%).

MS m/z(ESI):140.1[M+1]。

Step 2: tert-butyl 5- carbonyl hexahydro cyclopentano [c] pyrroles -2 (1H)-formic acid esters (2C)

tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Compound 2B (39g, 202.2mmoL) is dissolved in glycol dimethyl ether (275mL), cobalt octacarbonyl is added (83g, 242.7mmoL), water (82.4mL) stirs 30 minutes, is warming up to 84 DEG C of return stirrings 16 hours.Reaction solution is concentrated, The hydrochloric acid (240mL) that saturated salt solution (500mL), ethyl acetate (250mL) and 1mol/L is added dissolves residual solid.Liquid separation, Water phase is extracted with ethyl acetate (250mL x 3), is merged organic phase, is washed with saturated salt solution (250mL × 2), anhydrous slufuric acid Sodium dries, filters, and pressurization concentration, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3:1~2:1) obtains Faint yellow solid 2C (27.6g, yield 61.3%).

MS m/z(ESI):170.1[M+1]；

¹H NMR(400MHz,CDCl₃):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)。

Step 3: (E)-tert-butyl 4- ((dimethylamino) methene) -5- carbonyl hexahydro cyclopentano [c] pyrroles -2 (1H)-formic acid esters (2D)

(E)-tert-butyl 4-((dimethylamino)methylene)-5-oxohexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate

2C (20g, 88.9mmoL) is dissolved in N,N-dimethylformamide dimethylacetal (13.7g, 115.6mmoL) heating It is stirred at reflux 4 hours.Reaction solution is concentrated, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2:1~1: 4) brown oil 2D (15.8g, yield 63%), is obtained.

MS m/z(ESI):281.2[M+1]。

Step 4: tert-butyl 7a- hydroxyl -3b, 4,6,6a, 7,7a- hexahydro -1H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (2H)-formic acid esters (2E)

tert-butyl 7a-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), is added hydrazine hydrate (4.2g, 67.7mmoL, 80%), It is stirred 16 hours at 45 DEG C.Reaction solution is cooled to room temperature, is filtered, filter cake is eluted with ethyl acetate, filter cake is dried, obtained White solid 2E (13.6g, yield 90%)

Step 5: tert-butyl 3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-formic acid esters (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 chloride (90mL), is cooled to 0 DEG C, p-methyl benzenesulfonic acid hydration is added Object (0.97g, 5.09mmoL) stirs 30 minutes.Into reaction solution be added saturated sodium bicarbonate solution adjust reacting liquid pH value 7~ 8, liquid separation.Water phase is extracted with methylene chloride (500mL × 3), merges organic phase, and washed with saturated salt solution (500mL x 2), Anhydrous sodium sulfate dries, filters, concentration, silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1:1~1:2), Obtain white solid intermediate 2 (10g, yield 78.8%).

¹H NMR(400MHz,CD₃OD):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 splits to obtain two single configuration compounds, Chiral HPLC color by chiral high performance liquid chromatography Compose separation condition:

Chiral column: CHIRALPAK AY-H；Chiral column specification: 0.46cm I.D. × 15cm L；Sample volume: 2 μ L；Flowing Phase: n-hexane/isopropanol (v/v)=90/10；Flow velocity: 1.0mL/min；Detection wavelength: UV 214nm；Temperature: 35 DEG C；

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

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

Intermediate 3

Tert-butyl 3- (trifluoromethyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrrole Azoles -5 (6H)-formic acid esters (intermediate 3)

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

Step 1: tert-butyl 5- carbonyl -4- (2,2,2- trifluoroacetyl group) hexahydro cyclopentano [c] pyrroles -2 (1H)-formic acid Ester (3A)

tert-butyl 5-oxo-4-(2,2,2-trifluoroacetyl)hexahydrocyclopenta[c] pyrrole-2(1H)-carboxylate

At room temperature, 2C (1.13g, 5.0mmol) is dissolved in tetrahydrofuran (15mL), is cooled to -70 DEG C.Diisopropyl is added Base amido lithium (2.5mL, 2mol/L) reacts 0.5 hour in -70 DEG C.Trifluoroacetic Acid Ethyl Ester (0.71g, 5.0mmol) is added to In reaction solution, it is warmed to room temperature reaction 4 hours naturally.Reaction system is cooled to -10 DEG C, ammonium chloride (15mL) is added dropwise and arrives reaction solution In.It is extracted with methyl tertiary butyl ether(MTBE) (40mL × 3), merges organic phase, washed with saturated common salt aqueous solution (30mL × 1).It is anhydrous Magnesium sulfate dries, filters, and filtrate decompression is concentrated.Residue silica gel column chromatography separating purification (ethyl acetate/petroleum ether (v/ V)=3:1-1:1), obtain brown liquid 3A (1.36g, yield 84%).

MS m/z(ESI):322.1[M+1]。

Second step, step 3:

Tert-butyl 3- (trifluoromethyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrrole Azoles -5 (6H)-formic acid esters (intermediate 3)

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

At room temperature, 3A (1.36g, 4.23mmol) is dissolved in toluene (20mL), addition hydrazine hydrate (0.26g, 5.08mmol), it reacts 2 hours for 40 DEG C.Water (30mL) is added into reaction system, is extracted, is associated with methylene chloride (50mL) Machine phase, anhydrous magnesium sulfate dry, filter, and filtrate decompression is concentrated to get 3B.Compound 3B is dissolved in methylene chloride (30mL), It is cooled to 0 DEG C, anhydrous methanol (10mL) solution of p-methyl benzenesulfonic acid (0.42g, 2.18mmol) is added drop-wise in reaction solution, in 0 DEG C reaction 1 hour.Sodium bicarbonate solution is added dropwise and adjusts reaction solution pH to 8, is extracted with methylene chloride (20mL × 4).Merge organic Phase is washed with saturated common salt aqueous solution (20mL × 1).Anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated.Residue is used Silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=5:1-1:1) purifying, obtains white solid intermediate 3 (0.44g, yield 32.8%).

