CN108341752A - The aminated compounds for inhibiting SSAO/VAP-1 and its application in medicine - Google Patents

Abstract

Application the present invention relates to the aminated compounds for inhibiting SSAO/VAP 1 and its in medicine.Specifically, the present invention relates to a kind of aminated compounds for inhibiting semicarbazide-sensitive oxidizing ferment (SSAO) and/or vascular adhesion protein 1 (VAP 1) inhibitor or its pharmaceutically acceptable salt, stereoisomer or E/Z isomers, further to the pharmaceutical composition containing the aminated compounds.The invention further relates to the purposes of the compound and pharmaceutical composition in the drug for preparing treatment inflammation, inflammation related disease and immunological diseases.

Description

The aminated compounds for inhibiting SSAO/VAP-1 and its application in medicine

Technical field

The invention belongs to field of medicaments, are related to a kind of for inhibiting semicarbazide-sensitive amine oxidizing ferment (SSAO) and/or blood The aminated compounds of pipe adhesion protein -1 (VAP-1), the method for preparing them, the pharmaceutical composition comprising the compound and institute State the application of compound and its composition in medicine.More particularly, it relates to logical formula (I) compound represented or its Pharmaceutically acceptable salt or its stereoisomer, E/Z isomers, and the pharmaceutical composition containing the compound and described Compound and pharmaceutical composition the drug for preparing treatment inflammation, inflammation related disease and immunological diseases purposes.

Background technology

Amine oxidase (Amine Oxidase, AO) is a kind of protein for having special biological function, in vivo extensively In the presence of for example, existing in higher mammal including people and microbial cell.Its energy metabolism various endogenous or exogenous Monoamine, diamines and polyamines compound.Well known there are two main classes amine oxidase, one kind is the amine oxidase of cupric, Include mainly semicarbazide-sensitive amine oxidizing ferment (Semicarbazide-Sensitive Amine Oxidase, SSAO) and two Amine oxidase (Diamine oxidase, DAO)；Another kind of is to contain flavine (Flavin-containg) amine oxidase, main to wrap Include monoamine oxidase (Monoamine oxidase) and polyamine oxidase (Polyamine oxidase).Wherein, semicarbazides is quick Perceptual amine oxidase (SSAO), be it is a kind of containing bivalent cupric ion, it is especially sensitive to semicarbazides by coenzyme of 6- hydroxydopa quinone Amine oxidase, mainly exist with dimeric forms.Diamine oxidase (DAO) only acts as diamines, especially histamine due to it With, therefore also known as histamine oxidase.Monoamine oxidase is divided into monoamine oxidase A (Monoamine oxidase A, MAO-A) With monoamine oxidase B (Monoamine oxidase B, MAO-B), it is primarily present in the mitochondria of most cells, and Using covalently bound flavin adenine dinucleotide (FAD) (FAD) as confactor.Polyamine oxidase is oxidative deamination spermine With another FAD dependences amine oxidase of spermidine.And SSAO its substrate, inhibitor, confactor, subcellular localization and It is different from MAO-A and MAO-B in terms of function, it is to belong to copper to rely on and using other substances such as three hydroxyls other than FAD Amine oxidase of the base phenylalanine quinone (Trihydroxyphenylalanine Quinone, TPQ) as confactor.

SSAO is widely present in the tissue of vascular rich content in the mammalian body, is mainly existed in two forms, one Kind is the form of solubility, is primarily present in blood circulation；One is the forms that film combines, and are distributed widely in organ and tissue In, especially in adipocyte, vascular endothelial cell and smooth muscle cell.SSAO is a kind of multifunctional enzyme, pathologic, physiologic Function has diversity because of the Tissue distribution of SSAO difference.In adipocyte and smooth muscle cell, SSAO can promote Portugal Grape saccharide transporter 4 (Glucose transport 4, GLUT 4) is transferred to cell membrane from adipocyte intracellular, and then adjusts Glucose transport.In endothelial cell, SSAO is with vascular adhesion protein-1 (Vascular adhesion protein1, VAP-1) Form exist, mediated leucocytes and endothelial cell stick and ooze outs process, participation inflammatory reaction.

Vascular adhesion protein-1 (VAP-1) is a kind of endothelial adhesion molecule, has dual function, is on the one hand lymphocyte Adhesion molecule, promote leukocyte adhesion in blood vessel endothelium；On the other hand, VAP-1 also has effects that enzyme, can be catalyzed primary Amine is corresponding aldehyde.VAP-1 is by being positioned at the AOC3 gene codes of No. 17 chromosomes of people.VAP-1 albumen can be with the shape of solute Formula is present in blood plasma, and the table of endothelial cell, adipocyte and smooth muscle cell can also be present in the form of being combined with film Face.The clone of VAP-1 antigens discloses it and belongs to semicarbazide-sensitive amine oxidizing ferment (Smith D.J, Salmi M, Bono P, et a1.JI.J ExpMed,1998,188(1):17-27), identical as SSAO in structure.Therefore, Recent study person usually will SSAO is equal to VAP-1 and is studied.So the present invention is unified to describe the albumen with SSAO/VAP-1.

Inflammation is first reaction of the immune system to infecting or stimulating.Leucocyte enters the movement of Weaving Cycle to the process It is important.Unsuitable inflammatory reaction can lead to the local inflammation of other health tissues, can lead to such as rheumatoid The diseases such as arthritis, inflammatory bowel disease, multiple sclerosis, asthma, chronic obstructive pulmonary disease (COPD), eczema, psoriasis.In vain Cell is first before they are by vascular wall by attaching to endothelium in conjunction with adhesion molecule.SSAO/VAP-1 is such as film combination Great expression in the vascular endothelial cell of the efficient venous endothelial cell (HVE) of lymphoid organ, and also in sinusoidal endothelial cell (HSEC), it is expressed in smooth muscle cell and adipocyte.SSAO/VAP-1 contains sialic acid, can induce cell adhesion, adjusts white Cell traffic participates in granulocyte extravasation, and its level increases in inflammatory process.Neutrophil leucocyte is from blood to inflammation part Migration is realized by adhesion molecule combining with vascular endothelial cell.The study found that turning in overexpression SSAO/VAP-1 pneumonia In DNA murine body, it is found that its SSAO/VAP-1 activity increases, histone-formaldehyde deposit is formed, bronchoalveolar lavage Liquid inflammatory cell obviously increases.It is neutral in Bronchopneumonia irrigating solution after inhibiting its activity with SSAO/VAP-1 selection inhibitor Granulocyte and macrophage inflammatory protein 1 alpha and tumor necrosis factor-alpha all substantially reduce, and illustrate what SSAO/VAP-1 was mediated Deamination have a significant effect to the occurrence and development of pneumonia (Smith DJ, Salmi M, Bono P, et a1, J Exp Med, 1998,188:17-27)。

In glucose transport systems, insulin is mainly by promoting glucose transporter (Glucose Transport, GLUT) from cell membrane is transferred into the cell, stimulate the insulin sensitive tissues such as adipose tissue, cardiac muscle, skeletal muscle Intake and utilization to glucose.GLUT 4 is a kind of important GLUT hypotypes for participating in glucose transport, mainly with vesica Form is stored in cytoplasm.Enrique-Tarancon etc. research SSAO/VAP-1 promote adipocyte glucose transport and GLUT 4 shift mechanism of action in find, the SSAO/VAP-1 in rat fat cell mainly in the form of film mating type expression with Adipocyte film surface, 18%-24%SSAO/VAP-1 are expressed in rat fat cell, 3T3-L1 adipocytes, Rat Skeletal Contain (Enrique-Tarancon G, Marti L, Morin N, et a1.J Biol in 4 vesicas of GLUT in myocyte Chem,1998,273(14):8025-8032).Mercader etc. gives uses SSAO/VAP- for a long time in FVB/n male mouse drinking water 1 inhibitor semicarbazides finds that FVB/n mouse body mass indexs have dropped 31%, and weight has dropped 15%, shows SSAO/VAP-1 Inhibitor can inhibit mouse adipose to deposit, and mitigate weight, play a significant role (Mereader in adjusting fat metabolism J,Iffiu-Soltesz Z,Bour S,et a1,J Obes,2011,2011:475-786)。

The thickness and SSAO/VAP-1 of vessel wall elasticity layer and the ratio of elastin laminin are positively correlated, and illustrate SSAO/VAP-1 The machine of elastomer may be participated in, and the characteristic of elastomer and quantity are to influence the mechanical performance and vascular smooth of arterial wall An important factor for myocyte breaks up.The increase of SSAO/VAP-1 activity can cause aortic tunica media elastomer structure to be destroyed, and companion It is reduced with the maturity of elastin laminin ingredient and collagen increases, finally aorta is caused to expand.SSAO/VAP-1 is in smooth muscle Overexpression can reduce arterial elasticity, damage its ability for adjusting blood pressure.The study found that although rodent is usually not easy to send out Lively pulse atherosclerosis, certain mouse strains, such as C57BL/6 mouse are in the High cholesterol diet for giving atharosclerosis Afterwards, atherosclerotic plaque can still occur.This C57BL/6 mouse its SSAO/VAP-1 for being easy to happen atherosclerosis Active significantly to increase, the deamination that SSAO/VAP-1 is mediated is likely present in atherosclerosis generation and vascular disorder In the process.

In conclusion SSAO/VAP-1 has enzymatic activity and adhesion activity, in addition, in many inflammatory disorders, SSAO/ There is significant correlation, these facts enable SSAO/VAP-1 to become all between VAP-1 and the up-regulation of its inflammatory factor The therapy target of above-mentioned disease event.Therefore SSAO/VAP-1 inhibitor has good medicinal development prospect.

Invention content

The present invention provides a kind of compounds with preferable SSAO/VAP-1 inhibitory activity, are used to prepare treatment inflammation The drug of disease, inflammation related disease or immunological diseases.Present invention provides prepare the method for these compounds, include these The pharmaceutical composition of compound, and prepare the upper for the treatment of mammal, the especially mankind using these compounds and composition The method for stating the drug of disease.Compared with existing similar compound, the compound of the present invention not only there is good pharmacology to live Property, also there are excellent pharmacokinetics property and internal pharmacodynamic properties.Preparation method is simple simultaneously, technique side Method is stablized, and industrialized production is suitble to.Therefore, compound provided by the invention is for current existing similar compound, With more excellent druggability.

Specifically：

On the one hand, the present invention relates to a kind of compounds, have structure or the structure as shown in formula (I) as shown in formula (I) Compound stereoisomer, all E/Z isomers, tautomer, nitrogen oxides, solvate, metabolite and medicine Acceptable salt or prodrug on,

Wherein, R₁There is meaning as described in the present invention with R.

In some embodiments, R₁For

R is following subformula：

Wherein, ring A is C₃-C₆The heterocycle of naphthenic base or 3-8 members, wherein each C₃-C₆Naphthenic base and 3-8 member it is miscellaneous Ring group is optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, sulfydryl, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, trifluoromethyl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced；

Each R₂And R₃It independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl ,-C (=O) OR_a,-C (=O) R_b,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_c, wherein the C₁-C₆Alkyl is optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, mercapto The substituent group of base or amino is replaced, and condition is R₂And R₃It is asynchronously H；

Each R₄And R₆It independently is H, D, F, Cl, Br, I, C₁-C₈Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₈Naphthenic base, C₁-C₆Alkoxy, C₁-C₆Alkylamino, C₁-C₆Alkylthio group, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members or 3-8 members, In, each C₁-C₈Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₈Naphthenic base, C₁-C₆Alkoxy, C₁-C₆Alkylamino, C₁-C₆Alkane Sulfenyl, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members and 3-8 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, sulfydryl ,-SR_c、-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d、- S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced, condition is, when R is When, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, C is formed₃-C₈The heterocycle of naphthenic base or 3-8 members, wherein described Each C₃-C₈The heterocycle of naphthenic base and 3-8 members is optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, ammonia Base, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a、-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_c Or-S (=O) R_cSubstituent group replaced；

R₅For-NHR₈；

R₈For H, D, C₁-C₆Alkyl or

Each R_a、R_b、R_c、R_dAnd R₉It independently is H, D or C₁-C₆Alkyl, wherein the C₁-C₆Alkyl is optionally by 1,2,3 Or 4 substituent groups independently selected from D, F, Cl, Br, I, hydroxyl, cyano or amino are replaced；

N is 0,1 or 2.

In some embodiments, ring A is C₃-C₆The heterocycle of naphthenic base or 5-6 members, wherein each C₃-C₆Cycloalkanes Base and the heterocycle of 5-6 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, Sulfydryl, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₂Hydroxy alkyl, trifluoromethyl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d、-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced.

In other embodiments, ring A is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidine Base, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl or piperazine Base, wherein each cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuran Base, tetrahydro-thienyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl and piperazinyl are optionally only by 1,2,3 or 4 On the spot be selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, sulfydryl, methyl, ethyl, hydroxymethyl, trifluoromethyl ,-C (= O)OR_a,-C (=O) R_b,-OC (=O) R_bOr-OC (=O) OR_aSubstituent group replaced.

In some embodiments, each R_aAnd R_bIt independently is H, D, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, each R₄And R₆It independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₂-C₄Alkenyl, C₂-C₄ Alkynyl, C₃-C₆Naphthenic base, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₁-C₄Alkylthio group, C₆-C₁₀Aryl, 5-10 members heteroaryl or The heterocycle of 3-6 members, wherein each C₁-C₆Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₁-C₄Alkylthio group, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members and 3-6 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₂Hydroxyl Alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (= O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced, condition is, when R isWhen, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, C is formed₃-C₆The heterocycle of naphthenic base or 3-6 members, wherein described Each C₃-C₆The heterocycle of naphthenic base and 3-6 members is optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, ammonia Base, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₂Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a、-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_c Or-S (=O) R_cSubstituent group replaced.

In other embodiments, each R₄And R₆It independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl Base, butyl, cyclopropyl, cyclobutyl, cyclopenta, methoxy or ethoxy, wherein each methyl, ethyl, n-propyl, isopropyl Base, butyl, cyclopropyl, cyclobutyl, cyclopenta, methoxyl group and ethyoxyl optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl substituent group replaced, Condition is, when R is When, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl are formed, wherein Each cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl are optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl Base, cyano, amino, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl substituent group replaced.

In some embodiments, each R₂And R₃It independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl ,-C (=O) OR_a、-C (=O) R_b,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_c, wherein the C₁-C₄Alkyl optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, sulfydryl or amino substituent group replaced, condition is R₂And R₃It is asynchronously H.

In some embodiments, each R₂And R₃It independently is H, D, F, Cl, Br, I, methyl, ethyl, isopropyl, positive third Base ,-C (=O) OR_a,-C (=O) R_b,-OC (=O) R_bOr-OC (=O) OR_a, wherein each methyl, ethyl, isopropyl and N-propyl is optionally by 1,2,3 or 4 substituent group institute independently selected from D, F, Cl, Br, I, hydroxyl, cyano, sulfydryl or amino Substitution, condition is R₂And R₃It is asynchronously H；

Each R_aAnd R_bStand alone as H, D, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, R₈For H, D, C₁-C₄Alkyl or

In some embodiments, R₈For H, D, methyl, ethyl, n-propyl, isopropyl or

On the other hand, there is the vertical of the compound of structure shown in formula (II) depicted structure or formula (II) the present invention relates to a kind of Body isomers, all E/Z isomers, tautomer, nitrogen oxides, solvate, metabolite and pharmaceutically acceptable Salt or prodrug,

Wherein, R₁、R₂、R₃、R₄、R₅、R₆, ring A and n have meaning as described in the present invention.

On the other hand, there is the compound of structure shown in formula (III) depicted structure or formula (III) the present invention relates to a kind of Stereoisomer, all E/Z isomers, tautomer, nitrogen oxides, solvate, metabolite and pharmaceutically acceptable Salt or prodrug,

Wherein, R₁、R₂、R₃、R₄、R₅、R₆There is meaning as described in the present invention with n.

In other embodiments, wherein

R₁For

R is following subformula：

Wherein, ring A is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrochysene Furyl, tetrahydro-thienyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl or piperazinyl, wherein each ring third Base, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydrochysene Thiapyran base, piperidyl, morpholinyl, thio-morpholinyl and piperazinyl optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, sulfydryl, methyl, ethyl, hydroxymethyl, trifluoromethyl ,-C (=O) OR_a,-C (=O) R_b、-OC (=O) R_bOr-OC (=O) OR_aSubstituent group replaced；

Each R₂And R₃It independently is H, D, F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OR_a,-C (= O)R_b,-OC (=O) R_bOr-OC (=O) OR_a, wherein each methyl, ethyl, isopropyl and n-propyl are optionally by 1,2,3 Or 4 substituent groups independently selected from D, F, Cl, Br, I, hydroxyl, cyano, sulfydryl or amino are replaced, condition is R₂And R₃No It is H simultaneously；

Each R₄And R₆It independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, ring fourth Base, cyclopenta, methoxy or ethoxy, wherein each methyl, ethyl, n-propyl, isopropyl, butyl, cyclopropyl, ring fourth Base, cyclopenta, methoxyl group and ethyoxyl are optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, ammonia Base, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl substituent group replaced, condition is, when R isWhen, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl are formed, wherein Each cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl are optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl Base, cyano, amino, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl substituent group replaced；

R₅For-NHR₈；

R₈For H, D, methyl, ethyl, n-propyl, isopropyl or

Each R_aAnd R_bStand alone as H, D, methyl, ethyl, n-propyl or isopropyl；

N is 0 or 1.

Also in some embodiments, the present invention relates to the structure of one of or its stereoisomer, all E/ Z isomers, tautomer, nitrogen oxides, solvate, metabolite and pharmaceutically acceptable salt or prodrug, but not It is limited to these compounds：

In some embodiments, the pharmaceutically acceptable salt is hydrochloride, hydrobromate or mesylate.

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

On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine preparation, Wherein, the drug is for inhibiting SSAO/VAP-1.

On the other hand, the use the invention further relates to compound of the present invention or pharmaceutical composition in medicine preparation On the way, wherein the drug is used to prevent or treat the disease in relation to or by SSAO/VAP-1 adjustings with SSAO/VAP-1 albumen, Wherein, the disease is inflammation disease, inflammation related disease or immunological diseases.

In some embodiments, purposes of the present invention, wherein the inflammation disease, inflammation related disease or Immunological diseases include arthritis, general inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammation Property enteropathy, fibrosis, hepatopathy, vascular diseases, breathing problem, disease of eye, skin disease, neuroinflammatory disorder, diabetes Caused inflammation, ischemic disease and organ and/or tissue transplantation rejection.

In other embodiments, purposes of the present invention, wherein the arthritis further includes Bones and joints Inflammation, rheumatic arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.

In other embodiments, purposes of the present invention, wherein the general inflammatory syndrome further includes General inflammatory pyemia.

In other embodiments, purposes of the present invention, wherein the inflammatory bowel disease further includes allergy Property enteropathy.

In other embodiments, purposes of the present invention, wherein the fibrosis further includes liver fiber The fibrosis that change, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity induce.

In other embodiments, purposes of the present invention, wherein the hepatopathy further includes liver itself and exempts from Epidemic disease disease, oneself immunity hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcohol Property hepatopathy or non-alcoholic hepatopathy.

In other embodiments, purposes of the present invention, wherein the vascular diseases further include artery congee Sample hardening, chronic heart failure or congestive heart failure.

In other embodiments, purposes of the present invention, wherein the breathing problem further includes heavy breathing Asthma, acute lung injury, acute respiratory distress syndrome, lung inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or bronchus expand .

In other embodiments, purposes of the present invention, wherein the disease of eye further includes wink Inflammation caused by plain layer inflammation, iritis, the retinitis, autoimmune ophthalmia disease, angiogenesis and lymph generate or macula lutea become Property.

In other embodiments, purposes of the present invention, wherein the skin disease further includes contact Dermatitis, scytitis, psoriasis or eczema.

In other embodiments, purposes of the invention, wherein the neuroinflammatory disorder further includes Parkinson Disease, Alzheimer disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.

In other embodiments, purposes of the invention, wherein inflammation further includes I caused by the diabetes Patients with type Ⅰ DM, type II diabetes, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetes are yellow Spot oedema.

In other embodiments, purposes of the present invention, wherein the ischemic disease further includes apoplexy With inflammatory cell after its complication, myocardial infarction and its complication or apoplexy to disorganization.

In some embodiments, purposes of the present invention, wherein the disease is mental illness, the mental disease Disease further includes severe depression, two-stage type melancholia or attention deficiency hyperactivity (Attention Deficit Hyperactivity Disorder)。

In some embodiments, purposes of the present invention, wherein the disease is cancer.

On the other hand, inhibiting SSAO/ using compound of the present invention or pharmaceutical composition the present invention relates to a kind of The active methods of VAP-1, the method are to give effectively controlling for the individual in need compound or described pharmaceutical composition Treatment amount.

On the other hand, the present invention relates to a kind of using compound of the present invention or pharmaceutical composition for preventing or controlling The method for treating following disease, the method include to give effectively controlling for patient's compound of the present invention or pharmaceutical composition Treatment amount, wherein the disease is inflammation disease, inflammation related disease or immunological diseases.Also, above-mentionedization provided by the invention Closing object or its pharmaceutical composition can be co-administered with other therapies or therapeutic agent.Method of application can be simultaneously, sequence or with Intervals carry out.

The dosage of the required compound or pharmaceutical composition of the effects that implementing treatment, preventing or delay generally depends on application Particular compound, patient, disease specific or illness and its severity, administration route and frequency etc., and need by curing mainly Doctor judges as the case may be.For example, by applying compound provided by the invention or pharmaceutical composition through intravenous route When, it can be even administered once a week with longer time interval.

In some embodiments, method of the present invention, wherein the inflammation disease, inflammation related disease or exempting from Epidemic disease includes arthritis, general inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammatory Enteropathy, fibrosis, hepatopathy, vascular diseases, breathing problem, disease of eye, skin disease, neuroinflammatory disorder, diabetes are drawn Inflammation, ischemic disease and the organ and/or tissue transplantation rejection risen.

In other embodiments, method of the present invention, wherein the arthritis further includes Bones and joints Inflammation, rheumatic arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.

In other embodiments, method of the present invention, wherein the general inflammatory syndrome further includes General inflammatory pyemia.

In other embodiments, method of the present invention, wherein the inflammatory bowel disease further includes allergy Property enteropathy.

In other embodiments, method of the present invention, wherein the fibrosis further includes liver fiber The fibrosis that change, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity induce.

In other embodiments, method of the present invention, wherein the hepatopathy further includes liver autoimmunity Property disease, oneself immunity hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, Alcoholic Hepatopathy or non-alcoholic hepatopathy.

In other embodiments, method of the present invention, wherein the vascular diseases further include artery congee Sample hardening, chronic heart failure or congestive heart failure.

In other embodiments, method of the present invention, wherein the breathing problem further includes heavy breathing Asthma, acute lung injury, acute respiratory distress syndrome, lung inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or bronchus expand .

In other embodiments, method of the present invention, wherein the disease of eye further includes ommochrome Inflammation or macular degeneration caused by layer inflammation, iritis, the retinitis, autoimmune ophthalmia disease, angiogenesis and lymph generate.

In other embodiments, method of the present invention, wherein the skin disease further includes contact Dermatitis, scytitis, psoriasis or eczema.

In other embodiments, method of the present invention, wherein the neuroinflammatory disorder further includes pa The gloomy disease of gold, Alzheimer disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.

In other embodiments, method of the present invention, wherein inflammation is further wrapped caused by the diabetes Containing Type I diabetes, type II diabetes, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetes Macular edema.

In other embodiments, method of the present invention, wherein the ischemic disease further includes apoplexy With inflammatory cell after its complication, myocardial infarction and its complication or apoplexy to disorganization.

