CN109988106A

CN109988106A - The aminated compounds for inhibiting SSAO/VAP-1 and its application in medicine

Info

Publication number: CN109988106A
Application number: CN201811624475.2A
Authority: CN
Inventors: 黎健豪; 顾峥; 李峥; 王伟华; 覃浩雄; 王绪礼; 崔云增; 余淑娜; 桑梓福
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2019-07-09
Anticipated expiration: 2038-12-28
Also published as: CN109988106B

Abstract

The present invention relates to a kind of aminated compounds as semicarbazide-sensitive amine oxidizing ferment (SSAO) and/or vascular adhesion protein-1 (VAP-1) inhibitor and its applications in medicine, further to the pharmaceutical composition comprising the compound.Compound of the present invention or pharmaceutical composition can be used for treating inflammation and/or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, fibrosis or tissue transplantation rejection.

Description

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

Technical field

The invention belongs to field of medicaments, and in particular to a kind of to be used as semicarbazide-sensitive amine oxidizing ferment (SSAO) and/or blood The aminated compounds of pipe adhesion protein -1 (VAP-1) inhibitor, the method for preparing them, the pharmaceutical composition comprising the compound The application of object and the compound and its composition in medicine.It is more particularly related to chemical combination shown in logical formula (I) Object or its pharmaceutically acceptable salt or its stereoisomer, geometric isomer, and the pharmaceutical composition containing the compound Object, further to the compound and pharmaceutical composition in preparation for preventing, treating or mitigating inflammation disease and/or inflammation Disease related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, fibrosis or group Knit the purposes in the drug of graft rejection.

Background technique

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, It mainly include semicarbazide-sensitive amine oxidizing ferment (Semicarbazide-Sensitive Amine Oxidase, SSAO) and two Amine oxidase (Diamine oxidase, DAO)；Another kind of is the main packet containing flavine (Flavin-containg) amine oxidase 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) is mainly expressed in kidney, placenta, intestines and seminal vesicle (Elmore et al, 2002), since it only works to diamines, especially histamine, therefore also known as histamine oxidase.Monoamine oxygen Change enzyme and is divided into monoamine oxidase A (Monoamine oxidase A, MAO-A) and monoamine oxidase B (Monoamine Oxidase B, MAO-B), it is primarily present in the mitochondria of most cells, and use covalently bound flavin adenine Dinucleotides (FAD) is used as confactor.Polyamine oxidase is another FAD dependence of oxidative deamination spermine and spermidine Amine oxidase.And SSAO is different from MAO-A and MAO- in terms of its substrate, inhibitor, confactor, subcellular localization and function B, it is to belong to copper to rely on and using other substances such as trihydroxy benzene alanine quinone other than FAD The amine oxidase of (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 soluble form, is primarily present in blood circulation；One is the forms that film combines, and are distributed widely in organ and tissue In, especially in fat cell, 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 fat cell and smooth muscle cell, SSAO can promote Portugal Grape saccharide transporter 4 (Glucose transport 4, GLUT 4) is transferred to cell membrane from fat cell is intracellular, and then adjusts Glucose transport.In endothelial cell, SSAO is with vascular adhesion protein-1 (vascular adhesion protein 1, 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 encoded by the AOC3 gene for being positioned at 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, fat cell and smooth muscle cell can also be present in the form in conjunction with film Face.The clone of VAP-1 antigen 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), it is 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 infection or stimulation.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.It is white Cell is first before they are by vascular wall by combining adhesion molecule to attach to endothelium.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 fat cell.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, which mainly passes through, promotes 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.GLUT4 is a kind of important GLUT hypotype for participating in glucose transport, mainly with the shape of vesica Formula is stored in cytoplasm.Enrique-Tarancon etc. research SSAO/VAP-1 promote fat cell glucose transport and GLUT4 transfer mechanism of action in find, the SSAO/VAP-1 in rat fat cell mainly in the form of film mating type expression with Fat cell film surface, 18%-24%SSAO/VAP-1 are expressed in rat fat cell, 3T3-L1 fat cell, Rat Skeletal Contain in GLUT4 vesica in myocyte (Enrique-Tarancon G, Marti L, Morin N, et a1.J Biol Chem, 1998,273(14):8025-8032).Mercader etc. using SSAO/VAP-1 to being inhibited for a long time in FVB/n male mouse drinking water Agent semicarbazides, discovery FVB/n mouse body mass index have dropped 31%, and weight has dropped 15%, show that SSAO/VAP-1 inhibits Agent can inhibit mouse adipose to deposit, and mitigate weight, play a significant role in adjusting fat metabolism (Mereader 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 significant raising, the deamination that SSAO/VAP-1 is mediated are likely present in atherosclerosis generation and vascular disorder In the process.

In conclusion SSAO/VAP-1 inhibitor, with enzyme and adhesion activity and its has in many inflammatory disorders increments The fact that significant correlation between adjusting, allows it to the therapy target as all above-mentioned disease events, and has good Good medicinal development prospect.

Abstract of invention

Have the present invention provides one kind and preferably inhibits the active noval chemical compound of SSAO/VAP-1, such compound and its group Closing object can prepare for preventing, treating or mitigating patient's inflammation disease and/or inflammation related disease, diabetes and/or glycosuria Sick related disease, mental illness, ischemic disease, vascular diseases, fibrosis or tissue transplantation rejection drug, especially prepare For preventing, treating or mitigating the drug of patient's non-alcohol fatty liver.

On the one hand, the present invention relates to a kind of compounds, are the vertical of compound shown in compound shown in formula (I) or formula (I) Body isomers, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or Their prodrug,

Wherein,

X is-N=or-CH=；

Y is-N (R⁷)-or-N=；

L is-O- ,-S- or-NH-；

Ring Cy is 5-8 former molecular nitrogen-containing heterocycle or 5-8 former molecular nitrogenous hetero-aromatic ring；

R⁷For H, D, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl or C_3-6Naphthenic base；

Each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a,-C (=O) OR^b,-C (=O) NR^cR^d、-SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、- OR^b、R^bO-C_1-4Alkylidene, R^dR^cN-C_1-4Alkylidene, C_1-6Halogenated alkyl, C_1-6Alkyl, C_2-8Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkanes Base, 3-8 former molecular heterocycle, C_6-10Aryl or 5-10 former molecular heteroaryl, wherein the C_1-6Alkyl, C_2-8Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 former molecular heterocycle, C_6-10Aryl and 5-10 original are molecular miscellaneous Aryl is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl, Br、I、CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With with it Respectively connected carbon atom or nitrogen-atoms together, form C_3-8Carbocyclic ring, 3-8 former molecular heterocycle, C_6-10Aromatic ring or 5-10 A molecular hetero-aromatic ring of original；The wherein C_3-8Carbocyclic ring, 3-8 former molecular heterocycle, C_6-10Aromatic ring and 5-10 atom group At hetero-aromatic ring it is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F、Cl、Br、I、CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Haloalkoxy Base；

R¹For H, D, F, Cl, Br, I, C_1-6Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、- NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、-SR^eOr-S (=O) R^e, In, the C_1-6Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently be D, F, Cl, Br, I、CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

R²For F, Cl, Br, I, C_1-6Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、-SR^eOr-S (=O) R^e, wherein The C_1-6Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently be D, F, Cl, Br, I, CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

R³And R⁴It is each independently H, D, C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-8 original are molecular miscellaneous Ring group, C_6-10Aryl, 5-10 former molecular heteroaryl orThe wherein C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-8 former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-10 is each independently not It is substituted or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、 C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

Or R³、R⁴Together with the nitrogen-atoms being connected with them, 3-8 former molecular heterocycle or 5-8 atom composition are formed Hetero-aromatic ring, wherein the 3-8 former molecular heterocycle and the 5-8 molecular hetero-aromatic ring of original are unsubstituted each independently Or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

Each R^a、R^b、R^c、R^d、R^eAnd R^fIt independently is H, D, hydroxyl, C_1-6Halogenated alkyl, C_1-6Alkyl, C_1-6Alkoxy, C_2-6 Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, 3-8 former molecular heterocycle, C_6-10Aryl or 5-10 former molecular heteroaryl Base, wherein the C_1-6Halogenated alkyl, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, 3-8 atom Heterocycle, the C of composition_6-10The former molecular heteroaryl of aryl and 5-10 is unsubstituted each independently or by 1,2,3 or 4 Replaced substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

Or R^c、R^dTogether with the nitrogen-atoms being connected with them, 3-8 former molecular heterocycle or 5-8 atom composition are formed Hetero-aromatic ring, wherein the 3-8 former molecular heterocycle and the 5-8 molecular hetero-aromatic ring of original are unsubstituted each independently Or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

N is 0,1 or 2.

In other embodiments, ring Cy is that 5-6 former molecular nitrogen-containing heterocycle or 5-6 are former molecular nitrogenous Hetero-aromatic ring.

In other embodiment, ring Cy is

In other embodiments, the present invention relates to the compound of structure shown in formula (II) or its stereoisomers, several What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

Wherein, X, R¹、R²、R³、R⁴、R⁵And R⁶With definition of the present invention.

In other embodiments, the present invention relates to the compound of structure shown in formula (III) or its stereoisomers, several What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

Wherein, X, R¹、R²、R³、R⁴、R⁵、R⁶And R⁷With definition of the present invention.

In other embodiments, the present invention relates to the compound of structure shown in formula (IV) or its stereoisomers, several What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

In other embodiments, the present invention relates to the compound of structure shown in formula (V) or its stereoisomers, geometry Isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

In other embodiments, the present invention relates to the compound of structure shown in formula (VI) or its stereoisomers, several What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

In other embodiments, R⁷For H, D, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Hydroxy alkyl or C_3-6Cycloalkanes Base.

In other embodiments, each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a、-C (=O) OR^b,-C (=O) NR^cR^d、-SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、-OR^b、R^bO-C_1-2Alkylidene, R^dR^cN-C_1-2Alkylidene, C_1-4Halogenated alkyl, C_1-4Alkyl, C_2-6Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein The C_1-4Alkyl, C_2-6Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl and 5-6 original Molecular heteroaryl is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, and the substituent group independently selects From D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4It is halogenated Alkoxy；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With with it Respectively connected carbon atom or nitrogen-atoms together, form C_3-6Carbocyclic ring, 3-6 former molecular heterocycle, C_6-10Aromatic ring or 5-6 A molecular hetero-aromatic ring of original；The wherein C_3-6Carbocyclic ring, 3-6 former molecular heterocycle, C_6-10Aromatic ring and 5-6 atom group At hetero-aromatic ring it is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F、Cl、Br、I、CN、NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4Haloalkoxy Base.

In other embodiment, R⁷For H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, Hydroxymethyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.

In other embodiment, each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a、-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) OCH₂CH₂CH₃,-C (=O) OCH (CH₃)₂,-C (=O) NR^cR^d、-SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、- OR^b, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, vinyl, 1- acrylic, 2- acrylic, cyclobutenyl, pentenyl, Hexenyl, propinyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, piperazine Piperidinyl, morpholinyl, thio-morpholinyl, piperazinyl, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, Tetrazole radical, oxazolyl, oxadiazoles base, 1,3,5-triazines base, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidine radicals, wherein The methyl, ethyl, n-propyl, isopropyl, vinyl, 1- acrylic, 2- acrylic, cyclobutenyl, pentenyl, hexenyl, third Alkynyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, piperidyl, morpholine Base, thio-morpholinyl, piperazinyl, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, evil Oxazolyl, oxadiazoles base, cyanuro 1,3,5, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidine radicals each independently not by Replace or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂、 Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, methylamino, trifluoromethoxy or difluoromethoxy Base；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With with it Respectively connected carbon atom or nitrogen-atoms together, form cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, ring penta Alkenyl, cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, pyrrolin base, tetrahydropyridine Base, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, phenyl, furans Base, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazolyl, oxadiazoles base, 1, 3,5- triazine radical, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidine radicals；Wherein the cyclobutyl, cyclopenta, cyclohexyl, Cyclobutane base, cyclopentenyl, cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, dihydro pyrrole Cough up base, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazine Piperazine base, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazole Base, oxadiazoles base, cyanuro 1,3,5, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidine radicals are not taken each independently Generation or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂, first Base, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, methylamino, trifluoromethoxy or difluoro-methoxy.

In other embodiments, R¹For H, D, F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein the methyl, Ethyl, isopropyl and n-propyl are unsubstituted each independently or replaced 1,2,3 or 4 substituent group, and the substituent group is only It is on the spot D, F, Cl, Br, I, CN, NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R²For F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein the methyl, ethyl, Isopropyl and n-propyl are unsubstituted each independently or replaced 1,2,3 or 4 substituent group, and the substituent group independently is D、F、Cl、Br、I、CN、NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R³And R⁴It is each independently H, D, methyl, ethyl, n-propyl, isopropyl, C_1-4Halogen Substituted alkyl, cyclopropyl, cyclobutyl, 5-6 former molecular heterocycle, phenyl, the molecular heteroaryl of 5-6 original orThe wherein methyl, ethyl, n-propyl, isopropyl, C_1-4Halogenated alkyl, cyclopropyl, cyclobutyl, 5-6 atom The former molecular heteroaryl of the heterocycle of composition, phenyl and 5-6 is unsubstituted each independently or is replaced by 1,2,3 or 4 Replaced base, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, ethyl, n-propyl, isopropyl, three Methyl fluoride, methoxy or ethoxy；

Or R³、R⁴Together with the nitrogen-atoms being connected with them, 5-6 former molecular heterocycle or 5-6 atom composition are formed Hetero-aromatic ring, wherein the 5-6 former molecular heterocycle and the 5-6 molecular hetero-aromatic ring of original are unsubstituted each independently Or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, second Base, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, each R^a、R^b、R^c、R^d、R^eAnd R^fIt independently is H, D, hydroxyl, trifluoromethyl, difluoro first Base, methyl, ethyl, isopropyl, n-propyl, normal-butyl, tert-butyl, methoxyl group, ethyoxyl, C_3-6Naphthenic base, 5-6 atom group At heterocycle, the former molecular heteroaryl of phenyl or 5-6, wherein the methyl, ethyl, isopropyl, n-propyl, positive fourth Base, tert-butyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl are respectively independent Ground is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy；

Or R^c、R^dTogether with the nitrogen-atoms being connected with them, 5-6 former molecular heterocycle or 5-6 atom composition are formed Hetero-aromatic ring, wherein the 5-6 former molecular heterocycle and the 5-6 molecular hetero-aromatic ring of original are unsubstituted each independently Or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, second Base, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, pharmaceutically acceptable salt of the present invention is hydrochloride, hydrobromate or methylsulphur Hydrochlorate.

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

In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable load Body, excipient, adjuvant, medium or their combination.

On the other hand, the present invention relates to compounds of the present invention or pharmaceutical composition of the present invention to prepare medicine Purposes in object, wherein the drug is for inhibiting SSAO/VAP-1.

On the other hand, in medicine preparation the present invention relates to compound of the present invention or the pharmaceutical composition Purposes, wherein the drug is for preventing, treating or mitigating related with SSAO/VAP-1 albumen or adjusted by SSAO/VAP-1 Disease.

In some embodiments, of the present invention related with SSAO/VAP-1 albumen or by SSAO/VAP-1 adjusting Disease is inflammation disease and/or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease Disease, vascular diseases, fibrosis or tissue transplantation rejection.

In other embodiments, inflammation disease and/or inflammation related disease of the present invention are arthritis, whole body inflammation Property syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, hepatopathy, respiratory disease, eye Eyeball disease, skin disease or neuroinflammatory disorder.

In other embodiments, diabetes of the present invention and/or diabetes related diseases are Type I diabetes, II Patients with type Ⅰ DM, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.

In other embodiments, mental illness of the present invention is severe depression, two polar form depression or attention Power deficiency hyperactivity.

In other embodiments, ischemic disease of the present invention is apoplexy and/or its complication, myocardial infarction And/or after its complication or apoplexy inflammatory cell to disorganization.

In other embodiments, fiber of the present invention turns to liver fibrosis, cystic fibrosis, kidney fibrosis, spy The fibrosis of the pulmonary fibrosis of hair property or radioactivity induction.

In other embodiments, vascular diseases of the present invention are atherosclerosis, chronic heart failure or fill Hemorrhagic heart failure.

In other embodiment, arthritis of the present invention is osteoarthritis, rheumatic arthritis, rheumatoid pass Section inflammation or juvenile rheumatoid arthritis.

In other embodiment, general inflammatory syndrome of the present invention is general inflammatory pyemia.

In other embodiment, inflammatory bowel disease of the present invention is irritable bowel disorder.

In other embodiments, hepatopathy of the present invention is liver autoimmune disease, oneself immunity hepatitis, original Hair property biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic fatty liver Disease.

In other embodiment, non-alcohol fatty liver of the present invention is non-alcoholic pure fat The related negative source type cirrhosis of liver, nonalcoholic fatty liver disease, non-alcohol fatty liver or primary carcinoma of liver.

In other embodiment, respiratory disease of the present invention is asthma, acute lung injury, acute respiratory distress Syndrome, lung inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or bronchiectasis.

In other embodiment, disease of eye of the present invention be uveitis, iritis, the retinitis, from Inflammation caused by body immunity ophthalmia disease, angiogenesis and/or lymph generate or macular degeneration.

In other embodiment, skin disease of the present invention is contact dermatitis, scytitis, psoriasis or wet Rash.

In other embodiment, neuroinflammatory disorder of the present invention is Parkinson's disease, Alzheimer disease, blood vessel Property dull-witted, multiple sclerosis or chronic multiple sclerosis.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and other The content of aspect will more specific complete description below.

Detailed description of the invention book

The present invention provides one kind have preferably inhibit the active aminated compounds of SSAO/VAP-1, preparation method and its Application in medicine.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.Especially need to refer to Out, all similar substitutions and modifications are apparent to those skilled in the art, they be considered as include Within the scope of this 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 where contradicting (term, term application, described technology defined in including but not limited to, etc.), with Subject to the application.

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

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element and element Periodic table CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can refer to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999 and " March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.

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

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

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

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that " optionally replacing " this term can be used interchangeably with " unsubstituted or by ... replace " this term.Term " optionally ", " optional " or " optional " refer to then described in event or situation can with but may not occur, and the description packet Include wherein that there is a situation where the event or situations, and wherein there is a situation where the event or situations.In general, unless its He shows that an optional substituent group can replace at various substitutable position of that group at aspect.When given knot More than one position can be replaced one or more substituent groups selected from specific group, then substituent group can be identical in structure formula Or differently replace at various locations.Wherein the substituent group can be, but be not limited to, D, F, Cl, Br, I, CN, NO₂、 OH、NH₂,-C (=O) R^a,-C (=O) OR^b,-C (=O) NR^cR^d,-OC (=O) OR^b,-OC (=O) R^a、-SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-OR^b、-NR^cR^d、R^bO- alkylidene, R^dR^cN- alkylidene, alkyl, halogenated alkyl, hydroxy alkyl, halogenated alkoxy, alkyl amino, alkoxy, alkenyl, alkynyl, cycloalkanes Base, naphthenic base-alkylidene, carbocylic radical, carbocylic radical-alkylidene, heterocycle, heterocycle-alkylidene, aryl, aryl-alkylidene, Heteroaryl, heteroaryl-alkylene andWherein, each R^a、R^b、R^c、R^d、R^eAnd R^fWith meaning as described in the present invention.

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

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C_1-6Alkyl " refers in particular to the C being individually disclosed₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkane Base, and " 5-6 former molecular heteroaryl " refers to the heteroaryl of the molecular heteroaryl of 5 originals and 6 annular atoms composition.

In each section of present specification, connect substituent is described.When the structure clearly needs linking group, for Markush variable cited by the group is interpreted as linking group.For example, if the structure needs linking group and is directed to The Markush group definition of the variable lists " alkyl " or " aryl ", then it should be appreciated that should " alkyl " or " aryl " generation respectively The alkylidene group or arylene group of table connection.

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

Term " alkyl " or " alkyl group " refer to containing 1-20 carbon atom, the hydrocarbon of the monovalence of the linear chain or branched chain of saturation Base group.Unless otherwise stated, alkyl group contains 1-20 carbon atom；In some embodiments, alkyl group contains 1- 10 carbon atoms；In other embodiments, alkyl group contains 1-8 carbon atom；In other embodiment, alkane Base group contains 1-6 carbon atom；Also in some embodiments, alkyl group contains 1-4 carbon atom；Also in some implementations In scheme, alkyl contains 1-2 carbon atom.Alkyl containing 1-6 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), n-propyl (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), tert-butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl (- CH (CH₃)CH₂CH₂CH₃), 3- amyl (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl-1-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyl (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyl (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl (- C (CH₃)₂CH₂CH₂CH₃), 3- first Base -2- amyl (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- penta Base (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl (- 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 be optionally replaced 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.

Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In some embodiments, sub- Alkyl group contains 1-6 carbon atom；In other embodiments, alkylidene group contains 1-4 carbon atom；In other reality It applies in scheme, alkylidene group contains 1-3 carbon atom；Also in some embodiments, it is former to contain 1-2 carbon for alkylidene group Son.Such example includes methylene (- CH₂), ethylidene (including-CH₂CH₂Or-CH (CH₃) -), isopropylidene (including- CH(CH₃)CH₂Or-C (CH₃)₂) etc..Wherein, the alkylidene can be optionally by one or more described in the invention Substituent group replaced.

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 Dai Ji comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".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..

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- key 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- propinyl (- C ≡ CH-CH₃), propargyl (- CH₂C ≡ CH), 1- fourth Alkynyl, 2- butynyl, 1- pentynyl, valerylene base, 3- methyl-1-butynyl, 1- hexin base, 1- heptynyl, 1- octynyl, etc. Deng.The alkynyl group can be individually optionally replaced one or more substituent groups described in the invention.

Term " alkoxy " or " alkyl oxy " refer to that alkyl group is connected by oxygen atom with molecule rest part, i.e. alkane Base-O-, wherein alkyl group has meaning as described in the present invention.In some embodiments, alkoxy base contains 1-20 A carbon atom；In other embodiments, alkoxy base contains 1-10 carbon atom；In other embodiment, alkane Oxygroup group contains 1-8 carbon atom；In other embodiment, alkoxy base contains 1-6 carbon atom；Other In embodiment, alkoxy base contains 1-4 carbon atom, and in other embodiment, alkoxy base contains 1-3 carbon Atom.The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,-OCH₂CH₃), 1- Propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- butoxy ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t-BuO, t- butoxy,-OC (CH₃)₃), 1- amoxy (n- amoxy ,-OCH₂CH₂CH₂CH₂CH₃), 2- amoxy (- OCH (CH₃)CH₂CH₂CH₃), penta oxygen of 3- Base (- OCH (CH₂CH₃)₂), 2- methyl -2- butoxy (- OC (CH₃)₂CH₂CH₃), 3- methyl -2- butoxy (- OCH (CH₃)CH (CH₃)₂), 3- methyl-l- butoxy (- OCH₂CH₂CH(CH₃)₂), 2- methyl-l- butoxy (- OCH₂CH(CH₃)CH₂CH₃), etc. Deng wherein the alkoxy base can be independently unsubstituted or be taken by one or more substituent groups described in the invention Generation.

Term " alkylamino " or " alkyl amino " include " N- alkylamino " and " N, N- dialkylamino ", and wherein amino group divides Not independently replaced one or two alkyl group.Some of embodiments are that alkylamino is one or two C_1-6Alkyl It is connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is that alkylamino is C_1-3Lower level alkane Base amino group.Suitable alkylamino radicals can be single alkylamino or dialkylamino, and such example includes, but and unlimited In, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..

Term " halogenated alkyl " refers to the alkyl with one or more halogenic substituent.In some embodiments, Halogenated alkyl group contains 1-10 carbon atom, and in other embodiments, halogenated alkyl group contains 1-8 carbon atom, In other embodiment, halogenated alkyl group contains 1-6 carbon atom, in other embodiment, halogenated alkyl base 1-4 carbon atom is contained in group, and also in some embodiments, halogenated alkyl group contains 1-3 carbon atom.The reality of halogenated alkyl Example 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- Dichloroethyl, bis- chloropropyl of 1,2- etc..The halogenated alkyl group can optionally by Replaced the substituent group that one or more present invention describe.

Term " halogenated alkoxy " refers to alkoxy base replaced one or more halogenic substituents.In some facts In scheme, halo alkoxy group contains 1-10 carbon atom, and in other embodiments, halo alkoxy group contains 1- 8 carbon atoms, in other embodiment, halo alkoxy group contains 1-6 carbon atom, in other embodiment In, halo alkoxy group contains 1-4 carbon atom, and also in some embodiments, halo alkoxy group contains 1-3 carbon Atom.The example of halogenated alkoxy includes, but is not limited to trifluoromethoxy, difluoro-methoxy etc..The halogenated alkoxy base Replaced the substituent group that group can optionally be described by one or more present invention.

Term " carbocylic radical " can be used alone or as most of " carbocylic radical alkyl " or " carbocyclylalkoxy ", Refer to saturation or containing one or more unsaturated units, the non-aromatic carbocyclic system containing 3-14 ring carbon atom.Term " carbocyclic ring ", " carbocylic radical " or " carbocyclic ring " is used interchangeably here.In some embodiments, the number of the ring carbon atom of carbocyclic ring Amount is 3-12；In other embodiments, the quantity of the ring carbon atom of carbocyclic ring is 3-10；In some other embodiment In, the quantity of the ring carbon atom of carbocyclic ring is 3-8；In some other embodiment, the quantity of the ring carbon atom of carbocyclic ring is 3-6 It is a；In some other embodiment, the quantity of the ring carbon atom of carbocyclic ring is 5-6；In some other embodiment, carbocyclic ring The quantity of ring carbon atom be 5-8.In some other embodiment, the quantity of the ring carbon atom of carbocyclic ring is 6-8.This " carbocylic radical " include monocycle, bicyclic or polycyclic condensed, spiral shell formula or bridging carbocylic radical ring system.Bicyclic carbocyclic group includes bridging bicyclic carbocyclic Base, fused bicyclic carbocycle base and spiral shell bicyclic carbocyclic group, " condensed " bicyclic ring system include two rings for sharing 2 adjacent cyclic atoms. Bridging bicyclic radicals include two rings for sharing 3 or 4 adjacent cyclic atoms.Spirocyclic ring system shares 1 annular atom.Suitable carbocyclic ring Group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbon ring group further comprises, but never limits In, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, hexamethylene Base, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, Cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..Bridging carbocylic radical base group includes but is not limited to two rings [2.2.2] octyl, two rings [2.2.1] heptyl, two rings [3.3.1] nonyl, two rings [3.2.3] nonyl, etc..

Term " naphthenic base " refers to the rest part for having one or more tie points to be connected to molecule, saturation, contains 3- The monocyclic, bicyclic or tricyclic system of 12 ring carbon atoms.In some embodiments, naphthenic base is containing 3-10 ring carbon atom Ring system, such as C_3-10Naphthenic base；In other embodiments, naphthenic base is the ring system containing 3-8 ring carbon atom, such as C_3-8Naphthenic base；In other embodiment, naphthenic base is the ring system containing 5-8 ring carbon atom, such as C_5-8Naphthenic base；? In other embodiment, naphthenic base is the ring system containing 3-6 ring carbon atom, such as C_3-6Naphthenic base；In other embodiment party In case, naphthenic base is the ring system containing 5-6 ring carbon atom, such as C_5-6Naphthenic base；The example of group of naphthene base includes, but simultaneously Be not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, etc., and the group of naphthene base can it is independently unsubstituted or Replaced one or more substituent groups described in the invention.

Term " heterocycle " can be used alone or as most of " heterocyclylalkyl group " or " heterocyclylalkoxy ", Refer to that the saturation comprising 3-12 annular atom or part are unsaturated, nonaromatic monocyclic, bicyclic or tricyclic system, wherein extremely A few annular atom is selected from nitrogen, sulphur and oxygen atom, wherein and the heterocycle is nonaromatic, and is free of any aromatic rings, And this ring system has one or more tie points to be connected with the rest part of molecule.Term " heterocycle " includes monocycle, it is bicyclic or Polycyclic condensed, spiral shell formula or bridged heterocyclic ring system.Bicyclic heterocyclic radical includes that bridging bicyclic heterocyclic radical, fused bicyclic heterocycle base and spiral shell are double Ring heterocycle.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base.Term " heterocycle " and " heterocycle " are commutative here It uses.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.In some embodiments, heterocycle is 3-8 ring Former molecular ring system；In other embodiments, heterocycle is the ring system of 3-6 annular atom composition；Other one In a little embodiments, heterocycle is the ring system of 5-7 annular atom composition；In other embodiments, heterocycle 5-8 The ring system of a annular atom composition；In other embodiments, heterocycle is the ring system of 6-8 annular atom composition；? In some other embodiment, heterocycle is the ring system of 5-6 annular atom composition；In other embodiments, heterocycle Base is the ring system of 4 annular atoms composition；In other embodiments, heterocycle is the ring system of 5 annular atoms composition； In other embodiments, heterocycle is the ring system of 6 annular atoms composition；In other embodiments, heterocycle Base is the ring system of 7 annular atoms composition；In other embodiments, heterocycle is the ring system of 8 annular atoms composition. In some embodiments, heterocycle can for 5-10,5-8,5-6,5 or 6 annular atoms composition and contain at least one insatiable hunger With the ring system of degree.In other embodiments, heterocycle can for 5-10,5-8,5-6,5 or 6 annular atoms composition and contain There is the ring system of 1 or 2 degree of unsaturation, the ring system contains 1,2 or 3 hetero atom for being selected from N, O or S.

The example of heterocycle includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring fourth Base, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, two thiophenes Alkyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, nafoxidine base, pyrrolin Base, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base.Bridged heterocyclic base group includes, but are not limited to 2- Oxabicyclo [2.2.2] octyl, 1- azabicyclic [2.2.2] octyl, 3- azabicyclic [3.2.1] octyl, etc..Described is miscellaneous Cyclic groups can be optionally replaced one or more substituent groups described in the invention.

Term " m former molecular ", wherein m is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is m in molecule.For example, piperidyl is the heterocycle of 6 annular atoms composition, and 1,2,3,4- tetralyl It is the carbocylic radical group of 10 annular atoms composition.

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 includes 3-7 annular atom, and has one or more attachment points to be connected with the rest part of molecule.Term " aryl " can be used interchangeably with term " aromatic ring " or " aromatic rings ", if aryl may include phenyl, naphthalene and anthryl.The virtue Base group can be independently unsubstituted or replaced one or more substituent group 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 atom, bicyclic and tricyclic armaticity system, wherein at least one ring includes one or more Hetero atom, wherein each ring includes 5-7 annular atom, and wherein at least one ring system is aromatic, meanwhile, the heteroaryl Base has one or more attachment points to be connected with molecule rest part.Unless otherwise stated, the heteroaryl groups can pass through Any reasonable 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.Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments In, heteroaryl is the heteroatomic 5-14 former molecular heteroaryl that O, S and N are independently selected from comprising 1,2,3 or 4.Another In some embodiments, heteroaryl is former molecular comprising 1,2,3 or 4 heteroatomic 5-12 for being independently selected from O, S and N Heteroaryl；In other embodiments, heteroaryl is the heteroatomic 5-10 that O, S and N are independently selected from comprising 1,2,3 or 4 A molecular heteroaryl of original；In other embodiments, heteroaryl is to 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 comprising 1,2,3 or 4 independent choosing From the heteroatomic 5-7 former molecular heteroaryl of O, S and N；In other embodiments, heteroaryl is to include 1,2,3 Or 4 heteroatomic 5-6 former molecular heteroaryls for being independently selected from O, S and N；In other embodiments, heteroaryl For the molecular heteroaryl of heteroatomic 5 originals for being independently selected from O, S and N comprising 1,2,3 or 4；In other embodiments In, heteroaryl is the molecular heteroaryl of heteroatomic 6 originals that O, S and N are independently selected from comprising 1,2,3 or 4.

Other embodiment is that heteroaryl includes monocyclic groups below, but is not limited to these monocyclic groups: furans Base (such as 2- furyl, 3- furyl), imidazole radicals (such as TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals), isoxazole Base (3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl), pyrrole radicals (such as N- pyrrole Cough up base, 2- pyrrole radicals, 3- pyrrole radicals), pyridyl group (such as 2- pyridyl group, 3- pyridyl group, 4- pyridyl group), pyrimidine radicals (2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyridazinyl (such as 3- pyridazinyl), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), four Oxazolyl (such as 5H- tetrazole radical, 2H- tetrazole radical), triazolyl (such as 2- triazolyl, 5- triazolyl, 4H-1,2,4- triazolyls, 1H-1, 2,4- triazolyls, 1,2,3-triazoles base), thienyl (such as 2- thienyl, 3- thienyl), pyrazolyl (such as 2- pyrazolyl and 3- pyrrole Oxazolyl), isothiazolyl, oxadiazoles base (such as 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,3,4- Oxadiazoles base), thio biphosphole base (1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base), pyrazine Base, 1,3,5-triazines base；Also include double or three cyclic groups below, but be not limited to these groups: benzimidazolyl, benzo Furyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline Base), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), phenoxazine thiophene base, bisbenzimidazole base, hexichol And furyl, dibenzothiophene.The heteroaryl groups are optionally by one or more substituent group institutes described in the invention Replace.

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 base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-, R are substituent group of the present invention).

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.

No matter term " carbonyl " is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", table Show-(C=O)-.

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

As described in the invention, substituent R is keyed to the ring system formed on the ring at center by one and represents and replaces Base R any on coupled ring may only may replace or any reasonable position is replaced.For example, formula a is represented on A ring Any possible substituted position can optionally be replaced by n R, but any possible substituted position cannot be taken by R on B ring Generation；When A ring is twin nuclei, R can be replaced any substitutive position on any one ring of A ring；In another example Formula b represents substituent R can replace any possible substituted position on C ring, as shown in formula b-1 to b-3:

As described in the invention, one be keyed to the ring system formed on the center of ring represent this connecting key can be Any attachable position is connected with molecule rest part in ring system.For example, formula c represent ring E can by it is any on ring can The position that can be connected is connected with molecule rest part, and when ring E is twin nuclei, ring E can be by any on any one ring The position that may be connected is connected with molecule rest part；In another example the representative pyrimidine ring of formula d can pass through any possible connection Position is connected with molecule rest part, as shown in formula d-1 to d-3:

As described in the invention,Refer to double bond, can be " cis-isomer ", " trans- with the structure of key bonding Isomers " or " mixture that cis-isomer and transisomer are formed in any proportion "；Such as formula e representative formula e-1, formula e- The mixture that 2 or both (e-1 and e-2) are formed in any proportion:

As described in the invention, " arbitrary two R and the carbon atom or nitrogen-atoms that are connected with each cyclization " generation The carbon atom or nitrogen-atoms that table any two R can be connected with them form loop coil, bridged ring or condensed ring.

As described in the invention, the specific group of some on ring is indicated with letter, illustrates group representated by the letter Position be it is determining, as shown in formula f, represent the position of group J on F ring be it is fixed, i.e., group J is connected directly with phenyl ring, and F Ring " camber line " partially can be a key, an atom/group or multiple atom/groups combination, position, key saturation degree, Number of atomic type, atom etc. is uncertain.

Term " blocking group " or " PG " refer to when other functional groups react in compound, for blocking or Protect specific functional substituent group.For example, " blocking group of amino " refers to that a substituent group is connected with amino group The functionality of amino in compound is blocked or protects, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertiary fourth Oxygen carbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " is Refer to that the substituent group of hydroxyl is used to block or protect 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 to block or The functionality of carboxyl is protected, general carboxyl-protecting group includes-CH₂CH₂SO₂Ph, 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..Description general for blocking group can refer to document: T W.Greene, Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

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 used in human body.

Term " carrier " includes any solvent, decentralized medium, coating agents, surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, adhesive, excipient, dispersing agent, lubricant, sweet taste Agent, flavoring agent, colorant, or combinations thereof object, these carriers be all skilled artisan it is known (such as Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990, Described in pp.1289-1329).Except in the case of any conventional carrier is incompatible with active constituent, cover it in treatment or drug Purposes in composition.

Term " pharmaceutical composition " indicate one or more compounds described herein or its physiologically/pharmaceutically can be with The mixture of the salt or pro-drug of receiving and other chemical constituents, other components for example physiologically/can pharmaceutically receive Auxiliary materials and 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 " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining 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, going 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 " 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 Documented by 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- hydroxyl-second Sulfonate, lactobionate, laruate, lauryl sulfate, malonate, 2- naphthalene sulfonate, nicotinate, nitrate, oil Hydrochlorate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid 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.

Term " solvate " refers to that one or more solvent molecules and the compound of the present invention are formed by associated matter.Shape The solvent of solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ammonia Base ethyl alcohol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

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

The shape that any asymmetric atom (for example, carbon etc.) of the compounds of this invention can be enriched with racemic or enantiomer Formula exists, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom is at (R)- Or there is at least 50% enantiomeric excess in terms of (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, until Few 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If it would be possible, the substituent group on atom with unsaturated double-bond can be deposited in the form of cis--(Z)-or trans--(E)- ?.

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

Resulting any isomer mixture 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 separated by chromatography and/or fractional crystallization.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated 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))。

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。

The compounds of this invention and the compound comprising other of aforementioned isotopes and/or other atoms isotope 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 Replace, it is possible to provide the advantage in some treatments from bigger metabolic stability, such as increased Half-life in vivo or reduction Volume requirements.It therefore, in some cases may be preferred.

The Stereochemical definitions and convention that the present invention uses are generally according to S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, definition and convention documented by 1994.The compounds of this invention can contain asymmetric center or chiral centre, Therefore exist with different stereoisomeric forms in any ratio.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, including but It is not limited to diastereoisomer, enantiomter and atropisomer (atropisomer) and their mixture such as racemic Mixture is also contained within the scope of the invention.Many organic compounds exist with optical active forms, i.e., they have and make to put down The ability that the plane of plane polarized light rotates.When describing compound with optical activation, prefix D and L or R and S is used To indicate the absolute configuration of the molecule for the chiral centre (or multiple chiral centers) in molecule.Prefix d and l or (+) and (-) It is the symbol for the rotation of linearly polarized light caused by appointed compound, wherein (-) or l indicate that compound is left-handed.Prefix is The compound of (+) or d are dextrorotation.For given chemical structure, other than these stereoisomers each other mirror image, these Stereoisomer is identical.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of the isomers The commonly referred to as mixture of enantiomter.The 50:50 mixture of enantiomter is known as racemic mixture or racemic modification, When there is no stereoselectivity or stereospecificity in chemical reaction or method, it may occur in which the racemic mixture or disappear outside Revolve body.

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 Son or chiral agents preparation, or split using routine techniques.If this compound contains a double bond, substituent group may be E or Z Configuration；If containing disubstituted naphthenic base in this compound, the substituent group of naphthenic base may for cis or trans (cis- or Trans-) configuration.

The compounds of this invention can contain asymmetric center or chiral centre, therefore be deposited with different stereoisomer forms ?.It is expected that all stereoisomer forms of the compounds of this invention, including but not limited to diastereoisomer, mapping Isomers and atropisomer (atropisomer) and geometry (or conformation) isomers and their mixture, as racemic is mixed Object is closed, is all within the scope of the present invention.

Unless otherwise noted, the structure that the present invention describes be also represented by including this structure all isomers (e.g., enantiomer, Diastereomer atropisomer (atropisomer) and geometry (or conformation)) form；For example, R the and S structure of each asymmetric center Type, (Z) and (E) double bond isomer, and (Z) and (E) conformer.Therefore, the single spatial chemistry of the compounds of this invention Isomers and mixture of enantiomers, non-enantiomer mixture and geometric isomer (or conformer) mixture are in this hair Within the scope of bright.

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

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

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As also referring to primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..Certain In embodiment, the study subject is primate.In other other embodiments, the study subject is people.

Term " subject " used in the present invention and " patient " convertibly use.Term " subject " and " trouble Person " refers to animal (for example, the birds such as chicken, quail or turkey or mammal), " feeding especially including non-primate Newborn animal " (for example, ox, pig, horse, sheep, rabbit, cavy, rat, cat, dog and mouse) and primate are (for example, monkey, black orangutan Orangutan and the mankind), the more particularly mankind.In one embodiment, subject is non-human animal, such as domestic animal (for example, Horse, ox, pig or sheep) or pet (for example, dog, cat, cavy or rabbit).In other embodiments, " patient " refers to the mankind.

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

" inflammation disease " used in the present invention, " inflammatory disease " or " diseases associated with inflammation " refer to due to excessive or out of control Any disease that excessive inflammatory symptoms caused by inflammatory responses, host tissue damage or function of organization lose, disorder 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 and leucocyte flow into And/or Neutrophil chemotaxis has significant connection.Inflammation can produce in 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 with disclosed compound of present invention treat inflammatory disease include: with specificity system of defense react and Non-specific defense system reacts relevant disease.