MS m/z(ESI):318.3[M+1]。

Embodiment 1

2- (5- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -3b, 4,5,6, 6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -2- base) ethyl alcohol (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) tetrahydro -2H- pyrans -3- base) -3b, 4,5,6, 6a, 7- hexahydro -1H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethyl alcohol (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

Step 1: tert-butyl 2- (2- ethyoxyl -2- carbonylethyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4': 3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-formic acid esters (1a-1)

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

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

Tert-butyl 1- (2- ethyoxyl -2- carbonylethyl) -3b, 4,6a, 7- tetrahydro-1 H-pyrrolo simultaneously [3', 4':3,4] ring penta And [1,2-c] pyrazoles -5 (6H)-formic acid esters (1a-2)

tert-butyl 1-(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 n,N-Dimethylformamide (20mL), cools to 0 DEG C, hydrogen is added Change sodium (385mg, 60%, 9.6mmoL), is warmed to room temperature lower stirring 1 hour.0 DEG C is cooled to again, is added dropwise to bromoacetate (1.6g, 9.6mmoL) is warmed to room temperature stirring 16 hours naturally.Reaction solution is poured into trash ice, is stirred, and suitable chlorine is added Change sodium, extracted with ethyl acetate (80mL × 3), merge organic phase, and washed with saturated salt solution (50mL x 3), organic phase is used Anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, with silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2:1), Obtain the mixture (2g, yield 74%) of colorless oil 1a-1 and 1a-2.

MS m/z(ESI):336.2[M+1]。

Step 2: tert-butyl 2- (2- hydroxyethyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-formic acid esters (1b-1)

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

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

Tert-butyl 1- (2- hydroxyethyl) -3b, 4,6a, 7- tetrahydro-1 H-pyrrolo simultaneously [3', 4':3,4] cyclopentano [1,2-c] Pyrazoles -5 (6H)-formic acid esters (1b-2)

tert-butyl 1-(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 methanol (15mL), boron hydrogen is added with stirring Change sodium (113mg, 2.973mmoL), stirs 4 hours at room temperature.Water (0.5mL) is added into reaction solution, reaction solution is concentrated, is added Enter saturated salt solution (50mL), extracted with methylene chloride (30mL x 5), merges organic phase, with saturated salt solution (30mL × 1) Washing, anhydrous sodium sulfate dry, filter, and are concentrated, obtain mixture (710mg, the yield of light yellow oil 1b-1 and 1b-2 97%).

MS m/z(ESI):294.2[M+1]。

Step 3: 2- (3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -2- Base) ethyl alcohol 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)ethanol benzenesulfonate

2- (3b, 4,5,6,6a, 7- hexahydro -1H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethyl alcohol 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)ethanol benzenesulfonate

By the mixture (580mg, 1.979mmoL) of 1b-1 and 1b-2, benzenesulfonic acid hydrate (476.5mg, 2.573mmoL) It is dissolved in methanol (10mL), after heating 60 DEG C of stirrings 4 hours and is stirred overnight at room temperature.Reaction solution is concentrated, ethyl acetate is used (10mL) stirring, is filtered, dry, obtains the mixture (700mg, yield 100%) of colorless oil 1c-1 and 1c-2.

MS m/z(ESI):194.2[M+1]。

Step 4: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (2- hydroxyethyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -2H- pyrans -3- base) amino Formic acid esters (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

Tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- (2- ethoxy) -3b, 4,6a, 7- tetrahydro -1H- Pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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, is protected after nitrogen displacement and in nitrogen Shield is lower to be added n,N-dimethylacetamide (7mL), stirs 1 hour at room temperature.Three (acetoxyl group) sodium borohydrides are added under ice bath (437.2mg, 1.994mmoL) is stirred at room temperature 16 hours.Concentrated ammonia liquor (20mL) is added into reaction solution under stirring, is stirred at room temperature 1 Hour, filtering, filter cake is washed with clear water (2mL × 5), is dissolved with methylene chloride and methanol mixed solvent (V/V=20:1), anhydrous Sodium sulphate dries, filters, and is concentrated to get the mixture (250mg, yield 32.5%) of white solid object 1d-1 and 1d-2.

Step 5: 2- (5- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -2- base) ethyl alcohol (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) tetrahydro -2H- pyrans -3- base) -3b, 4,5,6, 6a, 7- hexahydro -1H- pyrazoles [3', 4':3,4] cyclopentano [1,2-c] pyrazol-1-yl) ethyl alcohol (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 mixture (230mg, 0.456mmoL) of 1d-1 and 1d-2 is added in methylene chloride (1mL), is added three under ice bath Fluoroacetic acid (1mL) stirs 2 hours.Saturated sodium bicarbonate solution tune reaction solution is added into reaction solution to be in neutrality, saturation food is added Salt water (20mL) is extracted with methylene chloride (20mL × 3), merges organic phase, saturated salt solution (50mL × 2) washing, anhydrous sulphur Sour sodium dries, filters, and concentration, residue isolates and purifies (methylene chloride/methanol (v/v)=20:1) with thin-layered chromatography, obtains white Color solid chemical compound 1-1 (62mg, yield 33%) and compound 1-2 (48mg, yield 26%).

