CN109928971A - The amino tetrahydro pyran class compound and application thereof that aryl replaces - Google Patents

Abstract

The present invention relates to the amino tetrahydro pyran class compounds and application thereof that a kind of aryl replaces, further to the pharmaceutical composition comprising the compound.Compound of the present invention or described pharmaceutical composition may be used as dipeptidyl peptidase-IV (DPP-IV) inhibitor.

Description

The amino tetrahydro pyran class compound and application thereof that aryl replaces

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to the amino tetrahydro pyran class compound and its use that aryl replaces On the way, further to the pharmaceutical composition comprising the compound.The compound or described pharmaceutical composition may be used as two Peptidyl peptidase-IV (DPP-IV) inhibitor.

Background technique

Diabetes are the lysis of the blood glucose rise as caused by a variety of pathogenic factors.Usually there are two types of the sugar of type Urine disease.Type-1 diabetes mellitus also referred to as or insulin-dependent diabetes mellitus (IDDM) is mainly characterized by self-immunprocess damage pancreas β Cell.Type-2 diabetes mellitus, also referred to as Non-Insulin Dependent Diabetes Mellitus (NIDDM) are long-term, progressive metabolic diseases, special Point is hyperglycemia, hyperlipidemia and insulin resistance.Typical symptom is diuresis, more drinks and more foods.Type-2 diabetes mellitus is more common, in advance The health that will affect global 3,000,000,000 people is counted to type-2 diabetes mellitus in 2025.

Secretin plays an important role in the blood glucose balance under normal and pathological state is adjusted.In secretin Glucagon peptide (GLP-1) and glucose-dependent-insulinotropic polypeptide discharge after food intake from enteron aisle and to pancreas islet The secretion of element has an impact.GLP-1 is passed through in a manner of dependence on the glucose while promoting the secretion of insulin and reducing pancreas hyperglycemia Element secretion and reduce hyperglycemia.Meanwhile GLP-1 can slow down gastric emptying and as the full Drug inhibition appetite of increasing and reduction body Weight.In animal experiments, GLP-1 is to the nutritious effect of β cell, therefore increases the potential density by increasing β cell With function come a possibility that improving lysis.Recent research indicate that GLP-1 is helpful to cardiovascular system, this point is very heavy It wants, because cardiovascular complication is one of main cause of death in people with diabetes.To sum up, GLP-1 has perhaps More benefits, this makes it have many differences compared with existing treatment method.However, GLP-1 is cracking by widely distributed in vivo Serine protease dipeptidyl peptidase-IV (DPP-IV) degradation and inactivation.Therefore more interest are concentrated on for exploitation now The analog and dipeptidyl peptidase-iv inhibitor of the GLP-1 of long-acting resistance to peptase degradation.

Dipeptidyl peptidase-IV is glycoprotein and serine exopeptidase in cell membrane, can be from the N-terminal of polypeptide by X- dried meat ammonia Sour dipeptides is cut away.DPP-IV is widely distributed in each tissue of people, in the endothelial cell including enteron aisle and intestinal mucosa blood vessel. DPP-IV also expresses the T- lymphocyte in the circulatory system, is equal to t cell activation marker CD26, obtains from system model Data also illustrate that DPP-IV enzyme has potential coactivated effect during T- cell activation.In addition, DPP-IV also table Reveal the degradation of for many immunity regulatin remedies, endocrine and neural polypeptide.

DPP-IV inhibitor can cause undegradable biologically active GLP-1 is horizontal to increase, and can be II type Diabetes provide another candidate treatment method.In addition, DPP-IV inhibitor is oral to be had compared with secretin's analog Effect.Inhibit the activity of DPP-IV that can improve the control to blood glucose.The advantages of DPP-IV inhibitor, can increase insulin There is no the risks for increasing hypoglycemia simultaneously for release.However, as a member in exopeptidase family, DPP-IV inhibitor needs height Selectivity only inhibit DPP-IV activity and on other DPPs. without influence.

The principle that type-2 diabetes mellitus is treated with DPP-IV inhibitor is confirmed by strong.Many DPP-IV suppressions Preparation has the drug of multiple listings in each stage of clinical development, the sitagliptin including listing in 2006, The vildagliptin of listing in 2007, the Egelieting etc. of the saxagliptin of listing in 2009 and listing in 2010.But currently, still In the presence of for advantageous activity, stability, the demand of selectivity and the DPP-IV inhibitor of pharmacokinetic properties.

Summary of the invention

The present invention provides a kind of amino four for having and dipeptidyl peptidase-IV (DPP-IV) active aryl preferably being inhibited to replace The use of hydrogen pyran compounds and its pharmaceutical composition and the compound or described pharmaceutical composition in medicine preparation On the way, the drug is for treating, preventing or mitigating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic keratopathy kidney Disease, insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis Or hypertension.

On the one hand, the present invention relates to a kind of compounds, are the vertical of compound shown in compound shown in formula (I) or formula (I) It is body isomers, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or their prodrug,

Wherein,

R^1a、R^1bAnd R^1cIt is each independently H, deuterium, F, Cl, Br, I ,-CN ,-NO₂、-OH、-NH₂、C_1-6Alkyl, C_1-6Alcoxyl Base, C_1-6Halogenated alkyl or C_1-6Halogenated alkoxy；

W is

L is C_1-4Alkyl；

Each R⁵、R⁷、R⁸、R¹⁰And R¹⁴It independently is H, deuterium ,-CN, C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 Former molecular heterocycle, C_6-10Aryl, 5-6 former molecular heteroaryl ,-S (=O)₂R^a,-C (=O) R^b,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 it is unsubstituted each independently or by 1, 2 or 3 R^xIt is replaced；

R¹²For H, deuterium ,-CN, C_2-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10 Aryl, 5-6 former molecular heteroaryl ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_2-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle Base, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

Each R^a、R^b、R^cAnd R^dIt independently is C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 original are molecular miscellaneous Ring group, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3- The molecular heterocycle of 6 originals, C_6-10The former molecular heteroaryl of aryl and 5-6 it is unsubstituted each independently or by 1,2, Or 3 R^xIt is replaced；

R^eAnd R^fIt is each independently C_2-6Alkyl, C_4-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl or 5- 6 molecular heteroaryls of original, wherein the C_2-6Alkyl, C_4-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl It is unsubstituted each independently or by 1,2 or 3 R with 5-6 former molecular heteroaryl^xIt is replaced；

Each R^4a、R^4b、R^4c、R^4d、R^6a、R^6b、R^6c、R^6d、R⁶、R⁹、R¹¹And R¹³Independently be H, deuterium, F, Cl, Br, I ,=O ,- OH、-CN、-NH₂、-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkoxyacyl, C_1-6Alkanoyl, C_3-6Cycloalkanes Base, 3-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-6Alkyl, C_1-6 Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkoxyacyl, C_1-6Alkanoyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^yIt is replaced；

Each R^xAnd R^yIt independently is deuterium, F, Cl, Br, I ,-OH ,-CN, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6 Alkanoyl, C_1-6Alkoxyacyl or C_1-6Alkyl sulphonyl；

Each n, t or s independently are 1,2,3 or 4；

Q, p and u is each independently 0,1,2 or 3.

In some embodiments, each R⁵、R⁷、R⁸、R¹⁰And R¹⁴It independently is H, deuterium ,-CN, C_1-4Alkyl, C_1-4Alkyl halide Base, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl, 5-6 former molecular heteroaryl ,-S (=O)₂R^a、- C (=O) R^b,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_1-4Alkyl, C_1-4Halogen Substituted alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5-6 former molecular heteroaryl are respectively only It is on the spot unsubstituted or by 1,2 or 3 R^xIt is replaced.

In some embodiments, R¹²For H, deuterium ,-CN, C_2-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 atom Heterocycle, the C of composition_6-10Aryl, 5-6 former molecular heteroaryl ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b、-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_2-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 Former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 A R^xIt is replaced.

In some embodiments, each R⁵、R⁷、R⁸、R¹⁰And R¹⁴Independently be H, deuterium ,-CN, methyl, ethyl, n-propyl, Isopropyl, normal-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle Base, phenyl, 5-6 former molecular heteroaryl ,-S (=O)₂R^a,-C (=O) R^b,-OC (=O) R^b,-C (=O) OR^c,-S (= O)₂NHR^dOr-C (=O) NHR^d；The wherein methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl are each independently It is unsubstituted or by 1,2 or 3 R^xIt is replaced.

In some embodiments, R¹²For H, deuterium ,-CN, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, fluoroform Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl Base ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；It is wherein described Ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 original are molecular The former molecular heteroaryl of heterocycle, phenyl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced.

In some embodiments, each R^a、R^b、R^cAnd R^dIt independently is C_1-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-4Alkyl, C_1-4It is halogenated Alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5-6 former molecular heteroaryl are respectively independent Ground is unsubstituted or by 1,2 or 3 R^xIt is replaced.

In some embodiments, R^eAnd R^fIt is each independently C_2-4Alkyl, C_4-6Naphthenic base, 5-6 original are molecular miscellaneous Ring group, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_2-4Alkyl, C_4-6Naphthenic base, 5-6 atom composition Heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is taken Generation.

In some embodiments, each R^a、R^b、R^cAnd R^dIndependently be methyl, ethyl, n-propyl, isopropyl, normal-butyl, Tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidines Base, piperazinyl, tetrahydrofuran base, dihydrofuryl, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, Thiazolyl, thienyl, furyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, pyrrole Piperazine base or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, tetrahydrofuran base, dihydrofuryl, morpholine Base, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, furyl, pyrazolyl, imidazole radicals, three Oxazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, pyrazinyl and pyridazinyl it is unsubstituted each independently or by 1,2, Or 3 R^xIt is replaced.

In some embodiments, R^eAnd R^fIt is each independently ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, ring Butyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, tetrahydrofuran base, dihydro furan Mutter base, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, furyl, pyrazolyl, Imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, pyrazinyl or pyridazinyl, wherein the ethyl, just Propyl, isopropyl, normal-butyl, tert-butyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperazine Piperidinyl, piperazinyl, tetrahydrofuran base, dihydrofuryl, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine Base, thiazolyl, thienyl, furyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, Pyrazinyl and pyridazinyl are unsubstituted each independently or by 1,2 or 3 R^xIt is replaced.

In some embodiments, each R^4a、R^4b、R^4c、R^4d、R^6a、R^6b、R^6c、R^6d、R⁶、R⁹、R¹¹And R¹³Independently be H, Deuterium, F, Cl, Br, I ,=O ,-OH ,-CN ,-NH₂、-NO₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkoxy acyl Base, C_1-4Alkanoyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, The wherein C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkoxyacyl, C_1-4Alkanoyl, C_3-6Naphthenic base, 5-6 Former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 A R^yIt is replaced.

In some embodiments, each R^4a、R^4b、R^4c、R^4d、R^6a、R^6b、R^6c、R^6d、R⁶、R⁹、R¹¹And R¹³Independently be H, Deuterium, F, Cl, Br, I ,=O ,-OH ,-CN ,-NH₂、-NO₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, second Oxygroup, 1- propoxyl group, 2- propoxyl group, methoxyl group acyl group, ethoxyacyl, acetyl group, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, 5-6 former molecular heterocycle, phenyl or 5-6 former molecular heteroaryl, wherein the methyl, ethyl, positive third Base, isopropyl, methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, methoxyl group acyl group, ethoxyacyl, acetyl group, cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl are respectively It is independently unsubstituted or by 1,2 or 3 substituent R^yIt is replaced.

In some embodiments, each R^xAnd R^yIt independently is deuterium, F, Cl, Br, I ,-OH ,-CN, C_1-4Alkyl, C_1-4It is halogenated Alkyl, C_1-4Alkoxy, C_1-4Alkanoyl, C_1-4Alkoxyacyl or C_1-4Alkyl sulphonyl.

In some embodiments, each R^xAnd R^yIt independently is deuterium, F, Cl, Br, I ,-OH ,-CN, methyl, ethyl, positive third Base, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, n-butoxy, tert-butoxy, acetyl group, Methoxyl group acyl group, ethoxyacyl, methyl sulphonyl, ethylsulfonyl, n-propyl sulfonyl or isopropelsulfonyl.

In some embodiments, R^1a、R^1bAnd R^1cIt is each independently H, deuterium, F, Cl, Br, I ,-CN ,-NO₂、-OH、- NH₂、C_1-4Alkyl, C_1-4Alkoxy, C_1-4Halogenated alkyl or C_1-4Halogenated alkoxy.

In some embodiments, R^1a、R^1bAnd R^1cIt is each independently H, deuterium, F, Cl, Br, I ,-CN ,-NO₂、-OH、- NH₂, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, trifluoromethyl or trifluoromethoxy.

In some embodiments, L is methyl, ethyl or n-propyl.

In some embodiments, compound of the present invention is chemical combination shown in formula (II) compound represented or formula (II) The stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or their prodrug,

Wherein, R^1a、R^1b、R^1cThere is meaning described in the invention with W.

In some embodiments, compound of the present invention is the compound of one of,

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydration Object, solvate, metabolite, pharmaceutically acceptable salt or their prodrug.

On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds of the present invention.

In some embodiments, pharmaceutical composition of the present invention, further include pharmaceutically acceptable carrier, Excipient, adjuvant, medium or their combination.

In some embodiments, pharmaceutical composition of the present invention further include it is one or more other activity at Point, the other active components are selected from Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, renin inhibitor, angiotensin II receptor antagonist, beta-receptor and block Agent, acetylsalicylic acid, diuretics, calcium antagonist, Statins, digitalis derivative, calcium sensitizer, nitrate and antithrombus formation Agent.

On the other hand, the present invention relates to compounds of the present invention or pharmaceutical composition of the present invention in preparation two The purposes of peptidyl peptidase-IV (DPP-IV) inhibitor medicaments.

On the other hand, the present invention relates to compounds of the present invention or pharmaceutical composition of the present invention uses in preparation It is anti-in preventing, treating or mitigating diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin Property, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension drug Purposes.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.

There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Close object.Stereoisomer includes enantiomter, diastereoisomer, conformer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S, R)-configuration exist.In certain embodiments, each asymmetric atom There is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer in terms of (R)-or (S)-configuration It is excessive, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% mapping Body is excessive.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

Term " prodrug " used in the present invention represents a compound and is converted into shown in formula (I) or formula (II) in vivo Compound.Such conversion is hydrolyzed in blood by pro-drug or is precursor structure through enzymatic conversion in blood or tissue It influences.Pro-drug compounds of the present invention can be ester, and what ester can be used as pro-drug in existing invention has phenyl ester Class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as the present invention In a compound include hydroxyl, it can be acylated to obtain the compound of prodrug form.Other pro-drugs Form includes phosphate, if these phosphate compounds are obtaining through the di on parent.About pro-drug Complete discuss can refer to following documents: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compounds of this invention.Pharmacy Upper acceptable salt is known to us in fields, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, inorganic acid salt, Such as hydrochloride, hydrobromate, phosphate, sulfate, perchlorate；Acylate, such as acetate, oxalates, maleate, wine Stone hydrochlorate, citrate, succinate, malonate；Or pass through other methods described in the books or literature such as ion exchange Method obtains these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, Digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, phosphoglycerol Salt, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactic acid Salt, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearic acid Salt, rhodanate, tosilate, undecylate, valerate, etc..Include by the salt reacted with alkali appropriate Alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate the compound institute of any group comprising N The quaternary ammonium salt of formation.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.It can be with the alkali gold of forming salt Belong to or alkaline-earth metal includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic The amine cation that ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphorylation Object, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

" nitrogen oxides " of the invention refer to when compound is containing several amine functional groups, can nitrogen by 1 or greater than 1 it is former Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxidation of the N- oxide or nitrogen-containing heterocycle nitrogen-atoms of tertiary amine Object.The corresponding amine formation N- oxide of available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) processing (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent such as methylene chloride, react amine compounds with m- chloroperoxybenzoic acid (MCPBA).

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.

Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, that is, this is retouched It states and includes the case where the case where wherein event or situation occur and do not occur.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.Likewise, for describing mode " ... " independence " in individually optionally ", should also do above-mentioned broad understanding.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C_1-6Alkyl " refers in particular to the C being individually disclosed₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkane Base；"C_1-4Alkyl " refers in particular to the C being individually disclosed₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl (i.e. propyl, including n-propyl and Isopropyl), C₄Alkyl (i.e. butyl, including normal-butyl, isobutyl group, sec-butyl and tert-butyl).

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or The univalent hydrocarbyl group of branch, wherein the substituent group that the alkyl group can be described optionally by one or more present invention It is replaced.In some embodiments, alkyl group contains 1-12 carbon atom；In other embodiments, alkyl group Contain 1-6 carbon atom, i.e. C_1-6Alkyl；In other embodiments, alkyl group contains 2-6 carbon atom, i.e. C_2-6Alkane Base；In other embodiment, alkyl group contains 1-4 carbon atom, i.e. C_1-4Alkyl；Also in some embodiments, alkane Base group contains 1-3 carbon atom, i.e. C_1-3Alkyl；Also in some embodiments, alkyl group contains 2-6 carbon atom, i.e., C_2-6Alkyl.In some embodiments, heretofore described C_1-6Alkyl can be C_1-4Alkyl；In further embodiments, originally C described in invention_1-6Alkyl can be C_1-2Alkyl.

The example of alkyl group includes, but is not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including 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- diformazans Base -2- butyl, n-heptyl, n-octyl, etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.The example of alkoxy base includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group (including 1- propoxyl group or 2- propoxyl group), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy) etc..

Term " halogenated alkyl " or " halogenated alkoxy " indicate alkyl or alkoxy base by one or more halogen atoms Replaced, such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy, chloroethyl (for example, 2- chloroethyl), three Fluoro ethyl (for example, 2,2,2- trifluoroethyls), 2,2- bis-fluoro ethyls, the chloro- 1- Methylethyl of 2- etc..