In some embodiments, method of the present invention, wherein the disease is mental illness, the mental disease Disease further includes severe depression, two-stage type melancholia or attention deficiency hyperactivity.

In some embodiments, method of the present invention, wherein the disease is cancer.

On the other hand, the present invention relates to be used for compound of the present invention or pharmaceutical composition to inhibit SSAO/VAP-1 Activity.

On the other hand, the present invention relates to be used to prevent or treat following by compound of the present invention or pharmaceutical composition Disease mitigates following disease symptoms or delays the development or breaking-out of following disease, wherein the disease is inflammation disease, inflammation Disease relevant disease or immunological diseases.

In some embodiments, prevention or treatment disease of the present invention, wherein the inflammation disease, inflammation are related Disease or immunological diseases include arthritis, general inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis Inflammation, inflammatory bowel disease, fibrosis, hepatopathy, vascular diseases, breathing problem, disease of eye, skin disease, neuroinflammatory disorder, Inflammation caused by diabetes, ischemic disease and organ and/or tissue transplantation rejection.

In other embodiments, prevention or treatment disease of the present invention, wherein the arthritis further includes Osteoarthritis, rheumatic arthritis, rheumatoid arthritis or juvenile rheumatoid arthritis.

In other embodiments, it is of the present invention prevention or treatment disease, wherein the general inflammatory syndrome into One step includes general inflammatory pyemia.

In other embodiments, prevention or treatment disease of the present invention, wherein the inflammatory bowel disease is further Including irritable bowel disorder.

In other embodiments, prevention or treatment disease of the present invention, wherein the fibrosis further includes The fibrosis that liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity induce.

In other embodiments, prevention or treatment disease of the present invention, wherein the hepatopathy further includes liver Autoimmune disease, oneself immunity hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune bile duct Scorching, alcoholic liver disease or non-alcoholic hepatopathy.

In other embodiments, prevention or treatment disease of the present invention, wherein the vascular diseases are further wrapped Containing atherosclerosis, chronic heart failure or congestive heart failure.

In other embodiments, prevention or treatment disease of the present invention, wherein the breathing problem is further Including asthma, acute lung injury, acute respiratory distress syndrome, lung inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or branch Tracheaectasy.

In other embodiments, prevention or treatment disease of the present invention, wherein the disease of eye further wraps Containing uveitis, iritis, the retinitis, autoimmune ophthalmia disease, angiogenesis and lymph generate caused by inflammation or Macular degeneration.

In other embodiments, prevention or treatment disease of the present invention, wherein the skin disease further wraps Containing contact dermatitis, scytitis, psoriasis or eczema.

In other embodiments, prevention or treatment disease of the present invention, wherein the neuroinflammatory disorder is into one Step includes Parkinson's disease, Alzheimer disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis.

In other embodiments, prevention or treatment disease of the present invention, wherein inflammation caused by the diabetes Further include Type I diabetes, type II diabetes, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy Or diabetic macular edema.

In other embodiments, prevention or treatment disease of the present invention, wherein the ischemic disease is further Including inflammatory cell is to disorganization after apoplexy and its complication, myocardial infarction and its complication or apoplexy.

In some embodiments, prevention or treatment disease of the present invention, wherein the disease is mental illness, The mental illness further includes severe depression, two-stage type melancholia or attention deficiency hyperactivity.

In some embodiments, prevention or treatment disease of the present invention, wherein the disease is cancer.

In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Substance or composition must be with other ingredients comprising preparation and/or with the mammals of its treatment chemically and/or toxicology It is upper compatible.

The compound of the present invention further includes other salt of such compound, which is not necessarily pharmaceutically acceptable Salt, and may be used as being used to prepare and/or purify the compound of the present invention and/or for detaching the compound of the present invention The intermediate of enantiomer.

Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid.

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making the free alkali form of these compounds and chemistry count The suitable acid of amount amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two.One As, in appropriate cases, need to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.In example Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the other suitable for salt can be found in.

Moreover, the compounds of this invention including its salt can also be obtained in the form of its hydrate, or it to be used for including other The solvent of crystallization.The compounds of this invention can form the solvation with acceptable solvent (including water) inherently or by design Object；Therefore, the invention is intended to include solvated and unsolvated form.

Any structural formula that the present invention provides is also intended to the form and isotope mark for indicating that these compounds are not labeled The form of note.The structure that the general formula that there is the compound of isotope labelling the present invention to provide is described, in addition to one or more atoms It 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 include The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁶S,³⁷Cl or¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention with various isotope labellings, For example, wherein there is radioactive isotope, such as³H,¹⁴C and¹⁸Those of F compounds, or wherein there is non radioactive isotope, Such as²H and¹³C.The compound of such isotope labelling can be used for being metabolized research and (use¹⁴C), Reaction kinetics research (use example Such as²H or³H), detection or imaging technique are surveyed such as positron emission tomography (PET) or including drug or substrate tissue distribution Fixed single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound pair of F labels It is especially desirable for PET or SPECT researchs.Formula (I) compound of isotope labelling can pass through those skilled in the art Known routine techniques or embodiment in the present invention and preparation process are described is substituted using suitable isotope labeling reagent Originally prepared by used unmarked reagent.

In addition, higher isotope especially deuterium (that is,²H or D) substitution certain treatment advantages can be provided, these advantages are It is brought by metabolic stability higher.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 this context is seen as the substituent group of formula (I) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.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), at least for each specified D-atom 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、 Or DMSO-d₆Those of solvate.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects, otherwise interior Appearance will make more specific complete description below.

The detailed description of the invention

The present invention provides a kind of aminated compounds with SSAO/VAP-1 inhibitory activity, preparation method and its curing Application on medicine.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular It is that all similar substitutions and modifications are apparent to those skilled in the art, they are considered as being included in this In the range of invention.

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 scope of the invention.Art technology Personnel should be understood that many and similar or equivalent method and material described herein can be used in the practice present invention.The present invention is exhausted It is not limited to method described herein and material, in one or more and the application of the document, patent and similar material that are combined It is different or in the case of contradicting (term, term application, described technology, etc. defined in including but not limited to), with Subject to the application.

It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.

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 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 Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.

Unless otherwise indicated, the term used in the present invention in the specification and in the claims has following definitions.

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

There is apparent conflict unless otherwise indicated or in context, 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.

In general, term " substituted " or " substitution " indicate that one or more of given structure can substituted hydrogen original Son is replaced by specific substituent group.Unless otherwise indicated, the group of a substitution can be each in group there are one substituent group A commutable position is replaced.When in given structural formula more than one position can by one selected from specific group or Multiple substituent groups are replaced, then substituent group can replace at various locations identical or differently.

Term " optionally by ... replace " can exchange use, i.e., with term " unsubstituted or by ... replace " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group of the present invention Include, but are not limited to D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, hydroxy alkyl, halogenated alkyl, Halogenated alkoxy, carboxyl, sulfydryl, alkoxy, alkylthio group, alkylamino, naphthenic base, heterocycle, aryl, heteroaryl ,-NHR₈、- SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-C (=O) NHR_d,-S (=O)₂NHR_d,-NHS (=O)₂R_c,-S (=O)₂R_c,-S (=O) R_c、Trifluoromethyl, aryl alkyl, heteroaryl alkyl, Alkoxy aryl or heteroarylalkoxy, wherein each R_a、R_b、R_c、R_d、R₈And R₉With meaning as described in the present invention.

Term " optional " either " optionally " mean event described later or environment can with but need not occur, should Illustrate to include the thing occasion that either environment occurs or do not occur.For example, " optionally by alkyl-substituted heterocyclic group " anticipates Taste alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted scene and heterocyclic group not by alkyl Substituted scene.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " respectively ... independent () be " and " ... respectively independent () be " and " ... independently () be " can be interchanged, broad sense should all be done Understand, either referring among the different groups, does not influence mutually between expressed specific option between the same symbol, also may be used To indicate in the same group, do not influenced mutually between expressed specific option between the same symbol.

It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.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 “C₁-C₆Alkyl " refers in particular to individually disclosed C₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkane Base, and " heterocycle of 3-8 members " to refer to the molecular heterocycle of 3 originals, the molecular heterocycle of 4 originals, 5 originals molecular miscellaneous Ring group, the molecular heterocycle of 6 originals, the molecular heterocycle of 7 originals or 8 molecular heterocycles of original, " C₃-C₆Cycloalkanes Base " refers to C₃Naphthenic base (cyclopropyl), C₄Naphthenic base (cyclobutyl), C₅Naphthenic base (cyclopenta) and C₆Naphthenic base (cyclohexyl).

Term " halogen " refers to F, Cl, Br, I.

Term " alkyl " refers to the alkyl of the monovalence of containing 1-20 carbon atom, saturation linear chain or branched chain.Unless in addition Illustrate, alkyl group contains 1-20 carbon atom；In some embodiments, alkyl group contains 1-10 carbon atom；Another In some outer embodiments, alkyl group contains 1-8 carbon atom；In other embodiment, alkyl group contains 1-6 Carbon atom；Also in some embodiments, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl contains 1-2 carbon atom.Alkyl containing 1 to 6 carbon atom in the present invention is known as low alkyl group.

The example of alkyl group includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), propyl (positive third Base (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂)), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i- Bu、-CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tertiary butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyls (- CH (CH₃)CH₂CH₂CH₃), 3- amyls (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl-1s-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyls (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyls (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyls (- C (CH₃)₂CH₂CH₂CH₃), 3- first Base -2- amyls (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyls (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- penta Base (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyls (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl, etc..The alkyl Group can optionally be replaced by one or more substituent groups of the present invention.

Term " alkyl " used in the present invention and its prefix " alkane ", all include the saturated carbon chains of straight chain and branch.

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger It is carbon-to-carbon sp with site²Double bond, wherein the alkenyl group can optionally described in the invention be taken by one or more Replaced for base comprising the positioning of " cis " and " trans ", or " E " and " Z " positioning.In some embodiments, alkene Base group includes 2-8 carbon atom；In other embodiments, alkenyl group includes 2-6 carbon atom；In other implementation In scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH₂), acrylic (- CH₂CH=CH₂,-CH=CHCH₃), cyclobutenyl (- CH=CHCH₂CH₃、-CH₂CH=CHCH₃、-CH₂CH₂CH =CH₂,-CH=C (CH₃)₂,-CH=C (CH₃)₂、-CH₂C(CH₃)=CH₂), pentenyl (- CH₂CH₂CH₂CH=CH₂、- CH₂CH₂CH=CHCH₃、-CH₂CH₂CH=CHCH₃、-CH₂CH=CHCH₂CH₃,-CH=CHCH₂CH₂CH₃、-CH₂CH₂C(CH₃)= CH₂、-CH₂CH=C (CH₃)₂,-CH=CHCH (CH₃)₂、-C(CH₂CH₃)=CHCH₃、-CH(CH₂CH₃) CH=CH₂) etc..Institute Stating alkenyl group can optionally be replaced by one or more substituent groups of the present invention.

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger It is tri- keys of carbon-to-carbon sp with site.In some embodiments, alkynyl group includes 2-8 carbon atom；In other embodiments In, alkynyl group includes 2-6 carbon atom；In other embodiment, alkynyl group includes 2-4 carbon atom.Alkynyl Example includes, but is not limited to, acetenyl (- C ≡ CH), 1- propinyls (- C ≡ CH-CH₃), propargyl (- CH₂C ≡ CH), 1- fourths Alkynyl, 2- butynyls, 1- pentynyls, valerylene base, 3- methyl-1s-butynyl, 1- hexin bases, 1- heptynyls, 1- octynyls, etc. Deng.The alkynyl group can be replaced by one or more substituent groups described in the invention individually optionally.

Term " miscellaneous alkyl " indicates that one or more hetero atoms, wherein alkyl group and hetero atom can be inserted in alkyl chain With meaning as described in the present invention.Unless otherwise detailed instructions, miscellaneous alkyl group contains 1-10 carbon atom, in some implementations In scheme, miscellaneous alkyl group contains 1-8 carbon atom, and in other embodiments, it is former that miscellaneous alkyl group contains 1-6 carbon Son, in other embodiment, miscellaneous alkyl group contains 1-4 carbon atom, also in some embodiments, miscellaneous alkyl group Contain 1-3 carbon atom.The example of miscellaneous alkyl includes, but is not limited to, CH₃OCH₂-、CH₃CH₂OCH₂-、CH₃SCH₂-、(CH₃)₂NCH₂-、(CH₃)₂CH₂OCH₂-、CH₃OCH₂CH₂-、CH₃CH₂OCH₂CH₂Etc..The miscellaneous alkyl group can be optionally by one Or the substituent group that multiple present invention describe is replaced.

Term " halogenated alkyl " refers to the alkyl with one or more halogenic substituent.In some embodiments, Halogenated alkyl group contains 1-8 carbon atom, and in other embodiments, halogenated alkyl group contains 1-6 carbon atom, In other embodiment, halogenated alkyl group contains 1-4 carbon atom, also in some embodiments, halogenated alkyl group Containing 1-3 carbon atom, also in some embodiments, halogenated alkyl group contains 1-2 carbon atom.The example of halogenated alkyl It includes, but is not limited to, methyl fluoride (- CH₂F), difluoromethyl (- CHF₂), trifluoromethyl (- CF₃), fluoro ethyl (- CHFCH₃,- CH₂CH₂F), bis-fluoro ethyls (- CF₂CH₃,-CFHCFH₂,-CH₂CHF₂), perfluoro-ethyl, fluoropropyl (- CHFCH₂CH₃,- CH₂CHFCH₃,-CH₂CH₂CH₂F), two fluoropropyl (- CF₂CH₂CH₃,-CFHCFHCH₃,-CH₂CH₂CHF₂,-CH₂CF₂CH₃,- CH₂CHFCH₂F), trifluoro propyl, 1,1- Dichloroethyls, bis- chloropropyls of 1,2- etc..The halogenated alkyl group can optionally by The substituent group that one or more present invention describe is replaced.

Term " alkoxy " refers to that alkyl group is connected by oxygen atom with molecule rest part, i.e. alkyl-O-, wherein alkane Base group has meaning as described in the present invention.In some embodiments, alkoxy base contains 1-6 carbon atom；Another In some embodiments, alkoxy base contains 1-4 carbon atom；In other embodiment, alkoxy base contains 1-3 A carbon atom；In other embodiment, alkoxy base contains 1-2 carbon atom.The example of alkoxy includes, but not It is limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, tert-butoxy, 2- methyl propoxyl group, neopentyl epoxide, etc..Institute Stating alkoxy base can optionally be replaced by the substituent group that one or more present invention describe.

Term " alkylthio group " refers to that alkyl group is connected by sulphur atom with molecule rest part, i.e. alkyl-S-, wherein alkane Base group has meaning as described in the present invention.In some embodiments, alkylthio radicals contain 1-6 carbon atom；Another In some embodiments, alkylthio radicals contain 1-4 carbon atom；In other embodiment, alkylthio radicals contain 1-3 A carbon atom；In other embodiment, alkylthio radicals contain 1-2 carbon atom.The example of alkylthio group includes, but not It is limited to methyl mercapto, ethylmercapto group, etc..The substituent group that the alkylthio radicals can be described optionally by one or more present invention Replaced.

Term " halogenated alkoxy " refers to the alkoxy base with one or more halogenic substituent.Wherein alkoxy Group has meaning of the present invention.In some embodiments, halo alkoxy group contains 1-6 carbon atom；Another In some embodiments, halo alkoxy group contains 1-4 carbon atom；In other embodiment, halogenated alkoxy base 1-3 carbon atom is contained in group, and also in some embodiments, deer contains 1-2 carbon atom for alkoxy base.Halogenated alkoxy Embodiment include, but is not limited to difluoro-methoxy (- OCF₂), trifluoromethoxy (- OCF₃), difluoroethoxy (- OCF₂CH₃,-OCFHCFH₂,-OCH₂CHF₂), trifluoro ethoxy etc..The halo alkoxy group can optionally by one or The substituent group that multiple present invention describe is replaced.

Term " hydroxy alkyl " or " hydroxyalkyl " refer to the alkyl with one or more hydroxyl substituents, wherein alkyl base Group has meaning as described in the present invention.In some embodiments, hydroxyalkyl group contains 1-6 carbon atom；At other In embodiment, hydroxyalkyl group contains 1-4 carbon atom；In other embodiment, hydroxyalkyl group contains 1-3 carbon Atom, also in some embodiments, hydroxyalkyl group contain 1-2 carbon atom.The example of hydroxyalkyl includes, but is not limited to Methylol, 2- hydroxyethyls (- CH₂CH₂OH), 1- hydroxyethyls (- CHOHCH₃), 1,2- dihydroxy ethyls (- CHOHCH₂OH)、 2,3- dihydroxypropyls (- CH₂CHOHCH₂OH), 1- hydroxypropyls (- CH₂CH₂CH₂OH), 2- hydroxypropyls, 3- hydroxypropyls, hydroxyl Butyl, etc..The hydroxyalkyl group can optionally be replaced by the substituent group that one or more present invention describe.

Term " alkylamino " or " alkyl amino " they refer to the amino group with one or two alkyl substituents, including " N- alkylaminos " and " N, N- dialkylamino ".In some embodiments, alkylamino radicals contain 1-6 carbon atom；Another In a little embodiments, alkylamino radicals contain 1-4 carbon atom；In other embodiment, alkylamino radicals contain 1-3 Carbon atom.The example of alkylamino includes, but is not limited to methylamino, ethylamino, n-propylamine base, isopropylamino, n-butyl amine base, just Penta amino, N, N- dimethylaminos, N, N- diethylaminos, N- ethyl-N-methylaminos, N- methyl-N-n-propyls-amino, Etc..The alkylamino radicals can optionally be replaced by the substituent group that one or more present invention describe.

Term " naphthenic base " refers to monovalent or multivalence, the saturation monocyclic, bicyclic or tricyclic containing 3 to 12 carbon atoms System (including condensed, bridging and/or spiral shell type ring system).In some embodiments, naphthenic base is to include 3-12 carbon atom Saturation carbocylic radical；In other embodiments, naphthenic base includes 3-8 carbon atom；In other embodiment, ring Alkyl includes 3-6 carbon atom；Also in some embodiments, naphthenic base includes 5-6 carbon atom.The example packet of naphthenic base It includes, but is not limited to：Cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.The group of naphthene base can it is independently unsubstituted or by One or more substituent groups described in the invention are replaced.

Term " heterocycle " and " heterocycle " are used interchangeably here, and it includes 3-12 annular atom all to refer to, it is monovalent or Multivalence, saturation or part it is undersaturated, nonaromatic monocyclic, bicyclic or tricyclic, wherein at least one annular atom be selected from nitrogen, Sulphur and oxygen atom wherein the heterocycle is nonaromatic, and are free of any aromatic rings.Unless otherwise stated, heterocycle can To be carbon-based or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-, and the sulphur atom of ring can be aoxidized optionally At S- oxides, the nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The heterocycle has one or more Tie point is connected with the rest part of molecule.In some embodiments, heterocycle is the heterocycle of 3-8 annular atom composition； In other embodiments, heterocycle is the heterocycle of 3-6 annular atom composition；In other embodiments, heterocycle For the heterocycle of 5-6 annular atom composition；In other embodiments, heterocycle is the heterocycle of 3 annular atoms composition； In other embodiments, heterocycle is the heterocycle of 4 annular atoms composition；In other embodiments, heterocycle is 5 The heterocycle of annular atom composition；In other embodiments, heterocycle is the heterocycle of 6 annular atoms composition；In some realities It applies in scheme, heterocycle is the heterocycle of 7 annular atoms composition；Also in some embodiments, heterocycle is that 8 atoms form Heterocycle.

The example of heterocycle includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring fourth Base, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrochysene furan It mutters base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, two Hydrogen pyranose, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl , bis- Evil Alkyl, dithianyl, thioalkyl, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, nafoxidine Base, pyrrolin base, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydrochysene pyrazinyl, tetrahydro pyridazine base.- CH in heterocycle₂Group 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidones are included, but are not limited to by the example of-C (=O)-substitutions Base, 3,5- dioxy piperazine piperidinyls, hybar X base.The example that sulphur atom is aoxidized in heterocycle includes, but are not limited to sulfolane Base and 1,1- dioxothiomorpholinyls.Bridged heterocyclic base group includes, but are not limited to 2- oxabicyclos [2.2.2] octyl, 1- Azabicyclic [2.2.2] octyl, 3- azabicyclics [3.2.1] octyl, etc..The heterocyclyl groups can be optionally by one A or multiple substituent groups described in the invention are replaced.

Term " aryl " can be used alone or as most of " aryl alkyl " or " alkoxy aryl ", indicate to contain There are the monocycle of 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, bicyclic and tricyclic armaticity carbocyclic ring body System, wherein each ring include 3-7 annular atom, and there are one or multiple attachment points be connected with the rest part of molecule.Term " aryl " can be exchanged with term " aromatic ring " or " aromatic rings " and be used, if aryl may include phenyl, naphthalene and anthryl.The virtue Base group can be independently unsubstituted or be replaced by one or more substituent groups described in the invention.

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate the monocycle containing 5-16 annular atoms, bicyclic and tricyclic armaticity system, wherein at least one ring includes one or more Hetero atom, wherein each ring include 5-7 annular atom, and wherein at least one member ring systems are aromatic, meanwhile, the heteroaryl There are one bases or multiple attachment points are connected with molecule rest part.Unless otherwise stated, the heteroaryl groups can pass through Any rational site (can be N in the C or NH in CH) is connected to molecule rest part (such as the main body knot in general formula Structure) on.As heteroaryl groups presence-CH₂When group ,-the CH₂Group can be substituted optionally by-C (=O)-.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments, heteroaryl is Including 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-14.In other embodiments In, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12；Another In some embodiments, heteroaryl is former molecular comprising 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-10 Heteroaryl；In other embodiments, heteroaryl is be independently selected from O, S and N comprising 1,2,3 or 4 heteroatomic 5-8 Former molecular heteroaryl；In other embodiments, heteroaryl is to be independently selected from the miscellaneous of O, S and N comprising 1,2,3 or 4 The former molecular heteroaryl of 5-7 of atom；In other embodiments, heteroaryl is to be independently selected from comprising 1,2,3 or 4 The heteroatomic 5-6 former molecular heteroaryl of O, S and N；In other embodiments, heteroaryl is to include 1,2,3 or 4 A molecular heteroaryl of heteroatomic 5 originals for being independently selected from O, S and N；In other embodiments, heteroaryl be comprising 1,2,3 or 4 molecular heteroaryl of heteroatomic 6 originals for being independently selected from O, S and N.

The example of heteroaryl groups includes that heteroaryl includes monocyclic groups below, but is not limited to these monocyclic groups： 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl groups, 3- Pyridyl group, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazoles Base, 5- thiazolyls, tetrazole radical (such as 5H- tetrazole radicals, 2H- tetrazole radicals), triazolyl (such as 2- triazolyls, 5- triazolyls, 4H-1,2, 4- triazolyls, 1H-1,2,4- triazolyls, 1,2,3-triazoles base), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls and 3- pyrazolyls), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4- oxadiazole Base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base； Including double or three cyclic groups below, but it is not limited to these groups：Indoline base, 1,2,3,4- tetrahydro isoquinolyls, benzene And imidazole radicals, benzofuranyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- Quinolyl, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyl) , phenoxathiin groups, hexichol And imidazole radicals, dibenzofuran group, dibenzothiophene.The heteroaryl groups are optionally retouched by one or more present invention The substituent group stated is replaced.

Term " aryloxy " refers to that aryl group is connected by oxygen atom with molecule rest part, i.e. aryl-O-, In, the aryl has meaning as described in the present invention.Such embodiment includes, but is not limited to phenoxy group, etc..Institute Aryloxy groups are stated optionally to be replaced by one or more substituent groups described in the invention.