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

¹H NMR(400MHz,CD₃OD):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:

¹H NMR(400MHz,CD₃OD):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- tetrahydro -2H- pyrrolo- [3', 4':3,4] ring Penta simultaneously [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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]cyclopent a[1,2-c]pyrazol-5(6H)-yl)tetrahydro-2H-pyran-3-amine

Step 1: (3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles benzene sulphur Hydrochlorate (2a)

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

At room temperature, intermediate 2 (0.250g, 1.00mmol), benzene sulfonic acid (0.250g, 1.50mmol) are dissolved in methanol In (6mL), 68 DEG C are reacted 12 hours.Reaction solution is concentrated under reduced pressure, white solid 2a (0.362g, yield 100%) is obtained.

MS m/z(ESI):150.3[M+1]。

Step 2: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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

At room temperature, 2a (0.350g, 1.14mmol) is dissolved in n,N-dimethylacetamide (4mL), intermediate 1 is added (0.338g, 1.04mmol) is stirred 1 hour at 0 DEG C.Three (acetoxyl group) sodium borohydrides (0.285g, 1.34mmol) are added Into reaction solution, it is warmed to room temperature reaction 16 hours naturally.Reaction solution is cooled to 0 DEG C, sequentially adds water, ammonium hydroxide adjusting pH to 8, White solid is precipitated.Reaction solution is filtered, filter cake is successively washed with water (5mL × 3), petroleum ether (10mL × 1).It drains, will filter Biscuit is dry, obtains white solid 2b (0.230g, yield 48.4%).

MS m/z(ESI):461.3[M+1]。

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

At room temperature, 2b (0.220g, 0.480mmol) is dissolved in methylene chloride (4mL), is cooled to 0 DEG C, trifluoro second is added Sour (2mL) reacts 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts pH to 8, uses methylene chloride (30mL × 3) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate dries, filters, will Filtrate decompression concentration, prepares plate with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), obtain shallow white solid chemical combination Object 2 (0.160g, yield 92.9%).

MS m/z(ESI):361.3[M+1]；

¹H NMR(400MHz,CD₃OD):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)。

The 2 optical isomers, that is, compound 3-1 and compound 3-2 of 3 compound 2 of embodiment

Using intermediate 2-1 as raw material, compound 3-1 is obtained referring to the synthetic method of embodiment 2；

MS m/z(ESI):361.3[M+1]；

¹H NMR(400MHz,CDCl₃):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)。

Using intermediate 2-2 as raw material, compound 3-2 is obtained referring to the synthetic method of embodiment 2；

MS m/z(ESI):361.3[M+1]；

¹H NMR(400MHz,CDCl₃):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

Tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (methyl sulphonyl) -3b, 4,6a, 7- tetrahydro - 2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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

Tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- (methyl sulphonyl) -3b, 4,6a, 7- tetrahydro - 1H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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

Step 1: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (methyl sulphonyl) -3b, 4,6a, 7- tetrahydro -2H- pyrroles

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

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

2b (0.240g, 0.680mmol) is dissolved in n,N-Dimethylformamide (20mL), cools to 0 under nitrogen protection DEG C, sodium hydride (0.040g, 1.12mmol) is added and stirs 30 minutes, methylsufonyl chloride (0.090g, 1.08mmol) slowly is added dropwise, It is stirred to react in 0 DEG C 2 hours.Reaction solution is down to 0 DEG C, is added water (100mL), is extracted with methylene chloride (60mL × 3), is merged Organic phase, saturated common salt aqueous solution (30mL × 1) washing, anhydrous sodium sulfate are dried, filtered, are concentrated, and it is pure that thin layer prepares plate separation Change (methylene chloride/methanol (v/v)=10:1), obtains the mixture (0.116g, yield 31.7%) of white solid 4a-1 and 4a-2

MS m/z(ESI):538.8[M+1]。

Step 2: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (methyl sulphonyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -2H- pyrans -3- base) amino Formic acid esters (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

(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- (methyl sulphonyl) -3b, 4,6a, 7- tetrahydro-1 H-pyrrolo And [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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 chloride (2mL), is added three under ice bath Fluoroacetic acid (1mL) stirs 2 hours.With saturated sodium bicarbonate solution tune reacting liquid pH value to 8, extracted with methylene chloride (20mL × 3) It takes, merges organic phase, saturated salt solution (50mL × 2) washing, anhydrous sodium sulfate is dried, filtered, is concentrated, and thin layer prepares plate separation Purify (methylene chloride/methanol (v/v)=10:1), obtain compound as white solid 4-1 and compound 4-2 mixture (0.040g, Yield 45.6%).

MS m/z(ESI):438.8[M+1]；

Compound 4-1 is made of the two kinds of compounds for being relatively diastereoisomer for having the following structure formula, by it One of number be compound 4-1a, another number is compound 4-1b；

Compound 4-2 is made of the two kinds of compounds for being relatively diastereoisomer for having the following structure formula, will be with The identical compound number of all chiral centre configurations of compound 4-1a is compound 4-2a, another number is compound 4- 2b；

Using intermediate 2-1 as raw material, the synthetic method of reference implementation example 2 and embodiment 4 be prepared compound 4-1a and The mixture of compound 4-2a.

