CN114728925A

CN114728925A - Amine derivative serving as SSAO/VAP-1 inhibitor and application thereof

Info

Publication number: CN114728925A
Application number: CN201980102424.XA
Authority: CN
Inventors: 顾峥; 黎健豪; 王伟华; 覃浩雄; 李峥
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2019-11-28
Filing date: 2019-11-28
Publication date: 2022-07-08
Anticipated expiration: 2039-11-28
Also published as: CN114728925B; WO2021102774A1

Abstract

An amine derivative as an SSAO/VAP-1 inhibitor and application thereof, and further relates to a pharmaceutical composition containing the compound. The compounds or pharmaceutical compositions are useful for treating inflammation and/or inflammation-related disorders or diabetes and/or diabetes-related disorders.

Description

Amine derivative serving as SSAO/VAP-1 inhibitor and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to an amine compound serving as a semicarbazide-sensitive amine oxidase (SSAO) and/or vascular adhesion protein-1 (VAP-1) inhibitor, a preparation method thereof, a pharmaceutical composition further containing the compound, and application of the compound and the pharmaceutical composition.

Background

Vascular adhesion protein-1 (VAP-1) is a dimeric glycoprotein with a relative molecular Mass (MW) of 170,000-180,000, and is a multifunctional protein widely existing in mammals. VAP-1 has double functions, on one hand, is an adhesion molecule of lymphocytes and promotes the lymphocytes to adhere to the vascular endothelium; VAP-1, on the other hand, also has the efficacy of semicarbazide-sensitive amine oxidase (SSAO). The VAP-1 protein may be present in the plasma as a solute, or may be present on the surface of endothelial cells, adipocytes and smooth muscle cells in a membrane-bound form. Researchers have often described this protein in SSAO/VAP-1 in recent years. In adipocytes and smooth muscle cells, SSAO/VAP-1 promotes intracellular transfer of Glucose transporter 4 (GLUT 4) from adipocytes to cell membranes, thereby regulating Glucose transport. In endothelial cells, SSAO/VAP-1 can mediate the adhesion and exudation process of leukocytes and endothelial cells, and participate in inflammatory reaction.

It has been reported that elevated levels of SSAO/VAP-1 have been observed in the following diseases: diabetes (Li, H, Y.et al.,2009, Clin.Chim.acta 404: 149-. For inflammatory Liver Disease, scientists have correlated SSAO/VAP-1 plasma activity levels with Liver fibrosis and used as a predictor for patients with Nonalcoholic Fatty Liver Disease (NAFLD).

In addition, SSAO/VAP-1 is also associated with: melanoma and lymphoma (Martila-lchihara, F.et al, 2010, J.Immunol.184: 3164-.

In conclusion, the development of a highly selective, potent and well tolerated SSAO/VAP-1 inhibitor would be beneficial in the treatment of various diseases, especially inflammation and/or inflammation-related diseases and diabetes and/or diabetes-related diseases in humans.

Disclosure of Invention

The invention provides an amine compound with better SSAO/VAP-1 inhibition activity, and the compound and a pharmaceutical composition thereof can be prepared into medicines for preventing, treating or relieving inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases of patients, in particular to medicines for preventing, treating or relieving non-alcoholic fatty liver diseases, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema of patients. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of using these compounds and compositions in the manufacture of medicaments for the treatment of the above-mentioned diseases in mammals, especially humans. Compared with the existing similar compounds, the compound of the invention has good pharmacological activity and/or excellent in vivo pharmacokinetic properties or in vivo pharmacodynamic properties. Meanwhile, the preparation method is simple and feasible, the process method is stable, and the method is suitable for industrial production. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein the ring A, R¹、R ²、R ³、R ^zAnd q has the meanings given in the inventionTherein are disclosed

The compound shown in the formula (I) can be in an 'E' configuration, a 'Z' configuration or a combination of the 'E' configuration and the 'Z' configuration in any proportion.

In some embodiments, R²Is F, Cl, Br or I.

In some embodiments, R³Is H, deuterium, C_1-6Alkyl or C_3-6A cycloalkyl group.

In some embodiments, ring a is an oxygen-containing heterocyclic ring of 5 to 8 atoms or an oxygen-containing heteroaromatic ring of 5 to 8 atoms, wherein ring a is unsubstituted or substituted with 1,2, or 3R^ySubstituted; wherein said R^yHaving the definitions set out in the present invention.

In some embodiments, R¹Is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^j、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms, wherein R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jEach independently is H, deuterium, C_1-6Alkyl or C _3-6A cycloalkyl group.

In some embodiments, each R is^zIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C_1-6A haloalkoxy group.

In some embodiments, each R is^yIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、＝O、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C_1-6A haloalkoxy group.

In some embodiments, q is 0, 1,2, or 3.

In other embodiments, ring A is an oxygen-containing heterocyclic ring of 5 to 6 atoms or an oxygen-containing heteroaromatic ring of 5 to 6 atoms, wherein ring A is unsubstituted or substituted with 1,2, or 3R^yIs substituted, wherein R is^yHaving the definitions set out in the present invention.

In still other embodiments, ring a is

Wherein said ring A is unsubstituted or substituted with 1,2 or 3R^yIs substituted, wherein R is^yHaving the definitions set forth herein.

In other embodimentsIn the embodiment, R¹Is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^j、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclic radical of 5-6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms, wherein R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jEach independently of the other is H, deuterium, C_1-4Alkyl or C_3-6A cycloalkyl group.

In other embodiments, R¹Is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^jMethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy, methylamino, methylthio, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Trifluoromethoxy, vinyl, allyl, propenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a heterocyclic group of 5 to 6 atoms, phenyl or 5 to 6 atomsA heteroaryl group of wherein R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In other embodiments, R³Is H, deuterium, C_1-4Alkyl or C_3-6A cycloalkyl group.

In still other embodiments, R³Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In other embodiments, each R is^zIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl or C_1-4A haloalkoxy group.

In yet other embodiments, each R is^zIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Or a trifluoromethoxy group.

In other embodiments, each R is^yIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、＝O、C _1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl or C_1-4A haloalkoxy group.

In yet other embodiments, each R is^yIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂- (O), methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Or a trifluoromethoxy group.

In some embodiments, the invention relates to a structure of one of, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

in some embodiments, the pharmaceutically acceptable salt of the invention is a hydrochloride, hydrobromide, phosphate, oxalate, maleate, tartrate, citrate, malate or mesylate salt.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, optionally further comprising pharmaceutically acceptable adjuvants.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the manufacture of a medicament for inhibiting SSAO/VAP-1; or the medicament is used for preventing, treating or relieving inflammation diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.

In another aspect, the present invention relates to the use of a compound or pharmaceutical composition according to the present invention for inhibiting the activity of SSAO/VAP-1; or for the prevention, treatment or alleviation of inflammatory diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.

In another aspect, the invention relates to a method of inhibiting SSAO/VAP-1 activity; or a method of preventing, treating or ameliorating an inflammatory disease and/or an inflammation-related disease or diabetes and/or a diabetes-related disease; the method is administering to the patient a therapeutically effective amount of the compound of the invention or the pharmaceutical composition.

In some embodiments, the inflammatory disease and/or inflammation-related disease of the present invention is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease.

In some embodiments, the diabetes and/or diabetes related disorders of the present invention are type i diabetes, type ii diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, or diabetic macular edema.

In still other embodiments, the non-alcoholic fatty liver disease of the present invention is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis, or primary liver cancer.

Detailed description of the invention

The invention provides an amine derivative with good SSAO/VAP-1 inhibition activity, a preparation method and application thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, the articles are used herein to refer to articles of one or more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

The terms "subject" and "patient" are used interchangeably herein. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The present invention also includes isotopically-labelled compounds of the present invention which are identical to those recited herein, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as²H， ³H， ¹³C， ¹⁴C， ¹⁵N， ¹⁶O， ¹⁷O， ³¹P， ³²P， ³⁶S， ¹⁸F and³⁷Cl。

compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g.³H and¹⁴incorporation of C into the compounds of the invention can be used in drug and/or substrate tissue distribution assays. Tritiated, i.e.,³h, and carbon-14, i.e¹⁴C, an isotope is particularly preferred. In addition, heavy isotopes are used, such as deuterium, i.e.²H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. Substituents on atoms having unsaturated double bonds may, if possible, be present in cis- (Z) -or trans- (E) -form.

Depending on the choice of starting materials and processes, the compounds of the invention may exist in the form of one of the possible isomers or mixtures thereof, for example, the racemic and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers may be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；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)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Thus, as described herein, the compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "metabolite" refers to the product of the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The term "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptableAcceptable salts are well known in the art, as in the literature: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C _1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulphonates and aromatic sulphonates.

The term "prodrug" denotes a compound which is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those phosphate esters which are phosphorylated via the parent hydroxy group. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.