" allergy " used in the present invention refers to that any symptom for generating allergy, histologic lesion or function of organization lose.Such as " arthritis disease " used in the present invention refers to any 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) Any immune response.Treatment method of the invention includes the method for treating disease relevant to inflammatory cell activation.

Term " cancer " and " cancer " refer to or describe the physiology in patient usually characterized by cell growth out of control Illness." tumour " includes one or more cancer cells.The example of cancer includes but is 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), bladder cancer, 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.

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

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

The description of the compounds of this invention

The present invention provides one kind to have the preferable inhibition active compound of SSAO/VAP-1, is used to prepare treatment inflammation Disease and/or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, The drug of fibrosis or tissue transplantation rejection is especially prepared for preventing, treating or mitigating patient's non-alcoholic fatty liver The drug of disease.Present invention provides prepare the method for these compounds, comprising the pharmaceutical composition of these compounds, and make With the method for these compounds and the drug of the above-mentioned disease of composition preparation treatment mammal, the especially mankind.With it is existing Similar compound compare, the compound of the present invention not only has a good pharmacological activity, also moves with excellent internal metabolism Mechanical property and internal pharmacodynamic properties, meanwhile, the compound of the present invention is high to the selectivity of SSAO/VAP-1.It is of the present invention Preparation method is simple for compound, and process is stablized, and is suitble to industrialized production.Therefore, compound provided by the invention For current existing similar compound, there is more excellent druggability.

Specifically:

Wherein, ring Cy, R¹、R²、R³、R⁴、R⁵、R⁶, X, Y, L and n have as described in the present invention definition.

In some embodiments,

X is-N=or-CH=；

Y is-N (R⁷)-or-N=；

L is-O- ,-S- or-NH-；

N is 0,1 or 2.

In other embodiment, ring Cy is

In other embodiment, wherein ring Cy is

In some embodiments, compound of the present invention is shown in compound shown in formula (II) or formula (II) The stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically may be used at geometric isomer The salt of receiving or their prodrug,

Wherein, X, R¹、R²、R³、R⁴、R⁵And R⁶With definition as described in the present invention.

In some embodiments, compound of the present invention, for compound shown in formula (III) or formula (III) institute Show the stereoisomer of compound, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or their prodrug,

Wherein, X, R¹、R²、R³、R⁴、R⁵、R⁶And R⁷With definition as described in the present invention.

In some embodiments, compound of the present invention is shown in compound shown in formula (IV) or formula (IV) The stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically may be used at geometric isomer The salt of receiving or their prodrug,

In some embodiments, compound of the present invention is compound or formula (V) shownization shown in formula (V) It closes the stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, can pharmaceutically connect The salt or their prodrug received,

In some embodiments, compound of the present invention is shown in compound shown in formula (VI) or formula (VI) The stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically may be used at geometric isomer The salt of receiving or their prodrug,

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With with it Respectively connected carbon atom or nitrogen-atoms together, form cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, ring penta Alkenyl, cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, pyrrolin base, tetrahydropyridine Base, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, phenyl, furans Base, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazolyl, oxadiazoles base, 1, 3,5- triazine radical, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidine radicals；Wherein the cyclobutyl, cyclopenta, cyclohexyl, Cyclobutane base, cyclopentenyl, cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, dihydro pyrrole Cough up base, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazine Piperazine base, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazole Base, oxadiazoles base, cyanuro 1,3,5, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidine radicals are not taken each independently Generation or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂, first Base, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, methylamino, trifluoromethoxy or difluoro-methoxy. In other embodiments, wherein R¹For H, D, F, Cl, Br, I, C_1-4Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (= O)R^a,-OC (=O) OR^a、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、-SR^eOr-S (=O) R^e, wherein the C_1-4Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, described to take Dai Ji stands alone as D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino Or C_1-4Halogenated alkoxy.

In other embodiments, wherein R¹For H, D, F, Cl, Br, I, C_1-4Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d、- S (=O)₂R^e、-SR^eOr-S (=O) R^e, wherein the C_1-4Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, The substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4Halogenated alkoxy.

In other embodiment, R¹For H, D, F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein the methyl, Ethyl, isopropyl and n-propyl are unsubstituted each independently or replaced 1,2,3 or 4 substituent group, and the substituent group is only It is on the spot D, F, Cl, Br, I, CN, NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R²For F, Cl, Br, I, C_1-4Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、- SR^eOr-S (=O) R^e, wherein the C_1-4Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group is only It stands as D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4Halogen For alkoxy.

In other embodiments, R²For F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein the methyl, ethyl, Isopropyl and n-propyl are unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group stand alone as D, F、Cl、Br、I、CN、NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R³And R⁴It is each independently H, D, C_1-4Alkyl, C_1-4Halogenated alkyl, C_3-6Cycloalkanes Base, 5-6 former molecular heterocycle, C_6-10Aryl, 5-6 former molecular heteroaryl orThe wherein C_1-4 Alkyl, C_1-4Halogenated alkyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, C_6-10Aryl and 5-6 original are molecular miscellaneous Aryl is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl, Br、I、CN、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy or C_1-4Alkyl amino；

Or R³、R⁴Together with the nitrogen-atoms being connected with them, 5-6 former molecular heterocycle or 5-6 atom composition are formed Hetero-aromatic ring, wherein the 5-6 former molecular heterocycle and the 5-6 molecular hetero-aromatic ring of original are unsubstituted each independently Or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy or C_1-4Alkyl amino.

Also in some embodiments, the present invention relates to the structure of one of or its stereoisomer, geometry are different Structure body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

Also in some embodiments, pharmaceutically acceptable salt of the present invention is hydrochloride, hydrobromate or first Sulfonate.

In some embodiments, pharmaceutical composition of the present invention further includes one or more other and controls Treat agent.

In other embodiments, the therapeutic agent is selected from SSAO/VAP-1 inhibitor.

In other embodiments, pharmaceutical composition of the present invention can be liquid, solid, semisolid, gel Or spray-type.

In other embodiment, pharmaceutical composition of the present invention, involved in therapeutic agent be Vapaliximab, PRX-167700, BTT-1023, ASP-8232, PXS-4728A or RTU-1096.

In some embodiments, of the present invention related with SSAO/VAP-1 albumen or adjusted by SSAO/VAP-1 Disease be inflammation disease and/or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease Disease, vascular diseases, fibrosis or tissue transplantation rejection.

In other embodiments, mental illness of the present invention is severe depression, two polar form depression or attention Power deficiency hyperactivity (Attention Deficit Hyperactivity Disorder).

In other embodiments, the purposes of compound of the present invention or pharmaceutical composition in medicine preparation, Wherein, the vascular diseases are atherosclerosis, chronic heart failure or congestive heart failure.

In other embodiment, hepatopathy of the present invention is liver autoimmune disease, oneself immunity hepatitis, original Hair property biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease or non-alcoholic fatty liver Disease.

In some embodiments, non-alcohol fatty liver of the present invention be non-alcoholic simple fatty liver, The related negative source type cirrhosis of nonalcoholic fatty liver disease, non-alcohol fatty liver or primary carcinoma of liver.

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

On the other hand, inhibit SSAO/ using compound of the present invention or pharmaceutical composition the present invention relates to a kind of The active method 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 are controlled comprising giving patient's compound of the present invention or the effective of pharmaceutical composition Treatment amount, wherein the disease is inflammation disease and/or inflammation related disease, diabetes and/or diabetes related diseases, spirit Illness, ischemic disease, vascular diseases, fibrosis or tissue transplantation rejection.Also, above compound provided by the invention or its Pharmaceutical composition can be co-administered with other therapies or therapeutic agent.Method of application can be simultaneously, sequentially or with certain time Interval carries out.

The dosage of the effects of implementing treatment, preventing or delay required compound or pharmaceutical composition 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 determines 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.

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, following the present invention relates to compound of the present invention or pharmaceutical composition to be used to prevent or treat Disease mitigates following disease symptoms or delays the development or breaking-out of following disease, wherein the disease be inflammation disease and/ Or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, fibrosis Or tissue transplantation rejection.

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 separating the compound of the present invention The intermediate of enantiomer.

Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

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

Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

It includes naturally occurring that the organic base that can obtain salt by its derivative, which includes primary amine, secondary amine and tertiary amine, substituted amine, Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

Officinal salt of the 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 free alkali form and chemistry meter by making these compounds The suitable acid reaction of amount amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both.One As, in appropriate cases, need using 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 that other is 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 is 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 forms.

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 By the atom replacement with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention include Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, 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 compound, 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 label It is especially desirable for PET or SPECT research.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 can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in 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.

The composition, preparation and administration of the compound of the present invention

The present invention relates to a kind of pharmaceutical compositions comprising the change of structure shown in compound of the present invention or embodiment Close object or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite and pharmaceutically Acceptable salt or their prodrug.Described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, tax Shape agent, adjuvant, medium or their combination, and optionally, other treatment and/or prevention ingredient.In some embodiment party Case, described pharmaceutical composition include a effective amount of at least one pharmaceutically acceptable carrier, excipient, adjuvant or medium. The amount of compound effectively can detectably inhibit the SSAO/ of biological sample or patient's body in pharmaceutical composition of the invention The activity of VAP-1.

Pharmaceutically acceptable carrier may containing will not extra-inhibitory compound bioactivity inert fraction.Pharmacy Upper acceptable carrier 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.

As described in the invention, pharmaceutical composition of the present invention or pharmaceutically acceptable composition further wrap Containing pharmaceutically acceptable carrier, adjuvant or excipient, as applied by the present invention, including it is suitable for distinctive target formulation , any solvent, diluent, liquid excipient, dispersing agent, suspending agent, surfactant, isotonic agent, thickener, emulsifier, Preservative, solid binder or lubricant, etc..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, which are disclosed, prepares pharmaceutically acceptable composition Used in various carriers and its known preparation method.In addition to the conventional carrier medium incompatible with the compound of the present invention, example Bad biological effect can such as be generated or harmful phase interaction occurs with any other component in pharmaceutically acceptable composition With other any conventional carrier mediums and their purposes are also the range of the invention considered.

The some examples that can be used as the substance of pharmaceutically acceptable carrier include but is not limited to ion-exchanger, oxidation Aluminium, aluminum stearate, lecithin, haemocyanin (such as human serum albumins), buffer substance (such as Tween 80, phosphate, sweet ammonia Acid, sorbic acid or potassium sorbate), the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (such as sulfuric acid essence Albumen, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic acid Ester, wax, polyethylene-polypropylene oxide-block copolymer, methylcellulose, hydroxypropyl methyl cellulose, lanolin, carbohydrate (example Such as lactose, dextrose and saccharose), starch (such as cornstarch and potato starch), cellulose and its derivates (such as carboxylic first Base sodium cellulosate, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gel, talcum, excipient (such as cocoa Oil and suppository wax), oily (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), second two Alcohol (such as propylene glycol or polyethylene glycol), ester (such as ethyl oleate and ethyl laurate), agar, buffer (such as hydroxide Magnesium and aluminium hydroxide), alginic acid, apirogen water, isotonic saline solution, Ringer's solution (Ringer'ssolution), ethyl alcohol and phosphorus Phthalate buffer and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and according to prepare people Judgement colorant, antitack agent, coating agent, sweetener and fumet, preservative and antioxidant also be present in composition.

The compound of the present invention or composition can be administered by any suitable method, can be according to by the serious journey for controlling infection Degree is oral, rectum, parenteral, in brain pond, in intravaginal, peritonaeum, part (as passed through pulvis, ointment or drops), oral cavity work Compound described above and pharmaceutically acceptable composition are applied to people or other animals for mouth or nasal spray etc..

For oral liquid dosage form include but is 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), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan aliphatic ester and its mixture.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, monoglycceride or glycerol including synthesis Diester.In addition, fatty acid, such as octadecenic acid, it is used to prepare injection.

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

For the effect for extending compound or composition of the present invention, it is often desirable to slow down compound by subcutaneously or intramuscularly infusing 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.Can also 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 the suppository of cupu oil, polyethylene glycol or suppository wax preparation, 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 excipient or carrier such as sodium citrate or Dicalcium Phosphate and/or a) filler Or swelling 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 (,) glycerol, d) disintegrating agent, such as fine jade Rouge -- agar, calcium carbonate, potato or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as Paraffin, f) absorbsion accelerator, for example (,) quaternary ammonium compound, g) wetting agent, for example (,) cetanol and glycerin monostearate, h) it absorbs Agent, such as kaolin and bentonite and i) lubricant, such as talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sulfuric acid Lauryl sodium and its mixture.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 optionally containing 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 a 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 also be 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.Generally, 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 optionally can containing opacifiers and also have the property of composition, so that optionally with party in delay Formula only discharge active component, or preferably, in certain a 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 dispersing compound in polymer substrate or gel Rate.

Can also oral, parenteral, applied through part, rectum, nose, oral cavity, vagina or by sucking spray by catheter indwelling With composition of the present invention.As terminology used in the present invention " parenteral " include but is not limited to subcutaneous, intravenous, muscle, It is intra-articular, synovial membrane is intracavitary, breastbone is interior, 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, fatty 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 dispersing agent, such as carboxymethyl cellulose or can pharmaceutically connect preparing Common similar dispersing agent in the dosage form (including emulsion with 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 is 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 in conjunction 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 solid at room temperature, but under rectal temperature For liquid, therefore will melt in rectum to discharge drug.This substance includes but is 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 as each of these regions or organ system 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.Applying the carrier of the compound of the present invention suitable for part drop includes but is not limited to mineral oil, vaseline 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 is not limited to that mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, spermaceti are hard Lipidol, 2- octyl dodecanol, benzyl alcohol and water.

For ophthalmology use, 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.

The spray that can also be gasified by nose or sucking application pharmaceutical composition.According to skill well-known 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 dispersing agent are prepared into the solution in salt water.

The compound for being used for method of the invention can be configured to unit dosage forms.Term " unit dosage forms " refer to be suitable as by The discrete unit of the physics of the unit dose of curer, per unit contain the active matter for being computed the predetermined amount for generating expected effect Matter, optionally in conjunction 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 composition

Compound provided by the invention or pharmaceutical composition can be used for preparing for inhibiting the active drug of SSAO/VAP-1.

Compound provided by the invention or pharmaceutical composition can be used for preventing, treating or mitigating to be had with SSAO/VAP-1 albumen The disease closed or adjusted by SSAO/VAP-1, wherein the disease is inflammation disease and/or inflammation related disease, diabetes And/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, fibrosis or tissue transplantation rejection.

Compound provided by the invention or pharmaceutical composition, which can be used for preparing, to be prevented, treated or mitigates and SSAO/VAP-1 egg The drug of Bai Youguan or the disease by SSAO/VAP-1 adjusting, wherein the disease is inflammation disease and/or inflammation correlation disease Disease, diabetes and/or diabetes related diseases, mental illness, ischemic disease, vascular diseases, fibrosis or tissue transplantation row Reprimand.

The present invention provide it is a kind of for treat, prevent or mitigate with SSAO/VAP-1 albumen in relation to or by SSAO/VAP-1 The method of the disease of adjusting, the method includes giving the above compound or its medicine of the bacterium that treatment needs Compositions.The disease is inflammation disease and/or inflammation related disease, diabetes and/or diabetes related diseases, mental disease Disease, ischemic disease, vascular diseases, fibrosis or tissue transplantation rejection.Also, above compound provided by the invention or its medicine Compositions can be co-administered with other therapies or therapeutic agent.Method of application can be simultaneously, sequentially or between certain time Every progress.

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

" effective quantity " of the compound of the present invention or pharmaceutically acceptable pharmaceutical composition, " effective therapeutic dose " " have Effect dosage " refers to processing or mitigates the effective quantity that one or more present invention are previously mentioned the severity of illness.Chemical combination of the 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 Closing 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, administration mode etc..The compound of the present invention or pharmaceutical composition can be with one or more other therapeutic agents It is administered in combination, as discussed in the present invention.

General synthesis and detection method

For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.

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

In the present specification, in the compound number of embodiment, the compound number in claims or specification The compound number of other positions is independently of each other, to be independent of each other.Wherein, the compound number institute in activity test embodiment Corresponding compound is the compound for preparing the same compound number in embodiment.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing 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 shift (δ) is provided with the unit of hundred a ten thousandths (ppm).¹H-NMR、¹³C-NMR、¹⁹The survey of F-NMR It surely is with 600 nuclear magnetic resoance spectrum of Bruker Ultrashield-400 nuclear magnetic resonance spectrometer and Bruker Avance III HD Instrument, measurement solvent are deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄) or deuterated dimethyl sulfoxide (DMSO- d₆).Use TMS (0ppm) or chloroform (7.25ppm) as reference standard.When there is multiplet, following contracting will be used It writes: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), and dd (doublet of doublets, double doublet), dt (doublet of triplets, double three Weight peak), td (triplet of doublets, three doublets), brs (broadened singlet, width unimodal).Coupling constant J, unit are indicated with hertz (Hz).

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

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

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

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

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

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

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

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

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

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

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

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

HPLC refers to high performance liquid chromatography；

The measurement of HPLC using 1200 high pressure liquid chromatograph of Agilent (Zorbax Eclipse Plus C18 150 × 4.6mm chromatographic column)；

HPLC test condition: runing time: 15min-20min column temperature: 35 DEG C of PDA:210nm, 254nm

Mobile phase: A phase: pH2.5 potassium dihydrogen phosphate B phase: 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 system of analysis in biological test test includes the serial vacuum degassing furnace of Agilent 1200, and two First syringe pump, orifice plate automatic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level four bars in the source (ESI) Mass spectrograph.Quantitative analysis carries out under MRM mode, MRM conversion parameter as shown in tableb:

Table B

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

Table C

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

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

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

DMSO-d₆: deuterated dimethyl sulfoxide；CDCl₃: deuterated chloroform； CD₃OD: deuterated methanol；

Ac: acetyl group；Bn: benzyl；Et: ethyl；

Me: methyl；Ms: mesyl；Boc: tertbutyloxycarbonyl；

PMB: to methoxy-benzyl；%wt, mass%: weight percent；ML, ml: milliliter；

Mol/L: mole every liter；Mol: mole；Mmol: mM；

G: gram；H: hour； H₂: hydrogen；

Min: minute； N₂: nitrogen； NH₃: ammonia；

MPa: megapascal.

General synthetic method

The typical synthesis step of disclosed compound of present invention is prepared as shown in following synthetic schemes 1.Unless otherwise stated, Each ring Cy, R⁵、R⁶, X, Y and n have as described in the present invention definition, PG is amino protecting group, and LG is leaving group.

Synthetic schemes 1:

Compound with the structure as shown in general formula (I-A) can be described by synthetic schemes 1 synthetic method system Standby to obtain, specific steps can refer to embodiment.Compound (I-a) under alkaline condition (such as potassium carbonate), is sent out with compound (I-b) Raw necleophilic reaction, obtains compound (I-c)；Compound (I-c) sloughs amino protecting group PG, obtains mesh shown in general formula (I-A) Mark compound.In some embodiments, target compound shown in formula (I-A) and acid form acid-addition salts to improve chemical stabilization Property.The example of acid-addition salts includes but is not limited to hydrochloride, hydrobromate and mesylate.

Synthetic schemes 2:

Compound with the structure as shown in general formula (I-B) can be described by synthetic schemes 2 synthetic method system Standby to obtain, specific steps can refer to embodiment.Hydrogenation occurs for compound (I-d) and sodium cyanoborohydride, obtains compound (I-e)；Compound (I-e) sloughs amino protecting group PG, obtains target compound shown in general formula (I-B).In some embodiments In, target compound shown in general formula (I-B) and acid form acid-addition salts to improve chemical stability.The example packet of acid-addition salts Include but be not limited to hydrochloride, hydrobromate and mesylate.