The mixture of compound 4-1a and compound 4-2a:¹H NMR(400MHz,CDCl₃):δ7.79(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- tetrahydro -2H- pyrrolo- [3', 4':3,4] ring Penta simultaneously [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluoromethyl) tetrahydro -2H- pyrans -3- amino (compound 5-1)

(2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo [3',4':3,4]cyclopen ta[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 simultaneously [3', 4':3,4] ring Penta simultaneously [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- amino (compound 5-2)

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

Step 1: tert-butyl ((2R, 3S, 5R) -5- (2- (Cyclopropylsulfonyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) amino Formic acid esters (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

Tert-butyl ((2R, 3S, 5R) -5- (1- (Cyclopropylsulfonyl) -3b, 4,6a, 7- tetrahydro-1 H-pyrrolo simultaneously [3', 4': 3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluorophenyl) tetrahydro -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

At room temperature, 2b (0.200g, 0.430mmol) is dissolved in tetrahydrofuran (20mL), is cooled to 0 DEG C, three second are added Amine (0.06g, 0.60mmol) reacts 30 minutes.Cyclopropyl sulfonyl chloride (0.080g, 0.560mmol) slowly is added dropwise, it is anti-at 0 DEG C It answers 2 hours.Reaction solution is down to 0 DEG C, is added water (30mL), is extracted with methylene chloride (30mL × 3), organic phase, saturation are merged Common salt aqueous solution (30mL × 1) washing, anhydrous sodium sulfate dry, filter, filtrate decompression are concentrated, and residue prepares plate with thin layer Isolate and purify (methylene chloride/methanol (v/v)=10:1), obtain mixture white solid 5a-1 and 5a-2 mixture (0.090g, Yield 37.2%).

MS m/z(ESI):564.8[M+1]。

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

(2R,3S,5R)-5-(2-(cyclopropylsulfonyl)-3b,4,6a,7-tetrahydro-2H-pyrrolo [3',4':3,4]cyclopen ta[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 simultaneously [3', 4':3,4] ring Penta simultaneously [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- amino (compound 5-2)

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

At room temperature, the mixture (0.110g, 0.200mmol) of 5a-1 and 5a-2 is dissolved in methylene chloride (3mL), is cooled down It to 0 DEG C, is added trifluoroacetic acid (1.5mL), is reacted 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution tune is added dropwise Reaction solution pH to 8 is saved, is extracted with methylene chloride (30mL × 3).Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1) It washs, anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated.Residue prepares plate with thin layer and isolates and purifies (methylene chloride/first Alcohol (v/v)=10:1), obtain the mixture (0.050g, yield 57.8%) of compound as white solid 5-1 and compound 5-2.

MS m/z(ESI):464.9[M+1]；

Compound 5-1 is made of the two kinds of compounds for being relatively diastereoisomer for having the following structure formula, by it One of number be compound 5-1a, another number is compound 5-1b；

Compound 5-2 is made of the two kinds of compounds for being relatively diastereoisomer for having the following structure formula, will be with The identical compound number of all chiral centre configurations of compound 5-1a is compound 5-2a, another number is compound 5- 2b；

Using intermediate 2-1 as raw material, the synthetic method of reference implementation example 2 and embodiment 5 be prepared compound 5-1a and The mixture of compound 5-2a.

The mixture of compound 5-1a and compound 5-2a:¹H NMR(400MHz,CDCl₃):δ7.78-7.77(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- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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

Step 1: 3- (trifluoromethyl) -3b, 4,5,6,6a, 7- hexahydro -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]pyrazo le benzenesulfonate

At room temperature, intermediate 3 (0.420g, 1.32mmol) and benzene sulfonic acid (0.368g, 2.00mmol) are dissolved in methanol In (14mL), 68 DEG C are reacted 12 hours.Reaction solution is concentrated under reduced pressure, yellow solid 6a (0.460g, yield 92.7%) is obtained.

MS m/z(ESI):218.1[M+1]；

Step 2: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (3- (trifluoromethyl) -3b, 4,6a, 7- Tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -2H- pyrans -3- base) amino first Acid esters (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

At room temperature, 6a (0.327g, 1.10mmol) is dissolved in n,N-dimethylacetamide (4mL), intermediate 1 is added (0.356g, 1.10mmol), 0 DEG C is stirred 1 hour.Three (acetoxyl group) sodium borohydrides (0.303g, 1.43mmol) are added to In reaction solution, it is warmed to room temperature reaction 16 hours naturally.Reaction solution is cooled to 0 DEG C, water is sequentially added and ammonium hydroxide adjusts pH to 8, White solid is precipitated.Filtering, filter cake are successively washed with water (5mL × 3) and petroleum ether (10mL × 1).It drains, by filtration cakes torrefaction, It obtains white solid 6b (0.367g, yield 63.7%).

MS m/z(ESI):529.1[M+H⁺]；

Step 3: (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (3- (trifluoromethyl) -3b, 4,6a, 7- tetrahydro -2H- Pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) tetrahydro -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

At room temperature, 6b (0.357g, 0.680mmol) is dissolved in methylene chloride (4mL), is cooled to 0 DEG C, trifluoro second is added Sour (2mL) reacts 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts pH to 8 in reaction solution.With Methylene chloride (30mL × 3) extraction merges organic phase, saturated common salt aqueous solution (50mL × 1) washing.Anhydrous magnesium sulfate is dry, Filtering, filtrate decompression is concentrated.Residue prepares plate with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), obtains shallowly Yellow solid compound 6 (0.350g, yield 70.7%).

MS m/z(ESI):428.1[M+1]；

¹H NMR(400MHz,CDCl₃):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) tetrahydro -2H- pyrans -3- base) -3b, 4,5,6, 6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -3- formic acid esters (compound 7)

methyl 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-carboxylate

Step 1: tert-butyl 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-formic acid esters (7a)

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

At room temperature, intermediate 2 (1.0g, 4.0mmol) is dissolved in n,N-Dimethylformamide (10mL), is cooled to 0 DEG C, Sodium hydride (0.176g, 4.4mmol) is added to stir 1 hour.By 2- (trimethylsilyl) ethoxymethyl chlorine (0.8g, It 4.8mmol) is added drop-wise in reaction solution, is stirred to react at room temperature 4 hours.Ammonium chloride solution (25mL) is added into reaction solution, It is extracted with methyl tertiary butyl ether(MTBE) (40mL × 3).Merge organic phase, successively uses water (30mL × 2), saturated common salt aqueous solution (30mL × 1) it washs.Anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated, and obtains light yellow liquid 7a (1.6g).