The term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, compounds of formula (I), or as specified in the examples, subclasses, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein.

Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. WhereinThe substituent may be, but is not limited to, H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂Oxo (═ O), -C (═ O) R^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^jA haloalkyl, an alkoxy, an alkylthio, an alkylamino, a haloalkoxy, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl or a heteroaryl, wherein each R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jHave the definitions as described in the present invention.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable, and should be understood in a broad sense, which means that the specific items expressed between the same symbols do not affect each other in different groups, or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "in particular denotes independently disclosed C₁Alkyl (methyl), C₂Alkyl (ethyl), C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group; the term "5-8 atom-containing oxygen-containing heterocyclic group" means 5 atom-containing oxygen-containing heterocyclic group, 6 atom-containing oxygenHeterocyclic group, oxygen-containing heterocyclic group consisting of 7 atoms and oxygen-containing heterocyclic group consisting of 8 atoms.

In the various parts of this specification, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, means a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1-8 carbon atoms, i.e., C_1-8An alkyl group; in some embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C_1-6An alkyl group; in some embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C_1-4An alkyl group; in some embodiments, the alkyl group contains 1-2 carbon atoms. The alkyl group is optionally substituted with one or more substituents described herein.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et, -CH)₂CH ₃) N-propyl (n-Pr, -CH)₂CH ₂CH ₃) Isopropyl (i-Pr, -CH (CH)₃) ₂) N-butyl (n-Bu, -CH)₂CH ₂CH ₂CH ₃) Isobutyl (i-Bu, -CH)₂CH(CH ₃) ₂) Sec-butyl (s-Bu, -CH (CH)₃)CH ₂CH ₃) Tert-butyl (t-Bu, -C (CH)₃) ₃) N-pentyl (-CH)₂CH ₂CH ₂CH ₂CH ₃) 2-pentyl (-CH (CH)₃)CH ₂CH ₂CH ₃) 3-pentyl (-CH (CH)₂CH ₃) ₂) 2-methyl-2-butyl (-C (CH)₃) ₂CH ₂CH ₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH ₃) ₂) 3-methyl-1-butyl (-CH)₂CH ₂CH(CH ₃) ₂) 2-methyl-1-butyl (-CH)₂CH(CH ₃)CH ₂CH ₃) N-hexyl (-CH)₂CH ₂CH ₂CH ₂CH ₂CH ₃) 2-hexyl (-CH (CH)₃)CH ₂CH ₂CH ₂CH ₃) 3-hexyl (-CH (CH)₂CH ₃)(CH ₂CH ₂CH ₃) 2-methyl-2-pentyl (-C (CH))₃) ₂CH ₂CH ₂CH ₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH ₃)CH ₂CH ₃) 4-methyl-2-pentyl (-CH (CH)₃)CH ₂CH(CH ₃) ₂) 3-methyl-3-pentyl (-C (CH)₃)(CH ₂CH ₃) ₂) 2-methyl-3-pentyl (-CH (CH)₂CH ₃)CH(CH ₃) ₂)2, 3-dimethyl-2-butyl (-C (CH)₃) ₂CH(CH ₃) ₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH ₃) ₃) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In some embodiments, the alkenyl group comprisesContaining 2 to 8 carbon atoms, i.e. C_2-8An alkenyl group; in some embodiments, the alkenyl group contains 2 to 6 carbon atoms, i.e., C_2-6An alkenyl group; in some embodiments, the alkenyl group contains 2 to 4 carbon atoms, i.e., C_2-4An alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH ₂) Propenyl (-CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms, i.e., C_2-8An alkynyl group; in some embodiments, alkynyl groups contain 2-6 carbon atoms, i.e., C_2- ₆An alkynyl group; in some embodiments, alkynyl groups contain 2-4 carbon atoms, i.e., C_2-4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like.

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule via an oxygen atom, i.e. -O-alkyl, wherein the alkyl group has the meaning as described herein. In some embodiments, the alkoxy group contains 1 to 12 carbon atoms, i.e., C_1-12An alkoxy group; in some embodiments, the alkoxy group contains 1 to 6 carbon atoms, i.e., C_1-6An alkoxy group; in some embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C_1- ₄An alkoxy group; in some embodiments, the alkoxy group contains 1-3 carbon atoms, i.e., C_1-3An alkoxy group.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH ₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH ₂CH ₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃) ₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH ₂CH ₂CH ₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH ₃) ₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH ₂CH ₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃) ₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH ₂CH ₂CH ₂CH ₃) 2-pentyloxy (-OCH (CH)₃)CH ₂CH ₂CH ₃) 3-Pentoxy (-OCH (CH))₂CH ₃) ₂) 2-methyl-2-butoxy (-OC (CH))₃) ₂CH ₂CH ₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH ₃) ₂) 3-methyl-l-butoxy (-OCH)₂CH ₂CH(CH ₃) ₂) 2-methyl-l-butoxy (-OCH)₂CH(CH ₃)CH ₂CH ₃) And so on.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is one or two C_1-6Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-6An alkylamino group. In some embodiments, alkylamino is one or two C_1-4Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-4An alkylamino group. In some embodiments, alkylamino is one or two C_1-3Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-3An alkylamino group. In some embodiments, alkylamino is one or two C_1-2Alkylamino radicals in which the alkyl radical is bound to the nitrogen atom, i.e. C_1-2An alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), N, N-dimethylamino, N, N-diethylamino, and the like.

The term "alkylthio" refers to a group containing C_1-10Is linked to a divalent sulfur atom, in some embodiments alkylthio is C_1-6An alkylthio group; in some embodiments, alkylthio is C_1-4Alkylthio groups, and such examples include, but are not limited to methylthio (-SCH)₃). The alkylthio group is optionally substituted with one or more substituents described herein.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" respectively denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms. Examples include, but are not limited to, fluoromethyl (-CH)₂F) Difluoromethyl (-CHF)₂) Trifluoromethyl (-CF)₃) Fluoroethyl (-CHFCH)₃,-CH ₂CH ₂F) Difluoroethyl (-CF)₂CH ₃,-CHFCH ₂F,-CH ₂CHF ₂) Perfluoroethyl, fluoropropyl (-CHFCH)₂CH ₃,-CH ₂CHFCH ₃,-CH ₂CH ₂CH ₂F) Difluoropropyl (-CF)₂CH ₂CH ₃,-CFHCFHCH ₃,-CH ₂CH ₂CHF ₂,-CH ₂CF ₂CH ₃,-CH ₂CHFCH ₂F) Trifluoroethyl (-CH)₂CF ₃,-CHFCHF ₂,-CF ₂CH ₂F) Trifluoropropyl, 1-dichloroethyl, 1, 2-dichloropropyl, alpha-hydroxy-n-butyl, alpha-butyl, beta-ethyl, beta-butyl, beta-ethyl, beta-butyl, beta-methyl, beta-butyl, beta-ethyl, beta-methyl, beta-butyl, beta-methyl, beta-ethyl, beta-methyl, beta-butyl, beta-methyl, beta-ethyl, beta-butyl, beta-methyl, beta-ethyl, beta-methyl, beta-ethyl, beta-butyl, beta-ethyl, beta-,Trifluoromethoxy (-OCF)₃) Difluoromethoxy (-OCHF)₂)2, 2, 2-trifluoroethoxy (-OCH)₂CF ₃) And the like.

The term "cycloalkyl" denotes a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 14 ring atoms. In some embodiments, cycloalkyl contains 3 to 12 carbon atoms, i.e., C_3-12A cycloalkyl group; in some embodiments, cycloalkyl contains 3 to 8 carbon atoms, i.e., C_3-8A cycloalkyl group; in some embodiments, cycloalkyl contains 3 to 6 carbon atoms, i.e., C_3-6A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "aryl" or "aromatic ring" are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a 3 to 7 atom-forming carbocyclic ring with one or more attachment points to the remainder of the molecule. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may be optionally substituted with one or more substituents described herein.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent as described herein).

The term "heterocyclyl" refers to a mono-, bi-or tricyclic ring system containing 3 to 14 ring atoms, wherein at least one ring atom is selected from heteroatoms, said heteroatoms having the meaning as indicated in the present invention. "Heterocyclyl" may be fully saturated or contain one or more unsaturations, but not one aromatic ring. The terms "heterocyclyl", "heterocyclic" and "heterocycle" are used interchangeably herein. In some embodiments, heterocyclyl is a heterocyclyl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., a heterocyclyl consisting of 5 to 10 atoms; in some embodiments, heterocyclyl is a heterocyclyl consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., a heterocyclyl consisting of 5 to 8 atoms; in some embodiments, heterocyclyl is a heterocyclyl consisting of 3-6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., a heterocyclyl consisting of 3-6 atoms; in some embodiments, heterocyclyl is a heterocyclyl consisting of 5-6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., a heterocyclyl consisting of 5-6 atoms; in some embodiments, heterocyclyl is a 5-8 ring member containing 1,2,3, or 4 heteroatoms of O and 0, 1,2,3, or 4 heteroatoms independently selected from S and N, i.e., an oxygen-containing heterocyclyl group of 5-8 atoms; in some embodiments, heterocyclyl is a 5-6 ring member containing 1,2,3, or 4 heteroatoms of O and 0, 1,2,3, or 4 heteroatoms independently selected from S and N, i.e., an oxygen-containing heterocyclyl group of 5-6 atoms.

Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, thiazolidinyl, dioxanyl, dithianyl, thiaoxazanylAlkyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepanyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]A hept-5-yl group, a pharmaceutically acceptable salt thereof,

and so on. In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "heteroaryl" denotes a mono-or polyvalent mono-, bi-or tricyclic ring system containing 5 to 10 ring atoms, or 5 to 8 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, said heteroatoms having the definitions described herein. The terms "heteroaryl", "heteroaromatic ring" or "heteroaromaticThe compounds "are used interchangeably herein. When a heteroaryl group is present-CH₂When said radical is-CH₂-the group is optionally replaced by-C (═ O) -. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., heteroaryl consisting of 5 to 10 atoms. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., heteroaryl consisting of 5 to 8 atoms. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N, i.e., heteroaryl consisting of 5 to 6 atoms. In some embodiments, heteroaryl is heteroaryl consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms of O and 0, 1,2,3, or 4 heteroatoms independently selected from S and N, i.e., an oxo-heteroaryl consisting of 5 to 8 atoms; in some embodiments, heteroaryl is heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3, or 4 heteroatoms of O and 0, 1,2,3, or 4 heteroatoms independently selected from S and N, i.e., an oxo-heteroaryl consisting of 5 to 6 atoms. The heteroaryl group is optionally substituted with one or more substituents described herein.

Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl, 3-pyrazolyl), isothiazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl), thiadiazolyl (e.g., 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl), pyrazinyl, 1,3, 5-triazinyl; the following bicyclic or tricyclic groups are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, and the like. The heteroaryl group is optionally substituted with one or more substituents described herein.

The term "m-atomic" where m is an integer typically describes the number of ring-forming atoms in the molecule, which is m. For example, piperidinyl is a heterocyclyl consisting of 6 ring atoms, and naphthyl is an aryl group consisting of 10 atoms.

The term "halogen" refers to F, Cl, Br or I.

The term "D" refers to deuteration, i.e.²H。

The term "carboxy", denotes — COOH, whether used alone or in combination with other terms, such as "carboxyalkyl".

The term "carbonyl", denotes- (C ═ O) -, whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy".

The term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc).Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH ₂SO ₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

As described in the present invention, the substituent R⁰The ring system formed by a ring bound to the center represents the substituent R⁰Substitution may only be made at any substitutable or any reasonable position on the ring to which it is attached. For example, formula b represents a substituent R⁰May be substituted at any possible substituted position on the C ring as shown in formulas b-1 to b-3:

the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The term "syndrome X", also referred to as a condition, disease of metabolic syndrome, the condition of which is described in detail in Johannsson et al, j.clin.endocrinol.metab.,1997,82, 727-.

As used herein, "inflammatory disease," "inflammatory disease," or "inflammatory disease" refers to any disease, disorder, or symptom of excessive inflammatory symptoms, host tissue damage, or loss of tissue function resulting from an excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation," "inflammatory" or "inflammatory" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Compositions, formulations and administration of the compounds of the invention

The present invention relates to a pharmaceutical composition comprising a compound of the present invention or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite and pharmaceutically acceptable salt thereof or a prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable adjuvant. The amount of compound in the pharmaceutical composition of the present invention is effective to detectably inhibit SSAO/VAP-1 activity in a biological sample or patient.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which as used herein, include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.

Some examples of substances that may be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), Powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifiers, coating agents, sweetening and flavoring agents, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.

The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), or by nasal spray, etc., depending on the severity of the disease.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections. For example, injectable formulations can be sterilized by filtration through a bacterial-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble, since the rate of absorption of the compound depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Alternatively, injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid, the rate of release of the compounds being controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating adjuvants, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable auxiliary, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar- -agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, sodium stearate, and sodium stearate, magnesium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using such adjuvants as lactose or milk sugar as well as high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

The active compound may also be in the form of a microencapsulated form with one or more of the above-mentioned excipients. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, for example tableting lubricants and other tableting auxiliaries, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

Formulations for topical or transdermal administration of the compounds of the present invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a dermal patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. These suspensions may be prepared following techniques known in the art using suitable dispersing or wetting agents and suspending agents. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers that are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing the agent and the non-irritating excipient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Local instillation to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical skin patches may also be used.

For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.

Use of the Compounds and compositions of the invention

The present invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the inhibition of SSAO/VAP-1 or for the prevention, treatment or alleviation of an inflammatory disease and/or an inflammation-related disease or diabetes and/or a diabetes-related disease.

The present invention relates to a method of inhibiting SSAO/VAP-1 activity, or a method of preventing, treating or ameliorating an inflammatory disease and/or an inflammation-related disease or diabetes and/or a diabetes-related disease using a compound or pharmaceutical composition described herein; the method is administering to an individual in need thereof a therapeutically effective amount of the compound or the pharmaceutical composition. Also, the present invention provides the above-mentioned compounds or pharmaceutical compositions thereof can be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.

The present invention relates to the use of a compound or pharmaceutical composition according to the invention for inhibiting SSAO/VAP-1 activity, or for preventing, treating or alleviating an inflammatory disease and/or an inflammation-related disease or diabetes and/or a diabetes-related disease.

In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

An "effective amount," "therapeutically effective amount," or "effective dose" of a compound of the invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or reduce the severity of one or more of the conditions referred to herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis and detection methods

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

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

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known drugs other than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The structure of the compound is determined by nuclear magnetic resonance¹H-NMR、 ¹³C-NMR or/and¹⁹F-NMR).¹H-NMR、 ¹³C-NMR、 ¹⁹F-NMR chemical shifts (δ) are given in parts per million (ppm).¹H-NMR、 ¹³C-NMR、 ¹⁹F-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer in deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD or MeOH-d₄) Or deuterated dimethyl sulfoxide (DMSO-d)₆). TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), dt (doublets of triplets, doublets), td (triplets of doublets, triplet), brs (broad singlets). Coupling constant J, in Hertz (Hz).

Preparative purification or preparative resolution generally uses a Novasep pump 250 high performance liquid chromatograph.

The LC-MS was determined using an Agilen-6120 Quadrupole LC/MS mass spectrometer.

The column chromatography generally uses 300-400 mesh silica gel in Qingdao ocean chemical industry as a carrier.

The starting materials of the present invention are known and commercially available, are available from Shanghai Accela Company, Annage Company, Bailingwei Company (J & K), Tianjin Afaha Angsa Company (Alfa Company), etc., or may be synthesized using or according to methods known in the art.

The nitrogen atmosphere refers to a reaction flask connected with a nitrogen balloon or steel kettle with the volume of about 1L.

The hydrogen atmosphere refers to a reaction bottle connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L.

In the examples, unless otherwise specified, the solution refers to an aqueous solution.

In the examples, unless otherwise specified, the reaction temperature was room temperature; in the examples, the room temperature is 20 ℃ to 40 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.

HPLC refers to high performance liquid chromatography;

HPLC was performed using Agilent 1260 high pressure liquid chromatograph (Eclipse Plus C184.6X 150mm 3.5um column);

HPLC test conditions: column temperature: 30 ℃ PDA: 210nm, 254nm

Mobile phase: phase A: 0.1% potassium phosphate phase B: flow rate of acetonitrile: 1.0mL/min

Mobile phase gradients are shown in table a:

TABLE A

Time (min)

Gradient of mobile phase A

Gradient of mobile phase B

0	90％	10％
5-8	70％	30％
12-18	80％	20％
18.1-22	90％	10％

The analytical LC/MS/MS system in the biological test experiment includes Agilent 1200 series vacuum degassing furnace, binary injection pump, orifice plate automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with electric spray ionization source (ESI). Quantitative analysis was performed in MRM mode, with the parameters of the MRM transformation as shown in table B:

TABLE B

Full scan	50→1400
Fragmentation voltage	230V
Capillary voltage	55V
Dryer temperature	350℃
Atomizer	0.28MPa
Flow rate of dryer	10L/min

Analysis 5. mu.L of sample was injected using an Agilent XDB-C18, 2.1X 30mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase was 0.1% aqueous formic acid (A) and 0.1% methanolic formic acid (B). The flow rate was 0.4 mL/min. Mobile phase gradients are shown in table C:

watch C

Time	Gradient of mobile phase B
0.5min	5％
1.0min	95％
2.2min	95％
2.3min	5％
5.0min	Terminate

Also used for the analysis was an Agilent 6330 series LC/MS spectrometer equipped with a G1312A binary syringe pump, a G1367A auto sampler and a G1314C UV detector; the LC/MS/MS spectrometer uses an ESI radiation source. The appropriate cation model treatment and MRM conversion for each analyte was performed using standard solutions for optimal analysis. During the analysis a Capcell MP-C18 column was used, with the specifications: 100X 4.6mm I.D., 5. mu.M (Phenomenex, Torrance, California, USA). The mobile phase was 5mM ammonium acetate, 0.1% aqueous methanol (a): 5mM ammonium acetate, 0.1% methanolic acetonitrile solution (B) (70/30, v/v); the flow rate is 0.6 mL/min; the column temperature was kept at room temperature; 20 μ L of sample was injected.