Term " aryloxy " refers to that heteroaryl groups are connected by oxygen atom with molecule rest part, i.e. heteroaryl-O-, Wherein, the aryl has meaning as described in the present invention.Such embodiment includes, but is not limited to pyridine -3- oxygroups, Pyrimidine -4- oxygroups, etc..The heterocyclic base oxygroup group is optionally taken by one or more substituent groups described in the invention Generation.

Term " hetero atom " refers to O, S, N, P and Si, including S, the form of N and any oxidation state of P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl replaced as N-).

Term " nitro " refers to-NO₂。

Term " sulfydryl " refers to-SH.

Term " hydroxyl " refers to-OH.

Term " amino " refers to-NH₂。

Term " cyano " refers to-CN.

Term " carboxylic acid " or " carboxyl " refer to-C (=O) OH.

Term " D " refer to it is deuterated, i.e.,²H。

Term " m former molecular " can exchange use with term " m members ", and wherein m is integer, typically describe point The number of ring member nitrogen atoms in son, the number of ring member nitrogen atoms is m in the molecule.For example, piperidyl is that 6 originals are molecular miscellaneous Ring group, and 1,2,3,4- tetralyl is the molecular carbocylic radical group of 10 originals.

As described in the invention, it draws a key and substituent group is connected to the member ring systems of ring being centrally formed (such as formula a institutes Show) it represents substituent group any commutable position in the member ring systems and can replace.For example, formula a represent substituent group can be Any possible substituted position on phenyl ring, as shown in formula b~formula d.

Term " blocking group " or " PG " refer to when other functional groups react in compound, for blocking or The specific functional substituent group of protection.It is connected with amino group for example, " blocking group of amino " refers to a substituent group Include acetyl group, trifluoroacetyl group, tertiary fourth to block or protect the functionality of amino in compound, suitable amido protecting group Oxygen carbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " is The substituent group for referring to hydroxyl is used for blocking or protecting the functionality of hydroxyl, suitable blocking group include, but are not limited to acetyl group, Benzoyl, benzyl, to methoxy-benzyl and silylation etc.." carboxy protective group " refer to carboxyl substituent group be used for block or It includes-CH to protect the functionality of carboxyl, general carboxyl-protecting group₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) second Base, 2- (trimethylsilyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..Document can refer to for the general description of blocking group：T W.Greene, Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

Term " leaving group " or " LG " refer to the atom being detached from from a bigger molecule in chemical reaction or functional group, It is the term applied in nucleophilic substitution and elimination reaction.In nucleophilic substitution, by the reactant of nucleopilic reagent attack Referred to as substrate, and the atom or atomic group that are broken away with pair of electrons from substrate molecule are known as leaving group.Common Leaving group is such as, but not limited to, halogen atom, ester group, sulfonate group, nitro, azido or hydroxyl etc..

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 and other chemical constituents of receiving, other components for example physiologically/can pharmaceutically receive Auxiliary materials and anti-diabetic reagent, antihyperglycemic reagent, the anti-obesity such as carrier, excipient, diluent, adhesive, filler The additional therapeutic agents such as disease reagent, anti-hypertension reagent, antiplatelet reagent, antiatherosclerotic agents or lipid-lowering agents. The purpose of pharmaceutical composition is to promote the administration of compound on organism body.

Term " X syndromes ", 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.

Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C₁-C₂₄) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.It is completely begged for about pro-drug By following documents can be referred to：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14, A.C.S.Symposium Series；Roche et al.,Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987；Rautio et al., Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008, 7,255-270,and Hecker et al.,Prodrugs of Phosphates and Phosphonates, J.Med.Chem.,2008,51,2328-2345。

Term " metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One The metabolite of a compound can be identified that activity can be by such as of the invention by technology well-known in the art Described adopt like that is experimentally characterized.Such product can be by, by aoxidizing, being gone back to drug compound Original, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes The metabolite of compound, including the compound of the present invention and mammal are come into full contact with into metabolism caused by a period of time and produced Object.

Term " nitrogen oxides " refers to the nitrogen-atoms oxygen that can be by 1 or more than 1 when compound contains several amine functional groups Change forms N- oxides.The particular example of N- oxides is the N- oxides of tertiary amine or the N- oxides of nitrogen heterocyclic ring nitrogen-atoms. Available oxidant, for example, hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine formed N- oxides (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxides 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 dichloromethane, amine compounds is made to be reacted with m- chlorine benzylhydroperoxide (MCPBA).

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents：Parker et al., McGraw-Hill Dictionary of Chemical Terms,1984,McGraw-Hill Book Company,New York and Eliel et al.,"Stereochemistry of Organic Compounds",John Wiley&Sons, Inc.,New York,1994.The compound of the present invention can include asymmetric center or chiral centre, therefore there are different Stereoisomer.All stereoisomeric forms in any ratio of the compound of the present invention, including but not limited to, diastereomer, enantiomerism Body, atropisomer and their mixture, such as racemic mixture constitute the part of the present invention.Diastereoisomer It is different that individual diastereomeric can be separated by the methods of chromatography, crystallization, distillation or distillation based on its physical chemical differences Structure body.Enantiomter can make chiral photo-isomerisation mixture be converted into diastereomeric mixtures by separation, mode be with Appropriate optically active compound (such as chiral adjuvant, for example chiral alcohol or MosherShi acyl chlorides) reaction, separation diastereomeric are different Structure body, and individual diastereoisomers is made to be converted into corresponding pure enantiomter.The intermediate of the present invention also may be used with compound To exist with different tautomeric forms, and all such form is comprised in the scope of the present invention.Many organic compounds All exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound, Prefix D, L or R, S are used for indicating the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming chemical combination object plane The symbol of polarised light rotation, (-) or l refer to that compound is left-handed, and it is dextrorotation that prefix (+) or d, which refer to compound,.These are vertical Atom or atomic group the interconnection order of body isomers are identical, but their stereochemical structure is different.It is specific three-dimensional different Structure body can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50:50 mixture of enantiomers quilt Referred to as racemic mixture or racemic modification, this may lead to do not have stereoselectivity or stereotaxis in chemical reaction process Property.

Term " racemic mixture " or " racemic modification " refer to the mixture of equimolar two enantiomters, are lacked Optical activity.

According to the selection of raw material and method, the compounds of this invention can be with one in possible isomers or they mixed The form for closing object exists, such as pure optical isomer, or as isomer mixture, such as different as racemic and non-corresponding Structure body mixture, this depends on the quantity of asymmetric carbon atom.Chiral synthesis can be used in (R)-or (S)-isomers of optical activity Prepared by son or chiral agents, or split using routine techniques.If this compound contains, there are one double bonds, and substituent group may be E or Z Configuration；If containing disubstituted naphthenic base in this compound, the substituent group of naphthenic base may be cis or trans (cis- or Trans-) configuration.

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)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.If it would be possible, the substituent group on atom with unsaturated double-bond can be with cis--(Z)-or trans--(E)-shape Formula exists.

Term " geometric isomer " is also referred to as " cis-trans-isomer ", because of double bond (including the double bond of alkene, C=N double bonds and N=N Double bond) or ring carbon atom list it is strong cannot rotate freely caused by isomers.

" stereoisomer " refers to having identical chemical constitution, but atom or the group spatially different change of arrangement mode Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (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 quality and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.

Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with The chemistry of tautomer can be reached if tautomerism is possible (as in the solution) by the mutual inversion of phases of low energy barrier Balance.Such as proton tautomer (protontautomer) (i.e. prototropic tautomer (prototropic Tautomer)) include change by proton transfer, such as the isomerization of keto-enol and imine-enamine.Valence Bond tautomerism body (valence tautomer) includes the mutual inversion of phases carried out by the recombination of some bonding electrons.Ketone- The specific example of enol tautomeric is the change of pentane -2,4- diketone and the amyl- 3- alkene -2- keto tautomers of 4- hydroxyls.Mutually Another example for becoming isomery is phenol-keto tautomerism.One specific example of phenol-keto tautomerism is pyridine -4- alcohol and pyrrole The change of pyridine -4 (1H) -one tautomer.Unless otherwise indicated, structural formula described in the invention includes all same Divide isomeric form (such as enantiomerism, diastereo-isomerism and geometrical isomerism)：Such as R, S configuration containing asymmetric center, double bond (Z), (E) isomers, and (Z), (E) rotamer.Therefore, the single three-dimensional chemical isomer of the compound of the present invention Or its enantiomter, the mixture of diastereoisomer or geometric isomer belong to the scope of the present invention.

The mixture of any stereoisomer of gained 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.

Therefore, as described in the present invention, the compound of the present invention can be with possible isomers, rotational isomeric A kind of form of or mixtures thereof form in body, atropisomer, tautomer exists, for example, substantially pure geometry Or mixtures thereof (cis or trans) isomers, diastereoisomer, optical isomer (enantiomer), racemic modification form.

Any isomer mixture of gained can be separated into pure or substantially pure according to the physical chemical differences of component Geometry or optical isomer, diastereoisomer, racemic modification, such as detached by chromatography and/or fractional crystallization.

Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high pressure liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can prepare (such as Jacques, et al., Enantiomers, Racemates and by asymmetric syntheses Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen, S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed., Univ.of Notre Dame Press,Notre Dame,IN 1972))。

" inflammation disease " used in the present invention, " inflammatory disease " or " diseases associated with inflammation " refers to due to excessive or out of control Any disease that excessive inflammatory symptoms, host tissue damage or function of organization caused by inflammatory responses are lost, disorderly or disease Shape." inflammation disease " also refers to by the pathologic state that leucocyte flows into and/or Neutrophil chemotaxis mediates.

" inflammation " used in the present invention, " inflammatory " or " inflammatory " refers to by tissue damaged or part caused by destroying is protected The response of shield property, it is used to destroying, dilute or separating (isolation) harmful substance and impaired tissue.Inflammation is flowed into leucocyte And/or Neutrophil chemotaxis has significant contact.Inflammation can result from pathogenic organism and virus infection with And non-infectious mode to the immune response of exotic antigen and itself is exempted from such as the wound or Reperfu- sion after myocardial infarction or apoplexy Epidemic disease response.Therefore, can include with the inflammatory disease that disclosed compound of present invention is treated：Reacted with specific system of defense and Non-specific defense system reacts relevant disease.

" immunological diseases " or " immunity disease " used in the present invention refer to that autoantigen immune response occurs for body And lead to the disease caused by damaged self tissue.The immunological diseases of broad sense are immunized caused by further including congenital or posteriority reason Exception in system structure or functionally.Under the influence of certain factors, the morphological element of body or immune system itself occur Certain exceptions cause immune system accidentally to attack itself composition as exotic.At this time immune system will produce for machine The antibody and activated lymphocytes of some compositions of body itself, damage destroy autologous tissue's internal organs, lead to disease.

" allergy " used in the present invention refers to that the arbitrary symptom for generating allergy, histologic lesion or function of organization lose.Such as " arthritis disease " used in the present invention refers to arbitrary characterized by being attributable to various etiologic etiological arthritis damages Disease." dermatitis " refers to the skin disease characterized by being attributable to various etiologic etiological scytitis as used in the present invention Large family in any one." graft rejection " refers to the funeral of the function of transplanting or surrounding tissue as used in the present invention Tissue is transplanted in the confrontation that mistake, pain, swelling, leukocytosis and decrease of platelet are characterized, such as organ or cell (such as marrow) Arbitrary immune response.The therapy of the present invention includes for treating and the method for the relevant disease of inflammatory cell activation.

Term " cancer " and " cancer " refer to or description patient in physiology usually characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including Small Cell Lung Cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), gastric cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterine cancer, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.

The invention also includes the compounds of this invention of isotope labelling, except for the following fact with it is those of of the present invention Compound is identical：One or more atoms are different from the original of natural common atomic quality or mass number by atomic mass or mass number Filial generation is replaced.The Exemplary isotopes that can be also introduced into the compounds of this invention include the same position of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine Element, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁶O,¹⁷O,³¹P,³²P,³⁶S,¹⁸F and³⁷Cl。

Include the compounds of this invention and the compound of other of aforementioned isotopes and/or other atoms isotopes Pharmaceutically acceptable salt is included within the scope of the present invention.The compounds of this invention of isotope labelling, such as the same position of radioactivity Element, such as³H and¹⁴C, which is incorporated into the compounds of this invention, can be used for drug and/or substrate tissue distributional analysis.Due to it is easily prepared with And detection, tritium generation, that is,³H and carbon-14, i.e.,¹⁴C, isotope are particularly preferred.In addition, with the isotope of weight, such as deuterium, i.e.,²H Substitution, it is possible to provide some are originated from the advantage in the treatment of the metabolic stability of bigger, such as increased Half-life in vivo or reduction Volume requirements.Therefore, may be preferred in some cases.

In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different Atom enriched isotope.

Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.Preferably, of the present invention " pharmaceutically acceptable " to refer to Federal regulator or national government approval United States Pharmacopeia or other it is general approve that pharmacopeias lift in animal, especially It is to be used in human body.

Term " pharmaceutically acceptable salt " refers to the organic salt and inorganic salts of the compound of the present invention.It is pharmaceutically acceptable Salt be known to us in fields, such as document：Berge et al.,describe pharmaceutically Recorded in acceptable salts in detail in J.Pharmacol Sci, 1997,66,1-19.It can pharmaceutically connect The non-limiting salt example received include inorganic acid salt formed by reacting with amino groups to form have hydrochloride, hydrobromate, phosphate, Metaphosphate, sulfate, nitrate, perchlorate and acylate such as mesylate, esilate, acetate, trifluoroacetic acid Salt, hydroxyl acetate, isethionate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, benzene sulfonate, tosilate, malate, fumarate, lactate, Lactobionate, or pass through institute in books, literature The other methods of record such as ion-exchanges obtains these salt.Other pharmaceutically acceptable salts include adipate, alginic acid Salt, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor tree Brain sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumaric acid Salt, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxyls-second Sulfonate, lactobionate, laruate, lauryl sulfate, malonate, 2- naphthalene sulfonates, nicotinate, nitrate, oil Hydrochlorate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acids salt, picrate, pivalate, propionate, Stearate, rhodanate, undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline earth gold Belong to, ammonium and N⁺(C_1-4Alkyl)₄Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium Salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, Lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions The amine cation of formation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8It is sulfonated Object and aromatic sulphonic acid compound.

" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.Formed solvate non-limiting solvent example include water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, Acetic acid or ethylaminoethanol etc..

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 stablizes 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.

Including the pharmaceutical composition of the compounds of this invention, preparation and administration

The present invention relates to a kind of pharmaceutical compositions comprising structural compounds or implementation shown in formula (I), (II) or (III) The compound of structure or its stereoisomer, all E/Z isomers, tautomer, solvate, metabolism production shown in example Object and pharmaceutically acceptable salt or prodrug, and pharmaceutically acceptable auxiliary material.Chemical combination in the pharmaceutical composition of the present invention The amount of object effectively can detectably inhibit the activity of SSAO/VAP-1.

Pharmaceutically acceptable auxiliary material may contain will not extra-inhibitory compound bioactivity inert fraction.Pharmacy Upper acceptable auxiliary material answers bio-compatible, such as nontoxic, non-inflammatory, non-immunogenic or is once administered to patient without other bad Reaction or side effect.Standard pharmaceutical techniques can be used.

There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt or energy of esters Other any adducts or derivative being directly or indirectly administered according to the needs of patient, the present invention other aspect described in Compound, metabolite or his residue.

As described in the invention, the pharmaceutically acceptable pharmaceutical composition of the present invention further includes pharmaceutically acceptable Auxiliary material, such as carrier, diluent, filler, adhesive, corrigent or excipient, these are applied as the present invention, including Any solvent, diluent or other liquid excipients, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsification Agent, preservative, solid binder or lubricant etc. are suitable for specific 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, it is comprehensive The content for closing document herein shows that different auxiliary materials can be applied to the preparation and their public affairs of pharmaceutically acceptable pharmaceutical composition The preparation method known.In addition to any conventional auxiliary material range incompatible with the compound of the present invention, for example, it is generated any Undesirable biological effect or the phase generated in harmful manner with any other component of pharmaceutically acceptable pharmaceutical composition Interaction, their purposes are also the range that the present invention is considered.

The substance that can be used as pharmaceutically acceptable auxiliary material 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 Fat 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.

The pharmaceutical composition of the present invention can be oral medication, drug administration by injection, Aerosol inhalation, local administration, per rectum Administration, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Term used herein " is administered to Medicine " include it is subcutaneous, vein, it is intramuscular, it is intra-articular, it is intrasternal in synovial membrane (chamber), in film, intraocular, in liver , intralesional and encephalic injection or infusion techniques.Preferred pharmaceutical composition is oral medication, to Intraperitoneal medication or Intravenous injection.The injection system of the medicament composition sterile of the present invention can be water or oil suspension.These suspend Liquid can be manufactured using suitable dispersant, wetting agent and suspending agent by formula according to known technology.Aseptic injection can be Aseptic parenteral solution or suspension are injection nontoxic acceptable diluents or solvent, such as 1,3-BDO solution.These can connect The excipient and solvent received can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, sterile non-volatile Oil can be used as solvent or suspension media by convention.

With this end in view, any mild non-volatile oil can be the list or glucosulfone base glycerol diester of synthesis. Aliphatic acid, if oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable Grease, such as olive oil or castor oil, especially their polyoxyethylene deriv.These oil solutions or suspension can include Long-chain alcohol diluents or dispersant are generally used for the medicine of pharmaceutically acceptable dosage form such as carboxymethyl cellulose or similar dispersing agents Object preparation includes emulsion and suspension.Other common surfactants, such as Tweens, spans and other emulsifiers or life The hardening agent of object drug effect rate is generally used for pharmaceutically acceptable solid, liquid or other dosage forms, and can be applied to target The preparation of pharmaceutical preparation.

For oral liquid dosage form include but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspending agent, Syrup and elixir.In addition to the active compound, liquid dosage form may contain inert diluent commonly used in the art, such as water or other Solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Ergol, the third two Alcohol, 1,3 butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor-oil plant Oil and sesame oil), the aliphatic ester and its mixture of glycerine, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan.Except inert diluent Outside, Orally administered composition may also comprise adjuvant, such as wetting agent, emulsification and suspending agent, sweetener, flavoring agent and fumet.

Injectable formulation can be prepared using suitable dispersion or wetting agent and suspending agent according to known technology, for example, it is sterile can Injection water or oil-suspending agent.Sterile injectable preparation is also likely to be the nothing in the acceptable diluent of nontoxic parenteral or solvent Solution in bacterium Injectable solution, suspending agent or emulsion, such as 1,3-BDO.It, can in acceptable medium and solvent Using water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, using sterile non-volatile oil by convention As solvent or suspension media.For this purpose, any tasteless fixed oil can be used, include the monoglycceride or glycerine of synthesis Diester.In addition, aliphatic acid, such as octadecenic acid, it is used to prepare injection.

For example, can be filtered by bacteria-retaining filter or by addition in aseptic solid composite form, before use The fungicide in sterile water or other sterile injectable mediums is dissolved in or is scattered in sterilize for injectable formulation.

To extend the effect of compound or composition of the present invention, it is often desirable to slow down compound by subcutaneously or intramuscularly noting The absorption penetrated.This can be realized by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Then, compound Absorption rate depends on its rate of dissolution, and rate of dissolution depends on crystal size and crystalline form.Alternatively, by the way that compound is molten It solves or is suspended in and realize that delay absorbs the compound of parenteral administration in oily medium.By in Biodegradable polymeric Such as the storage form of injectable is made in the microcapsules matrix of formation compound in polyactide-polyglycolic acid.According to compound With the property of the ratio between polymer and the particular polymer used, controllable produced compounds rate of release.It is other biodegradable poly- The example for closing object includes polyorthoester and polyanhydride.Also can by by compound be trapped in the liposome compatible with bodily tissue or The storage preparation of injectable is prepared in microemulsion.

Per rectum or the composition of vaginal application are particularly through the non-thorn for mixing compound of the present invention and being suitble to Swash property excipient or carrier, such as suppository prepared by cupu oil, polyethylene glycol or suppository wax, the excipient or carrier are in environment At a temperature of be solid but be under body temperature liquid and therefore in rectum or vaginal canal melt and release of active compounds.

Oral dosage form includes capsule, tablet, pill, pulvis and particle.In this solid dosage forms, reactive compound It is mixed at least one inert pharmaceutically acceptable auxiliary material such as sodium citrate or Dicalcium Phosphate and/or a) filler or expansion Agent, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive, such as carboxy methyl cellulose, alginates, Gel, polyvinylpyrrolidone, sucrose and Arabic gum, c) moisturizer, for example (,) glycerine, d) disintegrant, such as agar, carbonic acid Calcium, potato or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorb plus Fast agent, such as quaternary ammonium compound, g) wetting agent, such as cetanol and glycerin monostearate, h) absorbent, such as kaolin and Bentonite and i) lubricant, such as talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and its mixed Close object.For capsule, tablet and pill, dosage form also may include buffer.

It can also be used such as lactose or toffee and macromolecule polyethylene glycol excipient by the solid composite of similar type As the filler in soft hard gelatin capsules.Coating and shell, such as enteric coating and the well-known other packets of pharmaceutical field can be used Clothing prepares the solid dosage forms of tablet, lozenge, capsule, pill and particle.They can optionally contain opacifiers and can also have group The property of object is closed, so that optionally with delayed mode only discharge active component, or preferably, in certain part release of enteron aisle. The example of workable embedding composition includes polymer and wax.Lactose or toffee and macromolecule polyethylene glycol etc. can also be used The solid composite of similar type is used as the filler in soft hard gelatin capsules by excipient.

The microsealing form with one or more above-mentioned excipient can be also presented in reactive compound.Coating and shell can be used, Such as in enteric coating, controlled release coat and pharmaceutical field well-known other coatings prepare tablet, lozenge, capsule, pill and The solid dosage forms of grain.In this solid dosage forms, reactive compound may be mixed at least one inert diluent, such as sucrose, Lactose or starch.Usually, this dosage form may also include other substance besides inert diluents, such as tableting lubricant With other tabletting adjuvants, such as magnesium stearate and microcrystalline cellulose.For capsule, tablet and pill, dosage form It may include buffer.They can optionally containing opacifiers and can also be with the property of composition, so that optionally with party in delay Formula only discharge active component, or preferably, in certain part release of enteron aisle.The example of workable embedding composition includes poly- Close object and wax.

The part of compound of the present invention or transdermal administration dosage form include ointment, ointment, emulsifiable paste, lotion, gel, powder Agent, solution, spray, inhalant or patch.Aseptically, reactive compound and pharmaceutically acceptable carrier and any need The preservative wanted or the buffer that may be needed.Ophthalmic preparation, auristillae and eyedrops be also considered the scope of the present invention it It is interior.In addition, the present invention considers the purposes with the dermal patch for providing the control attendant advantages that compound is delivered to body.It can This dosage form is made by the way that compound to be dissolved or dispersed in appropriate medium.It is logical that sorbefacient can also be used for raising compound Cross the flow of skin.Speed can be controlled by providing rate controlling membranes or by the way that compound to be scattered in polymer substrate or gel Rate.

Also can oral, parenteral, by sucking spray through part, rectum, nose, oral cavity, vagina or being applied by catheter indwelling With composition of the present invention.As terminology used in the present invention " parenteral " include but not limited to subcutaneous, intravenous, muscle, In intra-articular, synovial membrane intracavitary, breastbone, intrathecal, liver is interior, intralesional and intracranial injection or infusion techniques.Particularly, oral, peritonaeum It is interior or intravenously apply composition.