MS m/z(ESI):380.0[M+1]。

Step 2: 5- tert-butyl 3- methyl 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -3b, 4,6a, 7- tetrahydro - 2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -3,5 (6H)-dicarboxylic acid esters (7b)

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

At room temperature, light yellow liquid 7a (1.14g, 3.0mmol) is dissolved in tetrahydrofuran (8mL).- 70 DEG C are cooled to, It is added dropwise n-butyllithium solution (1.8mL, 4.5mmol, 2.5mol/L), is reacted 0.5 hour in -70 DEG C.At -70 DEG C or less by chloromethane Sour methyl esters (0.37g, 3.9mmol) is added drop-wise in reaction solution, is kept for -70 DEG C react 4 hours.- 70 DEG C or less addition ammonium chlorides are molten Liquid (10mL).It is extracted with methyl tertiary butyl ether(MTBE) (25mL × 2), merges organic phase, washed with saturated common salt aqueous solution (20mL × 1) It washs, anhydrous magnesium sulfate dries, filters, and filtrate decompression is concentrated.Residue uses column chromatography purifying (ethyl acetate/petroleum ether (v/v)=20:1~5:1), obtain light yellow liquid 7b (0.52g, yield 30.6%).

MS m/z(ESI):338.1[M+1]。

Step 3: methyl 3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -3 Formic acid esters benzene sulfonate (7c)

methyl 3b,4,5,6,6a,7-hexahydro-2H-pyrrolo[3',4':3,4]cyclopenta[1,2-c] pyrazole-3-carbo-xylate benzenesulfonate

At room temperature, 7b (0.52g, 1.19mmol) is dissolved in anhydrous methanol (10mL), addition benzene sulfonic acid (0.33g, 1.79mmol), heating reflux reaction 16 hours.Reaction solution is concentrated under reduced pressure, light yellow solid 7c (1.22g, yield are obtained 100%).

MS m/z(ESI):208.0[M+1]。

Step 4: methyl 5- ((3R, 5S, 6R) -5- ((tertbutyloxycarbonyl) amino) -6- (2,5- difluorophenyl) tetrahydro - 2H- pyrans -3- base) -3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -3- formic acid Ester (7d)

methyl 5-((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-car boxylate

At room temperature, 7c (0.44g, 1.19mmol) is dissolved in n,N-dimethylacetamide (5mL), intermediate 1 is added (0.37g, 1.13mmol) is stirred at room temperature 1 hour.Three (acetoxyl group) sodium borohydrides (0.31g, 1.47mmol) are added to In reaction solution, it is stirred to react at room temperature 16 hours.Reaction solution is cooled to 0 DEG C, sequentially adds water (30mL) and ammonium hydroxide (5mL), White solid is precipitated.Reaction solution is filtered, filter cake is successively washed with water (10mL × 2) and petroleum ether (15mL × 2).It drains, filters Cake is dissolved with methylene chloride (50mL), and anhydrous magnesium sulfate dries, filters, filtrate decompression is concentrated.Residue silica gel column chromatography (methylene chloride/methanol (v/v)=100:1~80:1) is isolated and purified, light yellow solid 7d (0.28g, yield 47%) is obtained.

Step 5: methyl 5- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) - 3b, 4,5,6,6a, 7- hexahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -3- formic acid esters (compound 7)

methyl 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-carboxylate

At room temperature, 7d (0.08g, 0.154mmol) is dissolved in methylene chloride (2mL), is cooled to 0 DEG C, trifluoro second is added Sour (2mL), 0 DEG C is reacted 2 hours.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts reaction solution pH to 8, uses dichloro Methane (25mL × 2) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (20mL × 1).Anhydrous magnesium sulfate is dry, mistake Filter, filtrate decompression is concentrated.Residue prepares plate with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), and it is white to obtain class Color solid chemical compound 7 (0.02g, yield 34%).

¹H NMR(400MHz,CD₃OD):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)；

MS m/z(ESI):418.9[M+1]。

Embodiment 8

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

Step 1: tert-butyl ((2R, 3S, 5R) -5- (3- carbamoyl -3b, 4,6a, 7- tetrahydro -2H- pyrrolo- [3', 4':3,4] cyclopentano [1,2-c] pyrazoles -5 (6H)-yl) -2- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) carbamic acid Ester (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

At room temperature, 7d (0.1g, 0.19mmol) is dissolved in ammonia/methanol (5mL, 7mol/L), 100 DEG C of sealed cans reactions 16 are small When.Reaction solution is concentrated, light yellow solid 8a (0.08g, yield 82.3%) is obtained.

MS m/z(ESI):503.9[M+1]。

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

At room temperature, 8a (0.14g, 0.27mmol) is dissolved in methylene chloride (4mL), is cooled to 0 DEG C, trifluoroacetic acid is added (4mL) reacts 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts reaction solution pH to 8, uses dichloro Methane (30mL × 3) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate is dry, mistake Filter, filtrate decompression is concentrated.Residue prepares plate with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), and it is white to obtain class Color solid chemical compound 8 (0.01g, yield 11%).