Term " alkoxyacyl " indicates that alkoxy base is connected by-C (=O)-with molecule rest part, i.e.-C (= O)-alkoxy, wherein alkoxy base has meaning as described in the present invention.In some embodiments, alkoxyacyl base 1-6 carbon atom, i.e. C are contained in group_1-6Alkoxyacyl；In other embodiments, alkoxyacyl group contains 1-4 Carbon atom, i.e. C_1-4Alkoxyacyl；In other embodiment, alkoxyacyl group contains 1-2 carbon atom, i.e. C_1-2 Alkoxyacyl.Such example includes, but is not limited to, methoxyl group acyl group (- C (=O) O-CH₃), ethoxyacyl (- C (=O) O-CH₂CH₃) ,-C (=O) O-CH (CH₃)₂。

Term " alkanoyl " indicates that alkyl group is connected by-C (=O)-with molecule rest part, i.e.-C (=O)-alkane Base, wherein alkyl group has meaning as described in the present invention.In some embodiments, alkanoyl groups contain 1-6 carbon Atom, i.e. C_1-6Alkanoyl；In other embodiments, alkanoyl groups contain 1-4 carbon atom, i.e. C_1-4Alkanoyl；? In other embodiment, alkanoyl groups contain 1-2 carbon atom, i.e. C_1-2Alkanoyl.Such example includes, but not It is limited to, acetyl group (- C (=O) CH₃)。

Term " alkyl sulphonyl " indicates that alkyl group passes through-S (=O)₂Be connected with molecule rest part, i.e.-S (=O)₂- Alkyl, wherein alkyl group has meaning as described in the present invention.In some embodiments, alkyl sulphonyl contains 1-6 Carbon atom, i.e. C_1-6Alkyl sulphonyl；In some embodiments, alkyl sulphonyl contains 1-4 carbon atom, i.e. C_1-4Alkyl sulphur Acyl group；In some embodiments, alkyl sulphonyl contains 1-2 carbon atom, i.e. C_1-2Alkyl sulphonyl.Such example packet It includes, but is not limited to, methyl sulphonyl (- S (=O)₂CH₃), ethylsulfonyl (- S (=O)₂CH₂CH₃), n-propyl sulfonyl (- S (=O)₂CH₂CH₂CH₃), isopropelsulfonyl (- S (=O)₂CH(CH₃)₂)。

Term " amino " indicates group-NH₂。

Term " carboxyl " indicates group-COOH.

Term " hydroxyl " indicates group-OH.

Term " cyano " indicates group-CN.

Term " nitro " indicates group-NO₂。

Term " oxo " represents group=O.

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " naphthenic base " indicates the saturation monocyclic, bicyclic or tricyclic system containing 3-12 ring carbon atom.In some realities It applies in scheme, naphthenic base includes 3-10 ring carbon atom, such as C_3-10Naphthenic base；In other embodiments, naphthenic base packet Containing 3-8 ring carbon atom, such as C_3-8Naphthenic base；In other embodiments, naphthenic base includes 3-6 ring carbon atom, such as C_3-6Naphthenic base；In other embodiments, naphthenic base includes 4-6 ring carbon atom, such as C_4-8Naphthenic base.Group of naphthene base Example include, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, etc.；Wherein, institute The C stated_3-6Naphthenic base includes cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl；The C_4-6Naphthenic base includes cyclobutyl, ring penta Base and cyclohexyl.Replaced the substituent group that the group of naphthene base can be described optionally by one or more present invention.

Term " heterocycle " refers to comprising 3-12 annular atom, saturation or the unsaturated monocyclic, bicyclic or tricyclic in part System, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom；Wherein, the heterocycle is nonaromatic, and is not included Any aromatic rings.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH₂Group can optionally by-C (= O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.Term " heterocycle " can be used interchangeably with term " heterocycle ".The heterocyclyl groups can be optionally by one or more Replaced the substituent group that a present invention describes.The example of heterocycle includes, but are not limited to: Oxyranyle, azelidinyl, oxygen It is heterocycle butyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidyl, morpholinyl, thio Quinoline base, piperazinyl, tetrahydrofuran base, dihydrofuryl, etc..The heterocyclyl groups can be optionally one or more Replaced substituent group described in the invention.

Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring is aromatic, and has remaining of one or more attachment points and molecule Part is connected.Term " aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".Unless otherwise stated, group " C_6-10 Aryl " indicates the aryl group containing 6-10 ring carbon atom.The example of aryl group may include phenyl, 2,3- dihydro -1H- Indenyl, naphthalene and anthryl.Replaced the substituent group that the aryl group can be described optionally by one or more present invention.

Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring are aromatic, and at least one ring include 1,2,3 or 4 selected from nitrogen, oxygen, The ring hetero atom of sulphur, meanwhile, the heteroaryl has one or more attachment points to be connected with molecule rest part.Work as heteroaryl groups Middle presence-CH₂When group ,-the CH₂Group can be substituted optionally by-C (=O)-.Unless otherwise stated, described Heteroaryl groups can be connected to molecule rest part by any reasonable site (can be N in the C or NH in CH) In (such as main structure in general formula).Term " heteroaryl " can be exchanged with term " hetero-aromatic ring " or " heteroaromatics " to be made With.In some embodiments, heteroaryl is 5-10 former molecular heteroaryl, and it is former to indicate that heteroaryl contains 1-9 ring carbon Son and 1,2,3 or 4 ring hetero atom selected from O, S and N；In other embodiments, heteroaryl is 5-6 former molecular Heteroaryl indicates that heteroaryl contains 1-5 ring carbon atom and 1,2,3 or 4 ring hetero atom selected from O, S and N.Such example It includes, but is not limited to, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrrole radicals, pyrazolyl, imidazole radicals, triazolyl, four Oxazolyl, oxazolyl, isoxazolyl, oxadiazoles base, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, thienyl, thiazolyl, etc.. Replaced the substituent group that the heteroaryl groups can be described optionally by one or more present invention.

As described in the present invention, substituent R is keyed to the ring system formed on the ring at center by one and represents and replaces Base R any on coupled ring may only may replace or any reasonable position is replaced.Replace for example, formula b is represented Base R can replace any possible substituted position on C ring, but cannot be substituted on D ring, as shown in formula b-1 to b-3:

Term " pharmaceutical composition " indicate one or more compounds described herein or its physiologically/pharmaceutically can be with The mixture of the salt or pro-drug of receiving and other chemical constituents, other components for example physiologically/can pharmaceutically receive Auxiliary materials and the anti-diabetic reagent, anti-high blood such as carrier, excipient, adjuvant, medium, diluent, adhesive, filler Sugared reagent, anti-obesity reagent, anti-hypertension reagent, antiplatelet reagent, antiatherosclerotic agents or lipid-lowering agents Etc. additional therapeutic agents.The purpose of pharmaceutical composition is to promote the administration of compound on organism body.

Term " pharmaceutically acceptable " refers to when applying pharmaceutical formulation to people and general does not generate allergy Or the molecular entity and composition of similar unsuitable reaction, such as digestive discomfort, dizziness etc..Preferably, used herein Term " pharmaceutically acceptable " refers to federal regulator or national government are ratified or United States Pharmacopeia or other general approvals Pharmacopeia using in animal, particularly in human body of lifting.

Term " carrier " refers to the diluent applied together with the compound, adjuvant, excipient or matrix.These drugs carry Body can be sterile liquid, such as water and oils, including petroleum, animal, plant or synthesis source, such as peanut oil, soybean Oil, mineral oil, sesame oil etc..Water and aqueous solution (for example, saline solution, glucose solution, glycerine water solution) are preferably used Make carrier, particularly Injectable solution.Suitable pharmaceutical carrier is described in the " Remington ' s of E.W.Martin In Pharmaceutical Sciences ".

Term " X syndrome ", the also referred to as illness of metabolic syndrome, disease, illness are specified in Johannsson et Al., in J.Clin.Endocrinol.Metab., 1997,82,727-734.

" the compound of the present invention " used in the present invention, " compound described in the invention ", " of the present inventionization Close object " or similar statement, all refer in the present invention compound representated by formula (I) or formula (II).

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as³H,¹⁴C and¹⁸Those of F compound, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for being metabolized research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.

In addition, higher isotope especially deuterium (that is,²H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of formula (I) or formula (II) compound.Isotope enrichment can be used The factor defines the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to Ratio between the isotope abundance and natural abundance of specified isotope.If the substituent group of the compounds of this invention is designated as Deuterium, the compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), extremely for each specified D-atom Few 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 DMSO-d₆Those of solvate.

Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.

The abbreviation of any blocking group, amino acid and other compounds used in the present invention, unless otherwise indicated, all with Subject to their usually used, generally acknowledged abbreviations, or referring to IUPAC-IUBCommission on Biochemical Nomenclature (referring to Biochem.1972,11:942-944).

Pharmaceutical composition, preparation, administration and the purposes of the compounds of this invention

On the other hand, the characteristics of pharmaceutical composition of the invention includes the ammonia that aryl shown in formula (I) or formula (II) replaces Base oxinane class compound, the present invention listed by compound or embodiment compound and pharmaceutically acceptable load Body, excipient, adjuvant, medium or their combination.The amount of compound can effectively treat or subtract in composition of the invention The disease relevant to dipeptidyl peptidase-IV (DPP-IV) of light patient.

As described in the present invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load Body, excipient, adjuvant, medium or their combination, these are as applied by the present invention, including any solvent, diluent, or Other liquid excipients, dispersing agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid adhesion Agent or lubricant, etc. are suitable for distinctive target formulation.As described in following documents: In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology, Eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, comprehensive document herein Content, show that different carriers can be applied to the preparation and their well known preparation methods of pharmaceutically acceptable composition. In addition to any conventional carrier medium range incompatible with the compound of the present invention, such as generated any undesirable biology Effect or the interaction generated in harmful manner with any other component of pharmaceutically acceptable composition, their use Way is also the range that the present invention is considered.

The substance that can be used as pharmaceutically acceptable carrier includes, but is not limited to, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate are saturated vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；The derivative of cellulose and it Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Rouge and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Object, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethyl alcohol, phosphate buffer solution and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and perfume (or spice) Material, preservative and antioxidant.

Pharmaceutical composition of the invention can be directly administered or in company with suitable carrier or excipient with medical composition or medicine The administration of object form, this is known in the art.Treatment method of the invention may include imposing effectively to individual in need The compounds of this invention.In some embodiments, the individual is mammalian subject, and in certain preferred embodiments In, the individual is human individual.

The effective quantity of compound of the present invention, pharmaceutical composition or drug can readily be measured by routine experiment, most It can also effectively be measured by routine experiment with convenient administration route and optimal preparation.

The pharmaceutical dosage form of the compound of the present invention can be provided in the form of quick-release, controlled release, sustained release or target drug delivery system. For example, common formulations include solution and suspension, (micro-) lotion, ointment, gel and patch, liposome, tablet, dragee, Soft shell or hard-shell capsule, suppository, ovule, implantation material, amorphous or crystalline powder, aerosol and lyophilized preparation.It is given depending on used Depending on medicine approach, it may be necessary to drug is applied or given to special device, such as syringe and needle, inhalator, pump, injection pen, Medicator or special-purpose bottle (Special flask).Pharmaceutical dosage form is usually made of drug, excipient and container/sealing system.It can One or more excipient (also known as non-active ingredient) are added in the compound of the present invention to improve or promote drug Manufacture, stability, administration and safety, and can provide the method for obtaining required drug release patterns.Therefore, it is added to drug In excipient type can be depending on various factors, such as the physics and chemical characteristic of drug, administration route and preparation step.? There are pharmaceutical excipient and including those of listed in various pharmacopeia in the field.(referring to United States Pharmacopeia (U.S.Pharmacopeia, USP), Japanese Pharmacopoeia (Japanese Pharmacopoeia, JP), European Pharmacopoeia (European Pharmacopoeia, EP) and British Pharmacopoeia (British pharmacopoeia, BP)；U.S. Food and Drug Administration (the U.S.Food and Drug Administration, www.fda.gov) drug evaluation and research center (Center For Drug Evaluation and Research, CEDR) publication, such as " inactive ingredients guide " (Inactive Ingredient Guide,1996)；" medicated premix handbook " (Handbook of that Ash and Ash writes Pharmaceutical Additives, 2002, united information resource company (Synapse Information Resources, Inc.,Endicott NY；etc.).

The pharmaceutical dosage form of the compounds of this invention can be manufactured by any method well known in the art, such as by normal Rule mixing, dissolution, fusing, is granulated, manufacture dragee, tabletting, suspension, extruding, spray drying, grinding, emulsification, (receives screening Rice/micron order) it is encapsulated, Bao Li or lyophilized technique.As described above, composition of the invention may include one or more kinds of lifes Acceptable non-active ingredient in Neo-Confucianism, these non-active ingredients can promote bioactive molecule to be machined for the system of medical usage Agent.

Depending on administration route of the preparation appropriate needed for.For example, composition can be formulated in water for intravenous injection In solution, use the buffer of physical compatibility when necessary, including for example for adjust the phosphate of preparation pH value, histidine or Citrate, and the tonicity agent of such as sodium chloride or dextrose.For transmucosal or nasal administration, can preferred semisolid, Liquid preparation or patch may contain penetration enhancers；The bleeding agent is usually known in the art.For oral administration For, compound can be configured to liquid or solid dosage form and as quick-release or controlled release/sustained release preparation.For individual orally ingestible Dosage forms include tablet, pill, dragee, hard shell and soft shell capsule, liquid, gel, syrup, paste, suspension and cream Liquid.Compound can also be formulated in rectal compositions, such as suppository or enema,retention, such as contain conventional suppository base Matter such as cocoa butter or other glyceride.

Excipient can be used to obtain for solid oral dosage form, the excipient include filler, disintegrating agent, adhesive (it is dry and It is wet), dissolution delayer, lubricant, glidant, antiplastering aid, cationic exchanger resin, wetting agent, antioxidant, preservative, Colorant and flavoring agent.These excipient can be synthesis or natural origin.The example of the excipient include cellulose derivative, Citric acid, Dicalcium Phosphate, gelatin, magnesium carbonate, lauryl magnesium sulfate/NaLS, mannitol, polyethylene glycol, poly- second Alkene pyrrolidone, silicate, silica, sodium benzoate, D-sorbite, starch, stearic acid or its salt, sugar (i.e. dextrose, sugarcane Sugar, lactose etc.), talcum, tragacanth mucilage (tragacanth mucilage), vegetable oil (hydrogenation) and wax.Second alcohol and water is available Make granulation aid.In certain situations it is desirable to such as taste masking film, anti-gastric acid film or delay to discharge film come coated tablets.Usually It combines natural and synthesis polymer with colorant, sugar and organic solvent or water and is used for coated tablets, to generate sugar-coat medicine Ball.When capsule is better than tablet, its drug powder, suspension or molten can be delivered with compatible hard shell or soft shell capsule form Liquid.

In some embodiments, the compound of the present invention can local administration, such as pass through dermal patch, semisolid or liquid Body preparation, such as gel, (micro-) lotion, ointment, solution, (Nano/micron grade) suspension or foam.The skin and lower layer's group of drug Knitting infiltration can be adjusted in the following manner: for example using penetration enhancers；Use lipophilicity, hydrophily and amphipathic excipient Appropriate selection and combination, including water, organic solvent, wax, oil, synthesis and natural polymer, surfactant, emulsifier； By adjusting pH value；With use complexing agent.Such as other technologies of ionotherapy (iontophoresi) can be used for Adjust the Cutaneous permeation of the compound of the present invention.It, will be first such as in the case of needing with minimum systemic exposed local administration Select transdermal or local administration.

For through inhalation or nasal administration, compound used according to the invention is with solution, suspension, lotion Or the form of semisolid aerosol is easily administered from compression package or sprayer, generally by means of propellant, such as derived from The halohydrocarbon of methane and ethane, carbon dioxide or any other suitable gas.For local aerosol, such as butane, different The hydrocarbon such as butylene and pentane are applicable.In the case where pressurised aerosol, dosage unit appropriate can be by providing valve transmitting Metering is to measure.The capsule and cylindrantherae with such as gelatin that can be formulated in inhalator or insufflator.These are usually contained The mixture of powders of compound and suitable powder base (such as lactose or starch).

For being usually sterile and can be mentioned with unit dosage forms by injecting the composition that parenteral administration is prepared For, such as ampoule bottle, syringe, injection pen or multi-dose container, the latter usually contain preservative.Composition can be used in oil Forms such as property or the suspension in aqueous carrier, solution or lotion, and reagent preparation can be contained, for example, buffer, tonicity agent, Viscosity intensifier, surfactant, suspending agent and dispersing agent, antioxidant, biocompatible polymer, intercalating agent and anti-corrosion Agent.Depending on injection site, the carrier can contain water, synthesis or vegetable oil and/or organic cosolvent.In some cases, Such as lyophilized products or concentrate, can parenteral preparation be recombinated or be diluted before administration.It provides of the invention The controlled release of compound or the depot formulation (depot formulation) of sustained release may include Nano/micron grade particle or nanometer/ The injectable suspensions of micron order or non-miniaturization crystal.This field it is other known to matrix, poly- (lactic acid), poly- (glycolic) or The polymer such as its copolymer are used as controlled release/sustained-release matrix.It can be to provide it in the form of the implantation material and pump that need notch Its reservoir devices (depot) drug delivery system.

The suitable carrier of the compounds of this invention for intravenous injection is known in the art and including containing alkali (such as Sodium hydroxide) group water solution, be used to form ionic compound；Sucrose or sodium chloride as tonicity agent；Such as contain phosphoric acid The buffer of salt or histidine.The cosolvent such as polyethylene glycol can be added.These aqueous based systems can effectively dissolve change of the invention It closes object and generates hypotoxicity after systemic applications.In the case where not destroying dissolubility and toxic characteristic, can change significantly The ratio of the component of solution system.In addition, the characteristic of changeable component.For example, such as polysorbate or pool can be used The hypotoxicity surfactant of Luo Shamu (poloxamer), it is possible to use polyethylene glycol or other cosolvent can add such as poly- The biocompatible polymer of vinylpyrrolidone, and dextrose can be substituted with other sugar and polyalcohol.

The compounds of this invention can whole body and/or local action.They can be administered in a suitable manner, for example, passing through mouth Clothes administration, through enteral administration, transpulmonary administration, nose administration, sublingual administration, through tongue administration, buccal, rectally, transdermal administration, Percutaneous dosing, conjuctival administration, ear canal administration are administered as graft or bracket.The compounds of this invention preferably oral administration Or parenteral administration.