The sterile injection form of composition of the present invention can be water or oil suspension.These suspension can follow up ability Technology known to domain is prepared using suitable dispersion or wetting agent and suspending agent.Sterile injectable preparation is also likely to be in nontoxic It can be such as molten in 1,3-BDO through the sterile injectable solution or suspension in the external diluent or solvent received of stomach Liquid.In acceptable medium and solvent, adoptable is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, according to Convention is using sterile non-volatile oil as solvent or suspension media.For this purpose, any tasteless fixed oil can be used, including The monoglycceride or diglyceride of synthesis.In addition, as being especially in the natural pharmaceutically acceptable of polyoxyethylated versions Oil, such as olive oil or castor oil, aliphatic acid such as octadecenic acid and its glyceride ester derivatives are used to prepare injection.These oil Solution or suspension may also contain long-chain alcohol diluents or dispersant, such as carboxymethyl cellulose or can pharmaceutically be connect preparing Common similar dispersant in the dosage form (including emulsion and suspension) received.Other conventional surfactants, such as Tweens, Spans and common other emulsifiers or bioavailability in producing pharmaceutically acceptable solid, liquid or other dosage forms Reinforcing agent can also be used for the purpose prepared.

Acceptable dosage form, including but not limited to capsule, tablet, water slurry or solution can be taken orally with any, take orally this Invention described pharmaceutical composition.For for oral tablet, common carrier includes but not limited to newborn sugar and starch.Usually It is additionally added lubricant, such as magnesium stearate.In order to which with capsules per os, useful diluent includes that lactose and dry corn form sediment Powder.When it is oral need water slurry when, active constituent is combined with emulsifier and suspending agent.If desired, certain sweet tastes can also be added Agent, flavoring agent or colorant.

Alternatively, pharmaceutical composition of the present invention can be applied for the suppository form that rectum uses.It can be tried by mixing Agent and non-irritating excipient prepare these pharmaceutical compositions, and the excipient is at room temperature solid, but under rectal temperature For liquid, therefore will melt to discharge drug in rectum.This substance includes but not limited to cupu oil, beeswax and poly- second two Alcohol.

Especially when therapeutic purpose includes that part drop applies easily accessible region or organ, including eye, skin or low level It, can also local application pharmaceutical composition of the present invention when intestines problem.It is easy to make for each of these regions or organ Standby suitable topical formulations.

It can be realized with rectal suppository formulation (seeing above) or suitable enema preparation and the part drop of lower bowel is applied. Local skin patch can be used.

For locally drop is applied, pharmaceutical composition can be formulated as containing suspension or be dissolved in one or more carriers The suitable ointment of active component.It includes but not limited to mineral oil, vaseline to apply the carrier of the compound of the present invention suitable for part drop Oil, albolene, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, pharmaceutical composition can be prepared For containing suspending or be dissolved in the suitable lotion or emulsifiable paste of the active component in one or more pharmaceutically acceptable carriers.It is suitble to Carrier include but not limited to that mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, spermaceti are hard Lipidol, 2- octyl dodecanols, benzyl alcohol and water.

In order to which ophthalmology uses, pharmaceutical composition can be formulated as in isotonic pH with or without preservative such as benzalkonium chloride The micronized suspension in Sterile Saline is adjusted, or especially isotonic pH adjusts the solution in Sterile Saline.Alternatively, for ophthalmology It uses, pharmaceutical composition can be formulated as to ointment, such as vaseline.

Also pharmaceutical composition is applied in the spray that can be gasified by nose or sucking.According to well-known skill in pharmaceutical field Art prepare this composition and using benzyl alcohol and other suitable preservative, the sorbefacient that improves bioavailability, Fluorocarbon and/or other conventional solubilizer or dispersant are prepared into the solution in brine.

It can will be configured to unit dosage forms for the compound of the method for the present invention.Term " unit dosage forms " refer to be suitable as by The discrete unit of physics of the unit dose of curer, per unit contain the active matter for being computed the predetermined amount for generating expected effect Matter is optionally combined with suitable pharmaceutical carrier.Unit dosage forms can make single daily dose or multiple daily dose (for example, daily about 1-4 times or more time) it is wherein primary.It, can be identical or not for the unit dosage forms of each dosage when using multiple daily dose Together.

The purposes of the compounds of this invention and pharmaceutical composition

The amount of compound effectively can detectably inhibit SSAO/VAP- in the compound of the present invention or pharmaceutical composition 1 activity has good inhibiting effect to SSAO/VAP-1 activity.

SSAO/VAP-1 inhibitor can block inflammation and self-immunprocess and the SSAO/VAP- of other increases level 1 cycle amine substrate and/or product related medical conditions, therefore, it is related that the compound of the present invention will be used for inflammation disease, inflammation Disease or immunological 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 or treat patient's inflammation disease, inflammation related disease or immunological diseases.Such disease includes, But it is not limited to arthritis, general inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammatory Enteropathy, fibrosis, hepatopathy, vascular diseases, breathing problem, disease of eye, skin disease, neuroinflammatory disorder, diabetes are drawn Inflammation, ischemic disease and the organ and/or tissue transplantation rejection risen.

In addition, the compounds of this invention or pharmaceutical composition are further adapted for treating mental illness, such as severe depression, two polar form sorrows Strongly fragrant disease and attention deficiency hyperactive disorder (attention deficit hyperactivity disorder) and cancer.

The compound of the present invention to human treatment in addition to beneficial to other than, applying also for veterinary treatment pet, introduced variety 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.

" effective quantity " of the compound of the present invention or pharmaceutically acceptable pharmaceutical composition, " effective therapeutic dose " " have Effect dosage " refers to the effective quantity for handling or mitigating the severity that one or more present invention are previously mentioned illness.The chemical combination of the present invention Object or pharmaceutically acceptable pharmaceutical composition are effective in comparatively wide dosage range.For example, the dosage taken daily About within the scope of 0.1mg-1000mg/ people, it is divided into primary or is administered for several times.According to the method for the present invention, compound and medicine group Conjunction object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.It is required Accurately amount will change according to the case where patient, this depends on race, age, the general condition of patient, the serious journey of infection Degree, special factor, administering mode etc..The compound of the present invention or pharmaceutical composition can be with one or more other therapeutic agents Administering drug combinations, as discussed in the present invention.

General synthesis and detection method

Usually, 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) or formula (III).Following reaction scheme and embodiment are used In present disclosure is further illustrated.

Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known drug 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 generally acknowledged Ground is suitable for the preparation of 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 shifts (δ) are provided with the unit of hundred a ten thousandths (ppm).¹H-NMR、¹³C-NMR、¹⁹The survey of F-NMR Surely it is to use 600 nuclear magnetic resoance spectrum of Bruker Ultrashield-400 nuclear magnetic resonance spectrometers and Bruker Avance III HD Instrument, measurement solvent are deuterochloroform (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).

HPLC prepares purifying and generally uses 250 high performance liquid chromatographs of Novasep pump.

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

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 silica gel plates.

It is carrier that column chromatography, which generally uses the mesh silica gel of 300 mesh of Qingdao Haiyang chemical industry~400,.

The starting material of the present invention is known, and can be bought on the market, is bought from Shanghai Shao Yuan companies (Shanghai Accela Company), Ann Kyrgyzstan company (Energy Company), lark prestige company (J＆K), Tianjin Ah method The companies such as Ai Sha companies (Alfa Company), either may be used or are synthesized according to methods known in the art.

It is carried out under nitrogen atmosphere without specified otherwise, reaction in embodiment；

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

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

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

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

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

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have：Dichloromethane and methanol system, dichloromethane 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：Dichloromethane and ethyl acetate System, C：Dichloromethane 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 1200 high pressure liquid chromatograph of Agilent (Zorbax Eclipse Plus C18 150 × 4.6mm chromatographic columns)；

HPLC test conditions：Run time：15min-20min column temperatures：35℃ PDA：210nm, 254nm

Mobile phase：A phases：PH2.5 potassium dihydrogen phosphate B phases：Acetonitrile Flow rate：1.0ml/min

Eluent gradient is as in Table A：

Table A

Time	The gradient of mobile phase A	The gradient of Mobile phase B
			0min	90%	10%
15min	30%	70%

The LC/MS/MS systems of analysis in biological test experiment include 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 patterns, and the parameter of MRM conversions is 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 the Agilent μM columns of 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, also having 6330 series LC/MS/MS spectrometers of Agilent for analysis, noted equipped with G1312A binary Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cationic model treatment is carried out to each analyte and MRM conversions carry out best analysis.It uses during analysis Capcell MP-C18 columns, specification are：100×4.6mm I.D.,5μM(Phenomenex,Torrance,California, USA).Mobile phase is 5mM ammonium acetates, 0.1% methanol aqueous solution (A)：5mM ammonium acetates, 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 brief word below is through the present invention：

DMSO-d₆:Deuterated dimethyl sulfoxide；

CDCl₃:Deuterochloroform；

CD₃OD:Deuterated methanol；

THF:Tetrahydrofuran；

Wt.%:Mass percent；

Me:Methyl；

Et:Ethyl；

^tBu:Tertiary butyl；

HCl:Hydrochloric acid；

Boc:Tertbutyloxycarbonyl；

TBS:T-Butyldimethylsilyl；

Ms:Methyl sulphonyl；

Bn:Benzyl；

FCH₂PPh₃BF₄:Methyl fluoride (triphenyl)-phosphine tetrafluoroborate；

mL,ml:Milliliter；

μL,μl：Microlitre；

mol/L,M:Mole/every liter；

mol:Mole；

mmol:MM；

g:Gram；

h:Hour；

H₂：Hydrogen；

min:Minute；

N₂:Nitrogen.

General synthetic method

The typical synthesis step of disclosed compound of present invention is prepared as shown in following synthetic schemes 1~5.Unless in addition saying It is bright, each R₁、R₂、R₃、R₄、R₆, ring A and n have as described in the present invention definition；X is halogen；Each PG₁、PG₂、PG₃、PG₄And PG₅ It independently is suitable amido protecting group；PG₆For suitable hydroxy-protective group；PG₇For suitable carboxy protective group；LG For leaving group.

Synthetic schemes 1:

It can pass through one described in synthetic schemes 1 with the compound of structure as shown in general formula (I-A) or its E/Z isomers As synthetic method be prepared, specific steps can refer to embodiment.Compound (I-a) and amino protecting agent (such as two dimethyl dicarbonates Butyl ester) reaction, obtain compound (I-b)；Compound (I-b) under alkaline condition (such as triethylamine), with carboxyl activator (chloromethane Sour isobutyl ester) reaction, then diazo-reaction occurs with diazonium compound (such as trimethyl silicone hydride diazomethane), obtain compound (I-c)；Compound (I-c) carries out halogenating reaction, obtains compound (I-d)；Compound (I-d) (such as carbonic acid under alkaline condition Potassium), nucleophilic substitution occurs with compound (I-e), obtains compound (I-f)；Compound (I-f) and suitable Witting Reagent (such as methyl fluoride (triphenyl)-phosphine tetrafluoroborate) reacts, and obtains compound (I-g)；Compound (I-g) sloughs amino guarantor Protect base PG₁, obtain target compound shown in general formula (I-A).In general, will dissociate for convenience of handling and improving chemical stability Target compound is converted into acid-adducting salt shown in amino-compound, i.e. general formula (I-A).The example of acid-adducting salt includes but unlimited In hydrochloride, hydrobromate and mesylate.

Synthetic schemes 2：

It can pass through one described in synthetic schemes 2 with the compound of structure as shown in general formula (I-B) or its E/Z isomers As synthetic method be prepared, specific steps can refer to embodiment.Compound (I-h) is anti-with amino protecting agent (such as cylite) It answers, obtains compound (I-i)；Compound (I-i) reacts (such as diethylin sulfur trifluoride) with halide reagent, obtains compound (I-j)；Compound (I-j) sloughs amino protecting group PG₂, obtain compound (I-k)；Compound (I-k) and amino protecting agent are (such as Di-tert-butyl dicarbonate) reaction, obtain compound (I-l)；Compound (I-l) decarboxylize protecting group PG₇, obtain compound (I-m)；With compound (I-m) for starting material, the compound described by synthetic schemes 1 (I-b) arrives the synthesis side of (I-A) Method obtains target compound shown in general formula (I-B).In general, for convenience of handle and improve chemical stability and by free amine group Target compound is converted into acid-adducting salt shown in compound, i.e. general formula (I-B).The example of acid-adducting salt includes but not limited to salt Hydrochlorate, hydrobromate and mesylate.

Synthetic schemes 3:

It can pass through one described in synthetic schemes 3 with the compound of structure as shown in general formula (I-C) or its E/Z isomers As synthetic method be prepared, specific steps can refer to embodiment.General formula (I-A) compound (such as diisopropyl under alkaline condition Base ethamine), it is reacted with general formula (I-n) compound, obtains compound (I-o)；Compound (I-o) sloughs amino protecting group PG₄, obtain To target compound shown in general formula (I-C).In general, for convenience of handle and improve chemical stability and by free amine group chemical combination Target compound is converted into acid-adducting salt shown in object, i.e. general formula (I-C).The example of acid-adducting salt includes but not limited to hydrochloric acid Salt, hydrobromate and mesylate.

Synthetic schemes 4:

It can pass through one described in synthetic schemes 4 with the compound of structure as shown in general formula (I-D) or its E/Z isomers As synthetic method be prepared, specific steps can refer to embodiment.Compound (I-p) at low temperature with suitable Wittig reagents Compound (I-q) is obtained by the reaction in (the fluoro- 2- phosphonoacetates of such as 2-)；Compound (I-q) sloughs hydroxyl protection base PG₆ To compound (I-r)；Compound (I-r) is reacted with hydroxyl activity agent (such as methylsufonyl chloride), obtains compound (I-s)；Chemical combination Object (I-s) is reacted with organolithium reagent LiX, and LG groups are optionally substituted by halogen, and obtains compound (I-t)；Compound (I-t) is in alkalinity Under the conditions of (such as potassium carbonate), with compound (I-e) occur nucleophilic substitution, obtain compound (I-u)；Compound (I-u) is de- The protecting group that deaminizes PG₅, obtain target compound shown in general formula (I-D).In general, for convenience of handling and improving chemical stability And by free amino compound, i.e. target compound shown in general formula (I-D) is converted into acid-adducting salt.The example packet of acid-adducting salt Include but be not limited to hydrochloride, hydrobromate and mesylate.

Synthetic schemes 5:

Compound with the structure as shown in general formula (I-E) can be described by synthetic schemes 5 synthetic method system Standby to obtain, specific steps can refer to embodiment.Compound (I-q) is under organometallic reagent (such as diethyl zinc) effect, with halogen It is reacted for alkane (such as diiodomethane), obtains compound (I-v)；Compound (I-v) sloughs hydroxyl protection base PG₆, obtain chemical combination Object (I-w)；With hydroxyl activity agent (such as methylsufonyl chloride) esterification occurs for compound (I-w), obtains compound (I-x)；Change It closes object (I-x) to react with organolithium reagent LiX, LG groups are optionally substituted by halogen, and obtain compound (I-y)；Compound (I-y) is in alkali Property under the conditions of (such as potassium carbonate), with compound (I-e) occur nucleophilic substitution, obtain compound (I-z)；Compound (I-z) Slough amino protecting group PG₅, obtain target compound shown in general formula (I-E).In general, for convenience of handling and improving chemical stabilization Property and by free amino compound, i.e. target compound shown in general formula (I-E) is converted into acid-adducting salt.The example of acid-adducting salt Including but not limited to hydrochloride, hydrobromate and mesylate.

Embodiment

1 4- of embodiment [(2E, 3R) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamides hydrochloride 1

Step 1 (2R) -2- (t-butoxycarbonyl amino) propionic acid 1b

D-alanine 1a (9.0g, 0.10mol) is dissolved in tetrahydrofuran (100mL) and 10% sodium hydrate aqueous solution Di-tert-butyl dicarbonate (25mL, 0.11mol) is added dropwise in the mixed solution of (100mL), reacts at room temperature 3 hours.Use ethyl acetate (100mL × 2) extract, after water phase 4mol/L salt acid for adjusting pH value to 2, with methylene chloride/methanol solution (v/v=10/1, 100mL × 2) extraction, combined organic phase dried with anhydrous sodium sulfate, filters concentration, and it is that white is solid to obtain title compound 1b Body (14g, yield 73%) can be directly used for reacting in next step.

Step 2 N- [(1R) -3- diazonium -1- methyl -2- oxo-propylls] t-butyl carbamate 1c

(2R) -2- (t-butoxycarbonyl amino) propionic acid 1b (14g, 74mmol) is dissolved in tetrahydrofuran (100mL), is cooled to 0 DEG C is added triethylamine (14mL, 96mmol), and isobutyl chlorocarbonate (12mL, 89mmol) is added dropwise, and is kept for 0 DEG C react 2 hours, had White solid is precipitated.Acetonitrile (100mL) is added toward above-mentioned suspension, be added dropwise at 0 DEG C trimethyl silicone hydride diazomethane just Alkane solution (75mL, 150mmol, 2.0mol/L) reacts at room temperature 17 hours after 0 DEG C of holding reaction 3 hours.It is concentrated under reduced pressure, residual Object purifies [ethyl acetate/petroleum ether (v/v)=1/5] by silica gel column chromatography, and it is yellow solid to obtain title compound 1c (8.3g, yield 54%).

Step 3 N- [the bromo- 1- methyl -2- oxo-propylls of (1R) -3-] t-butyl carbamate 1d

N- [(1R) -3- diazonium -1- methyl -2- oxo-propylls] t-butyl carbamate 1c (8.3g, 39mmol) is dissolved in Ethyl acetate (80mL) is cooled to the acetic acid solution (7.5mL, 33wt.%) of -45 DEG C of dropwise addition hydrogen bromides, there is gas releasing.It protects - 45 DEG C are held to react 1 hour.The reaction solution after methyl tertiary butyl ether(MTBE) (200mL) is added, after being warmed to room temperature, uses unsaturated carbonate successively Hydrogen sodium solution (100mL) and saturated nacl aqueous solution (80mL) washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue [ethyl acetate/petroleum ether (v/v)=1/5] is purified by silica gel column chromatography, it is yellow solid to obtain title compound 1d (10.8g, yield 100%).

Step 4 N- [(1R) -3- [4- (tert-butylamine formoxyl) phenoxy group] -1- methyl -2- oxo-propylls] amino first Tert-butyl acrylate 1e

N- [the bromo- 1- methyl -2- oxo-propylls of (1R) -3-] t-butyl carbamate 1d (0.96g, 3.6mmol) is dissolved in N,N-Dimethylformamide (8mL) then sequentially adds potassium carbonate (0.84g, 6.0mmol) and N- tertiary butyl -4- hydroxyls thereto Base-benzamide (0.80g, 4.1mmol) reacts at room temperature 5 hours.Water (5mL) is added to be quenched, gained mixture ethyl acetate (20mL) is extracted, and organic phase is washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residual Object purifies [ethyl acetate/petroleum ether (v/v)=1/2] by silica gel column chromatography, and it is faint yellow solid to obtain title compound 1e (0.48g, yield 35%).

MS(ESI,pos.ion)m/z:401.5[M+Na]⁺。

Step 5 N- [(E, 1R) -2- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] fluoro- 1- methyl allyls of -3- Base] t-butyl carbamate 1f and N- [(Z, 1R) -2- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] fluoro- 1- first of -3- Base-allyl] t-butyl carbamate 1g

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (5.0g, 13mmol) is dissolved in tetrahydrofuran (20mL), at -20 DEG C Bis- (trimethyl silicon substrate) Sodamides (8.6mL, 17mmol, 2mol/L) are added, after ten minutes, N- [(1R) -3- [4- are added dropwise in stirring (tert-butylamine formoxyl) phenoxy group] -1- methyl -2- oxo-propylls] t-butyl carbamate 1e (2.5g, 6.6mmol) four Hydrogen furans (10mL) solution is slowly increased to room temperature, reacts 26 hours.Water (50mL) is added to be quenched, with ethyl acetate (100mL × 2) Extraction, combined organic phase are washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residual Object purifies [ethyl acetate/petroleum ether (v/v)=1/5] by silica gel column chromatography, and it is yellow solid to obtain title compound 1f (0.30g, yield 11%) and title compound 1g are yellow solid (0.17g, yield 7%).

MS(ESI,pos.ion)m/z:417.2[M+Na]⁺。

Step 6 4- [(2E, 3R) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamides hydrochloride 1

By N- [(E, 1R) -2- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] the fluoro- 1- methyl-allyls of -3-] ammonia Base t-butyl formate 1f (0.30g, 0.76mmol) is dissolved in ethyl acetate (0.5mL), and the ethyl acetate solution of hydrogen chloride is added (6mL, 4mol/L) reacts at room temperature 2 hours, there is white solid precipitation.Filtering, it is white solid to obtain title compound 1 (0.23g, HPLC purity:97.77%, yield 91%).

MS(ESI,pos.ion)m/z:295.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.53 (s, 3H), 7.81 (d, J=8.7Hz, 2H), 7.61 (s, 1H), 7.25 (d, J=81.9Hz, 1H), 7.03 (d, J=8.7Hz, 2H), 4.72 (m, 2H), 4.33-4.18 (m, 1H), 1.41 (d, J=6.9Hz, 3H), 1.39-1.34 (m, 9H).

2 4- of embodiment [(2Z, 3R) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamides hydrochloride 2

With N- [(Z, 1R) -2- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] the fluoro- 1- methyl-allyls of -3-] ammonia Base t-butyl formate 1g (0.15g, 0.38mmol) replaces compound 1f, according to the method that 1 step 6 of embodiment describes, is marked Topic compound 2 is white solid (0.12g, HPLC purity:98.12%, yield 95%).

MS(ESI,pos.ion)m/z:295.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.53 (s, 3H), 7.81 (d, J=8.6Hz, 2H), 7.61 (s, 1H), 7.32 (d, J=81.9Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 4.81 (dd, J=38.1,11.1Hz, 2H), 4.07- 3.92 (m, 1H), 1.40 (d, J=6.8Hz, 3H), 1.37 (s, 9H).

3 4- of embodiment [(2E, 3S) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamides hydrochloride 3

Step 1 (2S) -2- (tertbutyloxycarbonylamino) propionic acid 3b

L-Alanine 3a (20g, 0.22mol) is dissolved in tetrahydrofuran (200mL) and 10% sodium hydrate aqueous solution (200mL), is cooled to 5 DEG C, and di-tert-butyl dicarbonic acid ester (55mL, 0.24mol) is added dropwise, and restores to being stirred at room temperature 4 hours.It is added Water (200mL) is extracted with ethyl acetate (200mL × 2).After water phase 4mol/L salt acid for adjusting pH value to 2, with dichloromethane/ Methanol solution (v/v=10/1,200mL × 3) extracts, and combined organic phase is dried with anhydrous sodium sulfate.It filters, is concentrated under reduced pressure, It is white solid (33g, yield 78%) to obtain title compound 3b, is directly used in and reacts in next step.

Step 2 N- [(1S) -3- diazo -1- methyl -2- oxygen-propyl] t-butyl carbamate 3c

Under nitrogen protection, (2S) -2- (tertbutyloxycarbonylamino) propionic acid 3b (0.50g, 2.6mmol) is dissolved in drying Tetrahydrofuran (5mL) in, be cooled to 0 DEG C be added n,N-diisopropylethylamine (0.7mL, 4.0mmol), isobutyl chlorocarbonate (0.52mL, 3.9mmol) is stirred to react 4 hours at 0 DEG C, there is white solid precipitation.Acetonitrile is added into above-mentioned suspension Trimethyl silicone hydride diazomethane (2.6mL, 5.2mmol) is added dropwise after (3mL) dissolved clarification thereto again, continues stirring 3 hours, rises to Room temperature reaction 16 hours.It being concentrated under reduced pressure, residue purifies [petrol ether/ethyl acetate (v/v)=8/1] by silica gel column chromatography, It is yellow solid (0.28g, yield 50%) to obtain title compound 3c.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.27 (d, J=7.2Hz, 1H), 6.02 (s, 1H), 4.02-3.83 (m, 1H), 1.39 (s, 8H), 1.15 (d, J=7.2Hz, 3H).