¹H NMR(400MHz,CD₃OD):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

(2- methyl -4b, 5,7a, 8- nafoxidine are simultaneously [3', 4':3,4] by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- Cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -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]cycl openta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro- 2H-pyran-3-amine

Step 1: tert-butyl 2- methyl -4b, 5,7a, 8- nafoxidine simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine - 6 (7H)-formic acid esters (9a)

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

At room temperature, methylrnethwirnidamide hydrochloride (0.298g, 3.00mmol) and sodium ethoxide (0.450g, 5.00mmol) are dissolved in In ethyl alcohol (10mL), stir 15 minutes.The 2D (0.28g, 1.00mmol) being dissolved in ethyl alcohol is added dropwise in reaction solution, 85 DEG C anti- It answers 12 hours.Reaction solution is concentrated, is extracted with ethyl acetate (30mL × 3), organic phase, saturated common salt aqueous solution (50mL are merged × 1) it washs, anhydrous magnesium sulfate dries, filters, and is concentrated, obtains brown oil liquid 9a (0.280g, yield 100%).

MS m/z(ESI):276.0[M+1]。

Step 2: 2- methyl -4b, 5,6,7,7a, 8- hexahydropyrrolo simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine benzene Sulfonate (9b)

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

At room temperature, 9a (0.26g, 0.95mmol) and benzene sulfonic acid (0.262g, 1.40mmol) are dissolved in methanol (8mL), 68 DEG C are reacted 12 hours.Reaction solution is concentrated under reduced pressure to give brown solid 9b (0.386g, yield 100%).

MS m/z(ESI):176.1[M+1]。

Step 3: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl -4b, 5,7a, 8- tetrahydro pyrrole Cough up simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -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]cyclope nta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro- 2H-pyran-3-yl)carbamate

At room temperature, 9b (0.30g, 0.90mmol) is dissolved in n,N-dimethylacetamide (4mL), intermediate 1 is added (0.294g, 0.900mmol) is stirred 1 hour at room temperature.Three (acetoxyl group) sodium borohydrides (0.248g, 1.20mmol) are added Enter into reaction solution, in room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, water is sequentially added and ammonium hydroxide adjusts pH to 8, use Methylene chloride (30mL × 3) extraction.Merge organic phase, washed with saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate is dry Dry, filtrate is concentrated for filtering, and residue is obtained white with silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=40:1) Color solid 9c (0.203g, yield 49.0%).

MS m/z(ESI):486.9[M+1]。

Step 4: (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl -4b, 5,7a, 8- nafoxidine simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -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]cycl openta[1,2-d]pyrimidin-6(7H)-yl)tetrahydro- 2H-pyran-3-amine

At room temperature, 9c (0.140g, 0.280mmol) is dissolved in methylene chloride (3mL), is cooled to 0 DEG C, trifluoro second is added Sour (1.5mL) reacts 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts reaction solution pH to 8, uses Methylene chloride (30mL × 3) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate is dry Dry, filtrate decompression is concentrated for filtering, and residue prepares plate with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), It obtains compound as white solid 9 (0.030g, yield 28.8%).

MS m/z(ESI):386.9[M+1]；

¹H NMR(400MHz,CDCl₃):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

(simultaneously [3', 4':3,4] cyclopentano [1,2-d] is phonetic for 2- cyclopropyl -4b, 5,7a, 8- nafoxidine by (2R, 3S, 5R) -5- Pyridine -6 (7H)-yl) -2- (2,5- difluorophenyl) tetrahydro -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]pyri midin-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H- pyran-3-amine

Step 1: simultaneously [3', 4':3,4] cyclopentano [1,2-d] is phonetic for tert-butyl 2- cyclopropyl -4b, 5,7a, 8- nafoxidine Pyridine -6 (7H)-formic acid esters (10a)

tert-butyl

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

At room temperature, cyclopropyl amitraz hydrochloride (0.480g, 3.00mmol) and sodium ethoxide (0.45g, 5.00mmol) is molten In ethyl alcohol (10mL), stirs 15 minutes, the 2D (0.280g, 1.00mmol) being dissolved in ethyl alcohol is added dropwise to reaction solution, in 85 DEG C reaction 12 hours.Reaction solution is concentrated, is added water (30mL), is extracted with ethyl acetate (30mL × 3), organic phase is merged, is used Saturated common salt aqueous solution (50mL × 1) washing, anhydrous magnesium sulfate dry, filter, filtrate are concentrated, and obtain brown oil liquid 10a (0.308g, yield 100%).

MS m/z(ESI):302.1[M+1]。

Step 2: 2- cyclopropyl -4b, 5,6,7,7a, 8- hexahydropyrrolo simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine Benzene sulfonate (10b)

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

At room temperature, 10a (0.29g, 0.96mmol) and benzene sulfonic acid (0.268g, 1.40mmol) are dissolved in methanol (8mL), 68 DEG C are reacted 12 hours.Reaction solution is concentrated under reduced pressure, brown solid 10b (0.440g, yield 100%) is obtained.

MS m/z(ESI):202.1[M+1]。

Step 3: ((2- cyclopropyl -4b, 5,7a, 8- nafoxidine are simultaneously [3', 4':3,4] by (2R, 3S, 5R) -5- for tert-butyl Cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) -2- (2,5- difluorophenyl) tetrahydro -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]pyrimidi n-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H- pyran-3-yl)carbamate

At room temperature, 10b (0.33g, 0.92mmol) is dissolved in n,N-dimethylacetamide (4mL), intermediate 1 is added (0.301g, 0.92mmol) is stirred at room temperature 1 hour.Three (acetoxyl group) sodium borohydrides (0.253g, 1.21mmol) are added Into reaction solution, in room temperature reaction 16 hours.It is cooled to 0 DEG C, water (20mL) is sequentially added and ammonium hydroxide adjusts pH to 8, use dichloro Methane (30mL × 3) extraction.Merge organic phase, washed with saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate is dry, mistake Filter, filtrate is concentrated, and residue obtains white solid 10c with silica gel column chromatography (methylene chloride/methanol (v/v)=30:1) (0.114g, yield 24.2%).

