CN118063444A

CN118063444A - Azetidinamide derivatives and uses thereof

Info

Publication number: CN118063444A
Application number: CN202211414350.3A
Authority: CN
Inventors: 金传飞; 陈康智; 王祖圣
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2022-11-11
Filing date: 2022-11-11
Publication date: 2024-05-24

Abstract

The invention belongs to the technical field of medicines, discloses azetidine amide derivatives and application thereof, and particularly relates to novel azetidine amide derivatives and a pharmaceutical composition containing the compounds. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the manufacture of a medicament for the treatment of diseases modulated by MAO-B inhibitors, including neurodegenerative diseases, in particular Parkinson's disease.

Description

Azetidinamide derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound for treating parkinsonism, a pharmaceutical composition containing the compound, and a use method and application thereof. In particular, the compounds of the present invention are azetidinamide derivatives which are useful as MAO-B inhibitors.

Background

Parkinson's Disease (PD) is a common chronic degenerative disease of the nervous system, common to the elderly, and rarely seen in young parkinsonism with an average age of about 60 years and less than 40 years. The prevalence of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. Parkinson's disease is a disease that is insidious and slow in progression. The first symptoms are typically tremors or clumsiness of one limb, which in turn involves the opposite limb. Clinically, it is mainly manifested by resting tremor, bradykinesia, myotonia and postural gait disorder. In recent years, people increasingly pay attention to non-motor symptoms such as depression, constipation, sleep disturbance and the like, which are common complaints of parkinsonism patients, and influence on the life quality of patients even exceeds motor symptoms.

The most prominent pathological change in parkinson's disease is the degeneration and death of neurons by midbrain substantia nigra dopamine (dopamine, DA), which causes a significant decrease in striatal DA content to cause disease. The exact etiology leading to this pathological change is currently unknown, and genetic factors, environmental factors, age-related aging, oxidative stress, etc. may be involved in the degenerative death process of PD dopaminergic neurons.

Most cases are likely to be associated with environmental factors or as a result of interactions of environmental factors with genetic factors. Part of the pathogenesis involves free radicals, oxidative stress, glutamate excitotoxicity, lack of neurotrophic agents, inflammation, apoptosis and loss of mitochondrial complex I, and these mechanisms interact in cascade biochemical reactions ultimately leading to neuronal death (Teismann P,Schulz JB.Celluar pathology of Parkinson's disease.:astrocytes,microglia and inflammation[J].Cell Tissue Res,2004,318:149-161). part of the genetic factors in familial PD play a decisive role. Recent genetic studies have found that functional defects of the ubiquitin-proteinase system and abnormal aggregation of denatured proteins play an important role in the pathogenesis of most PD. In addition, factors such as oxidative stress and the formation of free radicals, excitotoxicity mediated by excessive glutamate release, mitochondrial dysfunction, inflammation, and neuronal apoptosis caused by damage to the ubiquitin-protease system are closely related to the progression of the disease.

Currently, the main treatment method for PD is symptomatic treatment with dopamine replacement, and levodopa (L-dopa) is still the most effective drug (RASCO O,GOETZ C,KOLLER W,et al.Treatment interventions for Parkinson's disease:an evidence based assessment[J].Lancet,2002,359(9317):1589-1598). for clinically controlling PD symptoms and signs, and although L-dopa can temporarily control PD symptoms, long-term administration can cause many adverse reactions such as abnormal symptoms, motor fluctuations and mental symptoms. Although the use of sustained DA can stimulate neurons, deep brain stimulation of surgical pathways (deep brain stimuli, DBS), long acting dopamine receptor agonists can reduce the occurrence of these complications to some extent (SCHAPIRA A H V,EMREB M,JENNER P,et al.Levodopa in the treatment of Parkinson's disease[J].Eur J Neurol,2009,16(9):982-989), but do not delay the progression of the disease. In addition, dopamine receptor agonists such as cabergoline (cabergoline), catechol-oxy-methyltransferase inhibitors (COMT) such as entacapone (Comtan), glutamate receptor antagonists such as memantine (memantine), anticholinergic agents such as benzomaric acid (benzhexol, ambam) all have adverse effects, but can be used as auxiliary drugs of levodopa, and the efficacy of the levodopa can be enhanced, the dosage of the levodopa can be reduced and the adverse effects can be reduced by combining different action mechanisms of the drug combination. Therefore, research and development of new drugs which can improve the symptoms of DA and non-DA systems of PD patients and slow down or even prevent the progression of diseases to exert neuroprotection are particularly important.

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible for oxidative deamination of endogenous monoamine neurotransmitters, including: dopamine, 5-hydroxytryptamine, epinephrine or norepinephrine, and trace amines such as phenylethylamine, many amine xenobiotics, and the like. Monoamine oxidase can be divided into two subtypes, MAO-A and MAO-B. Their gene codes are different (A.W.Bach et al, proc.Natl.Acad.Sci.USA 1988,85,4934-4938) and also differ in structure, tissue distribution and substrate specificity. MAO-A is present in liver, gastrointestinal mucosA, catecholamines that inactivate the blood circulation system and dietary vasoactive substances (e.g. tyrosine), thereby aiding in the degradation of neurotransmitters in the brain; MAO-B is found mainly in the brain and in platelets. MAO-A has higher affinity for octopamine, 5-hydroxytryptamine, epinephrine, and norepinephrine; whereas the natural substrates for MAO-B are tyramine and phenylethylamine. Both isoforms, however, oxidize dopamine.