Embodiment

Prepare embodiment

2 alkene -1- amine hydrochlorate 1 of the fluoro- 2- of embodiment 1 (E) -3- (6- quinoline oxygen methyl) propyl-

Step 1 N- [the fluoro- 2- of (E) -3- (6- quinoline oxygen methyl) allyl] t-butyl carbamate 1c and N- [(Z) -3- Fluoro- 2- (6- quinoline oxygen methyl) allyl] t-butyl carbamate 1d

N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.50g, 1.9mmol) is dissolved in N, N- bis- Potassium carbonate (0.39g, 2.8mmol) and 6- oxyquinoline (0.31g, 2.1mmol) is added, at room temperature instead in methylformamide (5mL) It answers 24 hours.Adding water (5mL) to be quenched, is extracted with ethyl acetate (20mL), organic phase is washed with saturated sodium chloride solution (10mL), Anhydrous sodium sulfate is dry, filters concentration, and gained residue is pure through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/2] Change, obtains title compound 1c (0.28g, yield 44%), 1d (0.13g, yield 31%), is white solid.

MS(ESI,pos.ion)m/z:333.1[M+H]⁺。

The fluoro- 2- of step 2 (E) -3- (6- quinoline oxygen methyl) -propyl- 2 alkene -1- amine hydrochlorates 1

By N- [the fluoro- 2- of (E) -3- (6- quinoline oxygen methyl) allyl] t-butyl carbamate 1c (0.28g, 0.84mmol) It is dissolved in ethyl acetate (0.5mL), the ethyl acetate solution (3mL, 4mol/L) of hydrogen chloride is added, reacts 20 minutes, has at room temperature White solid is precipitated, and suction filtration obtains title compound 1, and (0.16g, yield 82%, HPLC purity: 91.17%), being white solid.

MS(ESI,pos.ion)m/z:233.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 9.10 (d, J=4.6Hz, 1H), 9.00 (d, J=8.3Hz, 1H), 8.54 (s, 3H), 8.39 (d, J=9.1Hz, 1H), 8.00 (dd, J=8.1,5.1Hz, 1H), 7.85 (m, 2H), 7.44 (d, J= 81.6Hz, 1H), 4.90 (d, J=2.0Hz, 2H), 3.64 (d, J=4.5Hz, 2H).

2 alkene -1- amine hydrochlorate 2 of the fluoro- 2- of embodiment 2 (Z) -3- (6- quinoline oxygen methyl) propyl-

With N- [the fluoro- 2- of (Z) -3- (6- quinoline oxygen methyl) allyl] t-butyl carbamate 1d (0.13g, 0.39mmol) Instead of the method that compound 1c is described according to 1 step 2 of embodiment, obtaining title compound 2, (81mg, yield 89%, HPLC is pure Degree: 83.98%), being white solid.

MS(ESI,pos.ion)m/z:233.1[M-Cl]⁺；

¹HNMR(400MHz,DMSO-d₆) δ (ppm) 9.09 (d, J=4.5Hz, 1H), 8.94 (d, J=8.4Hz, 1H), 8.47 (s, 3H), 8.36 (d, J=9.0Hz, 1H), 7.98 (dd, J=8.2,5.1Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.32 (d, J=82.0Hz, 1H), 4.98 (s, 2H), 3.60 (s, 2H).

The fluoro- 2- of embodiment 3 (E) -3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 3 The fluoro- 2- of (Z) -3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 4

Step 1 2- (4- fluorophenyl) -6- methoxy-auinolin 3b

By the chloro- 6- methoxy-auinolin (2.00g, 10.3mmol) of 2-, (4- fluorophenyl) boric acid (1.88g, 13.4mmol) and After sodium carbonate (5.47g, 51.6mmol) is stirred, the mixed solvent of Isosorbide-5-Nitrae-dioxane (80mL) and water (20mL) is added, Gained mixture stirs 10 minutes at room temperature, is added tetrakis triphenylphosphine palladium (612mg, 0.529mmol), then raises temperature to 100 DEG C reflux 16 hours.Reaction solution is cooled to room temperature, with suction filtered through kieselguhr, ethyl acetate (100mL) filter wash cake, filtrate saturation chlorine Change ammonium salt solution (50mL) washing, anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [ethyl acetate/stone Oily ether (v/v)=1/20] purifying, title compound 3b (1.88g, yield 69%) is obtained, is yellow solid.

MS(ESI,pos.ion)m/z:254.2[M+H]⁺。

Step 2 2- (4- fluorophenyl) quinoline -6- alcohol 3c

2- (4- fluorophenyl) -6- methoxy-auinolin 3b (1.8g, 7.1mmol) is dissolved in methylene chloride (50mL), gained is mixed It closes object and is cooled to -30 DEG C under nitrogen protection, Boron tribromide (2.8mL, 30mmol) is added dropwise, is warming up to and reaction is stirred at room temperature 3 hours.Reaction solution is poured into ice water (20mL), concentration removal organic solvent filters, washed, obtained with water (20mL × 3) Solid is beaten with ethyl acetate (30mL), is filtered, is washed with ethyl acetate (20mL), is concentrated, is obtained title compound 3c (1.36g, yield 80%) is yellow solid.

MS(ESI,pos.ion)m/z:240.0[M+H]⁺。

Step 3 N- [the fluoro- 2- of 3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] allyl] carbamic acid tert-butyl Ester 3d

2- (4- fluorophenyl) quinoline -6- alcohol 3c (1.00g, 4.18mmol) is dissolved in n,N-Dimethylformamide (20mL), Potassium carbonate (788mg, 5.64mmol) and N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b is added (0.448g, 1.67mmol) is stirred 20 hours at room temperature.Water (20mL) is added to be quenched, ethyl acetate (20mL × 3) extraction merges Organic phase washed with saturated ammonium chloride solution (20mL × 2), anhydrous sodium sulfate is dry, filters concentration, gained residue is through silicon Plastic column chromatography [ethyl acetate/petroleum ether (v/v)=1/5] purifying, obtains title compound 3d (1.15g, yield 65%), is deep Yellow solid.

MS(ESI,pos.ion)m/z:427.0[M+H]⁺。

3 He of the fluoro- 2- of step 4 (E) -3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate (Z) the fluoro- 2- of -3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 4

By N- [the fluoro- 2- of 3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] allyl] carbamate 3d (1.15g, 2.70mmol) is dissolved in ethyl acetate (12mL), is cooled to 0 DEG C, and the ethyl acetate solution of hydrogen chloride is added dropwise (5mL, 4mol/L), gained mixture, which is warming up to, is stirred at room temperature reaction 16 hours, filters, is washed with ethyl acetate (20mL), is filtered Slag is split through preparation and the ethyl acetate solution of hydrogen chloride handles to obtain title compound 3 that (0.17g, yield 17%, HPLC is pure Degree: 94.22%) (43mg, yield 4.4%, HPLC purity: 94.78%), being white solid with 4.

Compound 3:

MS(ESI,pos.ion)m/z:327.0[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.62 (d, J=8.0Hz, 1H), 8.48 (s, 3H), 8.32 (s, 2H), 8.24 (dd, J=18.2,8.6Hz, 2H), 7.62 (d, J=8.7Hz, 2H), 7.44 (t, J=8.2Hz, 2H), 7.53-7.29 (m,1H),4.85(s,2H),3.66(s,2H)。

Compound 4:

MS(ESI,pos.ion)m/z:327.0[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.54 (d, J=8.5Hz, 1H), 8.39 (s, 3H), 8.32 (d, J= 5.7Hz, 2H), 8.19 (d, J=8.2Hz, 2H), 7.61 (s, 2H), 7.36 (dd, J=54.6,45.7Hz, 3H), 4.93 (s, 2H),3.61(s,2H)。

The fluoro- 2- of embodiment 4 (E) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine Hydrochloride 5

Step 1 6- methoxyl group -2- phenyl-quinolin 5a

Phenylboric acid (7.2g, 58mmol) and the chloro- 6- methoxy-auinolin (8.0g, 41mmol) of 2- are dissolved in anhydrous N, N- Anhydrous phosphoric acid potassium (22.9g, 108mmol) is added under nitrogen protection in dimethylformamide (100mL), gained mixture stirring 30 Minute, four (triphenyl phosphorus) palladiums (2.88g, 2.48mmol) are added, then raises temperature to 140 DEG C and is stirred to react 24 hours.It is cooled to Room temperature filters, and water (150mL) is added in filtrate, is extracted with ethyl acetate (200mL × 3), combined organic phase saturated sodium-chloride Solution (100mL × 3) washing, anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [petroleum ether/acetic acid Ethyl ester (v/v)=15/1] purifying, title compound 5a (3.6g, yield 37%) is obtained, is white solid.

MS(ESI,pos.ion)m/z:236.1[M+H]⁺。

Step 2 2- phenylchinoline -6- alcohol 5b

6- methoxyl group -2- phenyl-quinolin 5a (1.44g, 6.12mmol) is dissolved in methylene chloride (14mL), is cooled to 0 DEG C, It is added dropwise Boron tribromide (1.75mL, 18.3mmol), is stirred to react at room temperature 4 hours.Reaction solution is poured into ice water (20mL) to be quenched, PH=7 is adjusted with saturated sodium bicarbonate solution, is extracted with ethyl acetate (20mL × 3), combined organic phase saturated sodium-chloride Solution (10mL × 2) washing, anhydrous sodium sulfate is dry, filters concentration, obtains title compound 5b (1.35g, yield 99%), be Yellow solid.

MS(ESI,pos.ion)m/z:222.3[M+H]⁺。

Step 3 N- [the fluoro- 2- of 3- [(2- phenyl -6- quinolyl) oxygen methyl] allyl] t-butyl carbamate 5c

2- phenylchinoline -6- alcohol 5b (400mg, 1.81mmol) is dissolved in n,N-Dimethylformamide (10mL), N- is added [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (581mg, 2.17mmol) and potassium carbonate (504mg, 3.61mmol), gained mixture is stirred to react 18 hours at room temperature.It is added water (10mL), is extracted with ethyl acetate (10mL × 3) It takes, combined organic phase is washed with saturated sodium chloride solution (10mL × 2), and anhydrous sodium sulfate is dry, filters concentration, gained residual Object is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=6/1], obtains title compound 5c (574mg, yield It 78%), is white solid.

MS(ESI,pos.ion)m/z:409.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.38-8.29 (m, 1H), 8.17 (dd, J=53.1,8.0Hz, 2H), 8.03-7.93 (m, 2H), 7.58-7.38 (m, 5H), 7.28-7.00 (m, 2H), 4.78-4.54 (m, 2H), 3.74 (d, J= 59.5Hz, 2H), 1.33 (t, J=6.6Hz, 9H).

Step 4 N- [the fluoro- 2- of (E) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] allyl] amino T-butyl formate 5d and N- [the fluoro- 2- of (Z) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] allyl] amino T-butyl formate 5e

By N- [the fluoro- 2- of 3- [(2- phenyl -6- quinolyl) oxygen methyl] allyl] t-butyl carbamate 5c (662mg, 1.62mmol) be dissolved in the mixed solvent of acetic acid (5mL) and tetrahydrofuran (5mL), be added sodium cyanoborohydride (415mg, 6.47mmol), it is stirred to react at room temperature 18 hours.PH=7 is adjusted with saturated sodium bicarbonate solution, acetic acid is added in gained mixture Ethyl ester (10mL) is washed with saturated sodium chloride solution (5mL × 2), and anhydrous sodium sulfate is dry, filters concentration, gained residue warp Silica gel column chromatography [petrol ether/ethyl acetate (v/v)=10/1] purifying, obtain title compound 5d (190mg, yield 28%) and 5e (82mg, yield 12%), is yellow oil.

MS(ESI,pos.ion)m/z:413.4[M+H]⁺。

The fluoro- 2- of step 5 (E) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine salt Hydrochlorate 5

By N- [the fluoro- 2- of (E) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] allyl] carbamic acid Tert-butyl ester 5d (190mg, 0.46mmol) is dissolved in ethyl acetate (2mL), and ethyl acetate solution (4mL, the 4mol/ of hydrogen chloride is added L), gained mixture is stirred to react 30 minutes at room temperature.Concentration, obtaining title compound 5, (160mg, yield 99%, HPLC is pure Degree: 94.89%), being yellow solid.

MS(ESI,pos.ion)m/z:313.3[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.47 (s, 3H), 7.65 (d, J=6.6Hz, 2H), 7.52-6.89 (m, 8H), 4.68 (s, 2H), 4.57 (d, J=10.0Hz, 1H), 3.57 (d, J=3.8Hz, 2H), 2.95 (dd, J=58.3, 11.7Hz, 2H), 2.25 (d, J=45.3Hz, 2H).

The fluoro- 2- of embodiment 5 (Z) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine Hydrochloride 6

With N- [the fluoro- 2- of (Z) -3- [(2- phenyl -1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] allyl] carbamic acid The method that tert-butyl ester 5e (82mg, 0.20mmol) replaces compound 5d to be described according to 4 step 5 of embodiment, obtains title compound 6 (60mg, yield 87%, HPLC purity: 90.56%), being off-white powder.

MS(ESI,pos.ion)m/z:313.3[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.36 (s, 3H), 7.62 (d, J=6.7Hz, 3H), 7.37 (ddd, J =82.5,36.3,29.0Hz, 4H), 7.02 (d, J=79.4Hz, 3H), 4.75 (s, 2H), 4.55 (d, J=10.2Hz, 1H), 3.51 (s, 2H), 2.92 (dd, J=61.2,11.9Hz, 2H), 2.22 (d, J=32.2Hz, 2H).

The fluoro- 2- of embodiment 6 (E) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 7

The chloro- 7- methoxyl group -1,2,3,4- tetrahydro acridine 7b of step 1 9-

2- amino -5- methoxy-benzoic acid (5.0g, 30mmol) is added in cyclohexanone (4.8g, 49mmol), nitrogen is protected It is cooled to 0 DEG C under shield, is added dropwise phosphorus oxychloride (28mL), reaction solution back flow reaction 2.5 hours.Reaction solution is poured into ice water It is quenched in (100mL), adjusts pH to neutrality, with methylene chloride/methanol (v/v=1/9,200mL × 3) with unsaturated carbonate potassium solution Extraction, combined organic phase are washed with saturated ammonium chloride solution (50mL × 2), and anhydrous sodium sulfate is dry, are filtered concentration, are marked It inscribes compound 7b (5.35g, yield 78%), is yellow solid.

MS(ESI,pos.ion)m/z:248.2[M+H]⁺。

Step 2 7- methoxyl group -1,2,3,4- tetrahydro acridine 7c

By the chloro- 7- methoxyl group -1,2 of 9-, 3,4- tetrahydro acridine 7b (0.75g, 3.0mmol) are dissolved in methanol (50mL), are added 10% palladium/carbon (322mg), replacing hydrogen, mixture hydrogenate (0.1MPa) and react 15 hours.It filters, is washed with methanol (20mL) Filter residue, concentration, obtains title compound 7c (0.65g, yield 100%), is yellow solid.

Step 3 5,6,7,8- tetrahydro acridine -2- alcohol 7d

By 7- methoxyl group -1,2,3,4- tetrahydro acridine 7c (610mg, 2.86mmol) are dissolved in methylene chloride (20mL), gained Mixture is cooled to -30 DEG C under nitrogen protection, is slowly added to Boron tribromide (1.5mL, 16mmol), reaction solution is warming up to room temperature It is stirred to react 16 hours.Reaction solution is poured into ice water (10mL) and is quenched, is filtered, filter residue is dissolved with methanol (5mL), then dropwise It is added ethyl acetate (15mL), stirs 4 hours, there are a large amount of solids to be precipitated.It filters, collects solid and be dried to obtain title compound 7d (0.50g, yield 88%) is white solid.

MS(ESI,pos.ion)m/z:200.1[M+H]⁺。

Step 4 N- [the fluoro- 2- of (E) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) allyl] tertiary fourth of carbamic acid Ester 7e and N- [the fluoro- 2- of (Z) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) allyl] t-butyl carbamate 7f

5,6,7,8- tetrahydro acridine -2- alcohol 7d (0.55g, 2.7mmol) are dissolved in n,N-Dimethylformamide (10mL), according to Secondary addition potassium carbonate (0.52g, 3.7mmol) and N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.52g, 1.9mmol), reaction solution react at room temperature 22 hours.Water (20mL) quenching reaction is added, with ethyl acetate (20mL × 2) Extraction, combined organic phase is full to be washed with saturated sodium chloride solution (20mL), and anhydrous sodium sulfate is dry, filters concentration, and gained is residual It stays object to purify through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/4], obtains title compound 7e (0.18g, yield It 25%) is white solid with 7f (60mg, yield 8.2%).

The fluoro- 2- of step 5 (E) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 7

By N- [the fluoro- 2- of (E) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) allyl] t-butyl carbamate 7e (0.18g, 0.466mmol) is dissolved in ethyl acetate (15mL), is cooled to 0 DEG C, and the ethyl acetate solution of hydrogen chloride is added dropwise (5mL, 4.0mol/L), reaction solution, which is warming up to, to be stirred at room temperature 20 minutes.It filters, filter cake is washed with ethyl acetate (10mL × 2), obtained To title compound 7, (0.12g, yield 80%, HPLC purity: 98.6%), being white solid.

MS(ESI,pos.ion)m/z:287.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.67 (s, 1H), 8.38 (s, 3H), 8.28 (d, J=9.3Hz, 1H), 7.72 (d, J=9.1Hz, 1H), 7.66 (s, 1H), 7.54-7.31 (d, J=84Hz, 1H), 4.83 (d, J=2.7Hz, 2H), 3.66 (d, J=4.6Hz, 2H), 3.29 (t, J=6.1Hz, 2H), 3.04 (t, J=6.1Hz, 2H), 1.98-1.92 (m, 2H), 1.91-1.84(m,2H)。

The fluoro- 2- of embodiment 7 (Z) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 8

With N- [the fluoro- 2- of (Z) -3- (5,6,7,8- tetrahydro acridine -2- yloxymethyl) allyl] t-butyl carbamate 7f The method that (60mg, 0.16mmol) replaces compound 7e to be described according to 6 step 5 of embodiment, obtaining title compound 8, (35mg is produced Rate 70%, HPLC purity: 91.3%), being white solid.MS(ESI,pos.ion)m/z:287.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.62 (s, 1H), 8.23 (d, J=24.9Hz, 4H), 7.75-7.63 (m, 2H), 7.40-7.17 (d, J=84Hz, 1H), 4.92 (s, 2H), 3.61 (s, 2H), 3.27 (s, 2H), 3.04 (t, J= 6.1Hz, 2H), 1.98-1.93 (m, 2H), 1.88 (d, J=5.5Hz, 2H).

The fluoro- propyl- 2- alkene -1- amine hydrochlorate 9 of embodiment 8 (E) -2- (acridine -2- yloxymethyl) -3-

Step 1 2- bromobenzoic acid 9b

O-bromobenzoic acid methyl esters (4.00g, 18.6mmol) is dissolved in the mixed solution of ethyl alcohol (45mL) and water (15mL), is dropped Temperature is added sodium hydroxide (2.25g, 56.3mmol) to 10 DEG C, stirs 5 minutes, is then stirred to react at room temperature 1 hour.Concentration Ethyl alcohol is removed, the pH for adjusting reaction solution with hydrochloric acid (2.0mol/L) is extracted less than 1 with ethyl acetate (50mL × 2), and merging has Machine is mutually washed with saturated sodium chloride solution (50mL), and anhydrous sodium sulfate is dry, is filtered concentration, is obtained title compound 9b (3.74g, yield 100%) is white solid.

Step 2 2- (4- aminoanisole) benzoic acid 9c

2- bromobenzoic acid 9b (3.74g, 18.6mmol) is dissolved in glycol monoethyl ether (15mL), sequentially adds 4- methoxyl group Aniline (2.75g, 22.3mmol), cuprous oxide (92mg, 0.64mmol), copper (65mg, 1.0mmol) and potassium carbonate (2.86g, 20.7mmol), gained mixture is warming up to 140 DEG C of back flow reactions 3 hours.After reaction solution is cooling plus water (40mL) is quenched, and uses second Acetoacetic ester (50mL × 3) extraction, combined organic phase successively use saturated ammonium chloride solution (40mL) and saturated sodium chloride solution (40mL) washing, anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [ethyl acetate/petroleum ether (v/ V) it=1/4] purifies, obtains title compound 9c (2.2g, yield 49%), be yellow solid.

Step 3 2- methoxyl group -10H- acridine -9- ketone 9d

2- (4- aminoanisole) benzoic acid 9c (1.27g, 5.22mmol) is dissolved in polyphosphoric acids (15mL), gained mixing Object is warming up to 100 DEG C, is stirred to react 4 hours, pours into ice water (50mL) reaction solution be quenched while hot, is then cooled to 0 DEG C, will It is alkalescent that reaction solution, which adjusts pH with saturated sodium bicarbonate solution, is filtered, and filter cake is washed with water (20mL) and ethyl alcohol (20mL), obtained It is greenish yellow solid to title compound 9d (1.10g, yield 94%).