MS m/z(ESI):512.9[M+1]。

(2- cyclopropyl -4b, 5,7a, 8- nafoxidine simultaneously [3', the 4':3,4] cyclopentano step 4: (2R, 3S, 5R) -5- [1,2-d] pyrimidine -6 (7H)-yl) -2- (2,5- difluorophenyl) tetrahydro -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]pyri midin-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H- pyran-3-amine

At room temperature, 10c (0.10g, 0.20mmol) is dissolved in methylene chloride (3mL), is cooled to 0 DEG C, trifluoro second is added Sour (1.5mL) reacts 2 hours in 0 DEG C.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise to reaction solution pH to 8, with two Chloromethanes (30mL × 3) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate is dry, Filtering, filtrate decompression is concentrated, plate is prepared with thin layer and isolates and purifies (methylene chloride/methanol (v/v)=10:1), obtain white solid Compound 10 (0.060g, yield 74%).

MS m/z(ESI):412.9[M+1]；

¹H NMR(400MHz,CDCl₃):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- nafoxidine simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amino trifluoroacetate (compound 11)

(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 2,2,2-trifluoroacetate

Step 1: tert-butyl 2- (trifluoromethyl) -4b, 5,7a, 8- nafoxidine simultaneously [3', 4':3,4] cyclopentano [1,2- D] pyrimidine -6 (7H)-formic acid esters (11a)

tert-butyl

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

At room temperature, by trifluoromethyl amitraz hydrochloride (0.654g, 5.80mmol) and sodium ethoxide (0.646g, 9.50mmol) It is dissolved in ethyl alcohol (36mL), stirs minute, the 2D (0.54g, 1.90mmol) for being dissolved in ethyl alcohol is added dropwise to reaction solution, 85 DEG C of reactions 12 hours.Reaction solution is concentrated, is extracted with ethyl acetate (30mL × 3), merges organic phase, with saturated common salt aqueous solution (50mL × 1) it washs, anhydrous magnesium sulfate dries, filters, filtrate is concentrated, and obtains brown oil liquid 11a (0.398g, yield 63%).

MS m/z(ESI):330.1[M+1]。

Step 2: 2- (trifluoromethyl) -4b, 5,6,7,7a, 8- hexahydropyrrolo simultaneously [3', 4':3,4] cyclopentano [1,2-d] Pyrimidine benzene sulfonate (11b)

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

At room temperature, 11a (0.39g, 1.2mmol) and benzene sulfonic acid (0.333g, 1.80mmol) are dissolved in methanol (16mL), 68 DEG C are reacted 12 hours.Reaction solution is concentrated under reduced pressure, brown solid 11b (0.440g, yield 100%) is obtained.

MS m/z(ESI):202.1[M+1]。

Step 3: tert-butyl ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (trifluoromethyl) -4b, 5,7a, 8- Nafoxidine simultaneously [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -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

At room temperature, 11b (0.637g, 0.90mmol) is dissolved in n,N-dimethylacetamide (5mL), intermediate 1 is added (0.295g, 0.90mmol) is stirred at room temperature 1 hour.Three (acetoxyl group) sodium borohydrides (0.318g, 1.20mmol) are added to In reaction solution, in room temperature reaction 16 hours.Reaction solution is cooled to 0 DEG C, water is sequentially added and ammonium hydroxide adjusts pH to 8, use dichloro Methane (30mL × 3) extraction.Merge organic phase, washed with saturated common salt aqueous solution (50mL × 1), anhydrous magnesium sulfate is dry, mistake Filter, filtrate is concentrated, with silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30:1), obtains light yellow solid 11c (0.130g, yield 26%).

MS m/z(ESI):541.2[M+1]。

Step 4: (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (trifluoromethyl) -4b, 5,7a, 8- nafoxidine And [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -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

At room temperature, 11c (0.13g, 0.24mmol) is dissolved in methylene chloride (3mL), is cooled to 0 DEG C, trifluoro second is added Sour (1.5mL), 0 DEG C is reacted 2 hours.Reaction solution is concentrated under reduced pressure, sodium bicarbonate solution is added dropwise and adjusts reaction solution pH to 8, with two Chloromethanes (30mL × 3) extraction.Merge organic phase, is washed with saturated common salt aqueous solution (50mL × 1).Anhydrous magnesium sulfate is dry, Filtering, filtrate decompression is concentrated, thin layer prepares plate and isolates and purifies (methylene chloride/methanol (v/v)=10:1), obtains white solid 11d (0.070g, yield 69.8%).

MS m/z(ESI):441.2[M+1]。

Step 5: (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- (trifluoromethyl) -4b, 5,7a, 8- nafoxidine And [3', 4':3,4] cyclopentano [1,2-d] pyrimidine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amino 2,2,2- trifluoroacetate (compound 11)

(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 2,2,2-trifluoroacetate

At room temperature, 11d (0.07g, 0.16mmol) is dissolved in methylene chloride (10mL), trifluoroacetic acid (1mL) is added dropwise and stirs It mixes 10 minutes.Reaction solution is concentrated, compound as white solid 11 (88mg) is obtained.

MS m/z(ESI):441.2[M+1]；

¹H NMR(400MHz,CDCl₃):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)。

Biological test

1, the external enzyme activity determination of DPP-IV

DPP-IV using the zymetology reaction assay the compounds of this invention of recombined human DPP-IV and H-Ala-Pro-AFC is external Enzyme activity.Buffer, to be measured is prepared according to DPP-IV Fluorescent ActivityAssay Kit (BPS Bioscience) Sample working solution, DPP-IV enzyme dilution and AFC substrate dilution.