Step 3 N- [the bromo- 1- methyl -2- oxygen-propyl of (1S) -3-] t-butyl carbamate 3d

By N- [(1S) -3- diazo -1- methyl -2- oxygen-propyl] t-butyl carbamate 3c (0.28g, 1.33mmol) It is dissolved in ethyl acetate (5mL), is cooled to -45 DEG C, hydrobromic acid acetic acid solution (0.24mL, 1.3mmol, 33wt.%) is added dropwise.Stirring Reaction 1.5 hours.Be added methyl tertiary butyl ether(MTBE) (10mL), be warmed to room temperature, successively use saturated sodium bicarbonate solution (5mL × 2) and Saturated nacl aqueous solution (5mL × 2) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through silica gel column chromatography It purifies [petrol ether/ethyl acetate (v/v)=8/1], it is white solid (0.28g, yield 79%) to obtain title compound 3d.

MS(ESI,pos.ion)m/z:298.9[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.35 (d, J=6.7Hz, 1H), 4.50-4.36 (m, 2H), 4.20 (dd, J=14.2,7.1Hz, 1H), 1.38 (s, 9H), 1.19 (d, J=7.2Hz, 3H).

Step 4 N- [(1S) -3- [4- (t-Butylcarbamoyl) phenoxy group] -1- methyl -2- oxygen-propyl] amino first Tert-butyl acrylate 3e

N- [the bromo- 1- methyl -2- oxygen-propyl of (1S) -3-] t-butyl carbamate 3d (0.34g, 1.28mmol) is dissolved in N,N-Dimethylformamide (4mL) sequentially adds N- tertiary butyl-4-hydroxies-benzamide (0.74g, 3.85mmol) and carbonic acid Potassium (0.20g, 1.40mmol) is stirred at room temperature 3 hours.Water (5mL) is added to be quenched, is extracted with ethyl acetate (10mL × 3), merges Organic phase washed with saturated nacl aqueous solution (5mL × 3), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through Silica gel column chromatography purify [petrol ether/ethyl acetate (v/v)=6/1], obtain title compound 3e be yellow oil (0.35g, Yield 73%).

MS(ESI,pos.ion)m/z:401.5[M+Na]⁺。

Step 5 N- [(E, 1S) -2- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- 1- methyl allyls of -3- Base] t-butyl carbamate 3f and N- [(Z, 1S) -2- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- 1- first of -3- Base-allyl] t-butyl carbamate 3g

Under nitrogen protection, methyl fluoride (triphenyl)-phosphine tetrafluoroborate (0.50g, 1.31mmol) is dissolved in anhydrous four Hydrogen furans (7mL) is cooled to -20 DEG C, and bis- (trimethyl silicon substrate) Sodamides (0.85mL, 1.7mmol) are added dropwise, and stirs 10 minutes, It is added dropwise to N- [(1S) -3- [4- (t-Butylcarbamoyl) phenoxy group] -1- methyl -2- oxygen-propyl] tertiary fourth of carbamic acid again The tetrahydrofuran solution (1mL) of ester 3e (0.30g, 0.79mmol) is warmed to room temperature stirring 1 hour.Ice water (5mL) is added to be quenched, It is spin-dried for organic solvent, is extracted with ethyl acetate (10mL × 3), combined organic phase is washed with saturated nacl aqueous solution (10mL × 3) It washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [petrol ether/ethyl acetate (v/v) by silica gel column chromatography =6/1], obtain that title compound 3f is yellow oil (35mg, yield 7%) and title compound 3g is white solid (25mg, yield 5%).

Compound 3f

MS(ESI,pos.ion)m/z:417.3[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.78 (d, J=8.7Hz, 2H), 7.56 (s, 1H), 7.03 (s, 1H), 7.02-6.77 (m, 3H), 4.71-4.57 (m, 2H), 4.20 (s, 1H), 1.36 (d, J=4.8Hz, 18H), 1.19 (d, J =7.2Hz, 3H)；

Compound 3g

MS(ESI,pos.ion)m/z:417.5[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.78 (d, J=8.7Hz, 2H), 7.57 (s, 1H), 7.06 (s, 1H), 6.93 (t, J=24.7Hz, 3H), 4.64-4.54 (m, 1H), 4.49 (d, J=3.1Hz, 2H), 1.37 (s, 18H), 1.21 (d, J=7.2Hz, 3H).

Step 6 4- [(2E, 3S) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamides hydrochloride 3

By N- [(E, 1S) -2- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] the fluoro- 1- methyl-allyls of -3-] ammonia Base t-butyl formate 3f (0.19g, 0.47mmol) is dissolved in ethyl acetate (1mL), be added hydrogen chloride ethyl acetate solution (3mL, 4mol/L), it is stirred at room temperature 30 minutes.It is spin-dried for, it is faint yellow solid (0.15g, HPLC purity to obtain title compound 3: 98.9%, yield 97%).

MS(ESI,pos.ion)m/z:295.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.32 (s, 3H), 7.81 (d, J=8.8Hz, 2H), 7.59 (s, 1H), 7.22 (dd, J=66.4,37.9Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 4.75-4.60 (m, 2H), 4.34-4.19 (m,1H),1.42-1.35(m,12H)。

4 4- of embodiment [(2Z, 3S) -3- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamide hydrochlorides 4

With N- [(Z, 1S) -2- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] the fluoro- 1- methyl-allyls of -3-] ammonia Base t-butyl formate 3g (0.12g, 0.31mmol) replaces compound 3f, according to the method that 3 step 6 of embodiment describes, is marked Topic compound 4 is faint yellow solid (99mg, HPLC purity:97.7%, yield 98%).

MS(ESI,pos.ion)m/z:295.5[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.32 (s, 3H), 7.81 (d, J=8.7Hz, 2H), 7.59 (s, 1H), 7.29 (d, J=81.9Hz, 1H), 7.04 (d, J=8.7Hz, 2H), 4.79 (q, J=11.3Hz, 2H), 4.03 (dd, J= 14.2,7.1Hz, 1H), 1.39 (d, J=11.1Hz, 12H)

5 4- of embodiment [(E) -2- (1- amino cyclopropyl) the fluoro- allyloxys of -3-]-N- t-butyl-benzamide hydrochloric acid Salt 5

Step 1 1- (t-butoxycarbonyl amino) cyclopropyl-carboxylic acids 5b

1- amino cyclopropyl-carboxylic acid 5a (5.0g, 49mmol) are dissolved in tetrahydrofuran (60mL) and 10% sodium hydroxide is water-soluble Di-tert-butyl dicarbonate (12mL, 52mmol) is added dropwise in the mixed solvent of liquid (49mL), reacts at room temperature 22 hours.Water is added Reaction is quenched in (100mL), is washed with ethyl acetate (100mL × 2), water phase 4mol/L salt acid for adjusting pH value to 2, has white solid Body is precipitated, and filters, filtration cakes torrefaction, and it is white solid (7.0g, yield 70%) to obtain title compound 5b.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.38(s,1H),1.37(s,9H),1.25(dd,2H),0.94 (dd,2H)。

Step 2 N- [1R- (2- diazonium ethanoyls) cyclopropyl] t-butyl carbamate 5c

1- (t-butoxycarbonyl amino) cyclopropyl-carboxylic acid 5b (3.5g, 17mmol) are dissolved in tetrahydrofuran (40mL), are dropped N,N-diisopropylethylamine (4.6mL, 28mmol) is added to 0 DEG C in temperature, and isobutyl chlorocarbonate (3.4mL, 26mmol) is added dropwise, and protects It holds 0 DEG C to react 2 hours, there is white solid precipitation.Acetonitrile (20mL) is added, the normal hexane of trimethyl silicone hydride diazomethane is added dropwise Solution (17mL, 34mmol, 2.0mol/L) is kept for 0 DEG C react 3 hours.It is warmed to room temperature reaction 16 hours.It is concentrated under reduced pressure, residual Object purifies [ethyl acetate/petroleum ether (v/v)=1/6] by silica gel column chromatography, and it is light yellow solid to obtain title compound 5c (1.4g, yield 36%).

Step 3 N- [1- (2- acetyl bromides) cyclopropyl] t-butyl carbamate 5d

N- [1R- (2- diazonium ethanoyls) cyclopropyl] t-butyl carbamate 5c (1.35g, 6.0mmol) is dissolved in acetic acid Ethyl ester (20mL), is cooled to -45 DEG C, and the acetic acid solution (1.1mL, 33wt.%) of hydrogen bromide is added dropwise, there is gas releasing.Guarantor waits for -45 DEG C reaction 1.5 hours.It is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/5] through silica gel column chromatography, obtains Title compound 5d is yellow solid (0.99g, yield 59%).¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.78(s, 1H),4.42(s,2H),1.41(s,11H),1.14(dd,2H)。

Step 4 N- [1- [2- [4- (tert-butylamine formoxyl) nitrophenoxyacetyl] cyclopropyl] t-butyl carbamate 5e

N- [1- (2- acetyl bromides) cyclopropyl] t-butyl carbamate 5d (2.0g, 7.2mmol) is dissolved in N, N- diformazans Potassium carbonate (1.5g, 11mmol), N- tertiary butyl-4-hydroxies-benzamide -1,1,3,3- tetramethyls are added in base formamide (20mL) Base urea (2.4g, 7.8mmol) reacts at room temperature 5 hours.Add water (20mL) to be quenched, extracted with ethyl acetate (50mL), organic phase is used Saturated nacl aqueous solution (10mL) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue is pure by silica gel column chromatography Change [ethyl acetate/petroleum ether (v/v)=1/3], it is yellow oil (2.1g, yield 75%) to obtain title compound 5e.

MS(ESI,pos.ion)m/z:391.20[M+Na]⁺。

Step 5 N- [1- [(E) -1- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] the fluoro- vinyl of -2-] rings third Base] t-butyl carbamate 5f

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (3.5g, 9.2mmol) is dissolved in tetrahydrofuran (20mL), be cooled to- 20 DEG C, bis- (trimethyl silicon substrate) Sodamides (6mL, 12mmol, 2mol/L) are added, after ten minutes, N- [1- [2- [4- are added dropwise in stirring (tert-butylamine formoxyl) nitrophenoxyacetyl] cyclopropyl] t-butyl carbamate 5e (2.0g, 5.1mmol) tetrahydrofuran (6mL) solution is slowly increased to room temperature reaction 2 hours.Add water (30mL) to be quenched, is extracted with ethyl acetate (60mL × 2), merging Organic phase is washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through silica gel Column chromatography purifies [ethyl acetate/petroleum ether (v/v)=1/5], and it is yellow solid (0.40g, yield to obtain title compound 5f 11%).

MS(ESI,neg.ion)m/z:417.2[M+HCOO^-]^-。

Step 6 4- [(E) -2- (1- amino cyclopropyl) the fluoro- allyloxys of -3-]-N- t-butyl-benzamides hydrochloride 5

By N- [1- [(E) -1- [[4- (tert-butylamine formoxyl) phenoxy group] methyl] the fluoro- vinyl of -2-] cyclopropyl] ammonia Base t-butyl formate 5f (50mg, 0.12mmol) is dissolved in ethyl acetate (1mL), and the ethyl acetate solution of hydrogen chloride is added (2mL, 4mol/L) reacts at room temperature 25 minutes, there is white solid precipitation.Filtering, obtain title compound 5 be white solid (35mg, HPLC purity:94.55%, yield 83%).

MS(ESI,pos.ion)m/z:307.3[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.77 (s, 3H), 7.80 (d, J=8.7Hz, 2H), 7.61 (s, 1H), 7.28 (d, J=80.3Hz, 1H), 7.03 (d, J=8.7Hz, 2H), 4.72 (s, 2H), 1.36 (s, 9H), 1.26 (t, J= 6.2Hz, 2H), 1.04 (t, J=6.3Hz, 2H).

6 4- of embodiment [(2E, 3S) -3- amino -2- (fluorine methylene) -4- methyl-pentyloxies]-N- tertiary butyls-benzoyl Amine hydrochlorate 6

Step 1 (S) -2- ((t-butoxycarbonyl) amino) -3 Methylbutanoic acid 6b

Valine 6a (12g, 0.10mol) is dissolved in tetrahydrofuran (100mL) and 10% sodium hydrate aqueous solution (100mL) In the mixed solvent, be added dropwise di-tert-butyl dicarbonate (25mL, 0.11mol), react at room temperature 2 hours.With ethyl acetate (100mL × 2) extract, water phase with 4mol/L salt acid for adjusting pH value be 2 after, with methylene chloride/methanol mixed solution (v/v=10/1, 100mL × 3) it extracts, combined organic phase is dried with anhydrous sodium sulfate.It filters, is concentrated under reduced pressure, it is nothing to obtain title compound 6b Color grease (20g, yield 92%).

Step 2 N- [(1S) -3- diazonium -1- isopropyls -2- oxygen-propyl] t-butyl carbamate 6c

(S) -2- ((t-butoxycarbonyl) amino) -3 Methylbutanoic acid 6b (20g, 92mmol) is dissolved in tetrahydrofuran (130mL) is cooled to 0 DEG C, triethylamine (17mL, 121mmol) is added, and isobutyl chlorocarbonate (15mL, 113mmol) is added dropwise, and protects Hold 0 DEG C to react 2 hours, add acetonitrile (200mL), be added dropwise trimethyl silicane diazomethane hexane solution (90mL, 180mmol, 2mol/L), it is kept for 0 DEG C react 2 hours, is warmed to room temperature reaction 2 hours.Concentration, residue purify [acetic acid by silica gel column chromatography Ethyl ester/petroleum ether (v/v)=1/7], it is colorless oil (6.5g, yield 31%) to obtain title compound 6c.

MS(ESI,pos.ion)m/z:264.1[M+Na]⁺。

Step 3 N- [the bromo- 1- isopropyls -2- oxygen-propyl of (1S) -3-] t-butyl carbamate 6d

N- [(1S) -3- diazonium -1- isopropyls -2- oxygen-propyl] t-butyl carbamate 6c (6.5g, 27mmol) is dissolved in Ethyl acetate (50mL), is cooled to -45 DEG C, and the glacial acetic acid solution (6.0mL, 5mol/L, 30mmol) of hydrobromic acid is added dropwise, keep - 45 DEG C are reacted 1.5 hours.Methyl tertiary butyl ether(MTBE) (50mL) is added, is washed with saturated sodium bicarbonate solution (100mL × 3), it is anhydrous Sodium sulphate is dried.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/ by silica gel column chromatography 10], it is colorless oil (3.0g, yield 38%) to obtain title compound 6d.MS(ESI,pos.ion)m/z:316.1[M+ Na]⁺。

Step 4 N- [(1S) -3- [4- (tertbutyloxycarbonyl) phenoxy group] -1- isopropyls -2- oxygen-propyl] carbamic acid uncle Butyl ester 6e

By N- [the bromo- 1- isopropyls -2- oxygen-propyl of (1S) -3-] t-butyl carbamate 6d (1.2g, 4.1mmol) and N- Tertiary butyl-4-hydroxy benzamide (1.3g, 6.7mmol) is dissolved in n,N-Dimethylformamide (15mL), and cesium carbonate is added (2.6g, 8.0mmol) is reacted at room temperature 2 hours.Water (10mL) is added to be quenched, is extracted with ethyl acetate (30mL × 3), anhydrous sulphur Sour sodium drying.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/3] by silica gel column chromatography, obtains It is white solid (0.70g, yield 40%) to title compound 6e.

MS(ESI,pos.ion)m/z:429.3[M+Na]⁺。

Step 5 N- [(E, 1S) -2- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 1- isopropyls-allyls of -3-] T-butyl carbamate 6f and N- [(Z, 1S) -2- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] fluoro- 1- isopropyls-allyls of -3- Base] t-butyl carbamate 6g

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (0.50g, 1.6mmol) is dissolved in tetrahydrofuran (10mL), is cooled down To -20 DEG C, bis- (trimethyl silicon substrate) Sodamides (0.85mL, 2mol/L) are added dropwise, after ten minutes, N- [(1S) -3- are added dropwise in stirring [4- (tertbutyloxycarbonyl) phenoxy group] -1- isopropyls -2- oxygen-propyl] t-butyl carbamate 6e (0.32g, 0.79mmol) Tetrahydrofuran (2mL) solution is warmed to room temperature reaction 5 hours.Ice water (10mL) is added, reaction, ethyl acetate (20mL × 3) is quenched Extraction, saturated nacl aqueous solution (30mL × 2) washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through silica gel Column chromatography purifies [ethyl acetate/petroleum ether (v/v)=1/7], and it is colorless oil (33mg, yield to obtain title compound 6f 8%) and title compound 6g is colorless oil (7mg, yield 2%).

MS(ESI,pos.ion)m/z:445.2[M+Na]⁺。

Step 6 4- [(2E, 3S) -3- amino -2- (fluorine methylene) -4- methyl-propoxies]-N- t-butyl-benzamides Hydrochloride 6

By N- [(E, 1S) -2- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 1- isopropyls-allyls of -3-] amino T-butyl formate 6f (0.10g, 0.24mmol) is dissolved in the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, and room temperature reaction 1 is small When.It is concentrated under reduced pressure, it is yellow solid (50mg, HPLC purity to obtain title compound 6:89.19%, yield 59%).

MS(ESI,pos.ion)m/z:323.3[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.31 (s, 3H), 7.81 (d, J=8.7Hz, 2H), 7.60 (s, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.00 (d, J=8.7Hz, 2H), 4.62 (d, J=2.7Hz, 2H), 2.09 (dd, J= 6.4,3.4Hz, 1H), 1.37 (s, 9H), 1.04 (d, J=6.5Hz, 3H), 0.88 (d, J=6.6Hz, 3H).

7 4- of embodiment [(2Z, 3S) -3- amino -2- (fluorine methylene) -4- methyl-pentyloxies]-N- tertiary butyls-benzoyl Amine hydrochlorate 7

With N- [(Z, 1S) -2- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 1- isopropyls-allyls of -3-] amino T-butyl formate 6g (20mg, 0.05mmol) replaces compound 6f, according to the method that 6 step 6 of embodiment describes, obtains titled Conjunction object 7 is yellow oil (15mg, HPLC purity:78.10%, yield 88%).

MS(ESI,pos.ion)m/z:323.10[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.31 (s, 3H), 7.81 (d, J=8.7Hz, 2H), 7.60 (s, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.00 (d, J=8.7Hz, 2H), 4.62 (d, J=2.7Hz, 2H), 2.09 (dd, J= 6.4,3.4Hz, 1H), 1.37 (s, 9H), 1.04 (d, J=6.5Hz, 3H), 0.88 (d, J=6.6Hz, 3H).

8 4- of embodiment [(2E, 3S) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 8

Step 1 N- [(1S) -1- methyl -2- oxygen -3- (4- sulfonamide phenyls oxygroup) propyl] t-butyl carbamate 8a

By N- [the bromo- 1- methyl -2- oxygen-propyl of (1S) -3-] t-butyl carbamate 3d (1.0g, 3.8mmol) and 4- hydroxyls Base benzsulfamide (0.65g, 3.8mmol) is dissolved in n,N-Dimethylformamide (10mL), be added potassium carbonate (0.79g, 5.6mmol), reaction 4 hours is stirred at room temperature.Water (20mL) is added, is extracted with ethyl acetate (20mL × 3), saturated sodium-chloride is molten Liquid (20mL × 2) washs, anhydrous sodium sulfate drying.Filter, be concentrated under reduced pressure, residue by silica gel column chromatography purifying [petroleum ether/ Ethyl acetate (v/v)=3/1], it is white solid (0.85g, yield 63%) to obtain title compound 8a.

MS(ESI,pos.ion)m/z:381.1[M+Na]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.84 (d, J=8.7Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 5.14-4.98 (m, 2H), 4.33 (q, J=7.1Hz, 1H), 1.48 (s, 9H), 1.35 (d, J=7.2Hz, 3H).

Step 2 N- [the fluoro- 1- methyl -2- of (E, 1S) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] carbamic acid uncle Butyl ester 8b and N- [the fluoro- 1- methyl -2- of (Z, 1S) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 8c

Under nitrogen protection, methyl fluoride (triphenyl)-phosphine tetrafluoroborate (4.1g, 11mmol) is dissolved in anhydrous tetrahydrochysene furan Mutter (30mL), is cooled to -20 DEG C, and bis- (trimethyl silicon substrate) Sodamides (8.6mL, 17mmol) are added dropwise, and stirs 10 minutes, and N- is added dropwise The tetrahydrochysene of [(1S) -1- methyl -2- oxygen -3- (4- sulfonamide phenyls oxygroup) propyl] t-butyl carbamate 8a (2.0g, 5.5mmol) Tetrahydrofuran solution (20mL) is warmed to room temperature stirring 2 hours.Ice water (30mL) is added to be quenched, is spin-dried for organic solvent, ethyl acetate (30mL × 3) extract, saturated nacl aqueous solution (20mL × 3) washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue [petrol ether/ethyl acetate (v/v)=4/1] is purified by silica gel column chromatography, it is yellow solid to obtain title compound 8b (0.72g, yield 18%) and 8c are yellow solid (0.75g, yield 19%).

Compound 8b:MS(ESI,pos.ion)m/z:397.2[M+Na]⁺；

Compound 8c:MS(ESI,pos.ion)m/z:397.2[M+Na]⁺。

Step 3 4- [(2E, 3S) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 8

By N- [the fluoro- 1- methyl -2- of (E, 1S) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 8b (0.19g, 0.50mmol) is dissolved in ethyl acetate (1mL), and the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, room temperature is added Stirring 30 minutes.It is concentrated under reduced pressure, it is off-white powder (0.14g, HPLC purity to obtain title compound 8:98.1%, yield 88%).

MS(ESI,pos.ion)m/z:275.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.32 (s, 3H), 7.77 (d, J=8.7Hz, 2H), 7.38-7.13 (m, 5H), 4.79-4.62 (m, 2H), 4.29 (m, 1H), 1.40 (d, J=6.8Hz, 3H).

9 4- of embodiment [(2Z, 3S) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 9

With N- [the fluoro- 1- methyl -2- of (Z, 1S) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 8c (0.17g, 0.46mmol) replaces compound 8b, and according to the method that 8 step 3 of embodiment describes, it is Huang to obtain title compound 9 Color grease (0.12g, HPLC purity:96.3%, yield 86%).

MS(ESI,pos.ion)m/z:275.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.30 (s, 3H), 7.77 (d, J=8.7Hz, 2H), 7.24 (dd, J =62.0,31.7Hz, 5H), 4.90-4.70 (m, 2H), 4.02 (m, J=7.0Hz, 1H), 1.39 (d, J=6.8Hz, 3H).

10 4- of embodiment [(2E, 3R) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 10

Step 1 N- [(1R) -1- methyl -2- oxygen -3- (4- sulfonamide phenyls oxygroup) propyl] t-butyl carbamate 10a

By N- [the bromo- 1- methyl -2- oxygen-propyl of (1R) -3-] t-butyl carbamate 1d (2.0g, 7.5mmol) and 4- hydroxyls Base benzsulfamide (1.2g, 6.8mmol) is dissolved in n,N-Dimethylformamide (45mL), and potassium carbonate (1.6g, 11mmol), room is added Temperature reaction 2.5 hours.Ethyl acetate (50mL) is added into reaction solution to dilute, saturated nacl aqueous solution (20mL) washing is anhydrous Sodium sulphate is dried, and is filtered, and is concentrated under reduced pressure, and residue recrystallizes [dichloromethane/petroleum ether (v/v)=1/2,15mL], is marked It is white powdery solids (1.80g, yield 67%) to inscribe compound 10a.