Step 4 2- methoxyl group-acridan 9e

2- methoxyl group -10H- acridine -9- ketone 9d (950mg, 4.22mmol) is dissolved in tetrahydrofuran (25mL), liquid nitrogen is reacted Gas shielded is cooled to 0 DEG C, is slowly added to borine tetrahydrofuran solution (10.0mL, 10mmol, 1.0mol/L), 66 DEG C of back flow reactions 2 hours.It is cooled to 0 DEG C, saturated sodium chloride solution (10mL) is slowly added to and is quenched, is adjusted with sodium hydrate aqueous solution (1.0mol/L) Saving pH is neutrality, separates water phase ethyl acetate (20mL × 3) extraction, combined organic phase saturated ammonium chloride solution (20mL × 2) it washs, anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [ethyl acetate/petroleum ether (v/v) =1/4] it purifies, obtains title compound 9e (384mg, yield 43%), be white solid.

Step 5 2- methoxyacridine 9f

By 2- methoxyl group -9,10- acridan 9e (384mg, 0.09mmol), cuprous iodide (34.5mg, 0.18mmol), Diisopropyl azodiformate (36mg, 0.18mmol) and 4-methoxypyridine (41mg, 0.38mmol) are blended in reaction flask, Oxygen is replaced, is added acetonitrile (6mL), is stirred to react at room temperature 17 hours.Water (20mL) is added to be quenched, reaction solution is taken out through diatomite Filter, with ethyl acetate (100mL) filter wash slag, liquid separation, water phase is extracted with ethyl acetate (30mL), combined organic phase saturation chlorine Change sodium solution (30mL × 2) washing, anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [acetic acid second Ester/petroleum ether (v/v)=1/4] purifying, title compound 9f (283mg, yield 75%) is obtained, is yellow solid.

Step 6 acridine -2- alcohol 9g

2- methoxyacridine 9f (400mg, 1.91mmol) is dissolved in methylene chloride (20mL), gained mixture nitrogen protection - 20 DEG C are cooled to, Boron tribromide (0.90mL, 9.3mmol) then is added, reaction solution then raises temperature to is stirred to react 3 at room temperature Hour.Reaction solution is poured into ice water (20mL) and is quenched, is filtered, water phase is extracted with ethanol/methylene (v/v=1/9,60mL) It takes, organic phase is dry with anhydrous sodium sulfate, filters concentration, and residue merges drying with filter cake, obtains title compound 9g (250mg, yield 67%) is yellow solid.

Step 7 N- [(E) -2- (acridine -2- yloxymethyl) the fluoro- allyl of -3-] t-butyl carbamate 9h and N- [(Z) -2- (acridine -2- yloxymethyl) the fluoro- allyl of -3-] t-butyl carbamate 9i

Acridine -2- alcohol 9g (250mg, 1.28mmol) is dissolved in n,N-Dimethylformamide (20mL), sequentially adds carbonic acid Potassium (360mg, 2.6mmol) and N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (420mg, 1.6mmol), Reaction 24 hours is stirred at room temperature in reaction solution.Water (50mL) quenching reaction is added, is extracted with ethyl acetate (40mL × 3), merging Organic phase is washed with saturated sodium chloride solution (30mL × 2), and anhydrous slufuric acid is dry, filters concentration, gained residue is through silicagel column [ethyl acetate/petroleum ether (v/v)=1/4] purifying is chromatographed, title compound 9h (180mg, yield 36%) and 9i is obtained (80mg, yield 16%), is yellow solid.

MS(ESI,pos.ion)m/z:383.1[M+H]⁺。

The fluoro- propyl- 2- alkene -1- amine hydrochlorate 9 of step 8 (E) -2- (acridine -2- yloxymethyl) -3-

By N- [(E) -2- (acridine -2- yloxymethyl) the fluoro- allyl of -3-] t-butyl carbamate 9h (180mg, It 0.47mmol) is dissolved in ethyl acetate (5mL), gained mixture nitrogen protection is cooled to 0 DEG C, is slowly added to the acetic acid second of hydrogen chloride Ester solution (5mL, 4mol/L) is warming up to and reaction 1 hour is stirred at room temperature.It filters, obtains title compound 9 (124mg, yield 83%, HPLC purity: 99.5%), being yellow solid.

MS(ESI,pos.ion)m/z:283.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.46(s,1H),8.38-8.27(m,6H),8.06(s,1H),7.87 (d, J=8.2Hz, 1H), 7.83-7.76 (m, 2H), 7.47 (d, J=81.7Hz, 1H), 4.88 (d, J=2.7Hz, 2H), 3.70 (d, J=5.2Hz, 2H).

The fluoro- propyl- 2- alkene -1- amine hydrochlorate 10 of embodiment 9 (Z) -2- (acridine -2- yloxymethyl) -3-

With N- [(Z) -2- (acridine -2- yloxymethyl) the fluoro- allyl of -3-] t-butyl carbamate 9i (80mg, 0.21mmol) the method for replacing compound 9h to be described according to 8 step 8 of embodiment, obtains title compound 10 (51mg, yield 77%, HPLC purity: 98.6%), being yellow solid.

MS(ESI,pos.ion)m/z:283.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.66(s,1H),8.52-8.35(m,6H),8.20-8.10(m, 1H), 7.99 (d, J=9.1Hz, 1H), 7.91-7.83 (m, 2H), 7.34 (d, J=82.0Hz, 1H), 5.02 (s, 2H), 3.63 (s,2H)。

The fluoro- 2- of embodiment 10 (E) -3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) propyl- 2- alkene -1- amine salt acid Salt 11 and the fluoro- 2- of (Z) -3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 12

Step 1 N- [the fluoro- 2- of 3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) allyl] tertiary fourth of carbamic acid Ester 11b

N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.50g, 1.9mmol) is dissolved in N, N- bis- Potassium carbonate (0.39g, 2.8mmol) and 1H- pyrrolo- [2,3-b] pyridine -5- alcohol 11a is added in methylformamide (8mL) (0.28g, 2.1mmol), gained mixture react 22 hours at room temperature.Add water (5mL) quenching reaction, with ethyl acetate (20mL) Extraction, organic phase are washed with saturated sodium chloride solution (10mL), and anhydrous sodium sulfate is dry, filter concentration, gained residue is through column [ethyl acetate/petroleum ether (v/v)=1/1] purifying is chromatographed, title compound 11b (0.60g, yield 100%) is obtained, is yellow Solid.

MS(ESI,pos.ion)m/z:322.1[M+H]⁺。

The fluoro- 2- of step 2 (E) -3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 11 The fluoro- 2- of (Z) -3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 12

By N- [the fluoro- 2- of 3- (1H- pyrrolo- [2,3-b] pyridine -5- yloxymethyl) allyl] t-butyl carbamate 11b (0.55g, 1.7mmol) is dissolved in ethyl acetate (0.5mL), and the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, gained is added Mixture reacts 15 minutes at room temperature.Concentration, obtained solid are handled through the ethyl acetate solution of preparation purifying and hydrogen chloride, are obtained To title compound 11 (0.11g, yield 25%, HPLC purity: 97.03%) and 12 (51mg, yield 12%, HPLC purity: It 94.64%), is off-white powder.

Compound 11:

MS(ESI,pos.ion)m/z:222.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)12.06(s,1H),8.47(s,3H),8.18(s,1H),7.96(s, 1H), 7.56 (s, 1H), 7.31 (d, J=82.1Hz, 1H), 6.52 (s, 1H), 4.77 (s, 2H), 3.62 (d, J=4.9Hz, 2H)。

Compound 12:

MS(ESI,pos.ion)m/z:222.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 12.04 (s, 1H), 8.39 (s, 3H), 8.17 (d, J=2.0Hz, 1H), 7.96 (d, J=1.9Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=82.2Hz, 1H), 6.52 (s, 1H), 4.86 (s, 2H),3.56(s,2H)。

11 5- of embodiment [the fluoro- allyl oxygen of (E) -2- (aminomethyl) -3-] -1,2- dimethyl-indol -3- carboxylic acid, ethyl ester Hydrochloride 13 and 5- [the fluoro- allyl oxygen of (Z) -2- (aminomethyl) -3-] -1,2- dimethyl-indol -3- carboxylate hydrochloride 14

Step 1 5- [the fluoro- allyl oxygen of (E) -2- [(t-butoxycarbonyl amino) methyl] -3-] -1,2- dimethyl-indol - 3- carboxylic acid, ethyl ester 13b

N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.50g, 1.9mmol) is dissolved in N, N- bis- Cesium carbonate (0.91g, 2.8mmol) and 5- hydroxyl -1,2- dimethyl -1H- indole -3-carboxylic acid's second is added in methylformamide (8mL) Ester (0.48g, 2.1mmol) reacts 4.5 hours at 40 DEG C.Water (5mL) is added into reaction solution to be quenched, uses ethyl acetate (20mL) extraction, organic phase are washed with saturated sodium chloride solution (10mL), and anhydrous sodium sulfate is dry, filter concentration, gained residual Object is purified through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/1], obtains title compound 13b (0.74g, yield It 94%), is yellow solid.

Step 2 5- [the fluoro- allyl oxygen of (E) -2- (aminomethyl) -3-] -1,2- dimethyl-indol -3- carboxylic acid, ethyl ester hydrochloric acid Salt 13 and 5- [the fluoro- allyl oxygen of (Z) -2- (aminomethyl) -3-] -1,2- dimethyl-indol -3- carboxylate hydrochloride 14

By 5- [the fluoro- allyl oxygen of (E) -2- [(t-butoxycarbonyl amino) methyl] -3-] -1,2- dimethyl-indol -3- carboxylic Acetoacetic ester 13b (0.74g, 1.8mmol) is dissolved in ethyl acetate (0.5mL), be added hydrogen chloride ethyl acetate solution (5mL, 4mol/L), gained mixture reacts 30 minutes at room temperature.Concentration, acetic acid second of the obtained solid through preparation purifying and hydrogen chloride And 14 (54mg, yields ester solution processing obtains title compound 13 (0.26g, yield 41%, HPLC purity: 97.18%) 8.6%, HPLC purity: 98.95%), being off-white powder.

Compound 13:

MS(ESI,pos.ion)m/z:321.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.49 (s, 3H), 7.55 (d, J=2.2Hz, 1H), 7.44 (d, J= 8.9Hz, 1H), 7.31 (d, J=82.5Hz, 1H), 6.92 (dd, J=8.8,2.4Hz, 1H), 4.67 (d, J=2.9Hz, 2H), 4.29 (q, J=7.1Hz, 2H), 3.69 (s, 3H), 3.61 (d, J=4.5Hz, 2H), 2.69 (s, 3H), 1.36 (t, J= 7.1Hz,3H)。

Compound 14:

MS(ESI,pos.ion)m/z:321.1[M-Cl]⁺；

The fluoro- 2- of embodiment 12 (E) -3- (1,2,3,4- nafoxidine simultaneously [3,4-b] indoles -7- yloxymethyl) propyl- 2- alkene - 1- amine dihydrochloride 15

Step 1 7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15b

By 1- t-butoxycarbonyl -3- pyrrolidones (10.6g, 57.2mmol) and (4- methoxyphenyl) hydrazine hydrochloride (10g, 57.3mmol) is dissolved in methanol (100mL), gained mixture back flow reaction 18 hours.It filters, is washed with methanol (40mL), Title compound 15b (7.89g, yield 48%) is obtained, is white solid.

MS(ESI,pos.ion)m/z:311.1[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.91 (d, J=20.7Hz, 1H), 7.26 (dd, J=8.8, 6.1Hz, 1H), 7.07-6.86 (m, 1H), 6.70 (d, J=8.8Hz, 1H), 4.61-4.35 (m, 4H), 3.74 (d, J= 3.8Hz,3H),1.48(s,9H)。

Step 2 1,2,3,4- nafoxidine simultaneously [3,4-b] indoles -7- alcohol 15c

By 7- methoxyl group -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15b (7.68g, It 26.6mmol) is dissolved in methylene chloride (100mL), Boron tribromide (7.65mL, 79.9mmol) is added dropwise at 0 DEG C, gained mixture liter To being stirred to react at room temperature 3 hours.Reaction solution is poured into ice water (40mL) and is quenched, liquid separation, water phase sodium hydrate aqueous solution (2mol/L) adjusts pH to 7, directly casts single step reaction.

Step 3 7- hydroxyl -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15d

Toward the aqueous solution (40mL) of 1,2,3,4- nafoxidine simultaneously [3,4-b] indoles -7- alcohol 15c (4.64g, 26.6mmol) Middle addition tetrahydrofuran (40mL), sodium hydroxide (3.36g, 79.8mmol) and di-tert-butyl dicarbonate (6.46g, 29.3mmol), gained mixture is stirred to react 18 hours at room temperature.Ethyl acetate (200mL × 2) extraction is added, merging has Machine is mutually washed with saturated sodium chloride solution (10mL × 2), and anhydrous sodium sulfate is dry, filters concentration, gained residue is through silicagel column [petrol ether/ethyl acetate (v/v)=2/1] purifying is chromatographed, title compound 15d (1.94g, yield 27%) is obtained, for white Solid.

MS(ESI,pos.ion)m/z:297.1[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.75 (d, J=22.8Hz, 1H), 8.69 (s, 1H), 7.15 (dd, J =8.6,5.3Hz, 1H), 6.71 (d, J=2.9Hz, 1H), 6.57 (dd, J=8.7,2.1Hz, 1H), 4.55-4.37 (m, 4H), 1.47 (d, J=1.6Hz, 9H).

Step 4 (E) -2- [(tertbutyloxycarbonylamino) methyl] fluoro- allyloxy of -3-] -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15e and (Z) -2- [(tertbutyloxycarbonylamino) methyl] fluoro- allyloxy of -3-] -3, 4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15f

By 7- hydroxyl -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15d (686mg, 2.5mmol) N, N- dimethyl formyl are dissolved in N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (684mg, 2.5mmol) Amine (10mL), is added potassium carbonate (534mg, 3.8mmol), and gained mixture is stirred to react 24 hours at room temperature.Into reaction solution It is added water (15mL), is extracted with ethyl acetate (30mL × 2), combined organic phase is washed with saturated sodium chloride solution (20mL × 2) It washs, anhydrous sodium sulfate is dry, filters concentration, and gained residue is purified through preparation, obtains title compound 15e (554mg, yield It 48%) is white solid with 15f (86mg, yield 7.5%).

MS(ESI,pos.ion)m/z:484.1[M+Na]⁺。

The fluoro- 2- of step 5 (E) -3- (1,2,3,4- nafoxidine simultaneously [3,4-b] indoles -7- yloxymethyl) propyl- 2- alkene -1- Amine hydrochlorate 15

By (E) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -3,4- dihydro -1H- pyrrolo- [3, 4-b] indole-2-carboxylic acid tert-butyl ester 15e (583mg, 1.3mmol) is dissolved in ethyl acetate (2mL), the ethyl acetate of hydrogen chloride is added Solution (2mL, 4mol/L), gained mixture are stirred to react 30 minutes at room temperature.Concentration, obtain title compound 15 (120mg, Yield 32%, HPLC purity: 92.7%), being yellow solid.

MS(ESI,pos.ion)m/z:262.1[M-2Cl-H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)11.22(s,1H),10.35(s,2H),8.28(s,3H),7.31 (dd, J=45.6,36.7Hz, 2H), 7.08 (d, J=2.1Hz, 1H), 6.84 (dd, J=8.9,2.3Hz, 1H), 4.61 (d, J =3.2Hz, 2H), 4.45 (s, 2H), 4.40 (s, 2H), 3.61 (d, J=4.6Hz, 2H).

The fluoro- 2- of embodiment 13 (Z) -3- (1,2,3,4- nafoxidine simultaneously [3,4-b] indoles -7- yloxymethyl) propyl- 2- alkene - 1- amine dihydrochloride 16

With (Z) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -3,4- dihydro -1H- pyrrolo- [3, 4-b] indole-2-carboxylic acid tert-butyl ester 15f (95mg, 0.21mmol) replaces the side that describes according to 12 step 5 of embodiment compound 15e Method, obtaining title compound 16, (60mg, yield 98%, HPLC purity: 87.80%), being brown solid.

MS(ESI,pos.ion)m/z:262.2[M-2Cl-H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)11.26(s,1H),10.52(s,2H),8.35(s,3H),7.38- 7.28 (m, 2H), 7.09 (s, 1H), 6.85 (d, J=8.4Hz, 1H), 4.73 (s, 2H), 4.44 (s, 2H), 4.39 (s, 2H), 3.53(s,2H)。

Embodiment 14 (E) -2- (1,2,3,3a, 4,8b- hexahydropyrrolo simultaneously [3,4-b] indoles -7- yloxymethyl) -3- is fluoro- Propyl- 2- alkene -1- amine hydrochlorate 17

Step 1 7- hydroxyl -1,3a, 4,8b- tetrahydro-1 H-pyrrolo simultaneously [3,4-b] indole-2-carboxylic acid tert-butyl ester 17a

By 7- hydroxyl -3,4- dihydro -1H- pyrrolo- [3,4-b] indole-2-carboxylic acid tert-butyl ester 15d (0.94g, 3.4mmol) It is dissolved in the mixed solution of tetrahydrofuran (10mL) and acetic acid (8mL), is added sodium cyanoborohydride (0.88g, 14mmol), gained is mixed Object is closed to be stirred to react at room temperature 24 hours.Reaction solution with saturated sodium bicarbonate solution adjust pH to 7, with ethyl acetate (100mL × 3) it extracts, combined organic phase is washed with saturated sodium chloride solution (100mL × 2), and anhydrous sodium sulfate is dry, is filtered concentration, is obtained It is yellow solid to title compound 17a (0.95g, yield 100%).

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.49 (s, 1H), 6.53 (d, J=1.9Hz, 1H), 6.40 (dd, J= 8.2,2.3Hz, 1H), 6.33 (d, J=8.2Hz, 1H), 5.27 (s, 1H), 4.28 (s, 1H), 3.71 (s, 1H), 3.60 (t, J= 9.5Hz, 1H), 3.45 (dd, J=11.0,6.3Hz, 1H), 3.30 (d, J=9.8Hz, 1H), 3.21 (d, J=10.4Hz, 1H), 1.36(s,9H)。

Step 2 7- hydroxyl -1,3,3a, 8b- nafoxidine simultaneously [3,4-b] indoles -2,4- dicarboxyl tert-butyl acrylate 17b

By tert-butyl 7- hydroxyl -1,3a, 4,8b- tetrahydro-1 H-pyrrolo simultaneously [3,4-b] indole-2-carboxylic acid tert-butyl ester 17a (0.94g, 3.4mmol) is dissolved in tetrahydrofuran (15mL), be added sodium hydroxide (0.43g, 10.2mmol) water (4mL) solution and Di-tert-butyl dicarbonate (0.82g, 3.7mmol), gained mixture are stirred to react 2 hours at room temperature.Water is added in reaction solution (30mL) is extracted with ethyl acetate (50mL × 2), and combined organic phase is washed with saturated sodium chloride solution (30mL × 2), anhydrous Sodium sulphate is dry, filters concentration, and gained residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=4/1], obtained It is white solid to title compound 17b (0.50g, yield 39%).