The following acronyms are used throughout the invention:

DMSO-d ₆: deuterated dimethyl sulfoxide; boc: a tert-butoxycarbonyl group;

CDCl ₃: deuterated chloroform; % wt,% mass: weight percentage;

CD ₃OD: deuterated methanol; mL, mL: ml;

μ L, μ L: microliter; mol/L: moles per liter;

mol: molar ratio; mmol: millimole;

g: g; h: hours;

H ₂: hydrogen gas; min: the method comprises the following steps of (1) taking minutes;

N ₂: nitrogen gas; MPa: megapascals;

atm: standard atmospheric pressure.

General synthetic methods

A typical synthetic procedure for the preparation of the disclosed compounds is shown in scheme 1 below. Unless otherwise indicated, rings A and R¹With the definition as described herein, PG is an amino protecting group.

Synthesis scheme 1:

the compounds having the structure shown in general formula (I-A) can be prepared by general synthetic methods described in scheme 1, and specific procedures can be referred to examples. Firstly, diazotizing a carboxyl group of a compound (I-a) to obtain a compound (I-b); then reacting with organic solution of hydrogen bromide to obtain a compound (I-d); alternatively, the compound (I-d) can be obtained by subjecting the compound (I-c) to bromination. Then, carrying out amino substitution on the compound (I-d) to form salt, and obtaining salt of the compound (I-f); alternatively, the compound (I-d) may be subjected to azide to obtain the compound (I-e), and then subjected to azide reduction to form a salt to obtain the salt of the compound (I-f). Then, subjecting the salt of the compound (I-f) to amino protection to obtain a compound (I-g); alternatively, the compound (I-g) can be prepared from the compound (I-e) in the presence of an acid anhydride (e.g., Boc)₂O) is subjected to azide reduction in the presence of oxygen. Finally, carrying out a Wittig reaction on the compound (I-g) to obtain a compound (I-h); and removing amino protection from the compound (I-h) to obtain the target compound shown as the general formula (I-A). In general, the free amino compound, i.e., the target compound represented by the formula (I-A), is converted into an acid addition salt for convenient handling and improved chemical stability, and examples of the acid addition salt include, but are not limited to, hydrochloride, hydrobromide and methanesulfonate salts.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Preparation examples

Example 1 (E) -3-fluoro-2- (6-fluoro chroman-2-yl) prop-2-en-1-amino hydrochloride (Compound E1-1) and (Z) -3-fluoro-2- (6-fluoro chroman-2-yl) prop-2-en-1-amino hydrochloride (Compound E1-2)

Step 1) 2-diazo-1- (6-fluoro chroman-2-yl) ethanone

Dissolving 6-fluoro chroman-2-carboxylic acid (17.5g,89.2mmol) in tetrahydrofuran (500mL), adding triethylamine (27mL,162mmol) at 0 ℃, dropwise adding isobutyl chloroformate (16.5mL,125mmol), reacting for 20 hours at 40 ℃ with vigorous stirring, cooling the reaction solution to room temperature, adding acetonitrile (500mL), dropwise adding n-hexane solution of trimethylsilylated diazomethane (89mL,180mmol,2.0mol/L) at 0 ℃, and naturally heating to room temperature for reacting for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound 1b (19.6g, yield 99%) as a yellow oil.

Step 2) 2-bromo-1- (6-fluoro chroman-2-yl) ethanone

2-diazo-1- (6-fluoro chroman-2-yl) ethanone (19.6g,89.0mmol) was dissolved in ethyl acetate (100mL) and a solution of hydrogen bromide in acetic acid (18mL,33 mass%) was slowly added dropwise at 0 ℃. To the reaction solution was added petroleum ether (100mL), warmed to room temperature, washed successively with a saturated sodium chloride solution (50mL × 2) and a saturated sodium bicarbonate solution (50mL), the organic phase was dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/30] to give the title compound (23.5g, yield 97%) as a white solid.

Step 3) 2-azido-1- (6-fluorochroman-2-yl) ethanone

2-bromo-1- (6-fluoro-chroman-2-yl) ethanone (23.5g,86.0mmol) was dissolved in acetone (100mL), and sodium azide (5.6g,86mmol) was added to react at room temperature for 2 hours. The reaction was quenched with water (100mL), extracted with ethyl acetate (300mL), and the organic phase was washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound (18.4g, 91% yield) as a white solid.

Step 4) 2-amino-1- (6-fluoro chroman-2-yl) ethanone hydrochloride

2-azido-1- (6-fluorochroman-2-yl) ethanone (18.4g,78.2mmol) was dissolved in a solution of methanol (100mL) and hydrogen chloride in ethyl acetate (50mL,3.0mol/L), 10% palladium on carbon (1.8g) was added to replace hydrogen (3MPa), and the reaction was hydrogenated for 6 hours. The reaction solution was filtered, the filtrate was collected and concentrated, an ethyl acetate solution of hydrogen chloride (30mL,4.0mol/L) was added to the residue, a white solid precipitated, and the filtrate was filtered to collect a filter cake to obtain the title compound (5.6g, 29% yield).

Step 5) N- [2- (6-Fluorochroman-2-yl) -2-oxo-ethyl]Carbamic acid tert-butyl ester

2-amino-1- (6-fluoro-chroman-2-yl) ethanone hydrochloride (1.0g,4.1mmol) was added to di-tert-butyl dicarbonate (5.0mL,22mmol) and reacted at 40 ℃ for 24 hours. Water (10mL) was added to the reaction solution, extraction was performed with ethyl acetate (30mL), the organic phase was washed with a saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound (1.3g, yield 100%) as a colorless oil.

Step 6) N- [ 3-fluoro-2- (6-fluoro chroman-2-yl) allyl]Carbamic acid tert-butyl ester

Fluoromethyl (triphenyl) phosphine tetrafluoroborate (2.6g,6.8mmol) was dissolved in tetrahydrofuran (10mL,123mmol), -a solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (4.5mL,9.0mmol,2mol/L) was added at 20 ℃, after stirring for 12 minutes, a solution of tert-butyl N- [2- (6-fluoro chroman-2-yl) -2-oxo-ethyl ] carbamate (1.4g,4.5mmol) in tetrahydrofuran (3mL) was slowly added dropwise, allowed to warm to room temperature, and reacted for 3.5 hours. The reaction was quenched with water (5mL) at 0 ℃, extracted with ethyl acetate (10mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound (0.60g, yield 41%) as a yellow solid.

Step 7) (E) -3-fluoro-2- (6-fluorochroman-2-yl) prop-2-en-1-amino hydrochloride (Compound E1-1) and (Z) -3-fluoro-2- (6-fluorochroman-2-yl) prop-2-one Ene-1-amino hydrochloride (Compound E1-2)

Tert-butyl N- [ 3-fluoro-2- (6-fluorochroman-2-yl) allyl ] carbamate (0.60g,1.8mmol) was dissolved in ethyl acetate (0.5mL), and an ethyl acetate solution of hydrogen chloride (2mL,4mol/L) was added to the solution to react at room temperature for 2 hours. The reaction solution was concentrated, and the obtained solid was subjected to preparative purification and treatment with a solution of hydrogen chloride in ethyl acetate to give the title compound E1-1(0.23g, yield 47%) and the title compound E1-2(0.12g, yield 25%) as a yellow solid.