MS(ESI,pos.ion)m/z:381.2[M+Na]⁺。

Step 2 N- [the fluoro- 1- methyl -2- of (E, 1R) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] carbamic acid uncle Butyl ester 10b and N- [the fluoro- 1- methyl -2- of (Z, 1R) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 10c

Under nitrogen protection, methyl fluoride (triphenyl)-phosphine tetrafluoroborate (0.43g, 1.4mmol) is dissolved in anhydrous tetrahydrochysene Furans (10mL) is cooled to -20 DEG C, and double trimethyl silicon substrate Sodamides (0.86g, 4.7mmol) are added dropwise, and keeps -20 DEG C of reactions 10 After minute, N- [(1R) -1- methyl -2- oxygen -3- (4- sulfonamide phenyls oxygroup) propyl] t-butyl carbamate 10a is added dropwise The tetrahydrofuran solution (1mL) of (0.20g, 0.56mmol) is slowly increased to room temperature reaction 2 hours.Ice water (5mL) is added to be quenched, Saturated nacl aqueous solution (5mL) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, title compound is prepared in residue 10b is white solid (0.10g, yield 20%) and title compound 10c is white solid (80mg, yield 16%).

Step 3 4- [(2E, 3R) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 10

By N- [the fluoro- 1- methyl -2- of (E, 1R) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 10b (0.10g, 0.26mmol) is dissolved in the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, reacts at room temperature 1 hour.It depressurizes dense Contracting, it is white solid (50mg, HPLC purity to obtain title compound 10:95.91%, yield 60%).

MS(ESI,pos.ion)m/z:275.2[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.28(s,2H),7.77(d,2H),7.39(s,1H),7.25(s, 2H),7.20-7.12(m,3H),4.92-4.70(m,2H),4.00(d,1H),1.39(d,3H)。

11 4- of embodiment [(2Z, 3R) -3- amino -2- (fluorine methylene) butoxy] benzenesulfonamide, hydrochloride 11

With N- [the fluoro- 1- methyl -2- of (Z, 1R) -3- [(4- sulfonamide phenyls oxygroup) methyl] allyl] t-butyl carbamate 10c (80mg, 0.22mmol) replaces compound 10b, according to the method that 10 step 3 of embodiment describes, obtains title compound 11 For white solid (65g, HPLC purity:98.06%, yield 93%).

MS(ESI,pos.ion)m/z:275.2[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.41(s,3H),7.77(d,2H),7.37(s,1H),7.24(s, 2H),7.15(d,2H),4.71(s,2H),4.28(s,1H),1.99(s,1H),1.40(d,3H)。

12 4- of embodiment [(2E) -4- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamide hydrochlorides 12-1 and 4- [(2Z) -4- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamide hydrochlorides 12-2

Step 1 3- (tertbutyloxycarbonylamino) propionic acid 12b

3- alanines 12a (1.0g, 11mmol) is dissolved in tetrahydrofuran (10mL) and 10% sodium hydrate aqueous solution In (11mL), 5 DEG C are cooled to, di-tert-butyl dicarbonic acid ester (2.9mL, 12mmol) is added dropwise, is stirred at room temperature 12 hours.Water is added (40mL) is extracted with ethyl acetate (20mL × 2), after water phase 4mol/L salt acid for adjusting pH value to 2, with ethyl acetate (30mL × 3) it extracts, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, it is white solid (1.7g, yield to obtain title compound 12b 80%).

MS(ESI,pos.ion)m/z:212.2[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):3.41(s,2H),2.60(s,2H),1.46(s,9H)。

Step 2 N- (4- diazoes -3- oxygen-butyl) t-butyl carbamate 12c

Under nitrogen protection, 3- (tertbutyloxycarbonylamino) propionic acid 12b (1.7g, 9.0mmol) is dissolved in dry tetrahydrochysene furan It mutters in (17mL), is cooled to 0 DEG C, be added dropwise n,N-diisopropylethylamine (2.4mL, 14mmol), isobutyl chlorocarbonate (1.8mL, 14mmol), it is kept for 0 DEG C react 4 hours, there is white solid precipitation, acetonitrile (9mL) dissolved clarification is added, trimethyl silicone hydride weight is added dropwise N-formyl sarcolysine alkane (9mL, 18mmol) continues stirring 3 hours, is warmed to room temperature reaction 16 hours.It is spin-dried for solvent, residue passes through silicagel column Chromatographic purifying [petrol ether/ethyl acetate (v/v)=8/1], it is yellow solid (0.66g, yield to obtain title compound 12c 34%).

MS(ESI,pos.ion)m/z:236.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):5.08 (s, 1H), 3.42 (d, J=5.8Hz, 2H), 2.56 (s, 2H), 1.44(s,9H)。

Step 3 N- (the bromo- 3- oxygen-butyl of 4-) t-butyl carbamate 12d

By N- (4- diazoes -3- oxygen-butyl) t-butyl carbamate 12c (0.66g, 3.10mmol), it is dissolved in acetic acid second Ester (10mL), is cooled to -45 DEG C, and the acetic acid solution (0.6mL, 3mmol) of hydrobromic acid is added dropwise, and reacts 1 hour.Methyl- tert fourth is added It is warmed to room temperature after base ether (2mL), with saturated sodium bicarbonate adjusting pH value to 7, liquid separation, organic phase saturated nacl aqueous solution (2mL × 2) it washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [petroleum ether/acetic acid second by silica gel column chromatography Ester (v/v)=10/1], it is yellow oil (0.40g, yield 49%) to obtain title compound 12d.

¹H NMR(400MHz,CDCl₃)δ(ppm):3.91 (s, 2H), 3.43 (dd, J=11.6,5.8Hz, 2H), 2.91 (t, J=5.7Hz, 2H), 1.45 (s, 9H).

Step 4 N- [4- [4- (t-Butylcarbamoyl) phenoxy group] -3- oxygen-butyl] carbamate 12e

By N- (the bromo- 3- oxygen-butyl of 4-) t-butyl carbamate 12d (0.19g, 0.71mmol) and N- tertiary butyl -4- hydroxyls Base-benzamide (0.20g, 0.65mmol) is dissolved in n,N-Dimethylformamide (2mL), be added cesium carbonate (0.32g, 0.97mmol), it is stirred at room temperature 4 hours.Water (5mL) is added to be quenched, is extracted with ethyl acetate (10mL × 3), saturated sodium-chloride is molten Liquid (5mL × 3) washs, anhydrous sodium sulfate drying.Filter, be concentrated under reduced pressure, residue by silica gel column chromatography purifying [petroleum ether/ Ethyl acetate (v/v)=5/1], it is yellow oil (0.18g, yield 74%) to obtain title compound 12e.

MS(ESI,pos.ion)m/z:401.3[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.71 (d, J=8.7Hz, 2H), 6.90 (d, J=8.7Hz, 2H), 4.61 (s, 2H), 3.44 (d, J=5.7Hz, 2H), 2.85 (t, J=5.6Hz, 2H), 1.47 (s, 9H), 1.44 (s, 9H).

Step 5 N- [(E) -3- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- butyl -3- alkenyls of -4-] amino T-butyl formate 12f and N- [(Z) -3- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- butyl -3- alkenyls of -4-] ammonia The mixture of base t-butyl formate 12g

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (0.5g, 1.7mmol) is dissolved in anhydrous tetrahydro furan (4mL), is dropped Bis- (trimethyl silicon substrate) Sodamides (1.7mL, 3.4mmol) are added dropwise to -20 DEG C in temperature, stir 10 minutes, and N- [4- [4- (uncles are added dropwise Butylcarbamoyl) phenoxy group] -3- oxygen-butyl] and t-butyl carbamate 12e (0.32g, 0.85mmol) tetrahydrofuran Solution (1mL).It is slowly increased to room temperature reaction 5 hours.Ice water (3mL) is added to be quenched, is extracted with ethyl acetate (6mL × 3), saturation Sodium chloride solution (6mL × 3) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue is purified by silica gel column chromatography [petrol ether/ethyl acetate (v/v)=6/1], obtains the mixture of title compound 12f and title compound 12g, solid for white Body (0.15g, yield 45%).

MS(ESI,pos.ion)m/z:417.3[M+Na]⁺。

Step 6 4- [(2E) -4- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamide hydrochlorides 12-1 With 4- [(2Z) -4- amino -2- (fluorine methylene) butoxy]-N- t-butyl-benzamide hydrochlorides 12-2

By N- [(E) -3- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- butyl -3- alkenyls of -4-] carbamic acid The tert-butyl ester 12f and N- [(Z) -3- [[4- (tert-Butylcarbamoyl) phenoxy group] methyl] fluoro- butyl -3- alkenyls of -4-] amino first The mixture (0.5g, 1.27mmol) of tert-butyl acrylate 12g is dissolved in ethyl acetate (1mL), and the ethyl acetate solution of hydrogen chloride is added (3mL, 4mol/L) reacts 30 minutes.It is concentrated under reduced pressure, residue is prepared through HPLC and purified, and it is white to obtain title compound 12-1 Color solid (0.13g, HPLC purity:84.5%, yield 35%) and compound 12-2 be white solid (0.10g, HPLC purity: 96.6%, yield 27%).

Compound 12-1:

MS(ESI,pos.ion)m/z:295.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.00 (s, 3H), 7.80 (d, J=8.7Hz, 2H), 7.60 (s, 1H), 7.20 (d, J=83.6Hz, 1H), 6.99 (d, J=8.7Hz, 2H), 4.56 (d, J=2.7Hz, 2H), 2.92 (s, 2H), 2.34(s,2H),1.37(s,9H)；

Compound 12-2:

MS(ESI,pos.ion)m/z:295.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.00 (s, 3H), 7.80 (d, J=8.6Hz, 2H), 7.59 (s, 1H), 6.95 (dd, J=46.2,37.6Hz, 3H), 4.72 (s, 2H), 2.93 (s, 2H), 2.34 (s, 2H), 1.37 (s, 9H).

13 4- of embodiment [(2E) -4- amino -2- (fluorine methylene) -3- methyl-butoxies]-N- t-butyl-benzamides Hydrochloride 13

Step 1 3- (t-butoxycarbonyl amino) -2 Methylpropionic acid 13b

3- amino-2-methyl propionic acid 13a (6.9g, 67mmol) are dissolved in tetrahydrofuran (60mL) and 10% sodium hydroxide water Di-tert-butyl dicarbonate (16mL, 69mmol) is added dropwise in the in the mixed solvent of solution (60mL), reacts at room temperature 12 hours.Use acetic acid Ethyl ester (30mL × 2) extract, water phase 4mol/L salt acid for adjusting pH value to 2, with methylene chloride/methanol solution (v/v=10/1, 30mL × 2) extraction, anhydrous sodium sulfate drying.Filter, be concentrated under reduced pressure, obtain title compound 13b be colorless oil (13g, Yield 96%).

Step 2 (4- diazonium -2- methyl -3- oxygen-butyls) t-butyl carbamate 13c

3- (t-butoxycarbonyl amino) -2 Methylpropionic acid 13b (13g, 64mmol) is dissolved in tetrahydrofuran (90mL), is cooled down To 0 DEG C, triethylamine (6mL, 43mmol) is added, isobutyl chlorocarbonate (4.9mL, 37mmol) is added dropwise, keeps 0 DEG C of reaction 17 small When, acetonitrile (50mL) is added, the hexane solution (30ml, 60mmol, 2mol/L) of trimethyl silicane diazomethane is added dropwise, keeps 0 DEG C reaction 2 hours, be warmed to room temperature reaction 20 hours.It is concentrated under reduced pressure, concentrate purifies [ethyl acetate/stone by silica gel column chromatography Oily ether (v/v)=1/5], it is light yellow oil (2.7g, yield 16%) to obtain title compound 13c.

MS(ESI,pos.ion)m/z:250.1[M+Na]⁺。

Step 3 (the bromo- 2- methyl -3- oxygen-butyls of 4-) t-butyl carbamate 13d

(4- diazonium -2- methyl -3- oxygen-butyls) t-butyl carbamate 13c (2.5g, 11mmol) is dissolved in ethyl acetate (50mL), is cooled to -45 DEG C, and the glacial acetic acid solution (2.2mL, 11mmol, 5mol/L) of hydrobromic acid is added dropwise, and keeps -45 DEG C of reactions 1 Hour.Methyl tertiary butyl ether(MTBE) (50mL) is added, restores to room temperature, is washed with saturated sodium carbonate solution (30mL × 2), anhydrous slufuric acid Sodium is dried.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/5] by silica gel column chromatography, obtains Title compound 13d is colorless oil (1.0g, yield 32%).

MS(ESI,pos.ion)m/z:304.1[M+Na]⁺。

Step 4 N- [4- [4- (tertbutyloxycarbonyl) phenoxy group] -2- methyl -3- oxygen-butyl] t-butyl carbamate 13e

By (the bromo- 2- methyl -3- oxygen-butyls of 4-) t-butyl carbamate 13d (1.0g, 3.6mmol) and N- tertiary butyls -4- Hydroxybenzamide (0.80g, 4.0mmol) is dissolved in n,N-Dimethylformamide (20mL), be added potassium carbonate (0.80g, 6.0mmol), it reacts at room temperature 5 hours.Water (10mL) is added to be quenched, is extracted with ethyl acetate (60mL), organic phase washed with water (20mL) and saturated ammonium chloride solution (20mL) wash, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through silica gel Column chromatography purifies [ethyl acetate/petroleum ether (v/v)=1/3], and it is colorless oil (0.90g, production to obtain title compound 13e Rate 60%).

MS(ESI,pos.ion)m/z:415.1[M+Na]⁺。

Step 5 N- [(E) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 2- methyl of -4--butyl- 3- alkenyls] ammonia Base t-butyl formate 13f and N- [(Z) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 2- methyl of -4--butyl- 3- alkenyls] T-butyl carbamate 13g

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (1.2g, 4.0mmol) is dissolved in tetrahydrofuran (20mL), be cooled to- 20 DEG C, bis- (trimethyl silicon substrate) Sodamides (3.2mL, 2mol/L) are added dropwise, is kept for -20 DEG C react 10 minutes, N- [4- [4- is added dropwise (tertbutyloxycarbonyl) phenoxy group] -2- methyl -3- oxygen-butyl] t-butyl carbamate 13e (0.80g, 2.0mmol) tetrahydrochysene furan It mutters (2mL) solution, reacts at room temperature 2 hours.Ice water (10mL) is added, reaction is quenched, ethyl acetate (30mL × 3) extraction is saturated chlorine Change sodium solution (20mL) to wash, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [acetic acid by silica gel column chromatography Ethyl ester/petroleum ether (v/v)=1/5], then through HPLC preparative separations, it is colorless oil (12mg, production to obtain title compound 13f Rate 1%) and title compound 13g be colorless oil (90mg, yield 9%).

MS(ESI,pos.ion)m/z:409.2[M+H]⁺。

Step 6 4- [(2E) -4- amino -2- (fluorine methylene) -3- methyl-butoxies]-N- t-butyl-benzamide salt Hydrochlorate 13

By N- [(E) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 2- methyl of -4--butyl- 3- alkenyls] amino first Tert-butyl acrylate 13f (12mg, 0.03mmol) is dissolved in the ethyl acetate solution of hydrogen chloride (1mL, 4mol/L), and room temperature reaction 1 is small When.It is concentrated under reduced pressure, it is white solid (10mg, HPLC purity to obtain title compound 13:83.61%, yield 98%).

MS(ESI,pos.ion)m/z:309.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.98(s,3H),7.79(d,2H),7.59(s,1H),7.07(s, 1H), 6.99 (d, J=8.7Hz, 2H), 6.86 (s, 1H), 4.68 (dd, 2H), 3.02-2.75 (m, 2H), 2.64 (dd, 1H), 1.36(s,9H),1.10(d,3H)。

14 4- of embodiment [(2Z) -4- amino -2- (fluorine methylene) -3- methyl-butoxies]-N- t-butyl-benzamides Hydrochloride 14

With N- [(Z) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] the fluoro- 2- methyl of -4--butyl- 3- alkenyls] amino first Tert-butyl acrylate 13g (90mg, 0.03mmol) replaces compound 13f, according to the method that 13 step 6 of embodiment describes, obtains title Compound 14 is white solid (72mg, HPLC purity:97.21%, yield 95%).

MS(ESI,pos.ion)m/z:309.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.98(s,3H),7.79(d,2H),7.59(s,1H),7.07(s, 1H),6.99(d,2H),6.86(s,1H),4.68(dd,2H),3.02-2.75(m,2H),2.64(dd,1H),1.36(s,9H), 1.10(d,3H)。

15 4- of embodiment [(2Z, 3R) -4- amino -2- (fluorine methylene) -3- methoxyl groups-butoxy]-N- tertiary butyls-benzene Carboxamide hydrochloride 15-1 and 4- [(2E, 3R) -4- amino -2- (fluorine methylene) -3- methoxyl groups-butoxy]-N- tertiary butyls-benzene Carboxamide hydrochloride 15-2

Step 1 (2S) -3- (t-butoxycarbonyl amino) -2- hydroxy-propionic acids 15b

(S)-isoerine 15a (21g, 0.20mol) is dissolved in tetrahydrofuran (100mL) and 10% sodium hydrate aqueous solution Di-tert-butyl dicarbonate (50mL, 0.22mol) is added dropwise in the in the mixed solvent of (100mL), reacts at room temperature 9 hours.Water phase is used 4mol/L salt acid for adjusting pH value is extracted to 2 with methylene chloride/methanol solution (v/v=5/1,50mL × 3), and anhydrous sodium sulfate is dry It is dry.It filters, is concentrated under reduced pressure, it is colorless oil (35g, yield 85%) to obtain title compound 15b.

MS(ESI,pos.ion)m/z:228.1[M+Na]⁺。

Step 2 (2S) -3- (t-butoxycarbonyl amino) -2- hydroxy-propionic acid methyl esters 15c

(2S) -3- (t-butoxycarbonyl amino) -2- hydroxy-propionic acids 15b (35g, 0.17mol) is dissolved in dichloromethane The in the mixed solvent of (50mL) and methanol (50mL) are cooled to 0 DEG C, and the hexane solution of trimethyl silicane diazomethane is added dropwise (100mL, 0.20mol, 2mol/L) is reacted at room temperature 30 minutes.It is concentrated under reduced pressure, it is colorless oil to obtain title compound 15c (37g, yield 98%).

Step 3 (2S) -3- (t-butoxycarbonyl amino) -2- methoxy-propionic acid methyl esters 15d

(2S) -3- (t-butoxycarbonyl amino) -2- hydroxy-propionic acid methyl esters 15c (37g, 0.17mol) is dissolved in acetonitrile (200mL) is added silver oxide (45g, 0.19mol), iodomethane (30mL, 0.48mol) is added dropwise, and it is small to be warming up to 70 DEG C of reactions 13 When.It is cooled to room temperature suction filtration, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/ by silica gel column chromatography 4], it is white oil object (30g, yield 76%) to obtain title compound 15d.

MS(ESI,pos.ion)m/z:256.2[M+Na]⁺。

Step 4 (2S) -3- (t-butoxycarbonyl amino) -2- methoxy-propionic acids 15e

(2S) -3- (t-butoxycarbonyl amino) -2- methoxy-propionic acid methyl esters 15d (9.5g, 41mmol) is dissolved in tetrahydrochysene furan It mutters (100mL) and the in the mixed solvent of 10% sodium hydroxide solution (100mL), reacts at room temperature 2 hours.Water phase 4mol/L hydrochloric acid PH value is adjusted to after 2, is extracted with ethanol/methylene (v/v=1/10,100mL × 3), anhydrous sodium sulfate drying.It filters, subtracts Pressure concentration, it is white solid (8.2g, yield 92%) to obtain title compound 15e.

Step 5 N- [(2S) -4- diazonium -2- methoxyl groups -3- oxygen-butyl] t-butyl carbamate 15f

(2S) -3- (t-butoxycarbonyl amino) -2- methoxy-propionic acids 15e (2.2g, 10mmol) is dissolved in tetrahydrofuran (50mL) is added triethylamine (2mL, 14mmol), is cooled to 0 DEG C, and isobutyl chlorocarbonate (1.8mL, 14mmol) is added dropwise, and keeps 0 DEG C reaction 2 hours.Be added acetonitrile (30mL), be added dropwise trimethyl silicane diazomethane hexane solution (10mL, 2mol/L, 20mmol), it reacts at room temperature 14 hours.It is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v) by silica gel column chromatography =1/3], it is colorless oil (1.7g, yield 70%) to obtain title compound 15f.MS(ESI,pos.ion)m/z:266.1 [M+Na]⁺。

Step 6 N- [the bromo- 2- methoxyl groups -3- oxygen-butyl of (2S) -4-] t-butyl carbamate 15g

N- [(2S) -4- diazonium -2- methoxyl groups -3- oxygen-butyl] t-butyl carbamate 15f (1.3g, 5.3mmol) is molten In ethyl acetate (30mL), -45 DEG C are cooled to, the glacial acetic acid solution (1.1mL, 5.5mmol, 5mol/L) of hydrobromic acid is added dropwise, is protected - 45 DEG C are held to react 30 minutes.Methyl tertiary butyl ether(MTBE) (30mL) is added, with saturated sodium bicarbonate solution (30mL) and saturated sodium-chloride Solution (30mL) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [acetic acid second by silica gel column chromatography Ester/petroleum ether (v/v)=1/5)], it is colorless oil (1.2g, yield 76%) to obtain title compound 15g.

MS(ESI,pos.ion)m/z:320.0[M+Na]⁺。

Step 7 N- [the fluoro- 3- oxygen-butyl of (2S) -4- [4- (tert-butyl carbonyl) phenoxy group] -2-] t-butyl carbamate 15h

4- (2-hydroxybenzoyl)s tert-butylamine (3.2g, 11mmol) is dissolved in acetonitrile (50mL), be added cesium carbonate (7.0g, 22mmol), it reacts at room temperature 1 hour, tert-butyl-n-[the bromo- 2- methoxyl groups -3- oxygen-butyl of (2S) -4-] carbamate is added 15g (3.2g, 11mmol) is reacted at room temperature 3 hours.Water (10mL) is added to be quenched, ethyl acetate (30mL) extraction, anhydrous sodium sulfate is done It is dry.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/3] by silica gel column chromatography, obtains title Compound 15h is colorless oil (3.3g, yield 75%).

MS(ESI,pos.ion)m/z:431.2[M+Na]⁺。

Step 8 N- [two fluoro- butyl- 3- alkenyls of (Z, 2R) -3- [[4- (tert-butyl carbonyl) phenoxy group] methyl] -2,4-] ammonia Base t-butyl formate 15i and N- [two fluoro- butyl- 3- alkenyls of (E, 2R) -3- [[4- (tert-butyl carbonyl) phenoxy group] methyl] -2,4-] The mixture of t-butyl carbamate 15j

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (6.0g, 16mmol) is dissolved in tetrahydrofuran (100mL), be cooled to- 20 DEG C, bis- (trimethyl silicon substrate) Sodamides (10mL, 20mmol, 2mol/L) are added dropwise, is kept for -20 DEG C react 15 minutes, N- is added dropwise [the fluoro- 3- oxygen-butyl of (2S) -4- [4- (tert-butyl carbonyl) phenoxy group] -2-] t-butyl carbamate 15h (3.3g, 8.1mmol) Tetrahydrofuran (5mL) solution, react at room temperature 3 hours.Ice water (10mL) is added to be quenched, ethyl acetate (50mL) extraction, saturation Sodium chloride solution (10mL) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [second by silica gel column chromatography Acetoacetic ester/petroleum ether (v/v)=1/6], the mixture of title compound 15i and title compound 15j are obtained, is colorless oil Object (1.6g, yield 47%).