MS(ESI,pos.ion)m/z:399.2[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 6.91 (d, J=1.8Hz, 1H), 6.72 (dd, J=8.4,2.3Hz, 1H), 6.43 (d, J=8.4Hz, 1H), 5.88 (s, 1H), 4.39 (dd, J=8.3,6.1Hz, 1H), 3.80 (dd, J=8.0, 3.4Hz 1H), 3.61 (t, J=9.7Hz, 1H), 3.52-3.41 (m, 1H), 3.27 (d, J=8.4Hz, 2H), 1.47 (s, 9H), 1.36(s,9H)。

Step 3 7- [(E) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -1,3,3a, 8b- tetrahydro Pyrrolo- [3,4-b] indoles 2,4- di-tert-butyl dicarboxylate 17c and 7- [(Z) -2- [(tertbutyloxycarbonylamino) methyl] -3- Fluoro- allyloxy] -1,3,3a, 8b- nafoxidine simultaneously [3,4-b] indoles 2,4- di-tert-butyl dicarboxylate 17d

By 7- hydroxyl -1,3,3a, 8b- nafoxidine simultaneously [3,4-b] indoles -2,4- dicarboxyl tert-butyl acrylate 17b (310mg, 0.82mmol) and N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (242mg, 0.90mmol) is dissolved in acetonitrile (6mL), is added potassium carbonate (229mg, 1.64mmol), and gained mixture is stirred to react 24 hours at room temperature.Water is added in reaction solution (10mL) is extracted with ethyl acetate (20mL × 3), and combined organic phase is washed with saturated sodium chloride solution (20mL × 2), anhydrous Sodium sulphate is dry, filters concentration, and gained residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=6/1], obtained It is yellow solid to title compound 17c (372mg, yield 80%) and 17d (71mg, yield 15%).MS(ESI, pos.ion)m/z:564.4[M+H]⁺。

Step 4 (E) -2- (1,2,3,3a, 4,8b- hexahydropyrrolo simultaneously [3,4-b] indoles -7- yloxymethyl) fluoro- propyl- of -3- 2- alkene -1- amine hydrochlorate 17

By 7- [(E) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -1,3,3a, 8b- nafoxidine And [3,4-b] indoles 2,4- di-tert-butyl dicarboxylate 17c (372mg, 0.66mmol) are dissolved in ethyl acetate (2mL), and chlorination is added The ethyl acetate solution (2mL, 4mol/L) of hydrogen, gained mixture are stirred to react 30 minutes at room temperature.Concentration, obtains title compound (190mg, yield 96%, HPLC purity: 89.6%), being yellow solid to object 17.

MS(ESI,pos.ion)m/z:264.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.88(s,1H),9.15(s,1H),8.47(s,3H),7.15(d,J =82.9Hz, 1H), 6.64 (d, J=8.6Hz, 2H), 6.53 (dd, J=8.4,2.3Hz, 1H), 4.28-4.21 (m, 1H), 4.04-3.97 (m, 2H), 3.53 (t, J=12.8Hz, 4H), 3.34 (d, J=8.4Hz, 1H), 3.27-3.19 (m, 1H), 3.13-3.05(m,1H)。

Embodiment 15 (Z) -2- (1,2,3,3a, 4,8b- hexahydropyrrolo simultaneously [3,4-b] indoles -7- yloxymethyl) -3- is fluoro- Propyl- 2- alkene -1- amine hydrochlorate 18

With 7- [(Z) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -1,3,3a, 8b- nafoxidine And [3,4-b] indoles 2,4- di-tert-butyl dicarboxylate 17d (71mg, 0.13mmol) replaces compound 17c according to 14 step of embodiment The method of rapid 4 description, obtaining title compound 18, (35mg, yield 93%, HPLC purity: 87.7%), being yellow solid.

MS(ESI,pos.ion)m/z:264.2[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.76(s,1H),9.12(s,1H),8.41(s,3H),7.28(d,J =5.1Hz, 1H), 6.61 (dd, J=13.8,5.2Hz, 2H), 6.53 (dd, J=8.4,2.3Hz, 1H), 4.22 (dd, J= 8.3,4.8Hz, 1H), 4.00 (dd, J=9.1,5.2Hz, 1H), 3.95-3.84 (m, 2H), 3.45 (d, J=20.6Hz, 4H), 3.21 (d, J=5.1Hz, 1H), 3.11 (s, 1H).

The fluoro- 2- of embodiment 16 (E) -3- (2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles -8- oxygen methyl) propyl- 2- Alkene -1- amine hydrochlorate 19

Step 1 8- methoxyl group -1.3.4.5- tetrahydropyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19b

By N- tertbutyloxycarbonyl -4- piperidones (5g, 25.1mmol) and (4- methoxyphenyl) hydrazine hydrochloride (4.3g, It 25mmol) is dissolved in methanol (100mL), is stirred to react at 70 DEG C 18 hours.It is down to room temperature, filters, obtains title compound 19b (5.7g, yield 75%) is white solid.MS(ESI,pos.ion)m/z:303.1[M+H]⁺。

Step 2 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles -8- alcohol 19c

By 8- methoxyl group -1.3.4.5- tetrahydropyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19b (5.7g, 19mmol) It is dissolved in methylene chloride (100mL), Boron tribromide (5.4mL, 56mmol) is added dropwise at 0 DEG C, stirring is warmed to room temperature stirring 3 after ten minutes Hour.Reaction solution is poured into ice water (50mL) and is quenched, water phase is separated, adjusts pH to 7 with sodium hydrate aqueous solution (2mol/L), Directly cast single step reaction.

MS(ESI,pos.ion)m/z:189.4[M+H]⁺。

Step 3 8- hydroxyl -1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19d

Toward the aqueous solution of 2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles -8- alcohol 19c (3.5g, 19mmol) In (50mL), be added tetrahydrofuran (30mL), sodium hydroxide (2.3g, 55mmol) and di-tert-butyl dicarbonate (4.5g, 20mmol), reaction 16 hours is stirred at room temperature in gained mixture.Water (50mL) is added into reaction solution, uses ethyl acetate (100mL × 2) extraction, combined organic phase are washed with saturated sodium chloride solution (50mL × 2), and anhydrous sodium sulfate is dry, are filtered, Concentration removes most of solvent, and the solid of precipitation is cooled at 5 DEG C and stirs 1 hour, filters, and drying obtains title compound 19d (3.86g, yield 72%), off-white powder.

MS(ESI,pos.ion)m/z:289.4[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.55 (s, 1H), 8.59 (s, 1H), 7.07 (d, J=8.6Hz, 1H), 6.66 (s, 1H), 6.54 (dd, J=8.6,2.2Hz, 1H), 4.43 (s, 2H), 3.68 (t, J=5.6Hz, 2H), 2.72 (t, J=5.2Hz, 2H), 1.44 (s, 9H).

Step 4 8- [(E) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-] -1,3,4,5- tetrahydro pyrrole Pyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19e and 8- [(Z) -2- [(tertbutyloxycarbonylamino) methyl] fluoro- allyl of -3- Oxygroup] -1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19f

By 8- hydroxyl -1,3,4,5- tetrahydropyridine simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19d (0.7g, 2.43mmol) N, N- dimethyl methyl are dissolved in N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.65g, 2.43mmol) Amide (10mL) is added potassium carbonate (0.51g, 3.65mmol), is stirred to react at room temperature 24 hours.Water is added into reaction solution (20mL) is extracted with ethyl acetate (30mL × 2), and combined organic phase is washed with saturated sodium chloride solution (20mL × 2), anhydrous Sodium sulphate is dry, filters concentration, and obtaining title compound 19e (402mg, yield 36%) and 19f through preparation purifying, (97mg is produced Rate 8.6%), it is yellow solid.

MS(ESI,pos.ion)m/z:498.1[M+Na]⁺。

The fluoro- 2- of step 5 (E) -3- (2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles -8- oxygen methyl) propyl- 2- alkene - 1- amine hydrochlorate 19

By 8- [(E) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-], -1,3,4,5- tetrahydropyridine is simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19e (402mg, 0.85mmol) is dissolved in ethyl acetate (2mL), and the acetic acid of hydrogen chloride is added Ethyl ester solution (4mL, 4mol/L), gained mixture are stirred to react 30 minutes at room temperature, and concentration obtains title compound 19 (255mg, yield 96%, HPLC purity: 84.8%), being brown solid.

MS(ESI,pos.ion)m/z:276.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)11.06(s,1H),9.51(s,1H),8.31(s,3H),7.26(dd, J=45.5,36.8Hz, 2H), 7.09 (d, J=2.0Hz, 1H), 6.80 (dd, J=8.7,2.3Hz, 1H), 4.62 (d, J= 3.0Hz, 2H), 4.24 (s, 2H), 3.60 (d, J=4.8Hz, 2H), 3.44 (d, J=6.9Hz, 2H), 3.01 (s, 2H).

The fluoro- 2- of embodiment 17 (Z) -3- (2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indoles -8- oxygen methyl) propyl- 2- Alkene -1- amine hydrochlorate 20

With 8- [(Z) -2- [(tertbutyloxycarbonylamino) methyl] the fluoro- allyloxy of -3-], -1,3,4,5- tetrahydropyridine is simultaneously [4,3-b] indole-2-carboxylic acid tert-butyl ester 19f (97mg, 0.20mmol) replaces compound 19e to be described according to 16 step 5 of embodiment Method, obtain title compound 20 (60mg, yield 94%, HPLC purity: 82.2%), be brown solid.

MS(ESI,pos.ion)m/z:276.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)11.07(s,1H),9.53(s,1H),8.30(s,3H),7.32- 7.23 (m, 2H), 7.09 (s, 1H), 6.81 (dd, J=8.7,2.2Hz, 1H), 4.73 (s, 2H), 4.23 (s, 2H), 3.53 (s, 2H), 3.44 (d, J=4.6Hz, 2H), 3.01 (s, 2H).

The fluoro- 2- of embodiment 18 (E) -3- (pyridine [1,2-a] benzimidazole -8- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 21

Step 1 N- (4- methoxyphenyl) pyridine -2- amine 21b

Under nitrogen atmosphere protection, past 4- aminoanisole (924mg, 7.5mmol), palladium acetate (115mg, 0.50mmol), in 1,1'- dinaphthalene -2,2'- double diphenyl phosphines (311mg, 0.48mmol) and potassium tert-butoxide (1.12g, 9.5mmol) Toluene (10mL) solution of 2- bromopyridine (790mg, 5.0mmol), sealing is added, gained mixture stirs under the conditions of being placed in 110 DEG C Mix reaction 14 hours.Saturated sodium chloride solution (25mL) is added into reaction solution to be quenched, is extracted with ethyl acetate (25mL × 3), Combined organic phase is dry with anhydrous sodium sulfate, filters concentration, gained residue is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=10/1 it] purifies, obtains title compound 21b (936mg, yield 94%), be Orange red solid.

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.74 (s, 1H), 8.07 (d, J=4.7Hz, 1H), 7.57-7.28 (m, 3H), 6.96-6.77 (m, 2H), 6.77-6.59 (m, 2H), 3.71 (d, J=1.2Hz, 3H).

Step 2 8- methoxypyridine [1,2-a] benzimidazole 21c

N- (4- methoxyphenyl) pyridine -2- amine 21b (200mg, 1.0mmol) is dissolved in hexafluoroisopropanol (5mL), and Iodobenzene (11 μ L, 0.10mmol) and metachloroperbenzoic acid (250mg, 1.1mmol) is added, is stirred to react at 25 DEG C 2 hours. Saturated sodium chloride solution (25mL) is added into reaction solution, is extracted with ethyl acetate (25mL × 3), combined organic phase is with anhydrous Sodium sulphate is dry, filters concentration, and gained residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=3/1], obtained It is red liquid to title compound 21c (128mg, yield 65%).

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.99 (d, J=6.9Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.60 (d, J=9.3Hz, 1H), 7.50-7.39 (m, 1H), 7.13 (dd, J=8.9,2.5Hz, 1H), 6.94 (t, J=6.7Hz, 1H), 3.89 (s, 3H).

Step 3 pyridine [1,2-a] benzimidazole -8- alcohol 21d

8- methoxypyridine [1,2-a] benzimidazole 21c (250mg, 1.3mmol) is dissolved in methylene chloride (5.0mL), - 20 DEG C are cooled to, Boron tribromide (400 μ L, 4.1mmol) is slowly added to.After adding, gained mixture is moved under the conditions of 25 DEG C, It is stirred to react 6 hours.It under condition of ice bath, is added saturated sodium bicarbonate solution (15mL), is extracted with ethyl acetate (15mL × 3), Combined organic phase is dry with anhydrous sodium sulfate, filters concentration, gained residue is through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/1 it] purifies, obtains title compound 21d (112mg, yield 48%).

Step 4 N- [the fluoro- 2- of 3- (pyrido [1,2-a] benzimidazole -8- base-oxygen methyl) allyl] tertiary fourth of amine formic acid Ester 21e

Pyridine [1,2-a] benzimidazole -8- alcohol 21d (112.0mg, 0.61mmol) is dissolved in N,N-dimethylformamide In (3.0mL), N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (170mg, 0.63mmol) and carbon is added Sour caesium (391mg, 1.20mmol), gained mixture are placed under the conditions of 25 DEG C, are stirred to react 20 hours.It is added into reaction solution full It with sodium chloride solution (15mL), is extracted with ethyl acetate (20mL × 3), combined organic phase is dry with anhydrous sodium sulfate, filters Concentration, gained residue are purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=1/1], obtain title compound 21e (0.112g, yield 50%) is white solid.

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.97 (t, J=7.8Hz, 1H), 7.96 (d, J=15.8Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.60 (d, J=9.2Hz, 1H), 7.49-7.42 (m, 1H), 7.28-7.06 (m, 2H), 6.97 (dd, J=20.3,13.7Hz, 1H), 4.80-4.45 (m, 2H), 3.87-3.58 (m, 2H), 1.34 (d, J=5.9Hz, 9H).

The fluoro- 2- of step 5 (E) -3- (pyridine [1,2-a] benzimidazole -8- yloxymethyl) propyl- 2- alkene -1- amine hydrochlorate 21

By N- [the fluoro- 2- of 3- (pyrido [1,2-a] benzimidazole -8- base-oxygen methyl) allyl] amine t-butyl formate 21e (112mg, 0.3mmol) is dissolved in Hydrochloride/ethyl acetate (2mL, 4mol/L), is stirred to react at room temperature 14 hours.Concentration Obtain faint yellow solid, through preparative separation and Hydrochloride/ethyl acetate, obtain title compound 21 (40mg, yield 43%, HPLC purity: 99.57%).

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 9.53 (s, 1H), 8.39 (d, J=11.8Hz, 3H), 8.12-7.97 (m, 2H), 7.89 (d, J=9.1Hz, 1H), 7.51 (dd, J=36.4,11.2Hz, 2H), 7.34 (s, 1H), 7.21 (s, 0.5H),7.08(s,0.5H),4.83(s,2H),3.65(s,2H)。

The fluoro- 2- of embodiment 19 (E) -3- [[2- (4- pyridyl group) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 22

Step 1 6- methoxyl group -2- (4- pyridyl group) quinoline 22a

The chloro- 6- methoxy-auinolin (2.00g, 10.3mmol) of 2- is dissolved in acetonitrile (25mL), sequentially adds 4- pyridine boronic acid Frequency any ester (2.74g, 13.4mmol), bis- (diphenylphosphine) ferrocene-palladium chloride dichloromethane complex of 1,1'- (0.86g, 1.10mmol) and water (20mL) solution of potassium carbonate (5.77g, 41.7mmol), under nitrogen protection, reaction solution is warming up to 80 DEG C and stirs Mix reaction 7 hours.Reaction solution suction filtered through kieselguhr, ethyl acetate (50mL) washing, filtrate with hydrochloric acid (1mol/L) adjust pH to 7, organic phase is washed with saturated ammonium chloride solution (50mL × 3), and anhydrous sodium sulfate is dry, filters concentration, gained residue is through silicon Plastic column chromatography [ethyl acetate/petroleum ether (v/v)=1/5] purifying, obtains title compound 22a (2.14g, yield 88%), is Yellow solid.

Step 2 2- (4- pyridyl group) quinoline -6- alcohol 22b

6- methoxyl group -2- (4- pyridine) quinoline 22a (2.14g, 9.06mmol) is dissolved in methylene chloride (10mL), nitrogen is protected - 20 DEG C are cooled under shield, is added dropwise Boron tribromide (3.5mL, 36mmol), reaction solution, which is warming up to, to be stirred at room temperature 3 hours.It will be anti- Answer liquid to pour into ice water (40mL) to be quenched, concentration remove organic solvent, residual water phase with methylene chloride/methanol (v/v=9/1, 40mL × 3) it extracts, combined organic phase is washed with saturated sodium chloride solution (30mL), and anhydrous sodium sulfate is dry, concentration is filtered, Title compound 22b (0.87g, yield 43%) is obtained, is yellow solid.

Step 3 N- [the fluoro- 2- of (E) -3- [[2- (4- pyridyl group) -6- quinolyl] oxygen methyl] allyl] carbamic acid uncle Butyl ester 22c and N- [(Z) -3- fluoro- 2- [[2- (4- pyrrolePyridineBase) -6- quinolyl] oxygen methyl] allyl] t-butyl carbamate 22d

2- (4- pyridyl group) quinoline -6- alcohol 22b (0.87g, 3.92mmol) is dissolved in n,N-Dimethylformamide (20mL), Sequentially add N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.64g, 2.40mmol) and potassium carbonate (0.34g, 2.50mmol), gained mixture are stirred to react 15 hours at room temperature.Water (40mL) quenching reaction is added, with acetic acid second Ester (40mL × 3) extraction, combined organic phase successively use saturated sodium chloride solution (40mL) and saturated ammonium chloride solution (40mL) Washing, anhydrous sodium sulfate are dry, filter concentration, and residue is pure through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=1/5)] Change, obtains title compound 22c (0.55g, yield 34%) and 22d (0.25g, yield 16%), be white solid.

MS(ESI,pos.ion)m/z:410.0[M+H]⁺。

The fluoro- 2- of step 4 (E) -3- [[2- (4- pyridyl group) -6- Kui quinoline base] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 22

By N- [the fluoro- 2- of (E) -3- [[2- (4- pyridyl group) -6- quinolyl] oxygen methyl] allyl] t-butyl carbamate 22c (0.55g, 1.34mmol) is dissolved in ethyl acetate (15mL), and reaction solution is cooled to 0 DEG C, and the acetic acid second of hydrogen chloride is added dropwise Ester solution (5.0mL, 4.0mol/L) is warming up to and reaction 1 hour is stirred at room temperature.It filters, obtaining title compound 22, (0.23g is produced Rate 49%, HPLC purity: 97.78%), being white solid.

MS(ESI,pos.ion)m/z:281.3[M-Cl]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 9.06 (d, J=6.6Hz, 2H), 8.81 (d, J=6.4Hz, 2H), 8.58 (d, J=8.7Hz, 1H), 8.48 (d, J=8.6Hz, 1H), 8.38 (s, 1H), 8.14 (d, J=9.9Hz, 3H), 7.63- 7.60 (m, 2H), 7.52-7.36 (m, 1H), 4.86 (d, J=2.4Hz, 2H), 3.67 (s, 2H).

The fluoro- 2- of embodiment 20 (Z) -3- [[2- (4- pyridyl group) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 23

With N- [(Z) -3- fluoro -2- [[2- (4- pyridyl group) -6- quinolyl] oxygen methyl] allyl] the tertiary fourth of carbamic acid The method that ester 22d (0.25g, 0.61mmol) replaces compound 22c to be described according to 19 step 4 of embodiment, obtains title compound 23 (0.11g, yield 49%, HPLC purity: 98.54%), for light green solid.

MS(ESI,pos.ion)m/z:281.3[M-Cl]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 9.04 (d, J=6.6Hz, 2H), 8.77 (d, J=6.1Hz, 2H), 8.56 (d, J=8.6Hz, 1H), 8.46 (d, J=8.6Hz, 1H), 8.30 (s, 3H), 8.16-8.11 (m, 1H), 7.64-7.60 (m, 2H), 7.39-7.23 (m, 1H), 4.95 (s, 2H), 3.62 (d, J=3.2Hz, 2H).

The fluoro- 2- of embodiment 21 (E) -3- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 24

Step 1 6- methoxyl group -2- (2- pyridyl group) quinoline 24a

The chloro- 6- methoxy-auinolin (1.00g, 5.16mmol) of 2- is dissolved in Isosorbide-5-Nitrae-dioxane (25mL), is then successively added Enter bis- (diphenylphosphine) ferrocene-palladium chloride dichloromethane complex of 2- pyridine boronic acid (0.89g, 7.24mmol), 1,1'- Water (20mL) solution of (0.86g, 1.0mmol) and potassium carbonate (2.86g, 20.7mmol), the heating of gained mixture nitrogen protection Reaction 18 hours is stirred at reflux to 80 DEG C.Suction filtered through kieselguhr is used after cooling, filter residue is washed with ethyl acetate (50mL), uses hydrochloric acid (1.0mol/L) adjusts pH to 7, and organic phase is washed with saturated ammonium chloride solution (30mL × 3), and anhydrous sodium sulfate is dry, filters dense Contracting, gained residue are purified through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=2/3], obtain title compound 24a (0.22g, yield 18%) is yellow solid.