Compound E1-1: MS (ESI, pos.ion) M/z 226.2[ M-Cl ]] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)8.17(s,3H),7.24(d,J＝82.0Hz,1H),7.00-6.89(m,2H),6.84(dd,J＝8.8,5.0Hz,1H),4.66(d,J＝10.6Hz,1H),2.96-2.83(m,1H),2.83-2.70(m,1H),2.05(d,J＝7.9Hz,1H),1.95-1.81(m,1H)。

Compound E1-2: MS (ESI, pos.ion) M/z 226.2[ M-Cl ]] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)8.07(s,3H),7.12(d,J＝81.2Hz,1H),6.99-6.85(m,3H),4.99(d,J＝10.8Hz,1H),3.00-2.85(m,1H),2.76(dd,J＝16.9,3.7Hz,1H),2.07-1.88(m,2H),1.42-1.09(m,2H)。

EXAMPLE 2 (E) -2- [1- (aminomethyl) -2-fluoro-vinyl ] -N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (E2-1) and (Z) -2- [1- (aminomethyl) -2-fluoro-vinyl ] -N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (E2-2)

Step 1) Ethyl 2, 3-dibromopropionate

Ethyl acrylate (15g,150mmol) was dissolved in carbon tetrachloride (100mL), and a solution of bromine (9.3mL,180mmol) in carbon tetrachloride (15mL) was added dropwise at 0 ℃ and after stirring for 5 minutes, the temperature was raised to 60 ℃ for reaction for 2 hours. The reaction solution was concentrated to give the title compound (38.9g, yield 100%) as a yellow liquid.

Step 2) 2-ethoxycarbonyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxylic acid

Ethyl 2, 3-dibromopropionate (38.9g,150mmol) and 3-amino-4-hydroxy-benzoic acid (19g,124mmol) were dissolved in N, N-dimethylformamide (200mL), and potassium carbonate (51.9g,372mmol) was added and reacted at 45 ℃ for 18 hours. The reaction was quenched by addition of water (200mL), pH adjusted to 3 with 4N hydrochloric acid, extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound (13.0g, 42% yield) as a brown solid.

MS(ESI,pos.ion)m/z:252.1[M+1] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)7.31-7.14(m,2H),6.82(d,1H),5.04(s,1H),4.13(dd,2H),3.44(d,3H),1.17(t,3H)。

Step 3)6- (tert-butylcarbamoyl) -3, 4-dihydro-2H-1, 4-benzoxazine-2-carboxylic acid ethyl ester

Dissolving 2-ethoxycarbonyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxylic acid (13g,52mmol) in dichloromethane (100mL), adding 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (22.7g,57mmol), dropwise adding tert-butylamine (10.9mL,103mmol) and triethylamine (8.7mL,62mmol) at 0 ℃, and heating to room temperature for reaction for 4 hours. The reaction was quenched by addition of water (50mL), extracted with dichloromethane (100mL × 2), the combined organic phases were washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was subjected to silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1]Purification gave the title compound (13.1g, 82.6% yield) asYellow solid. MS (ESI, pos. ion) M/z 307.3[ M + 1]] ⁺。

Step 4) 4-benzyl-6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzoxazine-2-carboxylic acid ethyl ester

Ethyl 6- (tert-butylcarbamoyl) -3, 4-dihydro-2H-1, 4-benzoxazine-2-carboxylate (13.1g,42.8mmol) was dissolved in N, N-dimethylformamide, and potassium carbonate (17.9g,128mmol), benzyl bromide (15.6mL,129mmol) and tetrabutylammonium iodide (161mg,0.427mmol) were added in this order and reacted at 100 ℃ for 24 hours. The reaction was quenched by addition of water (200mL), extracted with ethyl acetate (100mL × 3), the combined organic phases were washed with saturated sodium chloride solution (70mL × 3), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 6/1] to give the title compound (16.8g, yield 99%) as a white solid.

MS(ESI,pos.ion)m/z:397.3[M+1] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)7.41(s,1H),7.39-7.23(m,6H),7.16(dd,J＝10.4,2.0Hz,2H),6.84(d,J＝8.1Hz,1H),5.12(t,J＝3.2Hz,1H),4.60(d,J＝15.7Hz,1H),4.37(dd,J＝15.5,9.5Hz,1H),4.05(dd,J＝12.8,5.5Hz,1H),3.46(ddd,J＝29.2,12.3,3.3Hz,2H),1.33(s,9H),1.14(t,J＝7.1Hz,3H)。

Step 5) 4-benzyl-6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzoxazine-2-carboxylic acid

Ethyl 4-benzyl-6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzoxazine-2-carboxylate (16.8g,42.4mmol) was dissolved in tetrahydrofuran (150mL), and an aqueous solution (30mL) of lithium hydroxide (3.11g,127mmol) was added to react at room temperature for 3 hours. Water (50mL) was added to the reaction solution, extraction was performed with ethyl acetate (50mL), the organic phase was washed with water (50mL × 2), the aqueous phase was collected, pH was adjusted to 2 with 1N hydrochloric acid, a white solid was precipitated, filtration was performed, and the cake was dried to obtain the title compound (7.47g, yield 48%) as a white solid.

MS(ESI,pos.ion)m/z:369.2[M+1] ⁺。

Step 6) 4-benzyl-N-tert-butyl-2- (2-diazoacetyl) -2, 3-dihydro-1, 4-benzoxazine-6-carboxamide

4-benzyl-6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzoxazine-2-carboxylic acid (7.47g,20.3mmol) was dissolved in tetrahydrofuran (70mL), isobutyl chloroformate (3.95mL,30.5mmol) and diisopropylethylamine (9.21mL,52.7mmol) were added dropwise at 0 ℃ and reacted at 0 ℃ for 4 hours, acetonitrile (20mL) was added, trimethylsilylated diazomethane (20mL,40mmol) was added dropwise and reacted at room temperature for 16 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound (4.97g, yield 62%) as a white solid.

MS(ESI,pos.ion)m/z:393.3[M+1] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm)7.42-7.31(m,2H),7.28(d,J＝4.8Hz,4H),7.20(s,1H),7.01(d,J＝8.2Hz,1H),6.90(d,J＝8.2Hz,1H),5.74(d,J＝22.7Hz,2H),4.55-4.43(m,2H),3.59-3.46(m,2H),1.42(s,9H)。

Step 7) 4-benzyl-2- (2-bromoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzoxazine-6-carboxamide

4-benzyl-N-tert-butyl-2- (2-diazoacetyl) -2, 3-dihydro-1, 4-benzoxazine-6-carboxamide (4.97g,12.7mmol) was dissolved in ethyl acetate (150mL), a solution of hydrobromic acid in acetic acid (2.52mL,13.9mmol, 33%) was added dropwise at 45 ℃ and the reaction was continued for 1 hour. To the reaction solution was added methyl tert-butyl ether (10mL), and after warming to room temperature, saturated sodium bicarbonate solution was added to adjust pH to 7, the organic phase was separated, washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give the title compound (2.8g, 50%) as a yellow solid.

MS(ESI,pos.ion)m/z:446.1[M+1] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)7.45-7.38(m,1H),7.35(t,J＝7.3Hz,2H),7.27(t,J＝8.1Hz,3H),7.21-7.12(m,2H),6.88(dd,J＝8.4,3.2Hz,1H),5.19(t,J＝3.7Hz,1H),4.64-4.44(m,4H),3.61(dd,J＝12.6,4.4Hz,1H),3.50(dd,J＝12.7,3.2Hz,1H),1.32(s,9H)。

Step 8)2- (2-azidoacetyl) -4-benzyl-N-tert-butyl-2, 3-dihydro-1, 4-benzoxazine-6-carboxamide

4-benzyl-2- (2-bromoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzoxazine-6-carboxamide (4.27g,9.59mmol) was dissolved in acetone (60mL), and sodium azide (693mg,10.5mmol) was added to react at room temperature for 3 hours. The reaction was quenched by the addition of water (10mL), extracted with ethyl acetate (50 mL. times.2), and the combined organic phases were washed with saturated sodium chloride solution (40 mL. times.2), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound (3.91g, 100% yield) as a pale yellow solid.

Step 9)2- (2-aminoacetyl) -N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride

2- (2-azidoacetyl) -4-benzyl-N-tert-butyl-2, 3-dihydro-1, 4-benzoxazine-6-carboxamide (3.7g,9.1mmol) was dissolved in methanol (20mL), and a solution of hydrogen chloride in ethyl acetate (10mL,4.0mol/L) and 10% palladium on carbon (0.40g) were added to replace the hydrogen (3MPa), followed by hydrogenation for 12 hours. The reaction solution was filtered, the filtrate was collected and concentrated, and to the residue was added a solution of hydrogen chloride in ethyl acetate (8mL,4.0mol/L) and concentrated to give the title compound (3.0g, yield 100%) as a white solid.

Step 10) N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-2H-1, 4-benzoxazin-2-yl]-2-oxo-ethyl]Carbamic acid tert-butyl ester

2- (2-Aminoacetyl) -N-tert-butyl-3, 4-dihydro-1, 4-benzoxazine-6-carboxamide hydrochloride (3.5g,11mmol) was added to tetrahydrofuran (20mL), di-tert-butyl dicarbonate (10mL,43mmol) and potassium carbonate (3.7g,27mmol) were added, and the reaction was carried out at room temperature for 12 hours. The reaction was quenched by addition of water (50mL), extracted with ethyl acetate (50mL × 3), the combined organic phases were washed with saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound (1.55g, yield 37%) as a yellow solid.