The suitable administration mode of oral administration is as follows: the mode to be worked according to the prior art, discharges rapidly and/or with improvement Method discharge the administration mode of the compound of the present invention, they include crystallization and/or sheets of amorphous and/or dissolution form The compound of invention, for example, tablet (uncoated tablets or for example with control the compound of the present invention release gastric fluid-resistant or It is delayed dissolved or insoluble be coated the tablet that is coated), the tablet of rapid fragmentation or film/thin slice, thin in the oral cavity Film/freeze-drying body, capsule (such as hard capsule or soft capsule), sugar coated tablet, granule, pill, pulvis, emulsion, suspension, gas are molten Glue or solution.

Parenteral administration can be around absorption step (such as in intravenous, intra-arterial, cardia, in intraspinal or waist) or packet Include absorption (such as: intramuscular absorption, subcutaneous absorption, it is intradermal absorb, percutaneous absorbtion or intraperitoneal absorption).It is suitable for parenteral administration Form of medication include solution, suspension, lotion, freeze-drying body or sterile powder the preparation for injecting and being transfused.

For other administration routes, suitable example is the medicament forms (including powder inhalator, sprayer) of sucking, drop Nose agent, solution or spray, for tongue, sublingual or buccal administration tablet, film/thin slice or capsule, suppository, ear or eye system Agent, vaginal capsule, aqueous suspension (lotion, shake mixture), lipophilic suspensions, ointment, creme, transdermal therapeutic system (such as Patch), emulsion (Milch), paste, foam, sprinkling pulvis, implantation material or bracket.

The therapeutically effective amount of the compounds of this invention should be with entire mixture about 0.1 to 99.5%, preferably from about 0.5 to The concentration of 95% weight is present in said medicine preparation.

In addition to the compounds of this invention, said medicine preparation can also include other medicines active constituent.

Treatment effective dose can be estimated using various methods well known in the art first.For the initial of zooscopy Dosage can be based on the effective concentration established in cell culture measurement.Be suitable for individual human dosage range for example can be used it is driven Object research and cell culture measure data obtained to determine.It in certain embodiments, can be by the compound of the present invention It is prepared as oral medicament.The compound of the present invention is being from about 0.01 for the illustrative dosage in oral medicament To about 100mg/kg (the wherein weight that kg indicates subject).In some embodiments, medicament includes from about 0.01 to about 20mg/kg (the wherein weight that kg indicates subject), or optionally from about 0.01 to about 10mg/kg, (wherein kg is indicated tested The weight of person), or optionally from about 0.01 to about 5.0mg/kg (the wherein weight that kg indicates subject).In some embodiments In, for the compounds of this invention through enteral administration, effective dosage is about 0.001-1mg/kg, preferably approximately 0.01- 0.5mg/kg weight.

Dosage regimen commonly used in the medicament of oral administration be three-times-weekly, twice a week, once a week, daily three It is secondary, twice daily or once a day.In certain embodiments, the compounds of this invention as active constituent with every 24 hours about 0.001 to about 50, preferably 0.001 is administered to the total amount of 10mg/kg weight, in order to obtain required as a result, optional can be with It is administered in the form of multiple single doses.One single dose preferably may include dosage be about 0.001 to about 30, it is special Be not 0.001 to 3mg/kg weight the compounds of this invention.

The effective quantity or therapeutically effective amount or dosage of medicament (such as the compound of the present invention) refer to causing individual symptom The amount of the medicament or compound of improvement or prolonging survival.The toxicity and therapeutic efficiency of the molecule can be in cell culture or experiments It is measured in animal by standard pharmaceutical program, such as by measuring LD₅₀(the 50% lethal dosage for making group) and ED₅₀It is (right The 50% effective dosage for the treatment of of group).Toxic effect and the dose ratio of therapeutic effect are therapeutic indexs, are represented by LD₅₀/ ED₅₀.The medicament of preferred display high therapeutic index.

Effective quantity or therapeutically effective amount will cause researcher, animal doctor, doctor or other clinicians and be sought Tissue, system, the amount of the compound of the biology of animals or humans or medical response or medical composition.Dosage is preferably including pole Small toxicity or avirulent ED₅₀Circulation composition in the range of.Dosage can change within this range, depending on used dosage form and/ Or depending on administration route used.Should according to procedures known in the art, it is correct to select to consider the particularity of individual state Preparation, administration route, dosage and delivery time.

Dosage and interval time can individually be adjusted to provide the blood plasma for the active part for being enough to obtain required effect It is horizontal；That is minimum effective concentration (minimal effective concentration, MEC).The MEC of each compound will Difference, but can be for example from external (in vitro) data and zoopery estimation.Individual will be regarded by obtaining dosage necessary to MEC Depending on feature and administration route.In the case where local administration or selectivity intake, effective local concentration of drug may be with blood It is unrelated to starch concentration.

The amount of the medicament or composition bestowed can depending on various factors, including treat individual gender, the age and Weight, ailing seriousness, administration mode and the judgement of prescriber.

When needed, composition of the invention can with contain one or more unit dosage forms (containing active constituent) Packaging or distributor provide.For example, it is described packaging or device may include metal or plastic foil (such as blister pack) or Glass and rubber stopper.The packaging or distributor can have medication instruction book.It can also prepare and be carried included in compatible sex medicine The composition for the compounds of this invention prepared in body, places it in appropriate containers, and plus for treating specified symptom Label.

The compound of the present invention can be individually alternatively, if desired, be used in combination with other reactive compounds.The present invention is also It provides including at least one the compound of the present invention and one or more further active materials, especially for treating And/or the drug of prevention disease of the present invention is used in combination.

The compound of the present invention is as DPP-IV inhibitor and shows the valuable pharmacotoxicological effect range that cannot be predicted. They are consequently adapted to be used as the drug for treating and/or preventing human and animal's disease.DPP-4 inhibitor can increase blood In active patio GIP (glucose-dependent-insulinotropic polypeptide) and GLP-1 (glucagon kind polypeptide-1) concentration, To promote insulin secretion, glucagon suppression abnormal secretion mitigates gastric emptying, reduces blood glucose level.Therefore, of the invention Compound will be applied to diabetes and related disease the symptom prevented, treated or improve these diseases.

The compound of the present invention will be applied to, but be not limited to, and use having for the compound of the present invention or pharmaceutical composition Effect amount administers to a patient to prevent, treat or mitigate diabetes mellitus and related disease or the damage of diabetes later period.It is such Disease includes, but is not limited to diabetes, especially type-2 diabetes mellitus and diabetic retinopathy, diabetic nerve Disease, nephrosis, insulin resistance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, especially high glycerine three Ester mass formed by blood stasis, X syndrome, atherosclerosis or hypertension.

The compound of the present invention is in addition to beneficial to other than, applying also for veterinary treatment pet, introduced variety to human treatment Animal and farm animal, including mammal, rodent etc..The example of other animal include horse, dog and Cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.

The compound of the present invention can be used alone or, being used in combination if necessary with other active constituents.This hair It is bright further to including at least one the compound of the present invention and one or more another active constituents (especially for controlling Treat and/or prevent above-mentioned illness) drug.Suitable active constituent for combination for example and preferably:

DPP-IV inhibitor, for example, Xi Gelieting (sitagliptin), vildagliptin (vidagliptin), A Ge Arrange spit of fland (alogliptin), Li Gelieting (linagliptin), saxagliptin (saxagliptin), Ao Gelieting (omarigliptin) and song Ge Lieting (trelagliptin)；

Biguanides, for example, insoral, melbine (metformin)；

Sulfonylureas, for example, acetodexamide, chlorpropamide (diabinese), glibenclamide (glibenclamide, glibenclamide), Glipizide (glipizide, Glipizide), (gliclazide reaches gliclazide Meikang), Glimepiride (glimepiride), Glipentide (glipentide), gliquidone (gliquidone), appropriate drawing sulphur Urea, orinase and meglitinide (meglitinide)；

Glinides, for example, Repaglinide and Nateglinide；

Alpha-glucosaccharase hydrolase inhibitor, for example, acarbose (acarbose)；

Alpha-glucosidase restrainer, for example, esterlysis is plain, Camiglibose (camiglibose), emiglitate (emiglitate), Miglitol (miglitol), voglibose (voglibose), pradimicin (pradimicin) and Husky glass rhzomorph (salbostatin)；

PPAR agonist, for example, Ba Lalie ketone (balaglitazone), Ciglitazone (ciglitazone), Da Ge Column ketone (darglitazone), Englitazone (englitazone), Ai Shalie ketone (isaglitazone), Pioglitazone (pioglitazone), Rosiglitazone (rosiglitazone) and troglitazone (troglitazone)；

The bis- activator of PPAR α/γ, for example, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L- 796449, LR-90, MK-0767 and SB-219994；

Glucagon-like-peptide-1 (GLP-1) agonist, for example, first -3 (exendin-3) of element of second and the first element -4 of second (exendin-4)；

Protein tyrosine phosphatase -1B (PTP1B) inhibitor, for example, curvature Kui Ming, Hai Tisuo extract and by Zhang, S. et al., modern medicines discovery, 12 (9/10), compound disclosed in 373-381 (2007)；

Sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor, such as Dapagliflozin (Dapagliflozin), grace Lattice arrange net (Empagliflozin), canagliflozin (Canagliflozin), Ipragliflozin (ASP-1941), Tofogliflozin, Luseogliflozin and Jung column are net.

Insulin, insulin are quasi- like object, glycogen phosphorglase inhibitor；

VPAC2 receptor stimulating agent；

Activators of glucokinase；

Glycogen phosphorylase inhibitors or Robison ester enzyme inhibitor；

α P2 inhibitor；

Acetyl-CoA carboxylase -2 (ACC-2) inhibitor；

- 10 inhibitor of phosphodiesterase (PDE)；

1 or 2 inhibitor of diacylglycerol acyltransferase (DGAT)；

Glucose transporter 4 (GLUT4) regulator；

Glutamine-fructose-6-phosphate amide transferase (GFAT) inhibitor.

General synthesis process

In the present specification, if there are any difference between chemical name and chemical structure, structure is dominant.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment is for further lifting Example illustrates the contents of the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare this Invention other compounds, and other methods for the preparation of the compounds of the present invention be considered as the scope of the present invention it It is interior.For example, the synthesis of the compound of those non-illustrations can successfully be passed through by those skilled in the art according to the present invention Method of modifying is completed, such as protection interference group appropriate, by using other known reagent in addition to described in the invention, or Reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also admittedly fitted Preparation for other compounds of the invention.

The structure of compound be by nuclear magnetic resonance (¹H-NMR、¹³C-NMR or/and¹⁹F-NMR it) determines.¹H-NMR、¹³C-NMR、¹⁹F-NMR chemical shift (δ) is provided with the unit of hundred a ten thousandths (ppm).¹H-NMR、¹³C-NMR、¹⁹The survey of F-NMR It surely is with 600 nuclear magnetic resoance spectrum of Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD Instrument, measurement solvent are deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄) or deuterated dimethyl sulfoxide (DMSO- d₆).Use TMS (0ppm) or chloroform (7.25ppm) as reference standard.When there is multiplet, following contracting will be used It writes: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), and dd (doublet of doublets, double doublet), dt (doublet of triplets, double three Weight peak), td (triplet of doublets, three doublets), brs (broadened singlet, width unimodal).Coupling constant J, unit are indicated with hertz (Hz).

Preparation purifying or preparation, which are split, generally uses 250 high performance liquid chromatograph of Novasep pump.

The measurement of LC-MS Agilen-6120Quadrupole LC/MS mass spectrograph.

Column chromatography is generally carrier using 300 mesh of Qingdao Haiyang chemical industry~400 mesh silica gel.

Starting material of the invention is known, and can be bought on the market, is bought from Shanghai Shao Yuan company (Shanghai Accela Company), Ann Kyrgyzstan company (Energy Company), Bellingwell company (J&K), Tianjin Ah method The companies such as Ai Sha company (Alfa Company), can either use or synthesize according to methods known in the art.

Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere；

Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon or steel kettle of an about 1L volume；

Atmosphere of hydrogen refers to that reaction flask connects the stainless of hydrogen balloon either about 1L volume of an about 1L volume Steel autoclave；

If without specified otherwise in embodiment, solution refers to aqueous solution；

If reaction temperature is room temperature without specified otherwise in embodiment；

If room temperature is 20 DEG C~30 DEG C without specified otherwise in embodiment.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have: methylene chloride and methanol system, methylene chloride and ethyl acetate system, petroleum ether and ethyl acetate system, the volume of solvent It is adjusted than the polarity difference according to compound.

The system of the eluant, eluent of column chromatography includes: A: petroleum ether and ethyl acetate system, B: methylene chloride and ethyl acetate System, C: methylene chloride and methanol system.The volume ratio of solvent is different according to the polarity of compound and is adjusted, and can also add Enter a small amount of ammonium hydroxide and acetic acid etc. to be adjusted.

HPLC refers to high performance liquid chromatography；

The measurement of HPLC using 1260 high pressure liquid chromatograph of Agilent (Eclipse Plus C18,4.6 × 150mm, 5um chromatographic column)；

HPLC test condition: column temperature: 35 DEG C of PDA:210nm, 254nm

Mobile phase: A phase: 0.1% phosphoric acid B phase: Acetonitrile Flow rate: 1.0mL/min

Eluent gradient is as in Table A:

Table A

The LC/MS/MS system of analysis in biological test test includes the serial vacuum degassing furnace of Agilent 1200, and two First syringe pump, orifice plate automatic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars in the source (ESI) Mass spectrograph.Quantitative analysis carries out under MRM mode, MRM conversion parameter as shown in tableb:

Table B

More reaction detection scannings	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	0.28MPa
		Drier flow velocity	10L/min

Analysis uses μM column of Agilent XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition: mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in C:

Table C

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	It terminates

In addition, the also 6330 series LC/MS/MS spectrometer of Agilent for analysis, is infused equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrometer uses ESI radioactive source.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversion carries out optimal analysis.It uses during analysis Capcell MP-C18 column, specification are as follows: 100 × 4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70/ 30,v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.

The use of logogram word below is through the present invention:

Following synthetic schemes describes the step of preparation disclosed compound of present invention.Wherein, unless otherwise stated, W has Meaning as described in the present invention.

Synthetic schemes

Synthetic schemes 1

Compound (I-A) can be prepared by method described in synthetic schemes 1.Compound (I-a) and compound (I-b) reductive amination process occurs under the conditions of reducing agent (for example, sodium triacetoxy borohydride, decaborane, etc.) is existing Obtain compound (I-c).Compound (I-c) removes the protecting group Boc on amino, obtains the compound of structure shown in formula (I-A).

The following examples can be with the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright range.

Embodiment

Prepare embodiment

Embodiment 1 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.5] Nonane -2- base) oxinane -3- amine

Step 1) 7- mesyl -2,7- diazaspiracyclic [3.5] nonane -2- t-butyl formate

2,7- diazaspiracyclic [3.5] nonane -2- t-butyl formate (0.50g, 1.5mmol) is dissolved in tetrahydrofuran (8mL) is added triethylamine (0.62mL, 4.5mmol), is slowly dropped into mesyl chloride (0.21mL, 2.7mmol) at 0 DEG C, keeps 0 DEG C reaction 1.5 hours.Water (10mL) quenching reaction is added, is extracted with ethyl acetate (30mL), organic phase saturated sodium-chloride is molten Liquid (10mL × 3) washing, anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [petrol ether/ethyl acetate (v/ V) it=3/1] purifies, obtains title compound (0.67g, yield 99%), be white solid.

MS(ESI,pos.ion)m/z:249.2[M-55]⁺。

Step 2) 7- mesyl -2,7- diazaspiracyclic [3.5] nonane hydrochloride

7- mesyl -2,7- diazaspiracyclic [3.5] nonane -2- t-butyl formate (0.67g, 2.2mmol) is dissolved in The ethanol solution (6mL, 2.0mol/L) of hydrogen chloride is added in ethyl acetate (2mL), reacts at room temperature 1.5 hours.Filtering, solid are used Ethyl acetate (5mL) washing, collects filter cake, obtains title compound (0.51g, yield 96%), is white solid.

MS(ESI,pos.ion)m/z:205.2[M-Cl]⁺。

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.5] nonane -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.20g, 0.61mmol) and 7- mesyl -2,7- diazaspiracyclic [3.5] nonane hydrochloride (0.15g, 0.62mmol) are molten At n,N-dimethylacetamide (3mL), 0 DEG C, nitrogen protection is added sodium triacetoxy borohydride (0.33g, 1.5mmol), Room temperature reaction 8 hours.Ammonia/water (v/v=2/3,10mL) quenching reaction is added, the solid being obtained by filtration is through silica gel column chromatography [100% ethyl acetate] purifying, obtains title compound (0.17g, yield 54%), is yellow solid.MS(ESI,pos.ion) m/z:516.4[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.5] nonyl Alkane -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.5] nonyl Alkane -2- base) tetrahydropyran -3-base] t-butyl carbamate (0.30g, 0.58mmol) is dissolved in ethyl alcohol (0.5mL), chlorination is added The ethanol solution (3mL, 2.0mol/L) of hydrogen reacts at room temperature 1 hour.It is concentrated under reduced pressure, is added ethyl alcohol (2.0mL), uses sodium bicarbonate Solid adjusts pH=8, filtering, and filtrate is concentrated, and residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], Title compound (73mg, yield 30%, HPLC purity 90.9%) is obtained, is white solid.