Step 2 2- (2- pyridyl group) quinoline -6- alcohol 24b

6- methoxyl group -2- (2- pyridyl group) quinoline 24a (220mg, 0.92mmol) is dissolved in methylene chloride (20mL), nitrogen Protection is cooled to -30 DEG C, and Boron tribromide (0.65mL, 6.7mmol) is added dropwise, and is warming up to and reaction 5 hours is stirred at room temperature.Reaction Liquid is poured into ice water (30mL) and is quenched, with saturated sodium bicarbonate solution adjust pH to 7, with methylene chloride/methanol (v/v=9/1, It 50mL) extracts, organic phase is dry with anhydrous sodium sulfate, filters concentration, gained residue is through silica gel column chromatography [ethyl acetate/stone Oily ether (v/v)=1/1] purifying, target compound 24b (0.12g, yield 59%) is obtained, is yellow solid.

MS(ESI,pos.ion)m/z:223.2[M+H]⁺。

Step 3 N- [the fluoro- 2- of (E) -3- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] allyl] carbamic acid uncle Butyl ester 24c and N- [the fluoro- 2- of (Z) -3- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] allyl] t-butyl carbamate 24d

2- (2- pyridyl group) quinoline -6- alcohol 24b (0.15g, 0.54mmol) is dissolved in n,N-Dimethylformamide (10mL), Sequentially add potassium carbonate (0.10g, 0.72mmol) and N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate 1b (0.19g, 0.71mmol), reaction solution are stirred to react 38 hours at room temperature.Water (20mL) quenching reaction is added, uses ethyl acetate (20mL × 3) extraction, combined organic phase are successively washed with saturated ammonium chloride (20mL) and water (20mL), and anhydrous sodium sulfate is dry It is dry, concentration is filtered, is split through preparation and obtains title compound 24c (15mg, yield 6.6%) and 24d (10mg, yield 4.4%), It is yellow liquid object.

The fluoro- 2- of step 4 (E) -3- [[2- (2- pyridyl group) -6- Kui Linji] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 24

By N- [the fluoro- 2- of (E) -3- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] allyl] t-butyl carbamate 24c (15mg, 0.037mmol) is dissolved in ethyl acetate (10mL), and reaction solution is cooled to 0 DEG C, and the acetic acid second of hydrogen chloride is added dropwise Ester solution (5.0mL, 4.0mol/L), following reaction liquid is warming up to be stirred to react 30 minutes at room temperature.It filters, obtains title compound (12mg, yield 95%, HPLC purity: 96.7%), being yellow solid to object 24.MS(ESI,pos.ion)m/z:310.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.85 (d, J=4.1Hz, 1H), 8.72 (d, J=7.9Hz, 1H), 8.59 (d, J=5.4Hz, 1H), 8.49 (s, 1H), 8.27 (d, J=7.6Hz, 3H), 8.18 (d, J=9.8Hz, 1H), 7.77- 7.70 (m, 1H), 7.62 (s, 2H), 7.50-7.34 (m, 1H), 7.22 (d, J=9.0Hz, 1H), 4.92 (d, J=35.2Hz, 2H),3.60(s,2H)。

The fluoro- 2- of embodiment 22 (Z) -3- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] propyl- 2- alkene -1- amine hydrochlorate 25

With N- [(Z) -3- fluoro -2- [[2- (2- pyridyl group) -6- quinolyl] oxygen methyl] allyl] the tertiary fourth of carbamic acid The method that ester 24d (11mg, 0.027mmol) replaces compound 24c to be described according to 21 step 4 of embodiment, obtains title compound 25 (9.0mg, yield 97%, HPLC purifying: 96.8%) be light green solid.

MS(ESI,pos.ion)m/z:310.0[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.85 (d, J=4.1Hz, 1H), 8.77 (d, J=6.1Hz, 1H), 8.73 (d, J=7.8Hz, 1H), 8.59 (d, J=9.9Hz, 4H), 8.29 (t, J=7.4Hz, 1H), 8.19 (d, J=9.0Hz, 1H), 7.75 (s, 1H), 7.54 (d, J=60Hz, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 4.89 (s, 2H), 3.65 (s, 2H)。

23 6- of embodiment [the fluoro- allyloxy of (E) -2- (amine methyl) -3-] -3H- quinazoline-4-one hydrochloride 26

Step 1 N- [the fluoro- 2- of 3- [(4- oxo -3H- quinazoline -6- base) oxygen methyl] allyl] t-butyl carbamate 26b

6- hydroxyl -3H- quinazoline-4-one (400mg, 2.47mmol) is dissolved in dimethyl sulfoxide (20mL), carbonic acid is added Potassium (465mg, 3.33mmol), N- [the fluoro- allyl of 2- (bromomethyl) -3-] t-butyl carbamate (400mg, 1.49mmol), Gained mixture is stirred to react 25 hours at room temperature.Water (40mL) quenching reaction is added, ethyl acetate (30mL × 3) extraction is closed And organic phase successively washed with saturated ammonium chloride solution (30mL) and saturated sodium chloride solution (30mL), anhydrous sodium sulfate is dry It is dry, concentration is filtered, gained residue is purified through silica gel column chromatography [ethyl acetate/petroleum ether (v/v)=2/3], obtained titled It closes object 26b (330mg, yield 38%), is white solid.

Step 2 6- [the fluoro- allyloxy of (E) -2- (amine methyl) -3-] -3H- quinazoline-4-one hydrochloride 26

By N- [the fluoro- 2- of 3- [(4- oxo -3H- quinazoline -6- base) oxygen methyl] allyl] t-butyl carbamate 26b (260mg, 0.74mmol) is dissolved in ethyl acetate (10mL), is cooled to 0 DEG C under nitrogen protection, and the acetic acid second of hydrogen chloride is added dropwise Ester solution (5.0mL, 4mol/L), gained mixture are stirred to react 8 hours at room temperature, there is white solid precipitation, are filtered, are passed through system It is standby to split and the ethyl acetate solution of hydrogen chloride is handled, obtain title compound 26 (23mg, yield 10%, HPLC purity: It 86.12%), is white solid.

MS(ESI,pos.ion)m/z:274.1[M-Cl]⁺；

1H NMR(400MHz,DMSO-d₆) δ (ppm) 8.48 (s, 1H), 8.28 (s, 3H), 7.60 (d, J=8.8Hz, 1H), 7.48 (d, J=2.8Hz, 1H), 7.33 (dd, J=8.8,2.8Hz, 1H), 7.41-7.19 (m, 1H), 4.72 (s, 2H), 3.50 (d, J=6.0Hz, 2H).

24 2- of embodiment [the fluoro- allyloxy of (E) -2- (aminomethyl) -3-] pyrido [2,1-b] quinazoline -11- ketone salt Hydrochlorate 27 and 2- [the fluoro- allyloxy of (Z) -2- (aminomethyl) -3-] pyrido [2,1-b] quinazoline -11- keto hydrochloride 28

Step 1 N- (4- methoxyphenyl) pyridine -2- amine 27b

Under nitrogen protection, past 4- aminoanisole (924mg, 7.5mmol), palladium acetate (115mg, 0.50mmol), 1, 2- bromopyridine is added in the double diphenyl phosphines (311mg, 0.48mmol) of 1'- dinaphthalene -2,2'-, potassium tert-butoxide (1.12g, 9.5mmol) Toluene (10mL) solution of (790mg, 5.0mmol), sealing, gained mixture are stirred to react 14 hours under the conditions of being placed in 110 DEG C. It is added saturated sodium chloride solution (25mL), is extracted with ethyl acetate (25mL × 3), combined organic phase is dry with anhydrous sodium sulfate It is dry, concentration is filtered, gained residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=10/1], obtained titled It closes object 27b (936mg, yield 94%), is Orange red solid.

Step 2 2- methoxypyridine simultaneously [2,1-b] quinazoline -11- ketone 27c

By N- (4- methoxyphenyl) pyridine -2- amine 27b (100mg, 0.5mmol), palladium acetate (6mg, 0.026mmol) and Potassium peroxydisulfate (405mg, 1.5mmol) is dissolved in trifluoroacetic acid (2.5mL), replaces carbon monoxide atmosphere, sealing, gained mixture It is reacted 6 hours under the conditions of being placed in 70 DEG C.Into reaction solution be added saturated sodium carbonate solution (50mL), with ethyl acetate (20mL × 3) it extracts, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, gained residue is through silica gel column chromatography [petroleum ether/second Acetoacetic ester (v/v)=1/1] purifying, title compound 27c (44mg, yield 39%) is obtained, is yellow solid.

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.81 (d, J=7.3Hz, 1H), 7.74 (d, J=9.0Hz, 1H), 7.68 (dd, J=15.3,5.4Hz, 2H), 7.58 (dd, J=9.0,2.9Hz, 1H), 7.52 (d, J=9.2Hz, 1H), 7.08 (t, J=6.7Hz, 1H), 3.92 (s, 3H).

Step 32 hydroxy pyrimidine simultaneously [2,1-b] quinazoline -11- ketone 27d

By 2- methoxypyridine, simultaneously [2,1-b] quinazoline -11- ketone 27c (160mg, 0.7mmol) is dissolved in methylene chloride In (5.0mL), and -20 DEG C are cooled to, Boron tribromide (205 μ L, 2.1mmol) is added thereto, then sets gained mixture It is stirred to react in 25 DEG C 4 hours.It is down at 0 DEG C, instills saturated sodium bicarbonate solution (2.5mL), with methylene chloride (20mL × 3) Extraction, combined organic phase is dry with anhydrous sodium sulfate, filters concentration, gained residue is through silica gel column chromatography [petroleum ether/acetic acid Ethyl ester (v/v)=3/1] purifying, title compound 27d (45mg, yield 30%) is obtained, is yellow solid.

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.13 (s, 1H), 8.73 (d, J=7.2Hz, 1H), 7.67 (d, J= 8.9Hz, 1H), 7.59 (t, J=6.3Hz, 2H), 7.48-7.40 (m, 2H), 6.99 (t, J=6.8Hz, 1H).

Step 4 N- [the fluoro- 2- of 3- [(11- oxy picolinate simultaneously [2,1-b] quinazoline -2- base) oxygen methyl] allyl] amine formic acid Tert-butyl ester 27e

By 2 hydroxy pyrimidine simultaneously [2,1-b] quinazoline -11- ketone 27d (45.0mg, 0.20mmol), N- [2- (bromomethyl) - The fluoro- allyl of 3-] t-butyl carbamate 1b (40mg, 0.15mmol) is dissolved in n,N-Dimethylformamide (3.0mL), it is added Cesium carbonate (79mg, 0.24mmol) is stirred to react 20 hours at 25 DEG C.Saturated sodium chloride solution is added into reaction solution (20mL) is extracted with ethyl acetate (15mL × 3), and combined organic phase is washed with saturated sodium chloride solution (10mL × 3), anhydrous Sodium sulphate is dry, filters concentration, and gained residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=2/1], obtained It is yellow solid to title compound 27e (54mg, yield 66%).

Step 5 2- [the fluoro- allyloxy of (E) -2- (aminomethyl) -3-] pyrido [2,1-b] quinazoline -11- keto hydrochloride 27 and 2- [the fluoro- allyloxy of (Z) -2- (aminomethyl) -3-] pyrido [2,1-b] quinazoline -11- keto hydrochloride 28

By N- [the fluoro- 2- of 3- [(11- oxy picolinate simultaneously [2,1-b] quinazoline -2- base) oxygen methyl] allyl] carbamic acid uncle Butyl ester 27e (59mg, 0.15mmol) is dissolved in the ethyl acetate solution (2mL, 4mol/L) of hydrogen chloride, and gained mixture is at room temperature It is stirred to react 1 hour.Concentration, obtained yellow solid is split through preparation and the ethyl acetate solution of hydrogen chloride is handled, and is marked Inscribe compound 27 (20mg, yield 40%, HPLC purity: 99.62%) and 28 (12mg, yield 24%, HPLC purity: It 86.37%), is yellow solid.

MS(ESI,pos.ion)m/z:300.1[M-Cl]⁺；

Compound 27:

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.90 (d, J=6.9Hz, 1H), 8.19 (s, 3H), 7.90 (s, 1H), 7.84 (d, J=9.0Hz, 1H), 7.77 (d, J=2.7Hz, 1H), 7.73-7.66 (m, 1H), 7.29 (d, J=10.7Hz, 1H), 7.23 (s, 1H), 7.12 (d, J=52Hz, 1H), 4.81 (s, 2H), 3.67 (d, J=5.0Hz, 2H)；

Compound 28:

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 8.95 (d, J=7.3Hz, 1H), 8.28 (s, 3H), 7.89 (d, J= 9.0Hz, 1H), 7.80 (d, J=2.6Hz, 1H), 7.74 (dd, J=9.1,2.7Hz, 1H), 7.37 (s, 1H), 7.28 (d, J= 80Hz,1H),7.24(s,1H),7.11(s,1H),4.94(s,2H),3.56(s,2H)。

The fluoro- 2- of embodiment 25 (E) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] propyl- 2- Alkene -1- amine hydrochlorate 29

Step 1 N- [the fluoro- 2- of (E) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] allyl Base] t-butyl carbamate 29a and N- [the fluoro- 2- of (Z) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen first Base] allyl] t-butyl carbamate 29b

By N- [the fluoro- 2- of 3- [[2- (4- fluorophenyl) -6- quinolyl] oxygen methyl] allyl] t-butyl carbamate 3d (600mg, 1.41mmol) is dissolved in tetrahydrofuran (20mL), and sodium cyanoborohydride (451mg, 7.03mmol) and acetic acid is added (10mL) is stirred to react 24 hours at room temperature.Be added saturated sodium bicarbonate solution adjust pH to 7, with ethyl acetate (100mL × 2) it extracts, combined organic phase is washed with saturated sodium chloride solution (70mL × 2), and anhydrous sodium sulfate is dry, filters concentration, gained Residue is purified through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=10/1], and obtaining title compound 29a, (145mg is produced Rate 24%) and 29b (114mg, yield 19%), it is light yellow oil.

MS(ESI,pos.ion)m/z:431.1[M+H]⁺。

The fluoro- 2- of step 2 (E) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] propyl- 2- alkene - 1- amine hydrochlorate 29

By N- [the fluoro- 2- of (E) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] allyl] ammonia Base carboxylate 29a (114mg, 0.26mmol) is dissolved in ethyl acetate (1mL), be added hydrogen chloride methanol solution (2mL, 20%wt), it is stirred to react at room temperature 30 minutes.Concentration, obtain title compound 29 (97mg, yield 99%, HPLC: It 96.80%), is faint yellow solid.

MS(ESI,pos.ion)m/z:331.3[M-Cl]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 8.44 (s, 3H), 7.71 (s, 2H), 7.28 (dt, J=51.9, 40.4Hz, 4H), 6.94 (s, 2H), 4.67 (s, 2H), 4.58 (d, J=10.4Hz, 1H), 3.58 (d, J=5.3Hz, 2H), 3.01 (d, J=6.4Hz, 1H), 2.87 (d, J=15.3Hz, 1H), 2.29 (s, 1H), 2.15 (d, J=10.4Hz, 1H).

The fluoro- 2- of embodiment 26 (Z) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] propyl- 2- Alkene -1- amine hydrochlorate 30

With N- [the fluoro- 2- of (Z) -3- [[2- (4- fluorophenyl) -1,2,3,4- tetrahydroquinoline -6- base] oxygen methyl] allyl] ammonia The method that base carboxylate 29b (145mg, 0.34mmol) replaces compound 29a to be described according to 25 step 2 of embodiment, obtains To title compound 30, (123mg, yield 99%, HPLC purity: 97.97%), being white solid.

MS(ESI,pos.ion)m/z:331.3[M-Cl]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 8.40 (s, 3H), 7.69 (s, 2H), 7.25 (dd, J=44.6, 36.1Hz, 4H), 6.93 (s, 2H), 4.76 (s, 2H), 4.58 (d, J=9.3Hz, 1H), 3.51 (s, 2H), 3.00 (s, 1H), 2.87(s,1H),2.27(s,1H),2.15(s,1H)。

The fluoro- 2- of embodiment 27 (E) -3- [(2- methyl-1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine Hydrochloride 31

Step 1 6- methoxyl group -2- methyl-1,2,3,4- tetrahydroquinoline 31b

6- methoxyl group -2- methylquinoline (100mg, 0.57mmol) is dissolved in acetic acid (2mL) and tetrahydrofuran (2mL) mixes Solvent is added sodium cyanoborohydride (152mg, 2.29mmol), is stirred to react 18 hours at room temperature, then heats to 50 DEG C of stirrings Reaction 6 hours.It is down to room temperature, pH to 7 is adjusted with saturated sodium bicarbonate solution, is extracted with ethyl acetate (10mL × 2), merging Organic phase is washed with saturated sodium chloride solution (5mL × 2), and anhydrous sodium sulfate is dry, filters concentration, gained residue is through silicagel column [petrol ether/ethyl acetate (v/v)=6/1] purifying is chromatographed, title compound 31b (70mg, yield 68%) is obtained, is yellow oil Shape object.

MS(ESI,pos.ion)m/z:178.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 6.66-6.59 (m, 2H), 6.48 (d, J=8.3Hz, 1H), 3.76 (s, 3H), 3.41-3.31 (m, 1H), 3.26 (s, 1H), 2.88 (ddd, J=17.3,11.6,5.9Hz, 1H), 2.74 (ddd, J= 16.6,5.2,3.3Hz, 1H), 1.94 (ddt, J=11.9,5.8,2.9Hz, 1H), 1.67-1.54 (m, 1H), 1.23 (d, J= 6.3Hz,3H)。

Step 2 2- methyl-1,2,3,4- tetrahydroquinoline -6- alcohol 31c

By 6- methoxyl group -2- methyl-1,2,3,4- tetrahydroquinoline 31b (1.7g, 9.6mmol) is dissolved in methylene chloride (20mL) is added dropwise Boron tribromide (3.8mL, 39mmol) at 0 DEG C, continues stirring 1 hour, pour into ice water (40mL) and be quenched, and uses Saturated sodium bicarbonate solution adjusts pH to 7, is extracted with ethyl acetate (60mL × 3), and combined organic phase saturated sodium-chloride is molten Liquid (50mL × 2) washing, anhydrous sodium sulfate is dry, filters concentration, obtains title compound 31c (1.6g, yield 100%), be Yellow oil.

MS(ESI,pos.ion)m/z:164.1[M+H]⁺。

Step 3 6- hydroxy-2-methyl -3,4- dihydro -2H- quinoline -1- carboxylic acid tert-butyl ester 31d

By 2- methyl-1,2,3,4- tetrahydroquinoline -6- alcohol 31c (184mg, 1.13mmol) are dissolved in tetrahydrofuran (6mL), add Enter sodium hydroxide (138mg, 3.38mmol) aqueous solution (1mL) and di-tert-butyl dicarbonate (0.52mL, 2.2mmol), at room temperature It is stirred to react 18 hours.Water (20mL) quenching reaction is added, is extracted with ethyl acetate (20mL × 3), combined organic phase is used full It is washed with sodium chloride solution (20mL × 2), anhydrous sodium sulfate is dry, filters concentration, gained residue is through silica gel column chromatography [petroleum Ether/ethyl acetate (v/v)=9/1] purifying, title compound 31d (200mg, yield 67%) is obtained, is white solid.

MS(ESI,pos.ion)m/z:264.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 6.63 (d, J=6.3Hz, 2H), 6.48-6.34 (m, 1H), 5.59 (s, 1H), 3.28 (s, 2H), 2.78-2.55 (m, 2H), 1.87-1.74 (m, 1H), 1.46 (s, 9H), 1.13 (d, J=6.2Hz, 3H)。

Step 4 6- [(E) -2- [(t-butoxycarbonyl amino) methyl] the fluoro- allyloxy of -3-] -2- methyl -3,4- dihydro - 2H- quinoline -1- carboxylic acid tert-butyl ester 31e and 6- [(Z) -2- [(t-butoxycarbonyl amino) methyl] the fluoro- allyloxy of -3-] -2- first Base -3,4- dihydro -2H- quinoline -1- carboxylic acid tert-butyl ester 31f

By 6- hydroxy-2-methyl -3,4- dihydro -2H- quinoline -1- carboxylic acid tert-butyl ester 31d (500mg, 1.9mmol), N- [2- The fluoro- allyl of (bromomethyl) -3-] t-butyl carbamate (60mg, 2.09mmol) is dissolved in n,N-Dimethylformamide (10mL), It is added cesium carbonate (1.26g, 3.79mmol), is stirred to react 48 hours at 50 DEG C.It is down to room temperature, water (20ml) is added and is quenched, uses Ethyl acetate (30mL × 2) extraction, combined organic phase are washed with saturated sodium chloride solution (20mL × 3), and anhydrous sodium sulfate is dry It is dry, concentration is filtered, gained residue obtains title compound through silica gel column chromatography [petrol ether/ethyl acetate (v/v)=9/1] 31e (98mg, yield 11%) and 31f (35mg, yield 3.9%), is yellow oil.