MS(ESI,pos.ion)m/z:414.2[M+Na] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)7.43(s,1H),7.07-6.97(m,3H),6.84-6.76(m,1H),5.96(s,1H),4.92(d,J＝3.5Hz,1H),4.07(dd,J＝18.9,5.6Hz,1H),3.86(dd,J＝18.9,5.9Hz,1H),3.43(dd,J＝17.3,7.7Hz,2H),1.37(s,9H),1.34(s,9H)。

Step 11) N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-2H-1, 4-benzoxazin-2-yl]-3-fluoro-allyl]Carbamic acid tert-butyl ester

Fluoromethyl (triphenyl) phosphine tetrafluoroborate (2.7g,7.1mmol) was dissolved in anhydrous tetrahydrofuran (40mL), sodium bis (trimethylsilyl) amide (5.4mL,11mmol) was added dropwise at-20 ℃, after stirring for 30 minutes, a solution of tert-butyl N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-1, 4-benzoxazin-2-yl ] -2-oxo-ethyl ] carbamate (1.4g,3.6mmol) in tetrahydrofuran (1mL) was added dropwise, slowly warmed to room temperature, and reacted for 12 hours. The reaction was quenched by addition of ice water (10mL), extracted with ethyl acetate (40mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30mL × 2), dried over anhydrous sodium sulfate, concentrated with suction filtration, and the resulting residue was subjected to silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound (1.0g, yield 69%) as a yellow solid.

MS(ESI,pos.ion)m/z:408.3[M+H] ⁺。

Step 12) (E) -2- [1- (aminomethyl) -2-fluoro-vinyl]-N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (Compound E2- 1) And (Z) -2- [1- (aminomethyl) -2-fluoro-vinyl]-N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (Compound E2-2)

3L (1.1g,2.7mmol) of tert-butyl N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-2H-1, 4-benzoxazin-2-yl ] -3-fluoro-allyl ] carbamate was dissolved in ethyl acetate (5mL), and a solution of hydrogen chloride in ethyl acetate (10mL,4.0mol/L) was added to the solution and reacted at room temperature for 30 minutes. The reaction solution was concentrated, and the obtained solid was subjected to preparative purification and treatment with an ethyl acetate solution of hydrogen chloride to give title compound E2-1(0.49g, yield 53%, HPLC purity: 93.1%) and title compound E2-2(0.12g, yield 13%, HPLC purity: 95.1%) as brown solids.

Compound E2-1: MS (ESI, pos.ion) M/z 308.2[ M-Cl ]] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)(s,3H),7.45(s,1H),7.37-7.10(m,2H),7.05(dd,J＝8.3,2.0Hz,1H),6.76(d,J＝8.3Hz,1H),5.15(d,J＝138.1Hz,1H),4.76(d,J＝7.9Hz,1H),3.60(s,2H),3.48(dd,J＝12.3,2.3Hz,1H),3.22(dd,J＝12.2,8.2Hz,1H),1.34(s,9H)。

Compound E2-2: MS (ESI, pos.ion) M/z 308.3[ M-Cl] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)8.22(s,3H),7.44(s,1H),7.17(dd,J＝41.4,39.5Hz,2H),7.06(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝8.3Hz,1H),4.97(dd,J＝7.2,4.1Hz,2H),3.54(s,2H),3.40-3.25(m,2H),1.35(s,9H)。

EXAMPLE 3 (E) -2- [1- (aminomethyl) -2-fluoro-vinyl ] -N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (Compound E3)

Step 1) 2-ethoxycarbonyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxylic acid

Ethyl 2, 3-dibromopropionate (10.3g,40mmol) and potassium carbonate (22.6g,164mmol) were added to a solution of 3, 4-dihydroxy-benzoic acid (5.0g,32mmol) in N, N-dimethylformamide (50mL) and reacted at 45 ℃ for 24 hours. After 0 ℃, pH was adjusted to 3 with 4N hydrochloric acid, extracted with ethyl acetate (100mL × 2), and the combined organic phases were washed successively with water (100mL) and saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound (8.2g, yield 100%) as a yellow oil.

MS(ESI,pos.ion)m/z:253.2[M+H] ⁺。

Step 2)6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzodioxin-2-carboxylic acid ethyl ester

2- (7-Azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (13.6g,36mmol) and tert-butylamine (4.1mL,39mmol) were added to a solution of 2-ethoxycarbonyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxylic acid (8.0g,32mmol) in dichloromethane (100mL), and diisopropylethylenediamine (7mL,42mmol) was added dropwise at 0 ℃ and reacted at room temperature for 11 hours. The reaction was quenched by addition of water (100mL), extracted with dichloromethane (50mL), the organic phase was washed with saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound (9.7g, yield 99.5%) as a white solid.

MS(ESI,pos.ion)m/z:308.1[M+H] ⁺。

Step 3)6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzodioxin-2-carboxylic acid

Lithium hydroxide (2.6g,62mmol) was added to a tetrahydrofuran/water mixed solution of ethyl 6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzodioxin-2-carboxylate (9.7g,32mmol) (v/v ═ 4/1,50mL), and the mixture was reacted at room temperature for 4 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid (4mol/L) at 0 ℃, extracted with ethyl acetate (100mL × 2), the combined organic phases were washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the obtained residue was slurried with ethyl acetate (30mL) to obtain the title compound (6.3g, yield 71%) as a white solid.

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)7.58(d,J＝8.7Hz,1H),7.37(dd,J＝28.7,20.1Hz,2H),6.92(dd,J＝33.2,8.4Hz,1H),5.17-5.03(m,1H),4.48(d,J＝10.2Hz,1H),4.33-4.24(m,1H),1.35(d,J＝3.9Hz,9H)。

Step 4) N-tert-butyl-2- (2-diazoacetyl) -2, 3-dihydro-1, 4-benzodioxin-6-carboxamide

Triethylamine (13mL,92mmol) was added to a solution of 6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzodioxin-2-carboxylic acid (18g,64mmol) in anhydrous tetrahydrofuran (2L) at 0 ℃ under nitrogen protection, isobutyl chloroformate (11mL,83mmol) was added dropwise, reacted for 2 hours, acetonitrile (2L) was added, trimethylsilylated diazomethane (60mL,120mmol,2mol/L) was added dropwise, and reacted at room temperature for 20 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound (12.2g, yield 62%) as a white solid.

MS(ESI,pos.ion)m/z:304.3[M+1] ⁺。

Step 5)2- (2-bromoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxamide

A hydrobromic acid acetic acid solution (8mL,44mmol, 33%) was added dropwise to a solution of N-tert-butyl-2- (2-diazoacetyl) -2, 3-dihydro-1, 4-benzodioxin-6-carboxamide (12.2g,40mmol) in ethyl acetate (200mL) at-45 ℃ for 1 hour of reaction. Saturated sodium bicarbonate was added dropwise at 0 ℃ to adjust pH 7, the organic phase was separated, washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was subjected to silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 6/1] to give the title compound (13.5g, yield 94%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:256.0[M+H] ⁺。

Step 6)2- (2-azidoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxamide

Sodium azide (2.5g,38mmol) was added to a solution of 2- (2-bromoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxamide (13.5g,38mmol) in acetone (100mL) and reacted at room temperature for 4.5 hours. The reaction was quenched by addition of water (80mL), extracted with ethyl acetate (80mL × 2), the combined organic phases were washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound (6.5g, yield 54%) as a pale yellow oil.

Step 7) N- [2- [6- (tert-butylcarbamoyl) -2, 3-dihydro-1, 4-benzodioxin-2-yl group]-2-oxo-ethyl radical]Carbamic acid tert-butyl ester

10% Palladium on carbon (0.60g) and di-tert-butyl dicarbonate (8.2g,38mmol) were added to a solution (150mL,4mol/L) of 2- (2-azidoacetyl) -N-tert-butyl-2, 3-dihydro-1, 4-benzodioxin-6-carboxamide (6.0g,19mmol) in ethyl acetate, and hydrogen (3MPa) was replaced, followed by hydrogenation for 9 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (50mL), the filtrate was collected, concentrated, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound (4.2g, yield 57%) as a white solid.

MS(ESI,pos.ion)m/z:393.1[M+H] ⁺。

Step 8) N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-1, 4-benzodioxin-2-yl group]-3-fluoro-allyl]Carbamic acid tert-butyl ester

Sodium bis (trimethylsilyl) amide (8.4mL,17mmol,2mol/L) was added dropwise to a suspension of fluoromethyl (triphenyl) phosphine tetrafluoroborate (4.82g,13mmol) in anhydrous tetrahydrofuran (40mL) at-20 ℃ under nitrogen, and after 20 minutes of reaction, a solution of N- [2- [6- (tert-butylcarbamoyl) -3, 4-dihydro-1, 4-benzoxazin-2-yl ] -2-oxo-ethyl ] carbamic acid tert-butyl ester (3.3g,8.4mmol) in tetrahydrofuran (15mL) was added dropwise and allowed to react at room temperature for 18 hours. The reaction was quenched by the addition of water (30mL) at 0 ℃, extracted with ethyl acetate (60mL × 2), the combined organic phases were washed with saturated sodium chloride solution (80mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound (0.61g, yield 18%) as a pale yellow thick substance.