MS(ESI,pos.ion)m/z:415.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.30 (s, 1H), 7.07-6.93 (m, 2H), 4.22 (d, J=9.4Hz, 1H), 3.92 (d, J=12.4Hz, 1H), 3.54 (d, J=11.0Hz, 1H), 3.21 (t, J=5.5Hz, 4H), 3.13 (d, J= 21.3Hz, 4H), 2.79 (s, 3H), 2.50 (s, 1H), 2.13 (d, J=12.7Hz, 1H), 1.92 (t, J=8.3Hz, 4H), 1.52-1.41(m,2H)。

Embodiment 2 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.4] Octane -2- base) oxinane -3- amine

Step 1) 2,7- diazaspiracyclic [3.4] octane -7- carboxylate

Sodium bicarbonate (10.0g, 119mmol) is added to 2,7- diazaspiracyclic [3.4] octane -7- carboxylate In water (10mL) solution of oxalates (3.0g, 9.9mmol), react at room temperature 1.5 hours.With methylene chloride/methanol (v/v=9/ 1,80mL × 3) it extracts, combined organic phase is washed with saturated sodium chloride solution (50mL × 2), and anhydrous sodium sulfate is dry, is filtered Concentration, obtains title compound (1.68g, yield 80%), is yellow oil.

MS(ESI,pos.ion)m/z:213.1[M+H]⁺。

Step 2) O2- benzyl O7- tert-butyl 2,7- diazaspiracyclic [3.4] octane -2,7- dicarboxylic acid esters

At 0 DEG C, triethylamine (2.1mL, 15.0mmol) and benzyl chloroformate (2.2mL, 15.0mmol) is added sequentially to In methylene chloride (20mL) solution of 2,7- diazaspiracyclics [3.4] octane -7- carboxylate (1.6g, 7.5mmol), room Temperature reaction 21 hours.It is added water (5mL), liquid separation, organic phase is washed with saturated sodium chloride solution (5mL × 2), and anhydrous sodium sulfate is dry It is dry, concentration is filtered, residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=3/1], obtains title compound (1.8g, yield 69%) is yellow oil.

MS(ESI,pos.ion)m/z:370.3[M+Na]⁺。

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.41-7.24 (m, 5H), 5.11 (s, 2H), 3.92 (dd, J=23.0, 9.3Hz, 4H), 3.53-3.30 (m, 4H), 2.04 (d, J=4.9Hz, 2H), 1.46 (s, 9H).

Step 3) 2,7- diazaspiracyclic [3.4] octane -2- benzyl formate

At 0 DEG C, trifluoroacetic acid (1.9mL) is added to O2- benzyl O7- tert-butyl 2,7- diazaspiracyclic [3.4] octane- In methylene chloride (8mL) solution of 2,7- dicarboxylic acid esters (0.85g, 2.45mmol), react at room temperature 1 hour.With unsaturated carbonate hydrogen Sodium solution (5mL) quenching reaction, methylene chloride/methanol (v/v=9/1,10mL × 3) extraction, the anhydrous sulphur of combined organic phase Sour sodium is dry, filters concentration, obtains title compound (0.60g, yield 99%), is yellow oil.

MS(ESI,pos.ion)m/z:516.4[M+H]⁺。

Step 4) 7- mesyl -2,7- diazaspiracyclic [3.4] octane -2- benzyl formate

2,7- diazaspiracyclic [3.4] octane -2- benzyl formate (0.60g, 2.4mmol) is dissolved in methylene chloride (8mL), It is added triethylamine (0.70mL, 5.0mmol), is slowly dropped into mesyl chloride (0.40mL, 5.0mmol) at 0 DEG C, room temperature reaction 2.5 Hour.Be added water (10mL) quenching reaction, with methylene chloride (30mL) extract, organic phase with saturated sodium chloride solution (10mL × 3) it washs, anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/1] Purifying, obtains title compound (0.69g, yield 87%), is colorless oil.

Step 5) 7- mesyl -2,7- azaspiro [3.4] octane

10% palladium/carbon (0.3g, 0.28mmol) is added to 7- mesyl -2,7- diazaspiracyclic [3.4] octane -2- In methanol (10mL) solution of benzyl formate (0.69g, 2.13mmol), replacing hydrogen, room temperature hydrogenation 2 hours.Filtering, filter Liquid is concentrated under reduced pressure, and residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=3/1], obtains title compound (0.30g, yield 74%) is colorless oil.

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 3.49 (d, J=7.5Hz, 2H), 3.38-3.35 (m, 2H), 3.33 (s, 2H), 3.22 (t, J=6.9Hz, 2H), 2.87 (s, 3H), 2.04 (t, J=6.9Hz, 2H), 1.23 (d, J=3.8Hz, 1H)。

Step 6) N- [(2R, 3S, 5R) -2- (2,5- trifluorophenyl) -5- (7- mesyl -2,7- diazaspiracyclic [3.4] octane -2- base) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.34g, 1.0mmol) and 7- mesyl -2,7- diazaspiracyclic [3.5] nonane hydrochloride (0.15g, 0.79mmol) are dissolved in Methanol (4mL), after reaction 6 hours, nitrogen protection at 0 DEG C, is added decaborane (0.06g, 0.48mmol), and room temperature reaction 12 is small When.Filtering, filtrate decompression concentration, residue are purified by silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], are marked It inscribes compound (0.32g, yield 81%), is yellow solid.

MS(ESI,pos.ion)m/z:502.3[M+H]⁺。

(7- mesyl -2,7- diazaspiracyclic [3.5] is pungent by step 7) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- Alkane -2- base) oxinane -3- amine

At 0 DEG C, trifluoroacetic acid (1.0mL) is added to N- [(2R, 3S, 5R) -2- (2,5- trifluorophenyl) -5- (7- methylsulphur Acyl group -2,7- diazaspiracyclic [3.4] octane -2- base) tetrahydropyran -3-base] carbamate (0.32g, In methylene chloride (10mL) solution 0.32mmol), react at room temperature 12 hours.It is quenched instead with saturated sodium bicarbonate solution (5mL) It answers, methylene chloride/methanol (v/v=9/1,10mL × 3) extraction, combined organic phase is dry with anhydrous sodium sulfate, concentration is filtered, Residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], obtains title compound (70mg, yield 55%, HPLC purity 97.3%), it is colorless oil.

MS(ESI,pos.ion)m/z:402.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 7.28-7.09 (m, 3H), 4.06 (dd, J=23.5,9.4Hz, 1H), 3.82 (dd, J=10.6,2.3Hz, 1H), 3.31 (s, 2H), 3.27-3.20 (m, 2H), 3.18-3.07 (m, 4H), 2.98 (t, J =10.5Hz, 1H), 2.88 (d, J=5.4Hz, 3H), 2.76-2.66 (m, 1H), 2.45-2.31 (m, 1H), 2.05 (dt, J= 14.1,6.9Hz, 3H), 1.24 (s, 2H), 1.05 (dd, J=23.3,11.6Hz, 1H).

Embodiment 3 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [(1S, 4S) -2- mesyl -2,5- diaza two Ring [2.2.1] heptane -5- base] oxinane -3- amine

Step 1) (1S, 4S) -2- mesyl -2,5- diazabicylo [2.2.1] heptane -5- carboxylate

At 0 DEG C, triethylamine (0.21mL, 1.5mmol) and mesyl chloride (0.1mL, 1mmol) is added to (1S, 4S) 2, In tetrahydrofuran (5mL) solution of 5- diazabicyclo [2.2.1] heptane -2- carboxylate (0.2g, 1mmol), room temperature Reaction 20 hours.Filtering, filtrate concentration, obtains title compound (0.36g, yield 100%), is white solid.

Step 2) (1S, 4S) -2- mesyl -2,5- diazabicylo [2.2.1] heptane

At 0 DEG C, the ethanol solution (4mL, 2.0mol/L) of hydrogen chloride is added to (1S, 4S) -2- mesyl -2,5- bis- In ethyl alcohol (2mL) solution of azabicyclic [2.2.1] heptane -5- carboxylate (0.15g, 0.54mmol), room temperature reaction 1 Hour.It is concentrated under reduced pressure and removes solvent, residue is dissolved in ethyl alcohol (5mL), adjusts pH=8 with sodium bicarbonate solid, filters, filtrate is dense Contracting, obtains title compound (95mg, yield 99%), is white solid.

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [(1S, 4S) -2- mesyl -2,5- diaza Two rings [2.2.1] heptane -5- base] tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.19g, 0.56mmol) and (1S, 4S) -2- mesyl -2,5- diazabicylo [2.2.1] heptane (0.10g, It 0.24mmol) is dissolved in n,N-dimethylacetamide (1mL), at 0 DEG C, sodium triacetoxy borohydride is added in nitrogen protection (0.31g, 1.4mmol) is reacted at room temperature 8 hours.Add water (5mL) quenching reaction at 0 DEG C, with methylene chloride/methanol (v/v=9/ 1,10mL × 2) it extracts, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [acetic acid Ethyl ester/methanol (v/v)=20/1] purifying, title compound (0.73g, yield 26%) is obtained, is faint yellow solid.

MS(ESI,pos.ion)m/z:488.3[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [(1S, 4S) -2- mesyl -2,5- diaza two Ring [2.2.1] heptane -5- base] oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [(1S, 4S) -2- mesyl -2,5- diazabicylo [2.2.1] heptane -5- base] tetrahydropyran -3-base] t-butyl carbamate (0.17g, 0.35mmol) is dissolved in methanol (0.5mL), The methanol solution (5mL, 3.0mol/L) of hydrogen chloride is added, reacts at room temperature 1 hour.Be concentrated under reduced pressure, residue be dissolved in methylene chloride/ Methanol/water (v/v/v=9/1/10,20mL) adjusts pH=8 with saturated sodium bicarbonate solution, with methylene chloride/methanol (v/v= 9/1,20mL × 3) it extracts, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [two Chloromethanes/methanol (v/v)=10/1] purifying, title compound (85mg, yield 63%, HPLC purity 90.2%) is obtained, is white Color solid.

MS(ESI,pos.ion)m/z:388.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.20-7.10(m,1H),7.07-6.94(m,2H),4.36-4.22(m, 2H), 4.07 (ddd, J=26.0,11.1,2.1Hz, 1H), 3.79 (d, J=43.3Hz, 1H), 3.61 (d, J=9.5Hz, 1H), 3.37-3.21 (m, 2H), 3.16-3.06 (m, 1H), 2.94-2.86 (m, 5H), 2.74 (d, J=9.6Hz, 1H), 2.56 (s, 2H), 2.40-2.28 (m, 1H), 1.91 (d, J=9.8Hz, 1H), 1.77 (d, J=9.9Hz, 1H), 1.51-1.39 (m, 1H).

Embodiment 4 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- isopropyl spiral shell [indazole -5 6,7- dihydro -4H-, 4 '-piperidines] -1 '-yl) oxinane -3- amine

Step 1) 3- oxo -9- azaspiro [5.5] hendecane -4- alkene -9- benzyl formate

4- formyl piperidine -1- benzyl formate (30.0g, 121mmol) is dissolved in toluene (200mL), is added to toluene sulphur Sour (3.4g, 18mmol) and butenone (20.0mL, 247mmol), 80 DEG C are reacted 20 hours.Reaction solution is cooled to room temperature, with full It is washed with sodium bicarbonate solution (600mL), organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/4] purifying, obtains title compound (15g, yield 41%), is yellow oil.

MS(ESI,pos.ion)m/z:300.3[M+H]⁺。

Step 2) 8- (dimethylamino methylene) -9- oxo -3- azaspiro [5.5] hendecane -10- alkene -3- formic acid benzyl Ester

3- oxo -9- azaspiro [5.5] hendecane -4- alkene -9- benzyl formate (14.5g, 48.4mmol) is dissolved in toluene Three (dimethylamino) methane (25mL) are added in (200mL), are heated to 100 DEG C and react 15 hours.Reaction solution is concentrated under reduced pressure, is obtained It is dark red oil to title compound (18g, yield 99%).

Step 3) spiral shell [1,4- dihydro-indazol -5,4 '-piperidines] -1 '-benzyl formate

By 8- (dimethylamino methylene) -9- oxo -3- azaspiro [5.5] hendecane -10- alkene -3- benzyl formate (30.0g, 121mmol) is dissolved in dehydrated alcohol (200mL), sequentially add hydrazine hydrate (3.0mL, 62mmol) and acetic acid (3.0mL, 50mmol), 80 DEG C are warming up to react 4 hours.Reaction solution is cooled to room temperature, and is concentrated under reduced pressure, unsaturated carbonate is added into residue Hydrogen sodium solution tune pH=8, is extracted with ethyl acetate (50mL × 4), and combined organic phase is washed with saturated sodium chloride solution (50mL) It washs, anhydrous sodium sulfate is dry, filters concentration, and residue is purified through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/1], Title compound (12.8g, yield 78%) is obtained, is light yellow oil.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺。

Step 4) 1- isopropyl spiral shell [4H- indazole -5,4 '-piperidines] -1 '-benzyl formate

Spiral shell [1,4- dihydro-indazol -5,4 '-piperidines] -1 '-benzyl formate (2.4g, 7.4mmol) is dissolved in N, N- dimethyl Formamide (8mL), sequentially adds potassium carbonate (1.2g, 8.7mmol) and 2- iodopropane (1.1mL, 11mmol), and room temperature reaction 18 is small When.Reaction solution is concentrated under reduced pressure, and water (20mL) is added into residue, is extracted with ethyl acetate (50mL × 3), combined organic phase It is washed with saturated sodium chloride solution (50mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [acetic acid second Ester/petroleum ether (v/v)=1/6] purifying, title compound (1.0g, yield 37%) is obtained, is yellow oil.

MS(ESI,pos.ion)m/z:366.1[M+H]⁺。

Step 5) 1- isopropyl spiral shell [6,7- dihydro -4H- indazole -5,4 '-piperidines]

1- isopropyl spiral shell [4H- indazole -5,4 '-piperidines] -1 '-benzyl formate (1.28g, 3.50mmol) is dissolved in no water beetle Alcohol (10mL) is added 10% palladium/carbon (128mg), replacing hydrogen, hydrogenation 3 hours.Filtering, filtrate decompression concentration, residue It is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=5/1], obtains title compound (0.49g, yield 60%), for Huang Color grease.

Step 6) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- isopropyl spiral shell [6,7- dihydro -4H- indazole - 5,4 '-piperidines] -1 '-yl) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.40g, 1.22mmol) and 1- isopropyl spiral shell [6,7- dihydro -4H- indazole -5,4 '-piperidines] (0.30g, 1.28mmol) are dissolved in Formaldehyde (10mL) is added decaborane (0.11g, 0.92mmol) after room temperature reaction 4 hours, continues room temperature reaction 8 hours.At 0 DEG C Add water (5mL) quenching reaction, extracted with ethyl acetate (10mL × 2), combined organic phase is dry with anhydrous sodium sulfate, filters dense Contracting, residue are purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/1], and obtaining title compound, (0.10g is produced Rate 15%), it is white solid.

MS(ESI,pos.ion)m/z:545.4[M+H]⁺。

Step 7) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- isopropyl spiral shell [indazole -5 6,7- dihydro -4H-, 4 '-piperidines] -1 '-yl) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1- isopropyl spiral shell [6,7- dihydro -4H- indazole -5,4 ' - Piperidines] -1 '-yl) tetrahydropyran -3-base] t-butyl carbamate (0.10g, 0.18mmol) is dissolved in methylene chloride (5mL), adds Enter trifluoroacetic acid (0.14mL, 1.9mmol), reacts at room temperature 3 hours.It is concentrated under reduced pressure, residue is dissolved in methylene chloride/methanol/water (v/v/v=9/1/10,10mL), with saturated sodium bicarbonate solution adjust pH=8, with methylene chloride/methanol (v/v=9/1, 10mL × 3) extraction, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [dichloromethane Alkane/methanol (v/v)=10/1] purifying, title compound (26mg, yield 32%, HPLC purity 93.8%) is obtained, it is solid for white Body.

MS(ESI,pos.ion)m/z:446.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.34 (s, 2H), 7.35 (dd, J=20.7,14.4Hz, 2H), 4.58 (d, J=10.1Hz, 1H), 4.45 (d, J=8.4Hz, 1H), 4.36 (dd, J=10.7,6.4Hz, 1H), 4.04 (dt, J= 12.9,6.5Hz, 1H), 3.69 (dd, J=27.9,17.8Hz, 3H), 3.18-3.03 (m, 2H), 2.73 (d, J=8.1Hz, 1H), 2.57 (d, J=22.6Hz, 2H), 2.29 (s, 1H), 2.08 (dd, J=20.7,9.1Hz, 1H), 2.02-1.95 (m, 1H), 1.71 (s, 3H), 1.54 (dd, J=14.1,7.5Hz, 2H), 1.42-1.26 (m, 6H), 1.23 (s, 2H), 0.91-0.84 (m,2H)。

Embodiment 5 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indoles - 2- yl) oxinane -3- amine

Step 1) 1,3,4,5- tetrahydropyridine simultaneously -2 t-butyl formate of [4,3-b] indoles

1,3- dimethyl urea (8.5g, 95mmol) and tartaric acid (3.6g, 24mmol) are mixed, are heated to 110 DEG C to admittedly Body melts clarification, phenylhydrazine (1.1g, 10mmol) and N- tertbutyloxycarbonyl -4- piperidones (2.0g, 10mmol) is added, the reaction was continued 6 hours.Add water (50mL) quenching reaction, extracted with ethyl acetate (80mL), organic phase is dry with anhydrous sodium sulfate, filters dense Contracting, residue are purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], and obtaining title compound, (0.24g is produced Rate 99%), it is white solid.

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.22 (s, 1H), 7.48 (s, 1H), 7.33 (d, J=7.6Hz, 1H), 7.23-7.07(m,2H),4.69(s,2H),3.85(s,2H),2.83(s,2H),1.56(s,9H)。

Step 2) 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indole hydrochloride

By 1,3,4,5- tetrahydropyridine, simultaneously -2 t-butyl formate (0.24g, 0.88mmol) of [4,3-b] indoles is dissolved in acetic acid second The ethyl acetate solution (2mL, 4.0mol/L) of hydrogen chloride is added in ester (0.5mL), reacts at room temperature 3 hours, is concentrated under reduced pressure, obtains Title compound (0.18g, 9 yields 98%).

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1,3,4,5- tetrahydropyridine simultaneously [4,3-b] Yin Diindyl -2- base) tetrahydropyran -3-base] carbamic acid uncleButyl ester

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.15g, 0.46mmol) and 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indole hydrochloride (0.18g, 0.86mmol) are dissolved in N,N-dimethylacetamide (1.5mL), at 0 DEG C, nitrogen protection, be added sodium triacetoxy borohydride (0.20g, 0.91mmol), it reacts at room temperature 8 hours.Add water (10mL) quenching reaction at 0 DEG C, filtering, obtained solid is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1] purifying, obtains title compound (60mg, yield 14%), is yellow solid.