MS(ESI,pos.ion)m/z:451.2[M+H]⁺。

The fluoro- 2- of step 5 (E) -3- [(2- methyl-1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine salt Hydrochlorate 31g

By 6- [(E) -2- [(t-butoxycarbonyl amino) methyl] the fluoro- allyloxy of -3-] -2- methyl -3,4- dihydro -2H- Quinoline -1- carboxylic acid tert-butyl ester 31h (98mg, 0.22mmol) is dissolved in ethyl acetate (1mL), and the ethyl acetate solution of hydrogen chloride is added (2mL, 4mol/L) is stirred to react 1 hour at room temperature.Concentration, obtaining title compound 31, (62mg, yield 99%, HPLC is pure Degree: 98.42%), being faint yellow solid.

MS(ESI,pos.ion)m/z:251.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.42(s,4H),7.13(d,1H),6.61(s,3H),3.65(s, 2H), 3.51 (s, 2H), 2.73 (d, J=29.0Hz, 3H), 1.75 (s, 1H), 1.24-1.16 (m, 4H).

The fluoro- 2- of embodiment 28 (Z) -3- [(2- methyl-1,2,3,4- tetrahydroquinoline -6- base) oxygen methyl] propyl- 2- alkene -1- amine Hydrochloride 32

With 6- [(Z) -2- [(t-butoxycarbonyl amino) methyl] the fluoro- allyloxy of -3-] -2- methyl -3,4- dihydro -2H- The method that quinoline -1- carboxylic acid tert-butyl ester 31f (35mg, 0.078mmol) replaces compound 31a to be described according to 27 step 5 of embodiment, Obtaining title compound 32, (22mg, yield 98%, HPLC purity: 93.65%), being faint yellow solid.

MS(ESI,pos.ion)m/z:251.1[M-Cl]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.30(s,4H),7.30-7.12(m,1H),6.55(s,3H),4.12 (s, 2H), 3.98 (s, 2H), 2.72 (dd, J=18.8,5.7Hz, 3H), 1.74 (s, 1H), 1.38 (t, J=24.2Hz, 1H), 1.16 (d, J=17.3Hz, 3H).

Activity test embodiment one, people recombinate the measurement of SSAO/VAP-1 inhibitory activity

Test purpose: method below is living for measuring the inhibition that the compounds of this invention recombinates SSAO/VAP-1 to people Property.

Test material:

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

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

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

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

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

DMSO (Dimethyl Sulfoxide, dimethyl sulfoxide) 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 concentration is added to containing People recombinates in each hole of SSAO/VAP-1, is incubated at room temperature 30min.After 30min is incubated for, by 25 μ LRed Monoamine Oxidase Assay Kit (contains 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 for 60min.After 60min, use PerkinElmer's Envision reads fluorescent value (RFU) at excitation 530-560nm and transmitting 590nm.Use 5 software of Graph Pad Prism It draws curve and calculates IC₅₀Value.The results are shown in Table 1 for it, and the corresponding compound of the compound number in table 1 is that preparation is implemented The compound of the same compound number in example:

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

Compound number	SSAO/VAP-1 (human recombination protein) IC₅₀/nM
		1	2.437
2	0.675
		7	0.45
8	0.81
		9	1.43
22	0.49
		23	0.37

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

Two, rat fat tissue's homogenate SSAO/VAP-1 inhibitory activity measurement

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

Test material:

N- piperazine-N- b sodium salt (HEPES SODIUM SALT) is 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；

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

Test method:

Stomach fat of the operation excision from Sprague Dawley rat, is the tissue rich in SSAO/VAP-1.It is right In every gram of Abdominal Fat tissue, be added 5ml HES buffer (20mM N- piperazine-N- b sodium salt, 1mM EDTA, 250mM sucrose, 1 × PMSF and 100mM β-phosphoglycerol disodium salt hydrate, pH7.4) it is homogenized.Use Bertin The 24 multifunctional sample homogenizer of Bertin Precellys of Technologies homogenizes adipose tissue 3min, at 4 DEG C, Adipose tissue homogenate is centrifuged 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 for 30min at 37 DEG C.After 30min incubation, 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 test chemical combination of 25 μ L various concentrations Object is added into each hole containing adipose tissue supernatant, is incubated for 30min 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, 30min is incubated 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 curve of Pad Prism simultaneously calculates IC₅₀Value.The results are shown in Table 2 for it, and the compound number in table 2 is corresponding Compound is the compound for preparing the same compound number in embodiment:

Table 2: the inhibitory activity of compound on fatty tissue homogenate SSAO/VAP-1 provided in an embodiment of the present invention

Compound number	SSAO/VAP-1 (adipose tissue homogenate) IC₅₀/nM
		1	9.332
2	6.726
		7	6.226
8	6.729
		22	9.234
23	7.117

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

Three, the pharmacokinetics measurement of the compounds of this invention

Measure purpose: method below 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 rat: male, 180-220g, 7-8 week old are purchased from Hunan Si Laike experimental animal 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 dissolution 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 stock 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 saved under the conditions of being placed in -20 DEG C stand-by.

(2) internal standard substance solution is prepared: precision draws a certain amount of 1mg/mL Propranolol stock solution, 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 calculation 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 is centrifuged 2min at 4 DEG C, and 800 μ L of Aspirate supernatant is volatilized in 96 hole nitrogen evaporators, 150 μ L first of residue Alcohol/water=50/50 is redissolved, vortex mixed, sample introduction, and sample volume 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 180 μ L of blank plasma is added in each 20 μ L of standard serial solution, is vortexed and mixes, 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 operated by " plasma sample pretreatment ", 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 method.

9, data processing

Using 6.1 software 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 embodiment or examples.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.

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

Claims

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

Wherein,

X is-N=or-CH=；

Y is-N (R⁷)-or-N=；

L is-O- ,-S- or-NH-；

Each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a,-C (=O) OR^b,-C (=O) NR^cR^d、- SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、-OR^b、R^bO- C_1-4Alkylidene, R^dR^cN-C_1-4Alkylidene, C_1-6Halogenated alkyl, C_1-6Alkyl, C_2-8Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 Former molecular heterocycle, C_6-10Aryl or 5-10 former molecular heteroaryl, wherein the C_1-6Alkyl, C_2-8Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, 3-8 former molecular heterocycle, C_6-10Aryl and 5-10 former molecular heteroaryl are respectively It is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With it is each with them Together from connected carbon atom or nitrogen-atoms, C is formed_3-8Carbocyclic ring, 3-8 former molecular heterocycle, C_6-10Aromatic ring or 5-10 original Molecular hetero-aromatic ring；The wherein C_3-8Carbocyclic ring, 3-8 former molecular heterocycle, C_6-10Aromatic ring and 5-10 original are molecular Hetero-aromatic ring is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl、Br、I、CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Haloalkoxy Base；

R¹For H, D, F, Cl, Br, I, C_1-6Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、-SR^eOr-S (=O) R^e, wherein The C_1-6Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently be D, F, Cl, Br, I, CN、NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

R²For F, Cl, Br, I, C_1-6Alkyl ,-C (=O) OR^b,-C (=O) R^a,-OC (=O) R^a,-OC (=O) OR^b、-NR^fC (= O)R^a、-NR^fS (=O)₂R^e,-C (=O) NR^cR^d,-S (=O)₂NR^cR^d,-S (=O)₂R^e、-SR^eOr-S (=O) R^e, wherein institute State C_1-6Alkyl is unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently be D, F, Cl, Br, I, CN, NO₂、OH、NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Alkyl amino or C_1-6Halogenated alkoxy；

R³And R⁴It is each independently H, D, C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-8 former molecular heterocycle, C_6-10Aryl, 5-10 former molecular heteroaryl orThe wherein C_1-6Alkyl, C_1-6Halogenated alkyl, C_3-6Cycloalkanes Base, 3-8 former molecular heterocycle, C_6-10The former molecular heteroaryl of aryl and 5-10 it is unsubstituted each independently or Replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

Or R³、R⁴Together with the nitrogen-atoms being connected with them, forms 3-8 former molecular heterocycle or 5-8 former molecular miscellaneous Aromatic ring, wherein the 3-8 former molecular heterocycle and the 5-8 molecular hetero-aromatic ring of original it is unsubstituted each independently or by 1, replaced 2,3 or 4 substituent groups, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6 Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

Each R^a、R^b、R^c、R^d、R^eAnd R^fIt independently is H, D, hydroxyl, C_1-6Halogenated alkyl, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, 3-8 former molecular heterocycle, C_6-10Aryl or 5-10 former molecular heteroaryl, wherein The C_1-6Halogenated alkyl, C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Naphthenic base, 3-8 original are molecular miscellaneous Ring group, C_6-10The former molecular heteroaryl of aryl and 5-10 is unsubstituted each independently or by 1,2,3 or 4 substituent group institute Replace, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy Or C_1-6Alkyl amino；

Or R^c、R^dTogether with the nitrogen-atoms being connected with them, forms 3-8 former molecular heterocycle or 5-8 former molecular miscellaneous Aromatic ring, wherein the 3-8 former molecular heterocycle and the 5-8 molecular hetero-aromatic ring of original it is unsubstituted each independently or by 1, replaced 2,3 or 4 substituent groups, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂、C_1-6Alkyl, C_1-6 Halogenated alkyl, C_1-6Alkoxy or C_1-6Alkyl amino；

N is 0,1 or 2.

2. compound according to claim 1, wherein ring Cy is 5-6 former molecular nitrogen-containing heterocycle or 5-6 atom The nitrogenous hetero-aromatic ring of composition.

3. compound according to claim 1 or 2, wherein ring Cy is

4. compound according to claim 3, wherein ring Cy is

5. compound according to claim 1, with shown in formula (II), formula (III), formula (IV), formula (V), formula (VI) Compound or formula (II), formula (III), formula (IV), formula (V), compound shown in formula (VI) stereoisomer, geometrical isomerism Body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or their prodrug,

6. compound according to claim 1, wherein R⁷For H, D, C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Hydroxy alkyl or C_3-6Naphthenic base；

Each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a,-C (=O) OR^b,-C (=O) NR^cR^d、- SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、-OR^b、R^bO- C_1-2Alkylidene, R^dR^cN-C_1-2Alkylidene, C_1-4Halogenated alkyl, C_1-4Alkyl, C_2-6Alkenyl, C_2-4Alkynyl, C_3-6Naphthenic base, 3-6 Former molecular heterocycle, C_6-10Aryl or 5-6 former molecular heteroaryl, wherein the C_1-4Alkyl, C_2-6Alkenyl, C_2-4 Alkynyl, C_3-6Naphthenic base, 3-6 former molecular heterocycle, C_6-10Aryl and 5-6 former molecular heteroaryl are respectively independent Ground is unsubstituted or replaced 1,2,3 or 4 substituent group, and the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、 OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4Halogenated alkoxy；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With it is each with them Together from connected carbon atom or nitrogen-atoms, C is formed_3-6Carbocyclic ring, 3-6 former molecular heterocycle, C_6-10Aromatic ring or 5-6 original Molecular hetero-aromatic ring；The wherein C_3-6Carbocyclic ring, 3-6 former molecular heterocycle, C_6-10Aromatic ring and 5-6 original are molecular Hetero-aromatic ring is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl、Br、I、CN、NO₂、OH、NH₂、C_1-4Alkyl, C_1-4Halogenated alkyl, C_1-4Alkoxy, C_1-4Alkyl amino or C_1-4Haloalkoxy Base.

7. compound according to claim 1, wherein R⁷For H, D, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, Difluoromethyl, hydroxymethyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；

Each R⁵And R⁶It independently is H, D, F, Cl, Br, I, CN, NO₂,-C (=O) R^a,-C (=O) OH ,-C (=O) OCH₃,-C (= O)OCH₂CH₃,-C (=O) OCH₂CH₂CH₃,-C (=O) OCH (CH₃)₂,-C (=O) NR^cR^d、-SR^e,-S (=O)₂R^e,-S (=O) R^e,-S (=O)₂NR^cR^d、-NR^fC (=O) R^a、-NR^fS (=O)₂R^e、-NR^cR^d、-OR^b, trifluoromethyl, methyl, ethyl, positive third Base, isopropyl, vinyl, 1- acrylic, 2- acrylic, cyclobutenyl, pentenyl, hexenyl, propinyl, cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, piperidyl, morpholinyl, thio-morpholinyl, piperazine Base, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, oxadiazoles base, 1,3, 5- triazine radical, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidine radicals, wherein the methyl, ethyl, n-propyl, isopropyl, Vinyl, 1- acrylic, 2- acrylic, cyclobutenyl, pentenyl, hexenyl, propinyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, phenyl, furan Mutter base, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, oxadiazoles base, cyanuro 1,3,5, Thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidine radicals are unsubstituted each independently or are taken by 1,2,3 or 4 substituent group In generation, the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂, methyl, ethyl, n-propyl, isopropyl, trifluoro Methyl, methoxyl group, ethyoxyl, methylamino, trifluoromethoxy or difluoro-methoxy；

Or arbitrary R⁵、R⁶Together with the carbon atom or nitrogen-atoms being connected with each or arbitrary two R⁶With it is each with them Together from connected carbon atom or nitrogen-atoms, formed cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, cyclopentenyl, Cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, pyrrolin base, tetrahydro pyridyl, four Hydrogen pyrimidine radicals, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, phenyl, furyl, pyrrole Cough up base, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazolyl, oxadiazoles base, 1,3,5- Triazine radical, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidine radicals；The wherein cyclobutyl, cyclopenta, cyclohexyl, ring fourth Alkenyl, cyclopentenyl, cyclohexenyl group, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, nafoxidine base, pyrrolin Base, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro pyrazinyl, tetrahydro pyridazine base, piperidyl, morpholinyl, thio-morpholinyl, piperazine Base, phenyl, furyl, pyrrole radicals, pyridyl group, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, triazolyl, tetrazole radical, oxazole Base, oxadiazoles base, cyanuro 1,3,5, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidine radicals are not taken each independently Generation or replaced 1,2,3 or 4 substituent group, the substituent group is independently selected from D, F, Cl, Br, I, CN, NO₂、OH、NH₂, first Base, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, methylamino, trifluoromethoxy or difluoro-methoxy.

8. compound according to claim 1, wherein R¹For H, D, F, Cl, Br, I, methyl, ethyl, isopropyl, positive third Base ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein The methyl, ethyl, isopropyl and n-propyl are unsubstituted each independently or replaced 1,2,3 or 4 substituent group, described Substituent group independently is D, F, Cl, Br, I, CN, NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl；

R²For F, Cl, Br, I, methyl, ethyl, isopropyl, n-propyl ,-C (=O) OH ,-C (=O) OCH₃,-C (=O) OCH₂CH₃,-C (=O) R^a,-OC (=O) R^aOr-OC (=O) OR^a, wherein the methyl, ethyl, isopropyl and n-propyl are respectively It is independently unsubstituted or replaced 1,2,3 or 4 substituent group, the substituent group independently be D, F, Cl, Br, I, CN, NO₂、OH、NH₂, methyl, ethyl, n-propyl or isopropyl；

R³And R⁴It is each independently H, D, methyl, ethyl, n-propyl, isopropyl, C_1-4Halogenated alkyl, cyclopropyl, cyclobutyl, 5- The molecular heterocycle of 6 originals, phenyl, 5-6 former molecular heteroaryl orThe wherein methyl, ethyl, just Propyl, isopropyl, C_1-4Halogenated alkyl, cyclopropyl, cyclobutyl, 5-6 former molecular heterocycle, phenyl and 5-6 atom group At heteroaryl it is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F、Cl、Br、I、CN、OH、NH₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy；

Or R³、R⁴Together with the nitrogen-atoms being connected with them, forms 5-6 former molecular heterocycle or 5-6 former molecular miscellaneous Aromatic ring, wherein the 5-6 former molecular heterocycle and the 5-6 molecular hetero-aromatic ring of original it is unsubstituted each independently or by 1, replaced 2,3 or 4 substituent groups, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, ethyl, just Propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

9. compound according to claim 1, wherein each R^a、R^b、R^c、R^d、R^eAnd R^fIt independently is H, D, hydroxyl, trifluoro Methyl, difluoromethyl, methyl, ethyl, isopropyl, n-propyl, normal-butyl, tert-butyl, methoxyl group, ethyoxyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, phenyl or the 5-6 molecular heteroaryl of original, wherein the methyl, ethyl, isopropyl, just Propyl, normal-butyl, tert-butyl, C_3-6Naphthenic base, 5-6 former molecular heterocycle, phenyl and 5-6 former molecular heteroaryl Base is unsubstituted each independently or replaced 1,2,3 or 4 substituent group, the substituent group independently selected from D, F, Cl, Br, I、CN、OH、NH₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy；

Or R^c、R^dTogether with the nitrogen-atoms being connected with them, forms 5-6 former molecular heterocycle or 5-6 former molecular miscellaneous Aromatic ring, wherein the 5-6 former molecular heterocycle and the 5-6 molecular hetero-aromatic ring of original it is unsubstituted each independently or by 1, replaced 2,3 or 4 substituent groups, the substituent group is independently selected from D, F, Cl, Br, I, CN, OH, NH₂, methyl, ethyl, just Propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

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

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically may be used The salt of receiving or their prodrug.

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

12. a kind of pharmaceutical composition, it includes compounds described in claim 1-11 any one, optionally, further wrap Containing pharmaceutically acceptable carrier, excipient, adjuvant, medium or their combination.

13. pharmaceutical composition described in compound described in claim 1-11 any one or claim 12 is preparing drug In purposes, wherein the drug is for inhibiting SSAO/VAP-1；Or for preventing, treating or mitigating and SSAO/VAP-1 egg Bai Youguan or the disease adjusted by SSAO/VAP-1.

14. purposes according to claim 13, wherein described and SSAO/VAP-1 albumen is related or by SSAO/VAP-1 The disease of adjusting is inflammation disease and/or inflammation related disease, diabetes and/or diabetes related diseases, mental illness, ischemic Property disease, vascular diseases, fibrosis or tissue transplantation rejection.

15. purposes according to claim 14, wherein the inflammation disease and/or inflammation related disease be arthritis, complete Body inflammatory syndrome, pyaemia, synovitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, hepatopathy, respiratory tract disease Disease, disease of eye, skin disease or neuroinflammatory disorder；The diabetes and/or diabetes related diseases be Type I diabetes, Type II diabetes, X syndrome, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema；Institute Stating mental illness is severe depression, two polar form depression or attention deficiency hyperactivity；The ischemic disease be apoplexy and/ Or after its complication, myocardial infarction and/or its complication or apoplexy inflammatory cell to disorganization；The fiber turns to liver fibre Dimensionization, cystic fibrosis, kidney fibrosis, idiopathic pulmonary fibrosis or the fibrosis of radioactivity induction；The vascular diseases are Pulse atherosclerosis, chronic heart failure or congestive heart failure.

16. purposes according to claim 15, wherein arthritis is osteoarthritis, rheumatic arthritis, rheumatoid pass Section inflammation or juvenile rheumatoid arthritis；General inflammatory syndrome is general inflammatory pyemia；Inflammatory bowel disease is anaphylaxis Enteropathy；Hepatopathy be liver autoimmune disease, oneself immunity hepatitis, primary biliary cirrhosis, sclerosing cholangitis, from Body immunity cholangitis, alcoholic liver disease or non-alcohol fatty liver；Respiratory disease is asthma, acute lung injury, urgency Property Respiratory Distress Syndrome(RDS), lung inflammation, Chronic Obstructive Pulmonary Disease, bronchitis or bronchiectasis；Disease of eye is eye Inflammation caused by Uveitis, iritis, the retinitis, autoimmune ophthalmia disease, angiogenesis and/or lymph generate or Huang Spot denaturation；Skin disease is contact dermatitis, scytitis, psoriasis or eczema；Neuroinflammatory disorder is Parkinson's disease, A Er Ci Haimo disease, vascular dementia, multiple sclerosis or chronic multiple sclerosis；

Wherein the non-alcohol fatty liver is non-alcoholic simple fatty liver, nonalcoholic fatty liver disease, non-wine The related negative source type cirrhosis of essence fatty liver disease or primary carcinoma of liver.