MS(ESI,pos.ion)m/z:409.3[M+H] ⁺。

Step 9) (E) -2- [1- (aminomethyl) -2-fluoro-vinyl]-N-tert-butyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxamide hydrochloride (Compound E3)

A solution of hydrogen chloride in ethyl acetate (10mL, 4mol/L) was added to a solution of tert-butyl N-3-fluoro-2- [ [6- (4-fluorophenyl) -3-pyridine ] methoxy ] allyl ] carbamate (0.60g,1.5mmol) in ethyl acetate (20mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated, and the obtained residue was subjected to preparative purification and treatment with an ethyl acetate solution of hydrogen chloride to give the title compound E3(0.20g, yield 39%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:309.4[M-Cl] ⁺；

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)8.36(s,3H),7.60(d,J＝2.8Hz,1H),7.47-7.16(m,3H),6.95(dd,J＝13.1,8.4Hz,1H),4.97(s,1H),4.49(dd,J＝11.6,2.1Hz,1H),4.15(ddd,J＝14.0,11.7,8.1Hz,1H),3.63(d,J＝4.2Hz,2H),1.36(s,9H)。

Example 42- [ (E) -1- (aminomethyl) -2-fluoro-vinyl ] benzofuran-5-carboxylic acid methyl ester hydrochloride (compound E4)

Step 1) 3-formyl-4-hydroxybenzoic acid

4-hydroxybenzoic acid (15.3g,111mmol) was dissolved in trifluoroacetic acid (40mL), and a solution of hexamethylenetetramine (15.8g,112mmol) in trifluoroacetic acid (45mL) was added dropwise and reacted at 90 ℃ for 4.5 hours. The reaction solution was cooled to room temperature, hydrochloric acid (4mol/L,300mL) was added, stirred for 3 hours, filtered, the filter cake was washed with water (60 mL. times.3), the filter cake was collected and dried to give the title compound (15.4g, 84% yield) as a white solid.

MS(ESI,poi.ion)m/z:167.2[M+H] ⁺；

¹H NMR(600MHz,DMSO-d ₆)δ(ppm)11.57(s,1H),10.30(s,1H),8.23(d,J＝2.1Hz,1H),8.04(dd,J＝8.7,2.1Hz,1H),7.11(d,J＝8.7Hz,1H)。

Step 2) methyl 3-formyl-4-hydroxybenzoate

3-formyl-4-hydroxybenzoic acid (15.4g,92.9mmol) was dissolved in methanol (200mL), concentrated sulfuric acid (10mL) was added, and the reaction was carried out at 60 ℃ for 6 hours. The reaction was concentrated, and the resulting residue was added to water (50mL), extracted with ethyl acetate (50 mL. times.3), and the combined organic phases were washed with saturated sodium bicarbonate solution (30mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give the title compound (12.5g, yield 75%) as a white solid.

MS(ESI,neg.ion)m/z:179.1[M-H] ^-；

¹H NMR(400MHz,CDCl ₃)δ(ppm)11.31(br,1H),9.95(s,1H),8.32(d,J＝1.9Hz,1H),8.19(dd,J＝8.8,1.9Hz,1H),7.03(d,J＝8.8Hz,1H),3.93(s,3H)。

Step 3) methyl 2-acetylbenzofuran-5-carboxylate

Methyl 3-formyl-4-hydroxybenzoate (12.5g,69.4mmol) was dissolved in acetonitrile (200mL), and chloroacetone (7.8mL,98mmol) and potassium carbonate (9.7g,70mmol) were added and reacted at 80 ℃ for 3 hours. The reaction was cooled to room temperature, filtered with suction, the filter cake rinsed with dichloromethane (60 mL. times.3), the filtrate collected and concentrated, and the resulting residue recrystallized from ethanol (100mL) to give the title compound (7.0g, 46% yield) as a white solid.

MS(ESI,poi.ion)m/z:260.20[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm)8.11(s,1H),7.85(d,J＝8.7Hz,1H),7.59(d,J＝8.7Hz,1H),7.52(s,1H),2.62(s,3H),1.49(s,9H).

Step 4) methyl 2- (2-bromoacetyl) benzofuran-5-carboxylate

Methyl 2-acetylbenzofuran-5-carboxylate (3.0g,14mmol) was dissolved in acetic acid (60mL), pyridine perbromide bromide (4.8g,15mmol) was added in portions at 55 deg.C, and the reaction was carried out for 4 hours. The reaction was cooled to room temperature, concentrated, and the resulting residue was added to a saturated sodium bicarbonate solution (80mL), stirred for 10 minutes, filtered with suction, and the yield cake was dried to give the title compound (3.90g, yield 95%) as a yellow solid.

¹H NMR(400MHz,CDCl ₃)δ(ppm)8.49(s,1H),8.22(d,J＝8.8Hz,1H),7.72(s,1H),7.64(d,J＝8.6Hz,1H),4.45(s,2H),3.96(s,3H)。

Step 5)2- (2-Aminoacetyl) benzofuran-5-formic acid methyl ester hydrochloride

Methyl 2- (2-bromoacetyl) benzofuran-5-carboxylate (1.4g,4.8mmol) was dissolved in chloroform (30mL), and hexamethylenetetramine (0.74g,5.2mmol) was added and reacted at room temperature for 4 hours. The reaction solution was filtered, the filter cake was collected, and the resulting pale yellow solid was dissolved in ethanol (10mL), concentrated hydrochloric acid (5mL) was added, stirred at 0 ℃ for 30 minutes, filtered, the filter cake was rinsed with ethanol (2 mL. times.2), and the filter cake was collected and dried to give the title compound (0.44g, yield 34%) as a white solid.

MS(ESI,poi.ion)m/z:234.1[M-Cl] ⁺；

¹H NMR(600MHz,D ₂O)δ(ppm)8.21(s,1H),7.96(d,J＝8.4Hz,1H),7.81(s,1H),7.50(d,J＝8.8Hz,1H),4.59(s,2H),3.85(s,3H)。

Step 6)2- [2- (tert-Butoxycarbonylamino) acetyl group]Benzofuran-5-carboxylic acid methyl ester

Methyl 2- (2-aminoacetyl) benzofuran-5-carboxylate hydrochloride (0.22g,0.82mmol) was dissolved in methanol (5mL) and water (5mL), and di-tert-butyl dicarbonate (0.30mL,1.3mmol) and sodium hydrogen carbonate (0.17g,2.0mmol) were added in this order to react at room temperature for 24 hours. Water (20mL) was added to the reaction solution, extraction was performed with ethyl acetate (30mL), the organic phase was washed successively with water (20mL) and a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound (0.12g, yield 44%) as a colorless liquid.

MS(ESI,poi.ion)m/z:356.3[M+Na] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm)8.35(s,1H),8.10(d,J＝8.7Hz,1H),7.58(s,1H),7.51(d,J＝8.7Hz,1H),5.51(s,1H),4.58(d,J＝4.1Hz,2H),3.88(s,3H),1.41(s,9H)。

Step 7)2- [ (E) -1- [ (tert-butoxycarbonylamino) methyl group]-2-fluoro-vinyl]Benzofuran-5-carboxylic acid methyl ester and 2- [ (Z) -1- [ (tert-butoxycarbonylamino) Methyl radical]-2-fluoro-vinyl]Benzofuran-5-carboxylic acid methyl ester

Fluoromethyl (triphenyl) phosphine tetrafluoroborate (0.88g,2.3mmol) was added to tetrahydrofuran (10mL) with nitrogen replaced, sodium bis (trimethylsilyl) amide (1.6mL,3.2mmol,2mol/L) was added dropwise at-78 deg.C, and after 10 minutes of reaction, a solution of methyl 2- [2- (tert-butoxycarbonylamino) acetyl ] benzofuran-5-carboxylate (0.50g,1.5mmol) in tetrahydrofuran (5mL) was added dropwise, followed by allowing the reaction to naturally return to room temperature for 18 hours. The reaction was quenched by the addition of an ice-water mixture (10mL), extracted with ethyl acetate (20mL × 3), the combined organic phases were washed successively with water (20mL) and a saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, concentrated by suction filtration, and the resulting residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 8/1] to give the title compound methyl 2- [ (E) -1- [ (tert-butoxycarbonylamino) methyl ] -2-fluoro-vinyl ] benzofuran-5-carboxylate (0.13g, yield 25%) and the title compound methyl 2- [ (Z) -1- [ (tert-butoxycarbonylamino) methyl ] -2-fluoro-vinyl ] benzofuran-5-carboxylate (50mg, yield 9.7%), all were white solids.