Prepare 96 orifice plates, 80 μ L buffers are first added in every hole, and 5 μ L DPP-AFC- substrates are added later.It adds different dense 5 μ L buffers are added to test sample working solution, every 5 μ L of hole, blank group in degree.10 μ L DPP-IV finally are added in test group control 10 μ L buffers are added in blank control group in enzyme.Statistical analysis is carried out to data with 7.5 software of Origin, obtains each test The IC of compound₅₀Value, the results are shown in Table 1.

The external enzyme activity measurement result of table 1DPP-IV

Serial number	Compound number	IC50(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 inhibitory activity of apparent DPP-IV enzyme.

2, oral glucose tolerance test

Utilize hypoglycemic effect of oral glucose tolerance test (OGTT) evaluation the compounds of this invention in mouse.It uses Animal is SPF grades of ICR mouse, four week old, half male and half female, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., animal Produce quality certification number: SCXK (capital) 2012-001.Then STZ solution is continuously injected intraperitoneally in first feeding high lipid food one week (50mg/kg) 4 days.It is grouped according to the basal plasma glucose value after fasting, every group 10.Test-compound is with 5%DMSO-5% Solutol-90% normal saline at 1mg/mL suspension.Gastric infusion, dosage 10mg/kg.Blank control group Give 5%DMSO-5%solutol-90% physiological saline.10% glucose solution (1g/kg) is given after administration 15min, And in 0,15,30,45,60,120min, using Johnson & Johnson, surely bold and unconstrained Instrument for Measuring Blood Sugar measures the blood glucose value of each mouse, calculate medicine-when Area under the curve (AUC) reduces ratio.Experimental result is shown in Table 2.

2 Mouse oral glucose tolerance test evaluation result of table

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

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

Claims (9)

1. ternary shown in logical formula (I) condenses cyclosubstituted amino hexatomic ring analog derivative or its pharmaceutically acceptable salt:

Wherein:

X is selected from-O-；

W is selected from

R¹And R^1cSelected from H, R^1aAnd R^1dSelected from F, R^1bSelected from H；

R²Selected from H, methyl, ethyl, propyl,

R³Selected from H, methyl, ethyl ,-CF₃、

R⁴Selected from methyl ,-CF₃Or

2. it is derivative that ternary shown in the logical formula (I) of any one according to claim 1 condenses cyclosubstituted amino hexatomic ring class Object or its pharmaceutically acceptable salt are selected from:

3. ternary described according to claim 1~any one of 2 condenses cyclosubstituted amino hexatomic ring analog derivative or its medicine Acceptable salt on, wherein the salt is selected from sodium salt, sylvite, calcium salt, magnesium salts, barium salt, ammonium salt, front three amine salt, triethylamine Salt, pyridiniujm, picoline salt, 2,6- lutidines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine Salt, dicyclohexyl ammonium salt, hydrochloride, hydrobromate, sulfate, nitrate, phosphate, formates, trifluoroacetate, acetic acid Salt, maleate, tartrate, citrate, succinate, mandelate, fumarate, malonate, malate, 2- Hydracrylate, oxalates, oxyacetate, salicylate, glucuronate salt, galacturonic hydrochlorate, citrate, door winter ammonia Hydrochlorate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, trifluoro Mesylate or their combination.

4. a kind of pharmaceutical composition, the composition include: effective dose according to claim 1~any one of 2 described in Ternary shown in logical formula (I) condenses cyclosubstituted amino hexatomic ring analog derivative or its pharmaceutically acceptable salt, or further Including one or more other therapeutic agents and pharmaceutically acceptable carrier or excipient.

5. pharmaceutical composition according to claim 4, wherein the other therapeutic agents include:

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

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

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

6. pharmaceutical composition according to claim 5, wherein the SGLT-2 inhibitor is selected from Dapagliflozin, Kan Gelie Only, A Gelie is net, En Palie is net, Yi Palie is net, Tuo Fulie is net, Lu Silie is net, Rui Gelie is net, Sergliflozin or support column are net； DPP-IV inhibitor be selected from BI 1356, sitagliptin, vildagliptin, Egelieting, saxagliptin, Na Lieting, Ka Gelie Ge Lieting, gigue column spit of fland or song Ge Lieting, dutogliptin, are replaced at melogliptin in spit of fland；Biguanides therapeutic agent is selected from melbine or benzene Second biguanides；Thiazolidinediones therapeutic agent is selected from Ciglitazone, pioglitazone, Rosiglitazone, troglitazone, Fa Gelie ketone or reaches Lattice column ketone, sulfonylurea treatment agent are selected from Glimepiride, orinase, Glibornuride, glibenclamide, gliquidone, lattice column Pyrazine or gliclazide, how class therapeutic agent is selected from Nateglinide, Repaglinide or Mitiglinide, alpha-glucosidase restrainer to column Selected from acarbose, voglibose or Miglitol, glucagon-like peptide-1 analogs are selected from Exenatide or Li Lalu Peptide.

7. leading to ternary shown in formula (I) described in any one of claim 1~2 condenses cyclosubstituted amino hexatomic ring analog derivative Or composition described in any one of its pharmaceutically acceptable salt or claim 4~6 is preparing dipeptidyl peptidase-IV suppression Application in preparation.

8. application according to claim 7, wherein the dipeptidyl peptidase-iv inhibitor is used to prepare treatment metabolism Property disease drug, wherein the metabolic disease be selected from diabetes, diabetic retinopathy, diabetic neuropathy, Nephrosis, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or the raised level of glycerol, hyperlipemia Disease, obesity, Hypertriglyceridemia, X syndrome, diabetic complication, atherosclerosis or hypertension.

9. application according to claim 8, wherein the diabetes are type-2 diabetes mellitus.