MS(ESI,pos.ion)m/z:447.3[M+Na]⁺。

Step 9 4- [(2Z, 3R) -4- amino -2- (fluorine methylene) -3- methoxyl groups-butoxy]-N- tertiary butyls-benzoyl Amine hydrochlorate 15-1 and 4- [(2E, 3R) -4- amino -2- (fluorine methylene) -3- methoxyl groups-butoxy]-N- tertiary butyls-benzoyl Amine hydrochlorate 15-2

By N- [two fluoro- butyl- 3- alkenyls of (Z, 2R) -3- [[4- (tert-butyl carbonyl) phenoxy group] methyl] -2,4-] amino first Tert-butyl acrylate 15i and N- [two fluoro- butyl- 3- alkenyls of (E, 2R) -3- [[4- (tert-butyl carbonyl) phenoxy group] methyl] -2,4-] amino The mixture (1.6g, 3.8mmol) of t-butyl formate 15j is dissolved in the ethyl acetate solution of hydrogen chloride (10mL, 4mol/L), room Temperature reaction 1 hour.It is concentrated under reduced pressure, residue is handled through HPLC preparative separations, then with Hydrochloride/ethyl acetate, obtains title Compound 15-1 is white solid (0.60g, HPLC purity:96.01%, yield 43%) and title compound 15-2 be that white is solid Body (0.20g, HPLC:99.23%, yield 14%).

Compound 15-1:

MS(ESI,pos.ion)m/z:325.3[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.12 (s, 3H), 7.79 (d, J=8.8Hz, 2H), 7.61 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 6.99 (d, J=8.8Hz, 2H), 4.52 (d, J=2.4Hz, 2H), 3.25 (s, 3H), 3.16-2.82(m,2H),1.36(s,9H)；

Compound 15-2：

MS(ESI,pos.ion)m/z:325.3[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.12 (s, 3H), 7.79 (d, J=8.7Hz, 2H), 7.61 (s, 1H), 7.17 (d, J=82.3Hz, 1H), 6.99 (d, J=8.8Hz, 2H), 4.80-4.43 (m, 2H), 4.05 (dd, J=8.8, 3.21 (s, 3H), 2.99 (d, J=4.8Hz, 2H), 1.35 (s, 9H).

16 4- of embodiment [(2Z, 3R) -4- amino -3- fluoro- 2- (fluorine methylene) butoxy]-N- t-butyl-benzamides Hydrochloride 16

Step 1 (2R)-(dibenzyl amido) -3- hydroxypropyl -ester 16b

D-Ser methyl ester hydrochloride 16a (30g, 0.19mol) is dissolved in acetonitrile (400mL), be added potassium carbonate (140g, 1.0mol), cylite (45mL, 0.37mol) is warming up at 70 DEG C and reacts 15 hours.Water (200mL) is added to be quenched, with acetic acid second Ester (200mL) extracts, and organic phase is washed with saturated nacl aqueous solution (50mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, Residue purifies [ethyl acetate/petroleum ether (v/v)=1/10] by silica gel column chromatography, and it is colourless to obtain title compound 16b Grease (40g, yield 69%).

MS(ESI,pos.ion)m/z:300.3[M+H]⁺。

Step 2 (3S)-(dibenzyl amido) -2- fluorine methyl propionates 16c

Diethylin sulfur trifluoride (20mL, 0.15mol) is dissolved in anhydrous tetrahydro furan (100mL), is cooled to 0 DEG C, drop Add the tetrahydrofuran solution (100mL) of (2R)-(dibenzyl amido) -3- hydroxy methyl propionates 16b (41g, 0.14mol), room temperature is anti- It answers 30 minutes.Reaction solution is poured into a large amount of trash ices and is quenched, and ethyl acetate (200mL) is added, is vigorously stirred lower addition sodium bicarbonate Solid, until bubble-free generates, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [acetic acid by silica gel column chromatography Ethyl ester/petroleum ether (v/v)=1/40], it is colorless oil (32g, yield 77%) to obtain title compound 16c.

MS(ESI,pos.ion)m/z:302.3[M+H]⁺。

Step 3 (3S)-amino -2- fluorine methyl propionates 16d

(3S)-(dibenzyl amido) -2- fluorine methyl propionates 16c (32g, 0.11mol) is dissolved in methanol (150mL), ice is added Acetic acid (10mL, 0.17mol), 10% palladium carbon (6.0g), replacing hydrogen react at room temperature 4 hours.Suction filtered through kieselguhr is padded, decompression is dense Contracting, it is colorless oil (12.8g, yield 99%) to obtain title compound 16d.

MS(ESI,pos.ion)m/z:122.2[M+H]⁺。

The fluoro- methyl propionate 16e of step 4 (2S) -3- (t-butoxycarbonyl amino) -2-

(3S)-amino -2- fluorine methyl propionates 16d (12.8g, 0.11mol) is dissolved in tetrahydrofuran (100mL), is added three Di-tert-butyl dicarbonate (25mL, 0.11mol) is added dropwise in ethamine (50mL, 0.36mol), reacts at room temperature 10 hours.Acetic acid second is added Ester (100mL) dilutes, and is washed with saturated ammonium chloride (50mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through Silica gel column chromatography purify [ethyl acetate/petroleum ether (v/v)=1/6], obtain title compound 16e be white crystal (16.5g, Yield 70%).

MS(ESI,pos.ion)m/z:244.2[M+Na]⁺。

The fluoro- propionic acid 16f of step 5 (2S) -3- (t-butoxycarbonyl amino) -2-

The fluoro- methyl propionate 16e of (2S) -3- (t-butoxycarbonyl amino) -2- (16.5g, 75mmol) are dissolved in tetrahydrofuran In the mixed solution of (50mL) and 10% sodium hydroxide solution (50mL), react at room temperature 2 hours.It is dilute that ethyl acetate (50mL) is added It releases, after water phase 4mol/L salt acid for adjusting pH value to 2, is extracted with methanol/dichloromethane solution (v/v=1/10,50mL × 3), Anhydrous sodium sulfate is dried.It filters, is concentrated under reduced pressure, it is white solid (11.7g, yield 75%) to obtain title compound 16f.

MS(ESI,pos.ion)m/z:230.1[M+Na]⁺。

Step 6 N- [the fluoro- 3- oxygen-butyl of (2S) -4- diazonium -2-] t-butyl carbamate 16g

The fluoro- propionic acid 16f of (2S) -3- (t-butoxycarbonyl amino) -2- (4.0g, 19mmol) are dissolved in tetrahydrofuran In (400mL), triethylamine (4mL, 28mmol) is added, is cooled to 0 DEG C, isobutyl chlorocarbonate (3.5mL, 26mmol) is added dropwise, protects 0 DEG C is held to react 2 hours.Be added acetonitrile (400mL), be added dropwise trimethyl silicane diazomethane hexane solution (20mL, 40mmol, 2mol/L), it reacts at room temperature 12 hours.It is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v) by silica gel column chromatography =1/3], it is clear crystal (3.2g, yield 72%) to obtain title compound 16g.

MS(ESI,pos.ion)m/z:254.2[M+Na]⁺。

Step 7 N- [the fluoro- 3- oxygen-butyl of the bromo- 2- of (2S) -4-] t-butyl carbamate 16h

N- [the fluoro- 3- oxygen-butyl of (2S) -4- diazonium -2-] t-butyl carbamate 16g (2.7g, 12mmol) is dissolved in second Acetoacetic ester (100mL), is cooled to -45 DEG C, and the glacial acetic acid solution (2.2mL, 11mmol, 5mol/L) of hydrobromic acid is added dropwise, and keeps -45 DEG C reaction 1 hour.Methyl tertiary butyl ether(MTBE) (50mL) is added, organic phase uses saturated sodium bicarbonate (50mL) and saturated sodium-chloride successively (50mL) is washed, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, it is colorless oil (2.5g, production to obtain title compound 16h Rate 75%).

MS(ESI,pos.ion)m/z:308.0[M+Na]⁺。

Step 8 N- [the fluoro- 3- oxygen-butyl of (2S) -4- [4- (tertbutyloxycarbonyl) phenoxy group] -2-] t-butyl carbamate 16i

N- tertiary butyl-4-hydroxies-benzamide (0.40g, 2.0mmol) is dissolved in acetonitrile (20mL), cesium carbonate is added (1.3g, 4.0mmol) is reacted at room temperature 30 minutes, N- [the fluoro- 3- oxygen-butyl of the bromo- 2- of (2S) -4-] t-butyl carbamate is added 16h (0.60g, 2.0mmol) is reacted at room temperature 1 hour.Add water (10mL) to be quenched, extracted with ethyl acetate (50mL), is saturated chlorination Ammonium salt solution (10mL) washs, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [acetic acid second by silica gel column chromatography Ester/petroleum ether (v/v)=1/3], it is colorless oil (0.20g, yield 20%) to obtain title compound 16i.

MS(ESI,pos.ion)m/z:419.3[M+Na]⁺。

Step 9 N- [two fluoro- butyl- 3- alkenyls of (Z, 2R) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] -2,4-] ammonia Base t-butyl formate 16j and N- [two fluoro- butyl- 3- alkenyls of (E, 2R) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] -2,4-] T-butyl carbamate 16k

Methyl fluoride (triphenyl)-phosphine tetrafluoroborate (0.40g, 1.0mmol) is dissolved in tetrahydrofuran (15mL), is cooled down To -20 DEG C, bis- (trimethyl silicon substrate) Sodamides (0.3mL, 0.60mmol, 2mol/L) are added dropwise, are kept for -20 DEG C react 15 minutes, Dropwise addition N- [the fluoro- 3- oxygen-butyl of (2S) -4- [4- (tertbutyloxycarbonyl) phenoxy group] -2-] t-butyl carbamate 16i (0.20g, Tetrahydrofuran solution (2mL) 0.50mmol) reacts at room temperature 3 hours.Ice water (10mL) is added to be quenched, organic phase saturation chlorine Change sodium solution (10mL) to wash, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [acetic acid by silica gel column chromatography Ethyl ester/petroleum ether (v/v)=1/6], it is colorless oil (15mg, yield 8%) and title compound to obtain title compound 16j Object 16k is colorless oil (15mg, yield 8%).

Compound 16j:

MS(ESI,pos.ion)m/z:413.3[M+H]⁺；

Compound 16k:

MS(ESI,pos.ion)m/z:435.2[M+Na]⁺。

Step 10 4- [(2Z, 3R) -4- amino -3- fluoro- 2- (fluorine methylene) butoxy]-N- t-butyl-benzamide salt Hydrochlorate 16

By N- [two fluoro- butyl- 3- alkenyls of (Z, 2R) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] -2,4-] amino first Tert-butyl acrylate 16j (0.10g, 0.24mmol) is dissolved in the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, reacts at room temperature 30 points Clock has solid precipitation.It filters, it is white solid (65mg, HPLC purity to obtain title compound 16:90.42%, yield 77%).

MS(ESI,pos.ion)m/z:313.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.33 (s, 3H), 7.79 (d, J=8.8Hz, 2H), 7.62 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 7.01 (d, J=8.8Hz, 2H), 4.64 (d, J=2.8Hz, 2H), 3.58 (dd, J= 10.2,3.0Hz,2H),1.36(s,9H)。

17 4- of embodiment [(2E, 3R) -4- amino -3- fluoro- 2- (fluorine methylene) butoxy]-N- t-butyl-benzamides Hydrochloride 17

With N- [two fluoro- butyl- 3- alkenyls of (E, 2R) -3- [[4- (tertbutyloxycarbonyl) phenoxy group] methyl] -2,4-] amino first Tert-butyl acrylate 16k (0.10g, 0.24mmol) replaces compound 16j, according to the method that 16 step 10 of embodiment describes, is marked Topic compound 17 is yellow solid (60mg, HPLC purity:87.21%, yield 71%).

MS(ESI,pos.ion)m/z:313.2[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.41 (s, 3H), 7.79 (d, J=8.4Hz, 2H), 7.60 (s, 1H), 7.46 (d, J=3.3Hz, 1H), 7.26 (d, J=3.4Hz, 1H), 7.01 (d, J=8.5Hz, 2H), 4.80 (d, J= 11.6Hz, 1H), 4.68 (d, J=10.7Hz, 1H), 3.29 (d, J=9.1Hz, 2H), 1.36 (s, 9H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-122.31(s),-182.67(s)。

Embodiment 18N- tertiary butyls -4- [(E) -3- fluoro- 2- (guanidinomethy) allyloxy] benzamide hydrochloride salt 18

Step 1 N- tertiary butyls -4- [the fluoro- 2- of (E) -3- (N, N- t-butoxycarbonyl-guanidino methyl) allyloxy] benzoyl Amine 18b

By 4- [the fluoro- 2- of (E) -3- (amino methyl)-propenyloxy group]-N- t-butyl-benzamide hydrochlorides 18a (0.50g, 1.6mmol) is dissolved with methanol (20mL), addition N, bis--tertbutyloxycarbonyls of N'--pyrazoles -1- first miaow (2.2g, 7.1mmol), diisopropylethylamine (4.0mL, 23mmol) is reacted at room temperature 24 hours.It is concentrated under reduced pressure, ethyl acetate (10mL) is molten Solution, organic phase use hydrochloric acid (0.2mol/L, 2mL), saturated sodium bicarbonate solution (5mL) and saturated nacl aqueous solution (5mL) successively Washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/ by silica gel column chromatography V)=1/10], it is colourless liquid (0.65g, yield 79%) to obtain title compound 18b.

MS(ESI,poi.ion)m/z:523.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):11.39 (s, 1H), 8.55 (s, 1H), 7.63 (d, J=8.7Hz, 2H), 6.91 (d, J=8.7Hz, 2H), 6.78 (d, J=81.8Hz, 1H), 5.91 (s, 1H), 4.48 (d, J=3.3Hz, 2H), 4.25 (d, J=2.6Hz, 2H), 1.45 (s, 9H), 1.44 (s, 9H), 1.42 (s, 9H).

Step 2 N- tertiary butyls -4- [(E) -3- fluoro- 2- (guanidinomethy) allyloxy] benzamide hydrochloride salt 18

Toward N- tertiary butyls -4- [the fluoro- 2- of (E) -3- (N, N- t-butoxycarbonyl-guanidino methyl) allyloxy] benzamide The methanol solution (5mL, 4mol/L) of hydrogen chloride is added in 20b (33mg, 0.063mmol), reacts at room temperature 4 hours.It is concentrated under reduced pressure, It is white solid (22mg, HPLC purity to obtain title compound 18:98.69%, yield 97%).

MS(ESI,poi.ion)m/z:323.3[M-Cl]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.75 (d, J=8.6Hz, 2H), 7.14 (d, J=72Hz, 1H), 7.04 (d, J=8.8Hz, 2H), 4.61 (d, J=3.1Hz, 2H), 4.12 (s, 2H), 1.46 (s, 9H).

19 N- tertiary butyls -4- of embodiment [(Z) -3- fluoro- 2- (guanidinomethy) allyloxy] benzamide hydrochloride salt 19

With N- tertiary butyls -4- [(Z) -3- fluoro- 2- (amino methyl) allyloxy] benzamide hydrochloride salt 19a (0.21g, 0.66mmol) replace 4- [the fluoro- 2- of (E) -3- (amino methyl)-propenyloxy group]-N- t-butyl-benzamide hydrochloride 18a, root The step of described in Ju embodiment 18, synthesizes compound 19, and it is white solid (0.21g, HPLC purity to obtain title compound 19: 99.13%, yield 89%).

MS(ESI,poi.ion)m/z:323.3[M-Cl]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.75 (d, J=8.7Hz, 2H), 7.11 (d, J=84Hz, 1H), 7.04 (d, J=8.7Hz, 2H), 6.90 (s, 1H), 4.81 (d, J=1.6Hz, 3H), 3.94 (d, J=2.1Hz, 2H), 1.46 (s, 9H)。

Embodiment 20 (Z) -3- (aminomethyl) -4- [4- (tert-butylamine formoxyl) phenoxy group] fluoro- but-2-ene acid second of -2- Ester hydrochloride 20

Step 1 (Z) -3- [(t-butoxycarbonyl amino) methyl]-[tertiary butyl (dimethyl) silicon substrate] fluoro- butyl- 2- of oxo -2- Olefin(e) acid ethyl ester 20b and (E) -3- [(t-butoxycarbonyl amino) methyl]-[tertiary butyl (dimethyl) silicon substrate] fluoro- butyl- 2- of oxo -2- The mixture of olefin(e) acid ethyl ester 20c

The fluoro- 2- phosphonoacetates (0.48g, 2.0mmol) of 2- are dissolved in tetrahydrofuran (5mL), are cooled to -78 DEG C, the tetrahydrofuran solution (0.83mL, 2.0mmol, 2.4mol/L) of n-BuLi is added, after stirring 30 minutes, 3- (uncles are added dropwise Butyldimethylsilyl oxygroup) -2- oxygroup propyl carbamic acid tertiary butyl ester 20a (0.30g, 0.99mmol) tetrahydrochysene furan It mutters (1.0mL) solution, after reaction 1 hour, is to slowly warm up to 0 DEG C and reacts 4.5 hours.Saturated aqueous ammonium chloride (5mL) is added It is quenched, is extracted with ethyl acetate (10mL × 2), saturated nacl aqueous solution (10mL) washing, anhydrous sodium sulfate drying.It filters, subtracts Pressure concentration, residue purify [ethyl acetate/petroleum ether (v/v)=1/20] by column chromatography, obtain title compound 20b and mark The mixture of compound 20c is inscribed, is pale yellow oil (0.18g, yield 47%).

MS(ESI,pos.ion)m/z:414.1[M+Na]⁺。

The fluoro- 4- hydroxyls of step 2 (Z) -3- [(t-butoxycarbonyl amino) methyl] -2--but-2-ene acetoacetic ester 20d

At 0 DEG C, the tetrahydrofuran solution (2.6mL, 2.6mmol, 1mol/L) of tetrabutyl ammonium fluoride is added drop-wise to (Z)- 3- [(t-butoxycarbonyl amino) methyl]-[tertiary butyl (dimethyl) silicon substrate] the fluoro- but-2-ene acetoacetic ester 20b of oxo -2- and (E) - The mixing of 3- [(t-butoxycarbonyl amino) methyl]-[tertiary butyl (dimethyl) silicon substrate] fluoro- but-2-ene acetoacetic ester 20c of oxo -2- In the tetrahydrofuran solution (10mL) of object (1.0g, 2.6mmol), kept for 0 DEG C react 50 minutes.Add water (10mL) that reaction is quenched, It is extracted with ethyl acetate (20mL), saturated nacl aqueous solution (10mL) washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, it is residual Object is stayed to purify [ethyl acetate/petroleum ether (v/v)=1/10] by column chromatography, it is faint yellow oily to obtain title compound 20d Object (0.19g, yield 27%).

MS(ESI,pos.ion)m/z:300.3[M+Na]⁺。

The fluoro- 4- mesyls oxo-but-2-ene acetoacetic esters of step 3 (Z) -3- [(t-butoxycarbonyl amino) methyl] -2- 20e

By the fluoro- 4- hydroxyls of (Z) -3- [(t-butoxycarbonyl amino) methyl] -2--but-2-ene acetoacetic ester 20d (0.17g, It 0.61mmol) is dissolved in acetone (5mL), triethylamine (0.13mL, 0.92mmol) is added, is cooled to 0 DEG C, methylsufonyl chloride is added dropwise (0.06mL, 0.80mmol) has white solid precipitation, reacts 40 minutes.It filters, obtains title compound 20e, mother liquor is directly used It is reacted in next step.

The fluoro- but-2-ene acetoacetic ester 20f of step 4 (Z) -3- (bromomethyl) -4- (t-butoxycarbonyl amino) -2-

At 0 DEG C, lithium bromide (0.27g, 3.1mmol) is added to (Z) -3- [(t-butoxycarbonyl amino) methyl] -2- In acetone (8mL) solution of fluoro- 4- mesyls oxo-but-2-ene acetoacetic ester 22e (0.22g, 0.62mmol), 15 points are reacted Clock.Add water (10mL) to be quenched, is extracted with ethyl acetate (20mL), saturated sodium-chloride (10mL) washing, anhydrous sodium sulfate drying.It takes out Filter is concentrated under reduced pressure, and residue purifies [ethyl acetate/petroleum ether (v/v)=1/10] by silica gel column chromatography, obtains title compound Object 20f is yellow oil (0.18g, yield 85%).

Step 5 (Z) -3- [(t-butoxycarbonyl amino) methyl] -4- [4- (tert-butylamine formoxyl) phenoxy group] -2- is fluoro- But-2-ene acetoacetic ester 20g

By the fluoro- but-2-ene acetoacetic ester 20f of (Z) -3- (bromomethyl) 4- (t-butoxycarbonyl amino) -2- (0.18g, 0.53mmol) be dissolved in n,N-Dimethylformamide (5mL), be added N- tertiary butyl-4-hydroxies-benzamide (0.12g, 0.62mmol) with potassium carbonate (0.11g, 0.80mmol), react 38 hours.Water (10mL) is added to be quenched, with ethyl acetate (20mL) Extraction, organic phase are washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through Silica gel column chromatography purify [ethyl acetate/petroleum ether (v/v)=1/3], obtain title compound 20g be yellow solid (0.13g, Yield 54%).

MS(ESI,neg.ion)m/z:497.2[M+HCOO^-]^-。

Step 6 (Z) -3- (aminomethyl) -4- [4- (tert-butylamine formoxyl) phenoxy group] fluoro- but-2-ene acetoacetic ester salt of -2- Hydrochlorate 20

Ethyl (Z) -3- [(t-butoxycarbonyl amino) methyl] -4- [4- (tert-butylamine formoxyl) phenoxy group] -2- is fluoro- But-2-ene ester 20g (0.13g, 0.29mmol) is dissolved in ethyl acetate (1mL), be added hydrogen chloride ethyl acetate solution (3mL, 4mol/L), it reacts at room temperature 30 minutes.It is concentrated under reduced pressure, is recrystallized with dichloromethane (2mL), it is white to obtain title compound 20 Solid (87mg, HPLC purity:96.74%, yield 78%).

MS(ESI,pos.ion)m/z:353.3[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.19 (s, 3H), 7.82 (d, J=8.6Hz, 2H), 7.61 (s, 1H), 7.07 (d, J=8.6Hz, 2H), 4.93 (s, 2H), 4.32 (dd, J=14.1,7.1Hz, 2H), 4.02 (s, 2H), 1.39 (s, 9H), 1.31 (t, J=7.1Hz, 3H).

21 4- of embodiment [[the fluoro- cyclopropyl of (1S, 2S) -1- (amino methyl) -2-] methoxyl group]-N- tertiary butyls-benzoyl Amine hydrochlorate 21

Step 1 N- [[the fluoro- 1- of (1S, 2S) -2- [[t-Butyldimethylsilyl] oxygen methyl]-cyclopropyl] methyl] amino T-butyl formate 21c and N- [[the fluoro- 1- of (1R, 2S) -2- [[t-Butyldimethylsilyl] oxygen methyl]-cyclopropyl] methyl] amino T-butyl formate 21d

By N- [(Z) -3- fluoro- 2- [t-Butyldimethylsilyl] oxygen methyl]-propylene -2-] t-butyl carbamate 21a and N- [(E) -3- fluoro- 2- [t-Butyldimethylsilyl] oxygen methyl]-propylene -2-] t-butyl carbamate 21b mixture (4.0g, 13mmol) is dissolved with dichloromethane (80mL), replaces nitrogen, is cooled to 0 DEG C, and diethyl zinc hexane solution is added dropwise (40mL,40mmol,1mol/L).Diiodomethane (7.0mL, 83mmol) is added in stirring 10 minutes, and it is small to be warming up to 0 DEG C of reaction 18 When.The aqueous ammonium chloride solution (60mL) that saturation is added is quenched, and organic phase is washed with saturated sodium-chloride (50mL), and anhydrous sodium sulfate is dry It is dry.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/petroleum ether (v/v)=1/40] by silica gel column chromatography, is marked Topic compound 21c is yellow liquid (2.2g, yield 52%) and title compound 21d is yellow liquid (0.22g, yield 5%).