MS(ESI,pos.ion)m/z:484.6[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indoles -2- Base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indoles -2- Base) tetrahydropyran -3-base] t-butyl carbamate (60mg, 0.12mmol) is dissolved in ethyl acetate (0.5mL), hydrogen chloride is added Ethyl acetate solution (2mL, 4.0mol/L), react at room temperature 3 hours.Solid sodium bicarbonate is added and adjusts pH=8, filters, filter Liquid concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], and obtaining title compound, (44mg is produced Rate 92%, HPLC purity 90.2%), it is yellow solid.

MS(ESI,pos.ion)m/z:384.5[M+H]⁺。

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.86 (s, 1H), 7.40 (d, J=7.6Hz, 1H), 7.29 (d, J= 7.8Hz, 1H), 7.16 (m, 2H), 7.09 (d, J=7.1Hz, 1H), 7.01 (m, 2H), 4.36-4.31 (m, 1H), 4.25 (d, J =9.4Hz, 1H), 4.00-3.88 (m, 2H), 3.59 (t, J=10.8Hz, 1H), 3.08 (t, J=5.6Hz, 4H), 2.93- 2.82(m,3H),2.56-2.46(m,1H)。

Embodiment 6 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -1,3,4,5- tetrahydropyridine simultaneously [4, 3-b] indoles -2- base) oxinane -3- amine

Step 1) 8- methoxyl group -1,3,4,5- tetrahydropyridine simultaneously -2 t-butyl formate of [4,3-b] indoles

1,3- dimethyl urea (7.88g, 89.4mmol) and tartaric acid (3.38g, 22.5mmol) are mixed, are heated to 75 DEG C Melt to solid and clarify, (4- methoxyphenyl) hydrazine hydrochloride (1.40g, 8.0mmol) and N- tertbutyloxycarbonyl -4- piperidines is added Ketone (1.5g, 7.5mmol), the reaction was continued 3 hours.Add water (10mL) quenching reaction, extracted with methylene chloride (20mL × 2), is closed And organic phase washed with saturated sodium chloride solution (30mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column layer [petrol ether/ethyl acetate (v/v)=2/1] purifying is analysed, title compound (1.53g, yield 67%) is obtained, is pale yellow colored solid Body.

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.10 (d, J=22.9Hz, 1H), 7.21 (d, J=8.7Hz, 1H), 6.92 (s, 1H), 6.87-6.75 (m, 1H), 4.64 (s, 2H), 3.85 (d, J=19.8Hz, 5H), 2.81 (t, J=5.5Hz, 2H),1.54(s,9H)。

Step 2) 8- methoxyl group -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles

By 8- methoxyl group 1,3,4,5- tetrahydropyridine, simultaneously -2 t-butyl formate (0.62g, 2.1mmol) of [4,3-b] indoles is molten In methylene chloride (2mL), the methanol solution (8mL, 3.0mol/L) of hydrogen chloride is added, reacts at room temperature 3 hours.Reaction solution saturation Sodium bicarbonate solution adjusts pH=9, is extracted with ethyl acetate/methanol (v/v=5/1,20mL × 4), combined organic phase nothing Aqueous sodium persulfate is dry, filters concentration, and residual solid is purified through silica gel column chromatography [ethyl acetate/methanol (v/v)=5/1], obtained Title compound (0.27g, yield 65%) is white solid.

[(8- methoxyl group -1,3,4,5- tetrahydropyridine is simultaneously by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- by step 3) N- [4,3-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.48g, 1.5mmol) and 8- methoxyl group -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles (0.27g, 1.3mmol) are molten At n,N-dimethylacetamide (4mL), 0 DEG C, nitrogen protection is added sodium triacetoxy borohydride (0.71g, 3.4mmol), Room temperature reaction 8 hours.Ammonia/water (v/v=2/3,10mL) quenching reaction is added, filtering, obtained solid is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1] purifying, obtains title compound 0.14g, yield 21%), it is yellow solid.

MS(ESI,pos.ion)m/z:514.5[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -1,3,4,5- tetrahydropyridine simultaneously [4,3- B] indoles -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -1,3,4,5- tetrahydropyridine simultaneously [4,3- B] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate (0.45g, 0.87mmol) is dissolved in methylene chloride (0.5mL), The methanol solution (5mL, 3.0mol/L) of hydrogen chloride is added, reacts at room temperature 1 hour.Solid sodium bicarbonate is added and adjusts pH=9, mistake Filter, filtrate concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], obtain title compound (0.16g, yield 44%, HPLC purity 92.2%) is faint yellow solid.

MS(ESI,pos.ion)m/z:414.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.70 (s, 1H), 7.20 (d, J=8.7Hz, 2H), 7.06 (d, J= 4.5Hz, 2H), 6.88 (d, J=2.3Hz, 1H), 6.81 (dd, J=8.7,2.4Hz, 1H), 4.35-4.30 (m, 1H), 4.25 (d, J=9.3Hz, 1H), 3.92 (d, J=8.7Hz, 2H), 3.87 (s, 3H), 3.58 (d, J=10.8Hz, 1H), 3.07 (t, J =5.6Hz, 4H), 2.89 (d, J=5.7Hz, 3H), 2.53 (dd, J=12.1,2.1Hz, 1H).

(the fluoro- 1,3,4,5- tetrahydropyridine of 8- is simultaneously [4,3-b] by embodiment 7 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- Indoles -2- base) oxinane -3- amine

The fluoro- 1,3,4,5- tetrahydropyridine of step 1) 8- simultaneously -2 t-butyl formate of [4,3-b] indoles

1,3- dimethyl urea (10.5g, 119mmol) and tartaric acid (4.5g, 30mmol) are mixed, are heated to 85 DEG C to admittedly Body thawing clarification, addition (4- fluorophenyl) hydrazine hydrochloride (1.8g, 11.1mmol) and N- tertbutyloxycarbonyl -4- piperidones (2.0g, 10.0mmol), the reaction was continued 3 hours.Add water (10mL) quenching reaction, with methylene chloride (20mL × 2) extract, merging it is organic It is mutually washed with saturated sodium chloride solution (30mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [petroleum Ether/ethyl acetate (v/v)=2/1] purifying, title compound (0.28g, yield 8.8%) is obtained, is faint yellow solid.

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.92 (s, 1H), 7.27-7.18 (m, 1H), 7.11 (d, J=9.1Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 4.61 (s, 2H), 3.83 (s, 2H), 2.84 (s, 2H), 1.53 (s, 9H).

Fluoro- 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles of step 2) 8-

By the fluoro- 1,3,4,5- tetrahydropyridine of 8-, simultaneously -2 t-butyl formate (0.25g, 0.87mmol) of [4,3-b] indoles is dissolved in The methanol solution (4mL, 3.0mol/L) of hydrogen chloride is added in methylene chloride (1mL), reacts at room temperature 2 hours.Reaction solution bicarbonate Sodium solid adjusts pH=9, filtering, and filtrate is concentrated, and residual solid is pure through silica gel column chromatography [ethyl acetate/methanol (v/v)=6/1] Change, obtain title compound (0.17g, yield 99%), is yellow solid.

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (the fluoro- 1,3,4,5- tetrahydropyridine of 8- simultaneously [4,3- B] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate Fluoro- 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles (0.16g, 0.84mmol) of (0.30g, 0.93mmol) and 8- is dissolved in N,N-dimethylacetamide (3mL), at 0 DEG C, nitrogen protection is added sodium triacetoxy borohydride (0.45g, 2.1mmol), room Temperature reaction 8 hours.Ammonia/water (v/v=2/3,10mL) quenching reaction is added, filtering, obtained solid is through silica gel column chromatography [stone Oily ether/ethyl acetate (v/v)=2/1] purifying, title compound (83mg, yield 20%) is obtained, is faint yellow solid.

MS(ESI,pos.ion)m/z:502.1[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (the fluoro- 1,3,4,5- tetrahydropyridine of 8- simultaneously [4,3-b] Yin Diindyl -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (the fluoro- 1,3,4,5- tetrahydropyridine of 8- simultaneously [4,3-b] Yin Diindyl -2- base) tetrahydropyran -3-base] t-butyl carbamate (75mg, 0.15mmol) is dissolved in methylene chloride (0.5mL), chlorine is added Change the methanol solution (3mL, 3.0mol/L) of hydrogen, reacts at room temperature 1 hour.Solid sodium bicarbonate is added and adjusts pH=9, filters, filter Liquid concentration, residue through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1] purify, obtain title compound (0.57g, Yield 95%, HPLC purity 97.7%), it is faint yellow solid.

MS(ESI,pos.ion)m/z:402.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.84 (s, 1H), 7.20 (d, J=4.2Hz, 2H), 7.06 (d, J= 9.2Hz, 3H), 6.89 (td, J=9.0,2.3Hz, 1H), 4.34 (d, J=8.2Hz, 1H), 4.25 (d, J=9.5Hz, 1H), 3.89 (d, J=7.8Hz, 2H), 3.59 (s, 1H), 3.07 (t, J=5.4Hz, 4H), 2.90 (d, J=4.8Hz, 3H), 2.53- 2.39(m,1H)。

Embodiment 8 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -5- mesyl -3,4- dihydro - 1H- pyrido [4,3-b] indoles -2- base) oxinane -3- amine

- 2 t-butyl formate of step 1) 8- methoxyl group -5- mesyl -3,4- dihydro -1H- pyrido [4,3-b] indoles

N-BuLi (0.90mL, 2.2mmol) at -78 DEG C, is slowly dropped to 8- methoxyl group 1,3,4,5- by nitrogen protection Tetrahydropyridine is simultaneously in anhydrous tetrahydro furan (15mL) solution of -2 t-butyl formate (0.50g, 1.7mmol) of [4,3-b] indoles, instead After answering 1 hour, it is slowly dropped into mesyl chloride (0.26mL, 3.4mmol), the reaction was continued 2 hours.Saturated ammonium chloride solution is added (10mL) quenching reaction is extracted with ethyl acetate (20mL), and organic phase is washed with saturated sodium chloride solution (20mL), anhydrous slufuric acid Sodium is dry, filters concentration, and residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/1], obtained titled It closes object (0.25g, yield 40%), is white solid.

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.84 (d, J=9.0Hz, 1H), 6.89 (dd, J=9.0,2.3Hz, 1H), 6.85 (d, J=2.2Hz, 1H), 4.54 (s, 2H), 3.84 (s, 3H), 3.76 (t, J=5.2Hz, 2H), 3.02 (s, 2H), 2.94(s,3H),1.51(s,9H)。

Step 2) 8- methoxyl group -5- mesyl -1,2,3,4- tetrahydropyridine simultaneously [4,3-b] indoles

By -2 t-butyl formate of 8- methoxyl group -5- mesyl -3,4- dihydro -1H- pyrido [4,3-b] indoles (0.23g, 0.60mmol) is dissolved in methylene chloride (0.5mL), the methanol solution (4mL, 3.0mol/L) of hydrogen chloride is added, room temperature is anti- It answers 2 hours.Reaction solution sodium bicarbonate solid adjusts pH=9, and filtering, filtrate concentration, residual solid is through silica gel column chromatography [acetic acid Ethyl ester/methanol (v/v)=9/1] purifying, title compound (0.15g, yield 89%) is obtained, is white solid.

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -5- mesyl -3,4- dihydro - 1H- pyrido [4,3-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.18g, 0.56mmol) and 8- methoxyl group -5- mesyl -1,2,3,4- tetrahydropyridine simultaneously [4,3-b] indoles (0.14g, It 0.51mmol) is dissolved in n,N-dimethylacetamide (2mL), at 0 DEG C, sodium triacetoxy borohydride is added in nitrogen protection (0.27g, 1.3mmol) is reacted at room temperature 8 hours.Ammonia/water (v/v=2/3,10mL) quenching reaction is added, filtering obtains Solid is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1], obtains title compound (0.30g, yield It 99%), is faint yellow solid.

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -5- mesyl -3,4- dihydro -1H- Pyrido [4,3-b] indoles -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (8- methoxyl group -5- mesyl -3,4- dihydro -1H- Pyrido [4,3-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate (0.30g, 0.51mmol) is dissolved in dichloromethane The methanol solution (5mL, 3.0mol/L) of hydrogen chloride is added in alkane (0.5mL), reacts at room temperature 1 hour.Solid sodium bicarbonate tune is added PH=9, filtering are saved, filtrate is concentrated, and residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], is marked It inscribes compound (0.15g, yield 60%, HPLC purity 91.3%), is faint yellow solid.

MS(ESI,pos.ion)m/z:492.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.72 (s, 1H), 7.20 (t, J=7.4Hz, 1H), 7.07 (td, J= 9.2,4.8Hz, 1H), 7.01 (dd, J=11.6,7.3Hz, 1H), 6.88 (d, J=1.9Hz, 1H), 6.81 (dd, J=8.7, 2.2Hz, 1H), 4.36 (d, J=10.7Hz, 1H), 4.26 (d, J=9.4Hz, 1H), 4.00-3.90 (m, 2H), 3.87 (s, 3H), 3.62 (t, J=10.7Hz, 1H), 3.10 (d, J=5.3Hz, 4H), 2.88 (d, J=17.4Hz, 3H), 2.67 (s, 3H), 2.54 (d, J=9.9Hz, 1H).

Embodiment 9 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3, 4-b] indoles -2- base) oxinane -3- amine

- 2 t-butyl formate of step 1) 7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indoles

1,3- dimethyl urea (7.18g, 81.5mmol) and tartaric acid (3.08g, 20.5mmol) are mixed, are heated to 85 DEG C Melt to solid and clarify, (4- methoxyphenyl) hydrazine hydrochloride (2.1g, 12mmol) and 1- tertbutyloxycarbonyl -3- pyrrolidines is added Ketone (2.0g, 11mmol), the reaction was continued 3 hours.Add water (30mL) quenching reaction, extracted with ethyl acetate (50mL × 2), is merged Organic phase washed with saturated sodium chloride solution (30mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1] purifying, obtains title compound (0.22g, yield 6.9%), is yellow solid.

Step 2) 7- methoxyl group -1,2,3,4- nafoxidine simultaneously [3,4-b] indoles

By -2 t-butyl formate (0.21g, 0.73mmol) of 7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indoles It is dissolved in methylene chloride (1mL), the methanol solution (6mL, 3.0mol/L) of hydrogen chloride is added, is reacted at room temperature 2 hours.Reaction solution is used full PH=9 is adjusted with sodium bicarbonate solution, is extracted with ethyl acetate/methanol (v/v=5/1,20mL × 4), combined organic phase is used Anhydrous sodium sulfate is dry, filters concentration, and residual solid is purified through silica gel column chromatography [ethyl acetate/methanol (v/v)=5/1], obtained It is faint yellow solid to title compound (0.11g, yield 82%).

MS(ESI,pos.ion)m/z:189.2[M+H]⁺。

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate Simultaneously [3,4-b] indoles (0.11g, 0.58mmol) is dissolved in for (0.21g, 0.64mmol) and 7- methoxyl group -1,2,3,4- nafoxidine N,N-dimethylacetamide (1mL), at 0 DEG C, nitrogen protection is added sodium triacetoxy borohydride (0.31g, 1.5mmol), room Temperature reaction 8 hours.Ammonia/water (v/v=2/3,10mL) quenching reaction is added, filtering, obtained solid is through silica gel column chromatography [stone Oily ether/ethyl acetate (v/v)=2/1] purifying, title compound (60mg, yield 21%) is obtained, is yellow solid.

MS(ESI,pos.ion)m/z:500.3[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4- B] indoles -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4- B] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate (0.45g, 0.87mmol) is dissolved in methylene chloride (0.5mL), The methanol solution (3mL, 3.0mol/L) of hydrogen chloride is added, reacts at room temperature 1 hour.Solid sodium bicarbonate is added and adjusts pH=9, mistake Filter, filtrate concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], obtain title compound (30mg, yield 63%, HPLC purity 96.9%) is faint yellow solid.

MS(ESI,pos.ion)m/z:400.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.99 (s, 1H), 7.23 (d, J=8.9Hz, 1H), 7.18 (t, J= 5.9Hz, 1H), 7.09-6.95 (m, 2H), 6.90 (d, J=2.0Hz, 1H), 6.80 (dd, J=8.8,2.3Hz, 1H), 4.29 (t, J=11.2Hz, 1H), 3.84 (s, 2H), 3.74-3.70 (m, 2H), 3.69-3.67 (m, 1H), 3.66 (s, 3H), 3.64- 3.57 (m, 2H), 3.52 (t, J=10.6Hz, 1H), 3.10-2.88 (m, 1H), 2.52 (d, J=10.9Hz, 1H).

Embodiment 10 (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,3a, 4,8b- tetrahydro -1H- pyrrole Cough up simultaneously [3,4-b] indoles -2- base) oxinane -3- amine

- 2 benzyl formate of step 1) 7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indoles

1,3- dimethyl urea (9.58g, 109mmol) and tartaric acid (4.10g, 27.3mmol) are mixed, are heated to 85 DEG C Melt to solid and clarify, (4- methoxyphenyl) hydrazine hydrochloride (1.80g, 10.3mmol) and 1- benzyloxycarbonyl group -3- pyrroles is added Alkanone (2.00g, 9.12mmol), the reaction was continued 3 hours.Add water (30mL) quenching reaction, is extracted with ethyl acetate (50mL × 2) It takes, combined organic phase is washed with saturated sodium chloride solution (30mL), and anhydrous sodium sulfate is dry, filters concentration, residue is through silicon Plastic column chromatography [petrol ether/ethyl acetate (v/v)=2/1] purifying, obtains title compound (1.99g, yield 68%), is yellow Solid.