Step 8)2- [ (E) -1- (aminomethyl) -2-fluoro-vinyl]Benzofuran-5-carboxylic acid methyl ester hydrochloride (compound E4)

Methyl 2- [ (E) -1- [ (tert-butoxycarbonylamino) methyl ] -2-fluoro-vinyl ] benzofuran-5-carboxylate (0.13g,0.37mmol) was dissolved in ethyl hydrogen chloride (5mL,4.0mol/L) and reacted at room temperature for 1 hour. The reaction solution was concentrated to give the title compound E4(0.11g, yield 100%) as a white solid.

MS(ESI,poi.ion)m/z:250.1[M-Cl] ⁺；

¹H NMR(400MHz,MeOD)δ(ppm)8.34(d,J＝1.5Hz,1H),8.05(dd,J＝8.7,1.7Hz,1H),7.84(d,J＝80.1Hz,1H),7.60(d,J＝8.7Hz,1H),7.19(s,1H),4.14(d,J＝2.1Hz,2H),3.95(s,3H)。

Example 52- [ (Z) -1- (aminomethyl) -2-fluoro-vinyl ] benzofuran-5-carboxylic acid methyl ester hydrochloride (compound E5)

Methyl 2- [ (Z) -1- [ (tert-butoxycarbonylamino) methyl ] -2-fluoro-vinyl ] benzofuran-5-carboxylate (50mg,0.14mmol) was dissolved in ethyl hydrogen chloride (5mL,4.0mol/L) and reacted at room temperature for 1 hour. The reaction solution was concentrated to give the title compound E5(40mg, yield 98%) as a pale yellow solid.

MS(ESI,poi.ion)m/z:250.1[M-Cl] ⁺；

¹H NMR(400MHz,MeOD)δ(ppm)8.39(d,J＝1.5Hz,1H),8.07(dd,J＝8.7,1.7Hz,1H),7.66(d,J＝8.7Hz,1H),7.38(d,J＝80Hz,1H),7.31(s,1H),4.06(d,J＝2.5Hz,2H),3.95(s,3H)。

Activity test examples

First, determination of inhibitory Activity of rat adipose tissue homogenate SSAO/VAP-1

The test purpose is as follows: the following method was used to determine the inhibitory activity of the compounds of the present invention on SSAO/VAP-1 in rat fat homogenates.

Test materials:

N-piperazine-N-ethanesulfonic acid SODIUM SALT (HEPES SODIUM SALT) available from AMRESCO, Cat.No. 0485-500G;

EDTA (Ethylenediaminetetraacetic acid) purchased from Sigma, cat. No. eds-100G;

sucrose (Sucrose) was purchased from Sigma, cat.no. v 900116;

PMSF (Phenylmethanesulfonyl fluoride) purchased from Beyotime, cat.no. st506;

beta-Glycerophosphate disodium salt hydrate (beta-glycophosphophosphate dihydrate) purchased from Sigma, cat.no. G5422-25G;

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

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

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

96-well plates were purchased from COSTAR, Cat.No. 3631;

red Hydrogen peroxiredoxin Assay Kit was purchased from Invitrogen, Cat.No. A22188.

The test method comprises the following steps:

abdominal fat from Sprague Dawley rats, a SSAO/VAP-1 rich tissue, was surgically excised. For each gram of abdominal adipose tissue of rats, 5ml of HES buffer (20mM N-piperazine-N-ethanesulfonic acid sodium salt, 1mM EDTA,250mM sucrose, 1 XPSF and100mM beta-glycerophosphoric acid disodium salt hydrate, pH 7.4) was added for homogenization. Adipose tissue was homogenized using a Bertin Precellys 24 multifunctional sample homogenizer from Bertin Technologies for 3min, the adipose tissue homogenate was centrifuged at 4 ℃ for 10min at 20000g, and the intermediate clear supernatant was taken. The supernatant was incubated with 0.5mM of perhexiline hydrochloride in HES buffer for 30min at 37 ℃. After 30min incubation, 25 μ l of adipose tissue supernatant was added to a standard 96-well plate. Test compounds were dissolved in DMSO and diluted 6 concentrations. Mu.l of different concentrations of test compound were added to each well containing the adipose tissue supernatant and incubated at 37 ℃ for 30 min. After incubation, 50. mu.l of the reaction mixture containing 80. mu.M benzylamine hydrochloride (containing 100. mu.M)

Red and 0.2U/ml HRP,

Red Hydrogen peroxiredoxin Assay Kit) was added to the respective wells and incubated at 37 ℃ for 30 min. After 30min, fluorescence values (RFU) were read at excitation 540nm and emission 580nm using a PHERAStar FSX microplate reader from BMG LABTECH. The IC was calculated using Graph Pad Prism 5 software to plot curves₅₀The value is obtained. IC for inhibitory Activity of Compounds of the present invention on adipose tissue homogenate SSAO/VAP-1₅₀Less than 15 nM. The results are shown in Table 1:

table 1: the compounds provided in the examples of the present invention have inhibitory activity against SSAO/VAP-1 in adipose tissue homogenates

The test results show that: the compound has obvious inhibition effect on the SSAO/VAP-1 of the adipose tissue homogenate.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

A compound which is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug thereof,

wherein,

R ²is F, Cl, Br or I;

R ³is H, deuterium, C_1-6Alkyl or C_3-6A cycloalkyl group;

ring A is an oxygen-containing heterocyclic ring of 5 to 8 atoms or an oxygen-containing heteroaromatic ring of 5 to 8 atoms, wherein ring A is unsubstituted or substituted with 1,2 or 3R^ySubstituted;

R ¹is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^j、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, a heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms, wherein R^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jEach independently is H, deuterium, C_1-6Alkyl or C_3-6A cycloalkyl group;

each R^zIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、C _1- ₆Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C_1-6A haloalkoxy group;

each R^yIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂、＝O、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl or C_1-6A haloalkoxy group;

q is 0, 1,2 or 3.
The compound of claim 1, wherein ring a is an oxygen-containing heterocyclic ring of 5-6 atoms or an oxygen-containing heteroaromatic ring of 5-6 atoms, wherein ring a is unsubstituted or substituted with 1,2 or 3R^yAnd (4) substituting.
The compound of claim 1 or 2, wherein said ring a is

Wherein said ring A is unsubstituted or substituted with 1,2 or 3R^yAnd (4) substituting.
A compound according to any one of claims 1-3, wherein R is¹Is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^j、C _1- ₄Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclic radical of 5-6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms, wherein R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱAnd R^jEach independently is H, deuterium, C_1-4Alkyl or C_3-6A cycloalkyl group.
The compound of any one of claims 1-4, wherein R is¹Is H, deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-SH、-C(＝O)R ^a、-C(＝O)OR ^b、-C(＝O)NR ^cR ^d、-S(＝O)R ^e、-S(＝O) ₂R ^f、-S(＝O)NR ^gR ^h、-S(＝O) ₂NR ⁱR ^jMethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy, methylamino, methylthio, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Trifluoromethoxy, vinyl, allyl, propenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a heterocyclyl of 5-6 atoms, phenyl or a heteroaryl of 5-6 atoms, wherein R is^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、 R ⁱAnd R^jEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The compound of any one of claims 1-5, wherein R is³Is H, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

each R^zIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Or a trifluoromethoxy group;

each R^yIndependently deuterium, F, Cl, Br, I, CN, NO₂、OH、NH ₂、-C(＝O)OH、-C(＝O)NH ₂、-S(＝O) ₂NH ₂- (O), methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF₃、-CH ₂F、-CHF ₂、-CH ₂CF ₃Or a trifluoromethoxy group.
The compound according to any one of claims 1-6, having the structure of one of:

or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
The compound according to any one of claims 1-7, having the structure of one of:

or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
The compound of any one of claims 1-8, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, phosphate, oxalate, maleate, tartrate, citrate, malate, or mesylate salt.
A pharmaceutical composition comprising a compound of any one of claims 1-9, optionally further comprising a pharmaceutically acceptable adjuvant.
Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for inhibiting SSAO/VAP-1; or the medicament is used for preventing, treating or relieving inflammation diseases and/or inflammation-related diseases or diabetes and/or diabetes-related diseases.
The use according to claim 11, wherein the inflammatory disease and/or inflammation-related disease is liver autoimmune disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, alcoholic liver disease, or non-alcoholic fatty liver disease;

the diabetes and/or diabetes-related diseases are type I diabetes, type II diabetes, syndrome X, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy or diabetic macular edema.
The use of claim 12, wherein the non-alcoholic fatty liver disease is non-alcoholic simple fatty liver, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease-associated cryptogenic cirrhosis, or primary liver cancer.