Compound 21c：

¹H NMR(400MHz,CDCl₃)δ(ppm):6.60 (d, J=83.7Hz, 1H), 5.12-4.78 (m, 1H), 4.09 (d, J=4.3Hz, 2H), 3.89 (d, J=3.1Hz, 2H), 3.75-3.46 (m, 1H), 1.43 (s, 9H), 0.90 (s, 9H), 0.07(s,6H)；

Compound 21d：

¹H NMR(400MHz,CDCl₃)δ(ppm):6.64 (d, J=84.5Hz, 1H), 4.75 (d, J=6.4Hz, 2H), 4.08(overlap,3H),3.63-3.19(m,1H),1.72(s,1H),1.46(s,9H),0.89(s,9H),0.07(s,6H)。

Step 2 N- [[(1S, 2S) -2- fluoro- 1- (methylol) cyclopropyl] methyl] t-butyl carbamate 21e

By N- [[the fluoro- 1- of (1S, 2S) -2- [[t-Butyldimethylsilyl] oxygen methyl]-cyclopropyl] methyl] carbamic acid Tert-butyl ester 21c (0.12g, 0.37mmol) tetrahydrofurans (10mL) dissolve, addition tetrabutyl ammonium fluoride (0.19g, 0.74mmol), it reacts at room temperature 3 hours.Ethyl acetate (30mL) and water (20mL), organic phase saturated nacl aqueous solution is added (10mL) is washed, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue purifies [ethyl acetate/stone by silica gel column chromatography Oily ether (v/v)=1/1], it is colourless liquid (74mg, yield 91%) to obtain title compound 21e.

MS(ESI,poi.ion)m/z:242.4[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):6.60 (d, J=83.7Hz, 1H), 4.96 (br, 1H), 4.02-3.88 (m,4H),3.77(br,1H),1.85(s,1H),1.44(s,9H)。

Step 3 [(1S, 2S) -1- [(tertbutyloxycarbonylamino) methyl] the fluoro- cyclopropyl of -2-] methylmethanesulfonate ester 21f

By N- [[(1S, 2S) -2- fluoro- 1- (methylol) cyclopropyl] methyl] t-butyl carbamate 21e (0.25g, It 1.1mmol) is dissolved in tetrahydrofuran (10mL), mesyl chloride (0.20g, 1.7mmol) is added, is cooled to 0 DEG C, triethylamine is added (0.5mL, 4mmol) is reacted at room temperature 1 hour.It filters, is concentrated under reduced pressure, obtains title compound 21f, crude product is straight without further purification It connects in next step.

Step 4N- [[the fluoro- 1- of (1S, 2S) -2- (bromomethyl)-cyclopropyl] methyl] t-butyl carbamate 21g

By [(1S, 2S) -1- [(tertbutyloxycarbonylamino) methyl] the fluoro- cyclopropyl of -2-] methylmethanesulfonate ester 21f (0.33g, 1.1mmol) is dissolved in acetone (5mL), and lithium bromide (0.29g, 3.3mmol) is added.Room temperature reaction 16 hours.It depressurizes dense Contracting, obtains title compound 21g, and crude product is directly used in next step without further purification.

Step 5N- [[(1S, 2S) -1- [[4- (tert-butylformamide) phenoxy group] methyl] the fluoro- cyclopropyl of -2-] methyl] ammonia Base t-butyl formate 21h

By N- [[the fluoro- 1- of (1S, 2S) -2- (bromomethyl)-cyclopropyl] methyl] t-butyl carbamate 21g (26mg, 0.091mmol) use n,N-Dimethylformamide (2mL) dissolve, add N- tertiary butyl-4-hydroxies-benzamide (19mg, 0.10mmol) with potassium carbonate (94mg, 0.67mmol), react at room temperature 13 hours.It is diluted with ethyl acetate (30mL), organic phase is used Water (20mL) washs, saturated salt solution (20mL) washing, anhydrous sodium sulfate drying.It filters, is concentrated under reduced pressure, residue passes through silica gel Column chromatography purifies [ethyl acetate/petroleum ether (v/v)=1/6], and it is colourless liquid (20mg, yield to obtain title compound 21h 55%).

MS(ESI,poi.ion)m/z:417.20[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.67 (d, J=8.8Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 6.74 (d, J=82.1Hz, 1H), 5.87 (s, 1H), 4.79 (br, 1H), 4.46 (d, J=3.1Hz, 2H), 3.98 (d, J= 5.0Hz,2H),1.75(br,1H),1.45(s,9H),1.40(s,9H)；

¹⁹F NMR(376MHz,CDCl₃)δ(ppm):-128.52(s)。

Step 6 4- [[the fluoro- cyclopropyl of (1S, 2S) -1- (amino methyl) -2-] methoxyl group]-N- t-butyl-benzamides Hydrochloride 21

Toward N- [[(1S, 2S) -1- [[4- (tert-butylformamide) phenoxy group] methyl] the fluoro- cyclopropyl of -2-] methyl] amino The ethyl acetate solution (3mL, 4mmol/L) of t-butyl formate 21h (15mg, 0.039mmol) and hydrogen chloride.It is small to react at room temperature 1 When.Be concentrated under reduced pressure, residue wash with methyl tertiary butyl ether(MTBE) (2mL × 2), obtain title compound 21 for white solid (12mg, HPLC purity:95.4%, yield 93%).

¹H NMR(400MHz,CD₃OD)δ(ppm):7.77 (d, J=8.5Hz, 2H), 7.25 (d, J=81.1Hz, 1H), 7.07 (d, J=8.7Hz, 2H), 4.79 (s, 1H), 4.69 (d, J=3.1Hz, 2H), 3.84 (s, 2H), 3.37 (s, 1H), 1.46 (s,9H)；

¹⁹F NMR(376MHz,CD₃OD)δ(ppm):-123.10(s)。

22 4- of embodiment [[the fluoro- cyclopropyl of (1R, 2S) -1- (amino methyl) -2-] methoxyl group]-N- tertiary butyls-benzoyl Amine hydrochlorate 22

With N- [[the fluoro- 1- of (1R, 2S) -2- [[t-Butyldimethylsilyl] oxygen methyl]-cyclopropyl] methyl] carbamic acid Tert-butyl ester 21d (0.22g, 0.68mmol) replaces compound 21c, and step 2 to step 6 synthesizes compound in root Ju embodiment 21 22, it is white solid (24mg, HPLC purity to obtain title compound 22:93.2%, yield 95%).

MS(ESI,poi.ion)m/z:295.25[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.15 (br, 3H), 7.81 (d, J=8.3Hz, 2H), 7.58 (s, 1H), 6.96 (d, J=8.3Hz, 2H), 4.94 (d, J=67.3Hz, 1H), 4.11 (d, J=9.7Hz, 1H), 3.80 (d, J= 10.4Hz, 1H), 3.24 (d, J=13.7Hz, 1H), 3.01 (d, J=13.7Hz, 1H), 2.03-1.97 (m, 1H), 1.37 (s, 9H),1.13-1.02(m,1H)；

¹⁹F NMR(376MHz,DMSO-d₆)δ(ppm):-73.48(s)。

Test case

One, people recombinates SSAO/VAP-1 inhibitory activity and measures

Test purpose：Following method is to recombinate the inhibition work of SSAO/VAP-1 to people for measuring the compounds of this invention Property.

Test material：

People recombinates SSAO/VAP-1 (AP-1, human) and is purchased from Sigma, Cat.No.SRP6241；

Red Monoamine Oxidase Assay Kit are purchased from Invitrogen, Cat.No.A12214；

384 orifice plates are purchased from Corning, Cat.No.6005174；

Red Hydrogen PeroxidePeroxidase Assay Kit are purchased from Invitrogen, Cat.No.A22188。

Benzylamine hydrochloride (Benzylamine hydrochloride) is purchased from Sigma, Cat.No.B5136-25G；

DMSO (Dimethyl Sulfoxide, dimethyl sulfoxide (DMSO)) is purchased from Sigma, Cat.No.D2650-100ML；

Test method：

Test compound is dissolved in DMSO to and is carried out 4 times of dilutions, dilutes 10 concentration altogether.In 384 orifice plates, by 25 μ l People recombinates SSAO/VAP-1 (1.6 μ g/ml) and is added into each hole.The test compound of 100nl various concentrations is added to containing People recombinates in each hole of SSAO/VAP-1, is incubated at room temperature 30min.After 30min is incubated, by 25Red Monoamine Oxidase Assay Kit (contain 200 μM of Amplex Red reagent, 1U/mL HRP and 1mM benzylamine hydrochloric acid The reaction mixture of salt) it is added into corresponding aperture, room temperature, which is protected from light, is incubated 60min.After 60min, use PerkinElmer's Envision reads fluorescent value (RFU) at excitation 530-560nm and transmitting 590nm.

Using 5 Software on Drawing curves of Graph Pad Prism and calculate IC₅₀Value.The results are shown in Table 1 for it：

Table 1：Compound provided in an embodiment of the present invention recombinates people the inhibitory activity of SSAO/VAP-1

Compound number	IC50(SSAO/VAP-1)/nM
		Compound (21)	9.87

Test result is shown：The compounds of this invention recombinates SSAO/VAP-1 to people and significantly inhibits.

Two, rat fat homogenate SSAO/VAP-1 inhibitory activity measures

Test purpose：Following method is to be homogenized the suppression of SSAO/VAP-1 to rat fat for measuring the compounds of this invention System activity.

Test material：

N- piperazine-N- b sodium salts (HEPES SODIUM SALT) are purchased from AMRESCO, Cat.No.0485-500G；

EDTA (Ethylenediaminetetraacetic acid, ethylenediamine tetra-acetic acid) is purchased from Sigma, Cat.No.EDS-100G；

Sucrose (Sucrose) is purchased from Sigma, Cat.No.V900116；

PMSF (Phenylmethanesulfonyl fluoride, phenylmethylsulfonyl fluoride) is purchased from Beyotime, Cat.No.ST506；

β-phosphoglycerol disodium salt hydrate (β-Glycerophosphate disodium salt hydrate) is purchased from Sigma, Cat.No.G5422-25G；

Pargyline hydrochloride (Pargyline hydrochloride) is purchased from Sigma, Cat.No.P8013-500MG；

DMSO (Dimethyl Sulfoxide, dimethyl sulfoxide (DMSO)) is purchased from Sigma, Cat.No.D2650-100ML；

Benzylamine hydrochloride (Benzylamine hydrochloride) is purchased from Sigma, Cat.No.B5136-25G；

96 orifice plates are purchased from COSTAR, Cat.No.3631；

Red Hydrogen PeroxidePeroxidase Assay Kit are purchased from Invitrogen, Cat.No.A22188。

Test method：

Stomach fat of the operation excision from Sprague Dawley rats, is the tissue rich in SSAO/VAP-1.It is right In every gram of Abdominal Fat tissue, be added 5mL HES buffer solutions (20mM N- piperazine-N- b sodium salts, 1mM EDTA, 250mM sucrose, 1 × PMSF and 100mM β-phosphoglycerol disodium salt hydrate, pH 7.4) it is homogenized.Use Bertin The 24 multifunctional sample homogenizers of Bertin Precellys of Technologies homogenize adipose tissue 3min, at 4 DEG C, Adipose tissue homogenate is centrifuged into 10min under conditions of 20000g, takes central, clear supernatant.Supernatant is delayed with HES is dissolved in The 0.5mM pargyline hydrochloride of fliud flushing is incubated 30min at 37 DEG C.After 30min incubations, 25 μ L adipose tissue supernatants are added Enter into 96 orifice plate of standard.Test compound is dissolved in DMSO and dilutes 6 concentration.By the experiment chemical combination of 25 μ L various concentrations Object is added into each hole containing adipose tissue supernatant, and 30min is incubated at 37 DEG C.After incubation, 50 μ L are contained into 80 μM of benzyls The reaction mixture of amine hydrochlorate (contains 100 μMRed and 0.2U/mL HRP,Red Hydrogen PeroxidePeroxidase Assay Kit) it is added into corresponding aperture, it is incubated 30min at 37 DEG C.After 30min, BMG is used The PHERAstar FSX microplate reader of LABTECH reads fluorescent value (RFU) at excitation 540nm and transmitting 580nm.Use Graph 5 Software on Drawing curves of Pad Prism simultaneously calculate IC₅₀Value.

Test result is shown：The compounds of this invention significantly inhibits adipose tissue homogenate SSAO/VAP-1.

Three, the pharmacokinetics of the compounds of this invention measures

Measure purpose:Following method is the pharmacokinetics for measuring the compounds of this invention.

Test material：

Experiment reagent and test sample used：Propranolol (Propranolol (internal standard)), methanol, ammonium acetate, K₂EDTA (ethylenediamine tetra-acetic acid potassium), formic acid, acetonitrile, MTBE (methyl tertiary butyl ether(MTBE)), (12 hydroxyl of polyethylene glycol is hard by KolliphorHS15 Resin acid ester), DMSO (dimethyl sulfoxide) be commercially available；

SD rats：Male, 180-220g, 7-8 week old are purchased from Hunan Si Laike experimental animals Co., Ltd.

Test method：

1, test sample is prepared

Test solution is configured by 5%DMSO+5%KolliphorHS15+90% physiological saline, with specific reference to eachization The dissolving situation for closing object is adjusted, and compound is enable to be completely dissolved.

2, zoopery designs

3, animal dosage table

Group	Gender	Size of animal	Dosage	Administration concentration	Administered volume
						It is injected intravenously I.V.	Male	3	1mg/kg	1mg/mL	1mL/kg
Oral P.O.	Male	3	5mg/kg	1mg/mL	5mL/kg

4, solution is prepared

(1) configuration of test sample storing solution：Precision weighs appropriate test sample, is dissolved with DMSO, with dilution in acetonitrile to 1mg/ ML shakes up to obtain the final product.It is preserved under the conditions of being placed in -20 DEG C for use.

(2) internal standard substance solution is prepared：Precision draws a certain amount of 1mg/mL Propranolol storing solutions, is diluted with water to 100ng/mL。

5, sample analysis

Sample is handled using liquid-liquid extraction method, carries out chromatographic isolation, on triple quadrupole bar tandem mass spectrometer, with multiple anti- It answers ion monitoring (MRM) mode to carry out quantitative analysis, concentration calculating is carried out to result with instrument quantitative software.

6, plasma sample pre-processes

Precision draws the plasma sample of 30 μ L, and 250 μ L internal standards are added, and vortex mixed is uniform.One is extracted with the MTBE of 1mL Secondary, 13000rpm centrifuges 2min at 4 DEG C, and 800 μ L of Aspirate supernatant are volatilized in 96 hole nitrogen evaporators, 150 μ L first of residue Alcohol/water=50/50 is redissolved, vortex mixed, sample introduction, and sample size is 8 μ L.

7, the preparation of standard sample

Suitable compound stock solution is accurately drawn, dilution in acetonitrile is added, standard serial solution is made.It accurately draws above-mentioned Each 20 μ L of standard serial solution, are added 180 μ L of blank plasma, vortex mixing, be configured to be equivalent to plasma concentration be 3,5,10, 30, the plasma sample of 100,300,1000,3000,5000 and 10000ng/mL is pressed " plasma sample pretreatment " and is operated, each Concentration carries out two-sample analysis, establishes standard curve.

8, analysis method

The untested compound content after different compounds are administered in rat plasma is measured using LC/MS/MS methods.

9, data processing

Using 6.1 softwares of WinNonlin, non-compartment model method calculates pharmacokinetic parameters.

Test result shows that the compounds of this invention has excellent pharmacokinetics.

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 embodiments or example.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, changes, replacing and modification.

Claims (13)

1. a kind of compound, the alloisomerism with the structure as shown in formula (I) or the compound of structure as shown in formula (I) Body, all E/Z isomers, tautomer, nitrogen oxides, solvate, metabolite and pharmaceutically acceptable salt or preceding Medicine,

Wherein, R₁For

R is following subformula：

Ring A is C₃-C₆The heterocycle of naphthenic base or 3-8 members, wherein each C₃-C₆The heterocycle of naphthenic base and 3-8 members is optionally By 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, sulfydryl, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, trifluoromethyl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cTake Replaced for base；

Each R₂And R₃It independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl ,-C (=O) OR_a,-C (=O) R_b,-OC (=O) R_b、-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_c, wherein the C₁-C₆Alkyl optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, sulfydryl or The substituent group of amino is replaced, and condition is R₂And R₃It is asynchronously H；

Each R₄And R₆It independently is H, D, F, Cl, Br, I, C₁-C₈Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₈Naphthenic base, C₁-C₆ Alkoxy, C₁-C₆Alkylamino, C₁-C₆Alkylthio group, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members or 3-8 members, wherein institute State each C₁-C₈Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₈Naphthenic base, C₁-C₆Alkoxy, C₁-C₆Alkylamino, C₁-C₆Alkylthio group, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members and 3-8 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (= O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced, condition is, when R isWhen, R₄ It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, C is formed₃-C₈The heterocycle of naphthenic base or 3-8 members, wherein each C₃- C₈The heterocycle of naphthenic base and 3-8 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₄Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (= O)R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr- S (=O) R_cSubstituent group replaced；

R₅For-NHR₈；

R₈For H, D, C₁-C₆Alkyl or

Each R_a、R_b、R_c、R_dAnd R₉It independently is H, D or C₁-C₆Alkyl, wherein the C₁-C₆Alkyl is optionally by 1,2,3 or 4 Substituent group independently selected from D, F, Cl, Br, I, hydroxyl, cyano or amino is replaced；

N is 0,1 or 2.

2. compound according to claim 1, wherein ring A is C₃-C₆The heterocycle of naphthenic base or 5-6 members, wherein described Each C₃-C₆The heterocycle of naphthenic base and 5-6 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, Cyano, amino, sulfydryl, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₂Hydroxy alkyl, trifluoromethyl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (= O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group replaced.

3. compound according to claim 2, wherein ring A is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidines Base, pyrazolidinyl, imidazolidinyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thiomorpholine Base or piperazinyl, wherein each cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, Tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl and piperazinyl optionally by 1,2, 3 or 4 independently selected from D, F, Cl, Br, I ,=O, hydroxyl, cyano, amino, sulfydryl, methyl, ethyl, hydroxymethyl, fluoroform Base ,-C (=O) OR_a,-C (=O) R_b,-OC (=O) R_bOr-OC (=O) OR_aSubstituent group replaced；

Each R_aAnd R_bIt independently is H, D, methyl, ethyl, n-propyl or isopropyl.

4. compound according to claim 1, wherein each R₄And R₆It independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Naphthenic base, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₁-C₄Alkylthio group, C₆-C₁₀Aryl, 5- The heterocycle of 10 yuan of heteroaryl or 3-6 member, wherein each C₁-C₆Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₆Cycloalkanes Base, C₁-C₄Alkoxy, C₁-C₄Alkylamino, C₁-C₄Alkylthio group, C₆-C₁₀The heterocycle of aryl, the heteroaryl of 5-10 members and 3-6 members Optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂- C₄Alkynyl, C₁-C₂Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (=O) R_b,-OC (=O) OR_a、-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr-S (=O) R_cSubstituent group taken Generation, condition are, when R isWhen, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, C is formed₃-C₆The heterocycle of naphthenic base or 3-6 members, wherein each C₃- C₆The heterocycle of naphthenic base and 3-6 members optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₂Hydroxy alkyl, sulfydryl ,-SR_c,-C (=O) R_b,-C (=O) OR_a,-OC (= O)R_b,-OC (=O) OR_a,-NHC (=O) R_b,-NHS (=O)₂R_c,-C (=O) NHR_d,-S (=O)₂NHR_d,-S (=O)₂R_cOr- S (=O) R_cSubstituent group replaced.

5. compound according to claim 4, wherein each R₄And R₆Independently be H, D, F, Cl, Br, I, methyl, ethyl, N-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, methoxy or ethoxy, wherein each methyl, ethyl, N-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, methoxyl group and ethyoxyl are optionally by 1,2,3 or 4 independence Ground is selected from taking for D, F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl Replaced for base, condition is, when R isWhen, R₄It is not H；

Or R₄、R₆Together with the carbon atom being connected with them, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl are formed, wherein described Each cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl are optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyanogen Base, amino, methyl, ethyl, ethylene, propylene, acetylene, hydroxymethyl or sulfydryl substituent group replaced.

6. compound according to claim 1, wherein each R₂And R₃Independently be H, D, F, Cl, Br, I, methyl, ethyl, Isopropyl, n-propyl ,-C (=O) OR_a,-C (=O) R_b,-OC (=O) R_bOr-OC (=O) OR_a, wherein each methyl, second Base, isopropyl and n-propyl are optionally by 1,2,3 or 4 independently selected from D, F, Cl, Br, I, hydroxyl, cyano, sulfydryl or amino Substituent group replaced, condition is R₂And R₃It is asynchronously H；

Each R_aAnd R_bStand alone as H, D, methyl, ethyl, n-propyl or isopropyl.

7. compound according to claim 1, wherein R₈For H, D, methyl, ethyl, n-propyl, isopropyl or

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

9. compound according to any one of claims 1 to 8, wherein the compound has one of Structure：

Or its stereoisomer, all E/Z isomers, tautomer, nitrogen oxides, solvate, metabolite and pharmacy Upper acceptable salt or prodrug.

10. according to compound described in any one of claim 1-9, wherein the pharmaceutically acceptable salt be hydrochloride, Hydrobromate or mesylate.

11. a kind of pharmaceutical composition, it includes compounds as described in claim 1-10 any one and pharmaceutically acceptable Auxiliary material.

12. prepared by the pharmaceutical composition described in compound or claim 11 according to claim 1-10 any one Purposes in drug, wherein the drug is for inhibiting SSAO/VAP-1；Or for preventing or treating and SSAO/VAP-1 albumen Disease in relation to or by SSAO/VAP-1 adjustings, wherein the disease is inflammation disease, inflammation related disease or immune disease Disease.

13. purposes according to claim 12, wherein the inflammation disease, inflammation related disease or immunological diseases include Arthritis, general inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, fiber Inflammation caused by change, hepatopathy, vascular diseases, breathing problem, disease of eye, skin disease, neuroinflammatory disorder, diabetes, Ischemic disease and organ and/or tissue transplantation rejection；

Wherein, the arthritis includes that osteoarthritis, rheumatic arthritis, rheumatoid arthritis or juvenile rheumatoid close Section is scorching；The general inflammatory syndrome includes general inflammatory pyemia；The inflammatory bowel disease includes irritable bowel disorder；The fibre Dimensionization includes the fibrosis of liver fibrosis, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or radioactivity induction；It is described Hepatopathy include liver autoimmune disease, oneself immunity hepatitis, primary biliary cirrhosis, sclerosing cholangitis, itself Immunity cholangitis, alcoholic liver disease or non-alcoholic hepatopathy；The vascular diseases include atherosclerosis, chronic heart failure It exhausts or congestive heart failure；The breathing problem includes asthma, acute lung injury, acute respiratory distress syndrome, lung Inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or bronchiectasis；The disease of eye include uveitis, iritis, Inflammation or macular degeneration caused by the retinitis, autoimmune ophthalmia disease, angiogenesis and lymph generate；The skin disease Including contact dermatitis, scytitis, psoriasis or eczema；The neuroinflammatory disorder includes Parkinson's disease, Alzheimer Disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis；Inflammation caused by the diabetes includes Type I diabetes, II Patients with type Ⅰ DM, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema；It is described Ischemic disease is comprising inflammatory cell after apoplexy and its complication, myocardial infarction and its complication or apoplexy to disorganization.