Step 2) 7- methoxyl group -1,2,3,3a, 4,8b- hexahydropyrrolo simultaneously [3,4-b] indoles

7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] -2 benzyl formates (1.99g, 6.17mmol) of indoles are molten It in methanol (20mL), is added 10% palladium/carbon (1.31g, 12.3mmol), replacing hydrogen, 50 DEG C of hydrogenations (4MPa) are reacted 2 hours. Filtering, filtrate concentrate solution, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], are obtained titled It closes object (0.41g, yield 35%), is tan solid.MS(ESI,pos.ion)m/z:191.1[M+H]⁺。

Step 3) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,3a, 4,8b- tetrahydro -1H- pyrrole Cough up simultaneously [3,4-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.72g, 2.18mmol) and 7- methoxyl group -1,2,3,3a, 4,8b- hexahydropyrrolo simultaneously [3,4-b] indoles (0.38g, It 1.99mmol) is dissolved in n,N-dimethylacetamide (5mL), at 0 DEG C, sodium triacetoxy borohydride is added in nitrogen protection (1.05g, 4.95mmol) is reacted at room temperature 8 hours.Ammonia/water (v/v=2/3,15mL) quenching reaction is added, filtering obtains Solid is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1], obtains title compound (0.40g, yield It 40%), is greenish yellow solid.

MS(ESI,pos.ion)m/z:502.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.21 (s, 1H), 6.95 (s, 2H), 6.70 (d, J=2.0Hz, 1H), 6.65 (d, J=8.4Hz, 1H), 6.58 (s, 1H), 4.43 (d, J=9.0Hz, 2H), 4.30-4.12 (m, 2H), 3.97-3.86 (m, 1H), 3.77 (s, 4H), 3.44-3.31 (m, 1H), 2.87 (dd, J=23.1,17.7Hz, 2H), 2.71 (s, 1H), 2.51 (s,1H),2.43(s,1H),1.51-1.43(m,1H),1.28(s,9H)。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (7- methoxyl group -3,3a, 4,8b- tetrahydro-1 H-pyrrolo And [3,4-b] indoles -2- base) oxinane -3- amine

By N-, [(7- methoxyl group -3,3a, 4,8b- tetrahydro-1 H-pyrrolo are simultaneously by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- [3,4-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate (0.38g, 0.76mmol) is dissolved in methylene chloride (0.5mL) is added the methanol solution (4mL, 3.0mol/L) of hydrogen chloride, reacts at room temperature 1 hour.Solid sodium bicarbonate is added to adjust PH=9, filtering, filtrate concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], obtain title Compound (0.23g, yield 76%, HPLC purity 94.8%) is faint yellow solid.

MS(ESI,pos.ion)m/z:402.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.18-7.11(m,1H),7.07-6.94(m,2H),6.71-6.62(m, 2H), 6.58 (d, J=8.4Hz, 1H), 4.47 (s, 1H), 4.21-4.10 (m, 3H), 3.95 (s, 1H), 3.77 (s, 3H), 3.48 (d, J=20.2Hz, 1H), 2.95 (d, J=4.0Hz, 3H), 2.81 (s, 2H), 2.57 (s, 1H), 2.39 (d, J=11.8Hz, 1H)。

Embodiment 11 (2R, 3S5R) -2- (2,5- difluorophenyl) -5- (6- methoxyl group -1,3,4,9- tetrahydropyridines simultaneously [3, 4-b] indoles -2- base) oxinane -3- amine

Step 1) 6- methoxyl group -1,3,4,9- tetrahydropyridine simultaneously [3,4-b] the indole-2-carboxylic acid tert-butyl ester

1,3- dimethyl urea (10.5g, 119mmol) and tartaric acid (4.5g, 30.0mmol) are mixed, are heated to 85 DEG C extremely Solid melts clarification, and (4- methoxyphenyl) hydrazine hydrochloride (1.87g, 10.7mmol) and N- tertbutyloxycarbonyl -3- piperidines is added Ketone (2.0g, 10.0mmol), the reaction was continued 3 hours.Add water (10mL) quenching reaction, extracted with methylene chloride (20mL × 2), is closed And organic phase washed with saturated sodium chloride solution (30mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column layer [petrol ether/ethyl acetate (v/v)=2/1] purifying is analysed, title compound (1.2g, yield 52%) is obtained, is faint yellow solid.

Step 2) 6- methoxyl group -1,3,4,9- tetrahydro -1H- pyrido [3,4-b] indoles

By 6- methoxyl group -1,3,4,9- tetrahydropyridine simultaneously [3,4-b] the indole-2-carboxylic acid tert-butyl ester (0.30g, 0.99mmol) It is dissolved in methanol (0.5mL), the methanol solution (5mL, 3.0mol/L) of hydrogen chloride is added, is reacted at room temperature 2 hours.Reaction solution carbonic acid Hydrogen sodium solid adjusts pH=8, and filtering, filtrate concentration, residual solid is through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1] Purifying, obtains title compound (0.20g, yield 99%), is black solid.

[(6- methoxyl group -1,3,4,9- tetrahydropyridine is simultaneously by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- by step 3) N- [3,4-b] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.33g, 1.00mmol) and 6- methoxyl group -1,3,4,9- tetrahydro -1H- pyrido [3,4-b] indoles (0.20g, 0.99mmol) It is dissolved in n,N-dimethylacetamide (5mL), at 0 DEG C, nitrogen protection, addition sodium triacetoxy borohydride (0.53g, 2.50mmol), it reacts at room temperature 8 hours.Ammonia/water (v/v=2/3,20mL) quenching reaction, filtering, obtained solid warp is added Silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1] purifying, obtains title compound (60mg, yield 12%), for Huang Color solid.

MS(ESI,pos.ion)m/z:514.3[M+H]⁺。

Step 4) (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6- methoxyl group -1,3,4,9- tetrahydropyridine simultaneously [3,4- B] indoles -2- base) oxinane -3- amine

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6- methoxyl group -1,3,4,9- tetrahydropyridine simultaneously [3,4- B] indoles -2- base) tetrahydropyran -3-base] t-butyl carbamate (60mg, 0.12mmol) is dissolved in methanol (0.5mL), chlorine is added Change the methanol solution (2mL, 3.0mol/L) of hydrogen, reacts at room temperature 1 hour.Solid sodium bicarbonate is added and adjusts pH=8, filters, filter Liquid concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], and obtaining title compound, (22mg is produced Rate 46%, HPLC purity 92.6%), it is yellow solid.

MS(ESI,pos.ion)m/z:414.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.70(s,1H),7.21-7.12(m,2H),7.07-6.95(m,2H), 6.93 (d, J=2.1Hz, 1H), 6.79 (dd, J=8.7,2.3Hz, 1H), 4.34-4.25 (m, 1H), 4.21 (d, J=9.4Hz, 1H), 3.95-3.77 (m, 5H), 3.53 (t, J=10.8Hz, 1H), 3.16-2.94 (m, 3H), 2.82 (m, 3H), 2.46 (d, J =10.4Hz, 1H), 1.55 (s, 1H).

Embodiment 12 (3R) -4- [(3R, 5S) -5- amino -6- (2,5- difluorophenyl) tetrahydropyran -3-base] -3- (tertiary fourth Yloxymethyl) piperazine -2- ketone

Step 1) (2R) -3- hydroxyl -2- (tritylamino) methyl propionate

D-Ser methyl ester hydrochloride (40g, 0.26mol) is dissolved in chloroform (360mL), triethylamine is added at 0 DEG C (90mL, 0.64mol) is slowly added to triphenylchloromethane (72g, 0.26mol), is reacted 1 hour.Chloroform is added at room temperature (200mL) is washed with water (500mL), and organic phase is dry with anhydrous sodium sulfate, filters concentration, and obtaining title compound, (93g is produced Rate 99%).

Step 2) (2R) -1- trityl aziridine -2- carboxylate methyl ester

(2R) -3- hydroxyl -2- (tritylamino) methyl propionate (93g, 0.26mol) is dissolved in chloroform (500mL), 0 Triethylamine (95mL, 0.68mol) and 4-dimethylaminopyridine (2.8g, 26mmol) are added at DEG C, stirring after five minutes, slowly adds Enter mesyl chloride (28mL, 0.36mol), after room temperature reaction 4 hours, is heated to 62 DEG C and reacts 12 hours.Reaction solution is cooled to room Temperature is washed with water (800mL) and saturated sodium chloride solution (600mL) respectively, and anhydrous sodium sulfate is dry, concentration is filtered, to remnants Ethyl alcohol (600mL) is added in solid, stirs 10 minutes, filtering collects filter cake, obtains title compound (67g, yield 76%), For white solid.

Step 3) (2R)-aziridine -2- carboxylate methyl ester

(2R) -1- trityl aziridine -2- carboxylate methyl ester (53g, 0.15mol) is dissolved in chloroform (150mL), at 0 DEG C, It is added trifluoroacetic acid (180mL), reacts 30 minutes.Reaction solution is concentrated under reduced pressure, and residue is dissolved with ethyl acetate (200mL), uses Sodium bicarbonate solid adjusts pH=8, liquid separation, and water phase is extracted with ethyl acetate (200mL × 2), the anhydrous sulphur of combined organic phase Sour sodium is dry, filters concentration, and residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], obtains title Compound (8.5g, yield 54%) is yellow oil.

¹H NMR(400MHz,CDCl₃) δ (ppm) 3.76 (s, 3H), 2.53 (dd, J=5.4,3.0Hz, 1H), 2.07- 1.95 (m, 1H), 1.87 (d, J=4.7Hz, 1H), 1.41 (s, 1H).

Step 4) O1- benzyl O2- methyl (2R)-aziridine -1,2- dicarboxylic ester

(2R)-aziridine -2- carboxylate methyl ester (9.0g, 90mmol) is dissolved in tetrahydrofuran (150mL), unsaturated carbonate is added Hydrogen sodium solution (150mL) at 0 DEG C, is added dropwise benzyl chloroformate (15.8mL, 90mmol), reacts 2 hours.Reaction solution concentration removes Tetrahydrofuran, remaining water phase are extracted with ethyl acetate (150mL), and organic phase is dry with anhydrous sodium sulfate, filter concentration, residue It is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], obtains title compound (15.5g, yield 74%), be Colorless oil.

MS(ESI,pos.ion)m/z:258.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.37 (q, J=2.7Hz, 5H), 5.16 (s, 2H), 3.72 (s, 3H), 3.12 (dd, J=5.4,3.2Hz, 1H), 2.61 (dd, J=3.2,1.2Hz, 1H), 2.50 (dd, J=5.4,1.2Hz, 1H).

Step 5) (2R) -2- (benzyloxycarbonyl amino) -3- tert-butoxy-methyl propionate

O1- benzyl O2- methyl (2R)-aziridine -1,2- dicarboxylic ester (15.5g, 66mmol) is dissolved in chloroform (160mL) is added the tert-butyl alcohol (270mL), at 0 DEG C, boron trifluoride ether solution (16mL, 132mmol), recovery room is slowly added dropwise Temperature is reacted 18 hours.Add water (100mL) quenching reaction, liquid separation, organic phase is dry with anhydrous sodium sulfate, filters concentration, residue It is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], obtains title compound (14.5g, yield 71%), be White solid.

MS(ESI,pos.ion)m/z:332.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.42-7.31 (m, 5H), 5.64 (d, J=8.5Hz, 1H), 5.15 (s, 2H), 4.49 (dt, J=8.8,2.8Hz, 1H), 3.84 (dd, J=9.0,2.8Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J= 9.0,3.1Hz,1H),1.14(s,9H)。

Step 6) (2R) -2- amino -3- tert-butoxy-methyl propionate

(2R) -2- (benzyloxycarbonyl amino) -3- tert-butoxy-methyl propionate (14.3g, 46mmol) is dissolved in methanol The mixed solution of (70mL) and ethyl acetate (14mL) are added 10% palladium/carbon (1.4g), replacing hydrogen, hydrogenation 1 hour. Filtering, filtrate concentration, obtains title compound (8.2g, 100%), is colorless oil.

MS(ESI,pos.ion)m/z:176.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)3.72(s,3H),3.58(s,3H),1.89(s,2H),1.15(s,9H)。

Step 7) (2R) -3- tert-butoxy -2- [2- (t-butoxycarbonyl amino) ethylamino] methyl propionate

(2R) -2- amino -3- tert-butoxy-methyl propionate (5.5g, 31mmol) is dissolved in methylene chloride (125mL), is added Enter 1-N- (2- oxygen ethyl) carboxylic acid tert-butyl ester (10g, 63mmol), reacts at room temperature 2 hours.At 0 DEG C, three second are added into reaction solution Triacetoxyborohydride (8.1g, 38mmol) reacts at room temperature 12 hours.Saturated sodium bicarbonate solution (30mL) is added to be quenched instead It answers, liquid separation, organic phase is washed with water (50mL) and saturated sodium chloride solution (50mL) respectively, and anhydrous sodium sulfate is dry, is filtered dense Contracting, residue are purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], obtain title compound (5.0g, yield It 50%), is yellow oil.

MS(ESI,pos.ion)m/z:319.3[M+H]⁺。

Step 8) (2R) -2- [benzyloxycarbonyl group-[2- (t-butoxycarbonyl amino) ethyl] amino] -3- tert-butoxy-propionic acid Methyl esters

By (2R) -3- tert-butoxy -2- [2- (t-butoxycarbonyl amino) ethylamino] methyl propionate (5.0g, 16mmol) It is dissolved in tetrahydrofuran (80mL), is added saturated sodium bicarbonate solution (80mL), at 0 DEG C, dropwise addition benzyl chloroformate (2.7mL, 19mmol), it reacts 8 hours.Reaction solution concentration removes tetrahydrofuran, and remaining water phase is extracted with ethyl acetate (60mL), organic phase It is dry with anhydrous sodium sulfate, concentration is filtered, residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=5/1], Title compound (3.7g, yield 52%) is obtained, is colorless oil.MS(ESI,pos.ion)m/z:353.3[M-99]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.45-7.19 (m, 5H), 5.73 (d, J=27.2Hz, 1H), 5.11 (dt, J=17.2,12.5Hz, 1H), 4.17 (dd, J=8.9,3.5Hz, 1H), 4.13-3.95 (m, 1H), 3.82 (ddd, J= 10.7,9.4,5.1Hz,1H),3.71(s,2H),3.67-3.56(m,1H),3.52(s,1H),3.47-3.23(m,3H),1.42 (d, J=7.6Hz, 9H), 1.14 (d, J=5.2Hz, 9H).

Step 9) (2R) -2- [2- aminoethyl (benzyloxycarbonyl group) amino] -3- tert-butoxy-methyl propionate

By (2R) -2- [benzyloxycarbonyl group-[2- (t-butoxycarbonyl amino) ethyl] amino] -3- tert-butoxy-methyl propionate (3.4g, 7.5mmol) is dissolved in isopropanol (15mL), and the aqueous isopropanol (25mL, 2.0mol/L) of hydrogen chloride is added, room temperature reaction 3 hours.Reaction solution is concentrated under reduced pressure, and saturated sodium bicarbonate solution is used in residue methylene chloride (100mL) and water (20mL) dissolution PH=8, liquid separation are adjusted, water phase is extracted with methylene chloride/methanol (v/v=9/1,100mL × 2), and combined organic phase is with anhydrous Sodium sulphate is dry, filters concentration, and residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], obtains title Compound (2.5g, yield 94%) is yellow oil.

MS(ESI,pos.ion)m/z:353.3[M+H]⁺。

Step 10) (2R) -2- (tertiary fourth oxygen methyl) -3- oxo-niperazin -1- benzyl carboxylate

(2R) -2- [2- aminoethyl (benzyloxycarbonyl group) amino] -3- tert-butoxy-methyl propionate (2.6g, 7.4mmol) is molten It in methylene chloride (75mL), is added triethylamine (7.4mL), nitrogen protection, trimethyl aluminium (9.0mL, 2.0M is slowly added dropwise at 0 DEG C Toluene solution), it is warmed to room temperature, reacts 12 hours.Saturated ammonium chloride solution (100mL) quenching reaction is slowly added dropwise at 0 DEG C, point Liquid, water phase are extracted with ethyl acetate (200mL), and combined organic phase is washed with saturated sodium chloride solution (100mL), anhydrous slufuric acid Sodium is dry, filters concentration, and residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/2], obtained titled It closes object (1.5g, yield 63%), is yellow solid.

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.48 (d, J=44.9Hz, 1H), 7.41-7.29 (m, 5H), 5.18 (d, J=7.7Hz, 2H), 4.57 (d, J=16.6Hz, 1H), 4.13 (dd, J=55.6,12.4Hz, 1H), 3.96 (dd, J=14.8, 9.1Hz,1H),3.83-3.56(m,2H),3.50-3.26(m,2H),1.12(s,9H)。

Step 11) (3R) -3- (tertiary fourth oxygen methyl)-piperazine -2- ketone

(2R) -2- (tertiary fourth oxygen methyl) -3- oxo-niperazin -1- benzyl carboxylate (1.5g, 4.7mmol) is dissolved in acetic acid second Ester/methanol (v/v=1/2,22.5mL) is added 10% palladium/carbon (0.15g), replacing hydrogen, room temperature hydrogenation 12 hours.It crosses Filter, filtrate concentration, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=9/1], obtain title compound (0.80g, yield 92%) is white solid.

MS(ESI,pos.ion)m/z:187.1[M+H]⁺；

¹HNMR(600MHz,CD₃OD) δ (ppm) 4.14 (dd, J=5.3,3.6Hz, 1H), 3.98 (dd, J=10.1, 5.5Hz, 1H), 3.86 (dd, J=10.1,3.5Hz, 1H), 3.65-3.59 (m, 2H), 3.57 (s, 1H), 3.51-3.43 (m, 1H),1.24(s,9H)。

Step 12) N- [(3S, 5R) -5- [(2R) -2- (tert-butyl oxygen methyl) -3- oxo-niperazin -1- base] -2- (2,5- Difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (0.60g, 2.0mmol) and (3R) -3- (tertiary fourth oxygen methyl)-piperazine -2- ketone (0.30g, 2.0mmol) is dissolved in N, N- dimethyl second Amide (5mL), at 0 DEG C, nitrogen protection is added sodium triacetoxy borohydride (0.50g, 2.0mmol), is reacted at room temperature 8 hours. Ammonia/water (v/v=2/3,20mL) quenching reaction is added, filtering, obtained solid is through silica gel column chromatography [100% ethyl acetate] Purifying, obtains title compound 21l (0.30g, yield 40%), is white solid.

MS(ESI,pos.ion)m/z:498.2[M+H]⁺。

Step 13) (3R) -4- [(3R, 5S) -5- amino -6- (2,5- difluorophenyl) tetrahydropyran -3-base] -3- (tertiary fourth Yloxymethyl) piperazine -2- ketone

Trifluoroacetic acid (1.5mL, 19.0mmol) is added to N- [(3S, 5R) -5- [(2R) -2- (tert-butyl oxygen methyl) - 3- oxo-niperazin -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate (0.32g, In dichloromethane solution 0.64mmol) (10mL), react at room temperature 2 hours.It is quenched instead with saturated sodium bicarbonate solution (20mL) It answers, methylene chloride/methanol (v/v=10/1,50mL × 2) extraction, combined organic phase is dry with anhydrous sodium sulfate, filters dense Contracting, residue are purified through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1], obtain title compound (0.15g, yield 59%, HPLC purity 98.8%), it is white solid.

MS(ESI,pos.ion)m/z:398.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 7.79 (s, 1H), 7.21 (tdd, J=15.8,7.6,4.8Hz, 3H), 4.09 (d, J=9.4Hz, 1H), 3.90 (dd, J=10.7,2.4Hz, 1H), 3.68 (dd, J=9.4,2.2Hz, 1H), 3.61 (dd, J=9.4,5.2Hz, 1H), 3.24 (dd, J=4.9,2.1Hz, 2H), 3.17-2.97 (m, 5H), 2.71 (tdd, J= 11.4,8.7,3.8Hz, 2H), 2.21 (d, J=11.8Hz, 1H), 1.37 (dd, J=15.0,8.3Hz, 1H), 1.25 (d, J= 5.8Hz, 1H), 1.14 (d, J=4.7Hz, 9H).

Embodiment 131- [(3aS, 6aS) -1- (3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] -2,2,2- trifluoro-ethanone

Step 1) (3aS, 6aS) -1- [(1R) -1- phenethyl] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrrole Cough up -5- carboxylic acid, ethyl ester

(R) -1- phenyl ethylamine guanidine-acetic acid (25g, 0.14mol) is dissolved in toluene (0.34L), is heated to 90 DEG C, N- alkene is added dropwise It is small to be then heated to 110 DEG C of reactions 26 for the toluene solution of propyl-N- (2- oxygen ethyl) urethanes (26g, 0.15mol) When.Reaction solution is concentrated under reduced pressure, residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=15/1], is marked It inscribes compound (19g, yield 47%), is yellow oil.MS(ESI,pos.ion)m/z:289.2[M+H]⁺。

Step 2) (3aS, 6aS) -1- [(1R) -1- phenethyl] -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] Pyrroles

By (3aS, 6aS) -1- [(1R) -1- phenethyl] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- Carboxylic acid, ethyl ester (25.0g, 86.7mmol) is dissolved in concentrated hydrochloric acid (217mL), and heating reflux reaction 8 hours.Reaction is cooled to room temperature, and is used Saturated sodium bicarbonate solution adjusts pH=8, is extracted with methylene chloride (1L × 5), and combined organic phase is dry with anhydrous sodium sulfate, Concentration is filtered, residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=15/1], obtains title compound (11.5g, yield 61%) is yellow oil.

MS(ESI,pos.ion)m/z:217.3[M+H]⁺。

Step 3) 1- [(3aS, 6aS) -1- [(1R) -1- phenethyl] -2,3,3a, 4,6,6a- hexahydro-pyrrolo- [3,4-b] Pyrroles -5- base] -2,2,2- trifluoro-ethanone

By (3aS, 6aS) -1- [(1R) -1- phenethyl] -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] pyrroles (0.39g, 1.80mmol) is dissolved in methylene chloride (10mL), and 4-dimethylaminopyridine (40mg, 0.32mmol) and three is added at 0 DEG C Then trifluoroacetic anhydride (0.38mL, 2.7mmol) is added dropwise in ethamine (0.38mL, 2.7mmol), reacts at room temperature 8 hours.Water is added dropwise (10mL) quenching reaction is extracted with methylene chloride (25mL × 2), and combined organic phase is dry with anhydrous sodium sulfate, filters concentration, Residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=50/1], obtains title compound (0.55g, yield It 98%), is yellow oil.

MS(ESI,pos.ion)m/z:313.2[M+H]⁺。

Step 4) 1- [(3aS, 6aS) -2,3,3a, 4,6,6a- hexahydro -1H- pyrrolo- [3,4-b] pyrroles -5- base] -2,2, 2- trifluoro-ethanone

By 1- [(3aS, 6aS) -1- [(1R) -1- phenethyl] -2,3,3a, 4,6,6a- hexahydro-pyrrolo- [3,4-b] pyrrole Cough up -5- base] -2,2,2- trifluoro-ethanones (0.53g, 1.7mmol) are dissolved in methanol (20mL), and 10% palladium dydroxide/carbon is added (0.24g), replacing hydrogen, hydrogenation 8 hours.Filtering, filtrate concentration, residue is through silica gel column chromatography [methylene chloride/methanol (v/v)=20/1 it] purifies, obtains title compound (0.22g, yield 63%), be yellow oil.

MS(ESI,pos.ion)m/z:209.2[M+H]⁺。

Step 5) N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2,2,2- trifluoroacetyl group) -2,3,3a, 4,6,6a- Hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl carbamate (2.0g, 6.1mmol) and 1- [(3aS, 6aS) -2,3,3a, 4,6,6a- hexahydro -1H- pyrrolo- [3,4-b] pyrroles -5- base] -2, 2,2- trifluoro-ethanones (1.0g, 4.8mmol) are dissolved in n,N-dimethylacetamide (10mL), nitrogen protection, at -10 DEG C, are added three Acetoxyl group sodium borohydride (1.4g, 6.3mmol) reacts 8 hours.Ammonia/water (v/v=2/3,20mL) quenching reaction is added, Filtering, obtained solid are purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1], obtain title compound (0.12g, yield 48%) is yellow solid.

MS(ESI,pos.ion)m/z:520.3[M+H]⁺。

Step 6) 1- [(3aS, 6aS) -1- (3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] -2,2,2- trifluoro-ethanone

At 0 DEG C, by trifluoroacetic acid (3.0mL, 39mmol) be added to N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2, 2,2- trifluoroacetyl group) -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) four Hydrogen pyrans -3- base] carbamate (2.5g, 2.4mmol) dichloromethane solution in (15mL), room temperature reaction is 2 small When.At 0 DEG C, with saturated sodium bicarbonate solution (30mL) quenching reaction, methylene chloride/methanol (v/v=10/1,50mL × 3) extraction It takes, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [methylene chloride/methanol (v/ V) it=20/1] purifies, obtains title compound (0.54g, yield 54%, HPLC purity 91.6%), be yellow oil.

MS(ESI,pos.ion)m/z:420.1[M+H]⁺；

¹HNMR(400MHz,CDCl₃) δ (ppm) 7.12-7.00 (m, 3H), 4.21 (d, J=8.0Hz, 1H), 4.05-4.02 (m,1H),3.69-3.58(m,5H),3.49-3.37(m,1H),3.04-2.80(m,4H),2.67-2.63(m,1H),2.34- 2.31(m,1H),2.21-2.18(m,1H),1.67-1.62(m,3H),1.46-1.42(m,1H)。

14 1- of embodiment [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane - 3- yl] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] the fluoro- 2- methyl -propyl- 1- ketone of -2-

Step 1) N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] Pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2,2,2- trifluoroacetyl group) -2,3,3a, 4,6,6a- hexahydro Pyrrolo- [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate (0.20g, It 0.40mmol) is dissolved in the mixed solvent of methanol (5mL) and water (1mL), is added potassium carbonate (70mg, 0.51mmol), room temperature reaction 8 Hour.Reaction solution concentration, be added water (8mL), with methylene chloride/methanol (v/v=10/1,20mL × 2) extract, merging it is organic It is mutually dry with anhydrous sodium sulfate, concentration is filtered, residue is purified through silica gel column chromatography [methylene chloride/methanol (v/v)=5/1], Title compound (63mg, yield 40%) is obtained, is yellow solid.

MS(ESI,pos.ion)m/z:424.3[M+H]⁺。

Step 2) N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (the fluoro- 2- methyl-propanoyl of 2-) -2,3,3a, 4,6, 6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] pyrroles - 1- yl] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate (63mg, 0.15mmol) and 2- fluorine isobutyl Sour (19mg, 0.18mmol) is dissolved in methylene chloride (4mL), and I-hydroxybenzotriazole (25mg, 0.18mmol), 1- are added at 0 DEG C (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (35mg, 0.18mmol) and triethylamine (20mg, 0.20mmol), Then react 8 hours at room temperature.Reaction solution concentration, residue are pure through silica gel column chromatography [methylene chloride/methanol (v/v)=30/1] Change, obtain title compound (49mg, yield 64%), is yellow oil.

MS(ESI,pos.ion)m/z:512.3[M+H]⁺。

Step 3) 1- [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] the fluoro- 2- methyl -propyl- 1- ketone of -2-

At 0 DEG C, trifluoroacetic acid (0.2mL, 3.0mmol) is added to N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2- Fluoro- 2- methyl-propanoyl) -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) Tetrahydropyran -3-base] carbamate (49mg, 0.096mmol) dichloromethane solution in (3mL), room temperature reaction 8 Hour.With saturated sodium bicarbonate solution (5mL) quenching reaction, methylene chloride/methanol (v/v=10/1,8mL × 3) extraction merges Organic phase it is dry with anhydrous sodium sulfate, filter concentration, residue is through silica gel column chromatography [methylene chloride/methanol (v/v)=10/ 1] it purifies, obtains title compound (20mg, yield 51%, HPLC purity 99.1%), be colorless oil.

MS(ESI,pos.ion)m/z:412.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.20(s,1H),7.08-7.01(m,2H),4.26-4.24(m,1H), 4.08-4.01(m,1H),3.81-3.68(m,5H),3.65-3.41(m,3H),2.87-2.64(m,5H),2.08(s,1H), 1.66-1.51(m,6H),1.45-1.27(m,3H)。

15 1- of embodiment [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane - 3- yl] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] -2,2- dimethyl -propyl- 1- ketone

Step 1) N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2,2- Dimethylpropanoyl) -2,3,3a, 4,6,6a- Hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] pyrroles - 1- yl] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate (0.10g, 0.24mmol) and pivalic acid (30mg, 0.29mmol) is dissolved in methylene chloride (4mL), and I-hydroxybenzotriazole (40mg, 0.29mmol), 1- (3- are added at 0 DEG C Dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (56mg, 0.29mmol) and triethylamine (30mg, 0.29mmol), then It reacts 8 hours at room temperature.Reaction solution concentration, residue are purified through silica gel column chromatography [100% ethyl acetate], obtain title compound Object (0.10g, yield 80%) is yellow oil.

MS(ESI,pos.ion)m/z:508.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 7.21 (s, 1H), 6.96 (s, 2H), 4.55 (d, J=4.0Hz, 1H), 4.32 (d, J=4.0Hz, 1H), 3.93 (s, 1H), 3.72-3.70 (m, 3H), 3.53-3.52 (m, 4H), 3.05 (s, 1H), 2.81 (d, J=16.0Hz, 2H), 2.61 (s, 1H), 2.42-2.40 (m, 1H), 1.75-1.63 (m, 4H), 1.25 (s, 10H).

Step 2) 1- [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base] -2,2- dimethyl -propyl- 1- ketone

At 0 DEG C, by trifluoroacetic acid (0.4mL, 5.0mmol) be added to N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (2, 2- Dimethylpropanoyl) -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) four Hydrogen pyrans -3- base] carbamate (0.10g, 0.20mmol) dichloromethane solution in (3mL), room temperature reaction is 8 small When.With saturated sodium bicarbonate solution (5mL) quenching reaction, methylene chloride/methanol (v/v=10/1,8mL × 3) is extracted, merging Organic phase is dry with anhydrous sodium sulfate, filters concentration, residue is through silica gel column chromatography [methylene chloride/methanol (v/v)=10/1] Purifying, obtains title compound (60mg, yield 94%, HPLC purity 99.1%), is colorless oil.MS(ESI, pos.ion)m/z:408.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 7.20-7.16 (m, 3H), 4.08 (d, J=8.0Hz, 1H), 3.92 (d, J=12.0Hz, 1H), 3.54-3.51 (m, 3H), 3.27-3.22 (m, 3H), 2.89-2.71 (m, 4H), 1.44-1.29 (m, 5H),1.25(s,9H)。

Embodiment 161- [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -5- base]-(3- methylsulfonyl phenyl)-ketone

Step 1) N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (3- methylsulphonyl benzoyl) -2,3,3a, 4,6, 6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate

By N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -3,3a, 4,5,6,6a- hexahydro -2H- pyrrolo- [3,4-b] pyrroles - 1- yl] -2- (2,5- difluorophenyl) tetrahydropyran -3-base] carbamate (0.10g, 0.24mmol) and 3- methyl Sulfonyl benzoic acid (57mg, 0.28mmol) is dissolved in methylene chloride (4mL), at 0 DEG C be added I-hydroxybenzotriazole (40mg, 0.29mmol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (56mg, 0.29mmol) and triethylamine (30mg, 0.29mmol) then reacts 8 hours at room temperature.Reaction solution concentration, residue is through silica gel column chromatography [100% acetic acid second Ester] purifying, title compound (0.11g, yield 77%) is obtained, is yellow oil.

MS(ESI,pos.ion)m/z:606.3[M+H]⁺。

Step 2) 1- [(3aS, 6aS) -1- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) oxinane -3- Base] -2,3,3a, 4,6,6a- hexahydropyrrolo is simultaneously [3,4-b]Pyrroles -5- base]-(3- methylsulfonyl phenyl)-ketone

At 0 DEG C, trifluoroacetic acid (0.4mL, 5.0mmol) is added to N- [(2R, 3S, 5R) -5- [(3aS, 6aS) -5- (3- Methylsulphonyl benzoyl) -2,3,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-b] pyrroles -1- base] -2- (2,5- difluorobenzene Base) tetrahydropyran -3-base] carbamate (0.11g, 0.18mmol) dichloromethane solution in (3mL), room temperature is anti- It answers 8 hours.With saturated sodium bicarbonate solution (5mL) quenching reaction, methylene chloride/methanol (v/v=10/1,8mL × 3) is extracted, Combined organic phase is dry with anhydrous sodium sulfate, filters concentration, residue through silica gel column chromatography [methylene chloride/methanol (v/v)= 10/1] it purifies, obtains title compound (45mg, yield 49%, HPLC purity 96.4%), be colorless oil.MS(ESI,_pos.ion)m/z:506.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.86-7.73(m,4H),7.21(s,3H),5.75(s,1H), 4.13-4.01(m,1H),3.70-3.64(m,3H),3.17-3.11(m,2H),2.95-2.92(m,1H),2.78-2.69(m, 3H),2.51-2.11(m,3H),1.51-1.36(m,6H)。

17 2- of embodiment [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydropyran -3-base] -5- methylsulfonyl Base -3,3a, 6,6a- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] pyrroles -4- ketone

Step 1) 3- [benzyl (ethylene oxide -2- methylene) amino] propionitrile

3- (benzyl amino) propionitrile (5.0g, 31mmol) and potassium carbonate (8.6g, 62mmol) are dissolved in acetonitrile (50mL), nitrogen Under protection, 2- (bromomethyl) ethylene oxide (5.1mL, 62mmol) is added, tube sealing is heated to 100 DEG C and reacts 22 hours.Reaction solution It is cooled to room temperature, filters, filter cake is eluted with ethyl acetate (20mL), and filtrate concentration, residue is through silica gel column chromatography [acetic acid second Ester/petroleum ether (v/v)=1/4] purifying, title compound (3.9g, yield 58%) is obtained, is light yellow oil.

MS(ESI,pos.ion)m/z:217.2[M+H]⁺。

Step 2) 1- benzyl -4- (methylol) pyrrolidines -3- formonitrile HCN

3- [benzyl (ethylene oxide -2- methylene) amino] propionitrile (1.0g, 4.6mmol) is dissolved in toluene (10mL), nitrogen Hexamethyl silicon substrate Sodamide (2.8mL, 5.6mmol) is added dropwise at 0 DEG C in gas shielded, reacts 10 minutes.Water is added to reaction solution (2.0mL) is extracted with toluene (10mL × 2), combined organic phase washed with water (10mL) and saturated sodium chloride solution (10mL) Washing, anhydrous sodium sulfate is dry, filters concentration, and residue is pure through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/1] Change, obtain title compound (0.28g, yield 28%), is light yellow oil.

MS(ESI,pos.ion)m/z:217.2[M+H]⁺。

Step 3) (1- benzyl -4- cyano-pyrolidin -3- base) methyl mesylate

1- benzyl -4- (methylol) pyrrolidines -3- formonitrile HCN (1.0g, 4.6mmol) is dissolved in methylene chloride (10mL), is added Methylsufonyl chloride (0.43mL, 5.6mmol) is added dropwise at 0 DEG C in triethylamine (1.0mL, 7.2mmol), nitrogen protection, reacts 1 hour. Water (5mL) quenching reaction, liquid separation is added, water phase is extracted with methylene chloride (15mL), and combined organic phase saturated sodium-chloride is molten Liquid (10mL × 2) washing, anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [ethyl acetate/petroleum ether (v/ V) it=1/1] purifies, obtains title compound (1.30g, yield 96%), be crocus grease.

MS(ESI,pos.ion)m/z:295.1[M+H]⁺。

Step 4) 1- benzyl -4- [(1,3- dioxoisoindole -2- base) methyl] pyrrolidines -3- formonitrile HCN

Potassium phthalimide (0.35g, 1.86mmol) is dissolved in n,N-Dimethylformamide (5.0mL), nitrogen It protects, (1- benzyl -4- cyano-pyrolidin -3- base) methyl mesylate (0.50g, 1.69mmol) is added at 75 DEG C, reaction 22 is small When.Reaction solution is cooled to room temperature, and water (15mL) is added to be quenched, and is extracted with ethyl acetate (10mL × 2), combined organic phase saturation Sodium chloride solution (10mL × 3) washing, anhydrous sodium sulfate is dry, filters concentration, residue through silica gel column chromatography [ethyl acetate/ Petroleum ether (v/v)=1/1] purifying, title compound (0.42g, yield 72%) is obtained, is off-white powder.

MS(ESI,pos.ion)m/z:346.2[M+H]⁺。

Step 5) 4- (aminomethyl) -1- benzy-pyrrolidin -3- formonitrile HCN

By 1- benzyl -4- [(1,3- dioxoisoindole -2- base) methyl] pyrrolidines -3- formonitrile HCN (1.10g, 3.18mmol) It is dissolved in methanol (11mL), hydrazine hydrate (1.9mL, 15.9mmol) is added at 60 DEG C, react 1 hour.Reaction solution is cooled to room temperature, and is subtracted Water (10mL) is added in pressure concentration, residue, is extracted with ethanol/methylene (v/v=1/9,10mL × 2), combined organic phase It is washed with saturated sodium chloride solution (10mL), anhydrous sodium sulfate is dry, filters concentration, residue is through silica gel column chromatography [methanol/bis- Chloromethanes (v/v)=1/9] purifying, title compound (0.50g, 73%) is obtained, is off-white powder.

MS(ESI,pos.ion)m/z:216.3[M+H]⁺。

Step 6) 5- benzyl -1,2,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-c] pyrroles -3- ketone

4- (aminomethyl) -1- benzy-pyrrolidin -3- formonitrile HCN (3.0g, 14mmol) is dissolved in methanol (120mL), hydrogen is added Water (30mL) solution of sodium oxide molybdena (1.1g, 28mmol), 60 DEG C are reacted 72 hours.Reaction solution is cooled to room temperature, with concentrated hydrochloric acid tune PH=7 is saved, is extracted with ethanol/methylene (v/v=1/9,100mL), organic phase is dry with anhydrous sodium sulfate, concentration is filtered, Residue is purified through silica gel column chromatography [ethanol/methylene (v/v)=1/9], is obtained title compound (2.50g, 83%), light Yellow oil.

MS(ESI,pos.ion)m/z:217.2[M+H]⁺。

Step 7) 2,3,3a, 5,6,6a- hexahydro -1H- pyrrolo- [3,4-c] pyrroles's -4- ketone

By 5- benzyl -1,2,3a, 4,6,6a- hexahydropyrrolo, simultaneously [3,4-c] pyrroles -3- ketone (2.00g, 9.25mmol) is dissolved in The mixed solution of tetrahydrofuran (5mL) and methanol (10mL), is added 10% palladium/carbon (0.20g), replacing hydrogen, and hydrogenation 8 is small When.Filtering, filter cake with methanol (10mL) elute, filtrate concentration, residue through silica gel column chromatography [ethanol/methylene (v/v)= 1/9] it purifies, obtains title compound (1.17g, yield 100%).

MS(ESI,pos.ion)m/z:256.1[M+H]⁺。

Step 8) 3- oxo -1,2,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-c] pyrroles -5- t-butyl formate

By 2,3,3a, 5,6,6a- hexahydro -1H- pyrrolo- [3,4-c] pyrroles -4- ketone (1.17g, 9.27mmol) is dissolved in two Chloromethanes (20mL) is added triethylamine (2.6mL, 19mmol), nitrogen protection, be added dropwise at 0 DEG C di-tert-butyl dicarbonate (2.6mL, 11mmol), it reacts at room temperature 3 hours.Add water (10mL) quenching reaction, liquid separation, organic phase is washed with water (5mL × 3), and organic phase is used Anhydrous sodium sulfate is dry, filters concentration, and residue is purified through silica gel column chromatography [100% ethyl acetate], obtains title compound (1.10g, yield 52%).

MS(ESI,pos.ion)m/z:249.2[M+Na]⁺。

Step 9) 5- mesyl -4- oxo -3,3a, 6,6a- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] pyrroles -2- formic acid uncle Butyl ester

By 3- oxo -1,2,3a, 4,6,6a- hexahydropyrrolo simultaneously [3,4-c] pyrroles -5- t-butyl formate (1.00g, It 4.42mmol) is dissolved in tetrahydrofuran (10.0mL), nitrogen protection, n-BuLi (2.2mL, 5.3mmol) is added dropwise at -78 DEG C, instead It answers 2 hours, methylsufonyl chloride (0.51mL, 6.6mmol) then is added dropwise, the reaction was continued 5 hours.Saturated ammonium chloride solution is added (5mL) quenching reaction is extracted with ethyl acetate (10mL), and organic phase is washed with saturated sodium chloride solution (5mL), anhydrous sodium sulfate It is dry, concentration is filtered, residue is purified through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/1], obtains title compound Object (0.96g, yield 71%) is off-white powder.

MS(ESI,pos.ion)m/z:327.2[M+H]⁺。

Step 10) 5- mesyl -1,2,3,3a, 6,6a- hexahydropyrrolo simultaneously [3,4-c] pyrroles -4- ketone

By 5- mesyl -4- oxo -3,3a, 6,6a- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] pyrroles -2- t-butyl formate (0.60g, 1.971mmol) is dissolved in the ethanol solution (10mL, 2mol/L) of hydrogen chloride, reacts 4 hours.Reaction solution is concentrated under reduced pressure, Title compound (0.40g, 99%) is obtained, is off-white powder.

MS(ESI,pos.ion)m/z:205.2[M+H]⁺。

Step 11) N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5- mesyl -4- oxo -3,3a, 6,6a- Tetrahydro-1 H-pyrrolo simultaneously [3,4-c] pyrroles -2- base] t-butyl carbamate

By N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- oXo-tetrahydro pyrans -3- base] t-butyl formate (0.50g, It 1.53mmol) is dissolved in n,N-dimethylacetamide (0.5mL), 5- mesyl -1,2 is added, 3,3a, 6,6a- hexahydropyrrolos are simultaneously [3,4-c] pyrroles -4- ketone (0.40g, 1.95mmol) is heated to 35 DEG C and reacts 2 hours.Triacetyl is added at 0 DEG C in nitrogen protection Oxygroup sodium borohydride (0.95g, 4.48mmol) reacts at room temperature 15 hours.Add water (8mL) quenching reaction, filters, filter cake water (8mL) elution, the solid of collection are purified through silica gel column chromatography (100% ethyl acetate), obtain title compound (0.41g, It 52%), is off-white powder.

MS(ESI,pos.ion)m/z:516.2[M+H]⁺。

Step 12) 2- [(3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydropyran -3-base] -5- methylsulfonyl Base -3,3a, 6,6a- tetrahydro-1 H-pyrrolo simultaneously [3,4-c] pyrroles -4- ketone

By N- [(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5- mesyl -4- oxo -3,3a, 6,6a- tetrahydro - 1H- pyrrolo- [3,4-c] pyrroles -2- base] t-butyl carbamate (0.40g, 0.77mmol) is dissolved in the methanol solution of hydrogen chloride (10mL, 3mol/L) is reacted at room temperature 4 hours.Sodium bicarbonate solid (1.0g) is added into reaction solution, reacts at room temperature 1 hour, mistake Filter, filtrate concentration, obtains title compound (0.17g, yield 53%, HPLC purity 98.6%), is faint yellow solid.

MS(ESI,pos.ion)m/z:416.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)7.15-7.09(m,1H),7.04-7.02(m,1H),6.99-6.96(m, 1H), 4.20 (d, J=24.0Hz, 1H), 4.09-4.06 (m, 1H), 3.60-3.58 (m, 1H), 3.32 (t, 2H), 3.27 (s, 3H), 3.24 (d, J=18.0Hz, 1H), 3.15-3.12 (m, 1H), 2.94 (t, 2H), 2.82-2.79 (m, 2H), 2.64-1.59 (m,1H),2.57-2.55(m,2H),2.54-2.52(m,1H),2.38-2.29(m,2H)。

Active testing embodiment

One, DPP-IV enzyme inhibits test

Test purpose: method below is for measuring the compounds of this invention to the inhibitory activity of DPP-IV enzyme.

Test material: DPP-IV enzyme is purchased from R&D, Catalog No.1180-SE.

Test method:

Untested compound is dissolved in suitable DMSO, the mother liquor that 100mM is made is divided in EP pipe, is stored in -20 ℃.When experiment, diluted according to required concentration with buffer living is surveyed.Add the 4 μ L of sample of various concentration in 384 orifice plates, adds 4 μ L Certain density DPP-IV.Reference book, selecting substrate Gly-Pro-AMC concentration is 10 μM.Substrate is configured to 16mM first Mother liquor, be stored in -20 DEG C for using.The mother liquor of 16mM is surveyed into buffer living when experiment and is diluted to required concentration.DPP-IV Survey buffer living be 25mM Tris, pH 8.0.Substrate mother liquor is diluted with work buffer is surveyed, adds 4 μ L dense to end in 384 orifice plates Degree.Whole process carries out under condition of ice bath.The completely rear centrifugation of ingredient sample-adding in live body system.It is placed in multi-function microplate reader In Infinite F200, every 30sec records a fluorescent value, records 20 values altogether.After running through, the soft of microplate reader is directly used Part calculates Slope (V₀), take data in the range of linearity.It is analyzed with corresponding inhibitor concentration reaction speed is measured, is inhibited Percentage is I (%)=(V₀-V_i)/V₀X100%.V_iRepresent initial velocity of reaction when different inhibitor concentrations, V₀Representative does not press down Initial velocity of reaction when preparation, with V_i/V₀Indicate the inhibition level of inhibitor.Using the concentration of institute's inhibiting as abscissa, with V_i/V₀Value be ordinate, make response curve, using Graph Pad Prism statistical analysis software calculate IC₅₀。

Test result: the results are shown in Table 1 for it:

Table 1: inhibitory activity of the compound provided in an embodiment of the present invention to DPP-IV

Embodiment number	DPP4IC50/nM
		Embodiment 2	20.00
Embodiment 6	28.19
		Embodiment 13	4.448
Embodiment 14	9.322
		Embodiment 15	7.988
Embodiment 16	4.167
		Embodiment 17	6.214

Conclusion: the compounds of this invention has obvious inhibiting effect to DPP-IV activity.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims (11)

1. a kind of compound, be the stereoisomer of compound shown in compound shown in formula (I) or formula (I), geometric isomer, Tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

Wherein:

R^1a、R^1bAnd R^1cIt is each independently H, deuterium, F, Cl, Br, I ,-CN ,-NO₂、-OH、-NH₂、C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl or C_1-6Halogenated alkoxy；

W is

L is C_1-4Alkyl；

Each R⁵、R⁷、R⁸、R¹⁰And R¹⁴It independently is H, deuterium ,-CN, C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 atom Heterocycle, the C of composition_6-10Aryl, 5-6 former molecular heteroaryl ,-S (=O)₂R^a,-C (=O) R^b,-OC (=O) R^b、-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 Former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 A R^xIt is replaced；

R¹²For H, deuterium ,-CN, C_2-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Virtue Base, 5-6 former molecular heteroaryl ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_2-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle Base, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

Each R^a、R^b、R^cAnd R^dIt independently is C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-6 original Molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

R^eAnd R^fIt is each independently C_2-6Alkyl, C_4-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl or 5-6 are a Former molecular heteroaryl, wherein the C_2-6Alkyl, C_4-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl and 5- 6 molecular heteroaryls of original are unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

Each R^4a、R^4b、R^4c、R^4d、R^6a、R^6b、R^6c、R^6d、R⁶、R⁹、R¹¹And R¹³Independently be H, deuterium, F, Cl, Br, I ,=O ,-OH ,- CN、-NH₂、-NO₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkoxyacyl, C_1-6Alkanoyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-6Alkyl, C_1-6It is halogenated Alkyl, C_1-6Alkoxy, C_1-6Alkoxyacyl, C_1-6Alkanoyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Virtue The former molecular heteroaryl of base and 5-6 is unsubstituted each independently or by 1,2 or 3 R^yIt is replaced；

Each R^xAnd R^yIt independently is deuterium, F, Cl, Br, I ,-OH ,-CN, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkane acyl Base, C_1-6Alkoxyacyl or C_1-6Alkyl sulphonyl；

Each n, t or s independently are 1,2,3 or 4；

Q, p and u is each independently 0,1,2 or 3.

2. compound according to claim 1, wherein each R⁵、R⁷、R⁸、R¹⁰And R¹⁴It independently is H, deuterium ,-CN, C_1-4Alkane Base, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl, 5-6 former molecular heteroaryl Base ,-S (=O)₂R^a,-C (=O) R^b,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；It is wherein described C_1-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5-6 original are molecular Heteroaryl is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

R¹²For H, deuterium ,-CN, C_2-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Virtue Base, 5-6 former molecular heteroaryl ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；The wherein C_2-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle Base, C_6-10The former molecular heteroaryl of aryl and 5-6 is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced.

3. compound according to claim 2, wherein each R⁵、R⁷、R⁸、R¹⁰And R¹⁴It independently is H, deuterium ,-CN, methyl, second Base, n-propyl, isopropyl, normal-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 atom Heterocycle, phenyl, 5-6 former molecular the heteroaryl ,-S (=O) of composition₂R^a,-C (=O) R^b,-OC (=O) R^b,-C (= O)OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；Wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl It is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

R¹²For H, deuterium ,-CN, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, 5-6 former molecular heterocycle, phenyl, 5-6 former molecular heteroaryl ,-S (=O)₂R^e,-C (=O) R^f,-OC (=O) R^b,-C (=O) OR^c,-S (=O)₂NHR^dOr-C (=O) NHR^d；Wherein the ethyl, n-propyl, isopropyl, Normal-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl and 5-6 are former Molecular heteroaryl is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced.

4. compound according to claim 1, wherein each R^a、R^b、R^cAnd R^dIt independently is C_1-4Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-4Alkane Base, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5-6 former molecular heteroaryl Base is unsubstituted each independently or by 1,2 or 3 R^xIt is replaced；

R^eAnd R^fIt is each independently C_2-4Alkyl, C_4-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl or 5-6 are a Former molecular heteroaryl, wherein the C_2-4Alkyl, C_4-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5- 6 molecular heteroaryls of original are unsubstituted each independently or by 1,2 or 3 R^xIt is replaced.

5. compound according to claim 4, wherein each R^a、R^b、R^cAnd R^dIt independently is methyl, ethyl, n-propyl, different Propyl, normal-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, miaow Oxazolidinyl, piperidyl, piperazinyl, tetrahydrofuran base, dihydrofuryl, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridine Base, pyrimidine radicals, thiazolyl, thienyl, furyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, evil Di azoly, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, tetrahydrofuran base, dihydro furan Mutter base, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, furyl, pyrazolyl, Imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, pyrazinyl and pyridazinyl are not taken each independently Generation or by 1,2 or 3 R^xIt is replaced；

R^eAnd R^fIt is each independently ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrole Cough up alkyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, tetrahydrofuran base, dihydrofuryl, morpholinyl, thiomorpholine Base, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, furyl, pyrazolyl, imidazole radicals, triazolyl, tetrazolium Base, oxazolyl, isoxazolyl, oxadiazoles base, pyrazinyl or pyridazinyl, wherein the ethyl, n-propyl, isopropyl, normal-butyl, Tert-butyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, tetrahydrofuran Base, dihydrofuryl, morpholinyl, thio-morpholinyl, phenyl, pyrrole radicals, pyridyl group, pyrimidine radicals, thiazolyl, thienyl, furans Base, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, oxadiazoles base, pyrazinyl and pyridazinyl are respectively only It is on the spot unsubstituted or by 1,2 or 3 R^xIt is replaced.

6. compound according to claim 1, wherein each R^4a、R^4b、R^4c、R^4d、R^6a、R^6b、R^6c、R^6d、R⁶、R⁹、R¹¹And R¹³ It independently is H, deuterium, F, Cl, Br, I ,=O ,-OH ,-CN ,-NH₂、-NO₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, Methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, methoxyl group acyl group, ethoxyacyl, acetyl group, cyclopropyl, cyclobutyl, ring Amyl, cyclohexyl, 5-6 former molecular heterocycle, phenyl or 5-6 former molecular heteroaryl, wherein the methyl, second Base, n-propyl, isopropyl, methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, methoxyl group acyl group, ethoxyacyl, acetyl Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 5-6 former molecular heterocycle, phenyl and 5-6 are former molecular miscellaneous Aryl is unsubstituted each independently or by 1,2 or 3 substituent R^yIt is replaced；

Each R^xAnd R^yIt independently is deuterium, F, Cl, Br, I ,-OH ,-CN, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy Base, ethyoxyl, 1- propoxyl group, 2- propoxyl group, n-butoxy, tert-butoxy, acetyl group, methoxyl group acyl group, ethoxyacyl, first Base sulfonyl, ethylsulfonyl, n-propyl sulfonyl or isopropelsulfonyl.

7. compound according to claim 1, wherein R^1a、R^1bAnd R^1cBe each independently H, deuterium, F, Cl, Br, I ,- CN、-NO₂、-OH、-NH₂, methyl, ethyl, n-propyl, isopropyl, methoxyl group, ethyoxyl, trifluoromethyl or trifluoromethoxy；

L is methyl, ethyl or n-propyl.

8. compound according to claim 1, with structure shown in formula (II):

9. a kind of compound, the structure with one of:

Or stereoisomer, geometric isomer, tautomer, nitrogen oxides, water Close object, solvate, metabolite, pharmaceutically acceptable salt or their prodrug.

10. a kind of pharmaceutical composition, it includes compounds described in any one of claim 1-9, optionally, further include Pharmaceutically acceptable carrier, excipient, adjuvant, medium or their combination.

11. compound described in any one of claim 1-9 or pharmaceutical composition described in any one of claim 10 are preparing drug In purposes, wherein the drug is for inhibiting dipeptidyl peptidase-IV (DPP-IV)；Or the drug for preventing, treating or Mitigate diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, hyperglycemia, high pancreas Island element mass formed by blood stasis, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or hypertension.