Monoamine oxidase B (monoamine oxidase B, MAO-B) is one of the key enzymes of DA catabolism, and can improve clinical symptoms by selectively and specifically inhibiting endogenous and exogenous dopamine decomposition and prolonging the acting time of dopamine, so that the monoamine oxidase B can be used for early single drug treatment of PD and adjuvant treatment after symptom fluctuation. The main effects are as follows: (1) Decomposing dopamine into 3, 4-dihydroxyphenylacetic acid and homovanillic acid, and simultaneously generating micromolecule H ₂O₂ to generate toxic effect on nerve cells; (2) Deamination of beta-phenylethylamine which stimulates dopamine secretion and inhibits dopamine reuptake is deactivated; (3) 1-methyl-4-phenyl-1, 2,3, 6-tetrahydropyrimidine (MPTP) can also be decomposed into neurotoxic l-methyl-4-phenylpyridine ion (MPP ⁺). Thus, according to the physiological function of MAO-B, on one hand, inhibiting the activity of MAO-B can reduce the degradation and reuptake of dopamine, increase the concentration of dopamine in brain, and improve the clinical symptoms of PD; on the other hand, slowing the death process (HEIKKILA R E,MANZINO L,CABBAT F S,et al.Protection against the dopaminergic neurotoxiciy of 1-methyl-1,2,3,6-tetrahydropyridine(MPTP)by monoamine inhibitors[P].Nature,1984,311(5985):467-469;YOUDIM M B H,BAKHLE Y S.Monoamine oxidase isoforms and inhibitors in Parkinson's disease and depressive illness[J].Br J Pharmacol,2006,147(S1):S287-S296;NAOI M,WAKAKO M.Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders[J].Curr Pharm Des,2010,16(25):2799-2817), of melanocytes by lowering neurotoxin levels such as H ₂O₂、MPP⁺ can alter PD progression. MAO-B inhibitors are hot spots in current anti-Parkinson's disease drug research because they not only improve PD symptoms, but also play a role in neuroprotection.

Currently, some studies are being conducted on MAO-B inhibitors:

WO 2016052928 A1 discloses a-aminoamide derivatives as MAO-B inhibitors having excellent stability and better efficacy than conventional reversible MAO-B inhibitors. Can be used for treating neurodegenerative diseases.

WO 2011022217 A1 discloses substituted aryl-cyclopropylamide compounds and substituted heteroaryl-cyclopropylamide compounds as selective LSD1/MAO-B inhibitors for the treatment of cancer and neurodegenerative diseases.

WO 2003106380 A2 discloses fluorobenzamide derivatives as selective MAO-B inhibitors for the treatment of alzheimer's disease and senile dementia.

WO 200306596 A1 discloses pyridine amido derivatives as selective MAO-B inhibitors for the treatment of neurological diseases including alzheimer's disease, senile dementia, parkinson's disease and depression.

However, there is still a need for further research in order to find more better and more effective MAO-B inhibitors.

Disclosure of Invention

The invention relates to a novel azetidine amide derivative which has a good inhibition effect on the activity of MAO-B, so that the azetidine amide derivative can be used for preparing medicines for treating neurodegenerative diseases, in particular medicines for treating parkinsonism. The compound has stable property, good safety, good pharmacodynamics and pharmacokinetics, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability, and the like, thus having better clinical application prospect.

The invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

In one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (I),

Wherein:

U is CR ^u or N;

V is O, S or NH;

R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, hydroxy-substituted C ₁-C₆ alkyl, C ₃-C₈ cycloalkyl, 3-8 membered heterocyclyl, C ₆-C₁₀ aryl or 5-10 membered heteroaryl;

R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy or hydroxy substituted C ₁-C₆ alkyl;

R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy or hydroxy substituted C ₁-C₆ alkyl;

R ¹¹ and R ¹² are each independently H, D, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, hydroxy-substituted C ₁-C₆ alkyl, C ₃-C₈ cycloalkyl, 3-8 membered heterocyclyl, C ₆-C₁₀ aryl or 5-10 membered heteroaryl; and

N is 1 or 2.

In one embodiment, R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, C ₁-C₄ alkylthio, C ₁-C₄ alkylamino, hydroxy-substituted C ₁-C₄ alkyl, C ₃-C₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl;

R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy or hydroxy-substituted C ₁-C₄ alkyl.

In another embodiment, R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, or quinolinyl;

R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, or hydroxy substituted C ₁-C₄ alkyl;

R ¹¹ and R ¹² are each independently H, D, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, C ₁-C₄ alkylthio, C ₁-C₄ alkylamino, hydroxy-substituted C ₁-C₄ alkyl, C ₃-C₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆-C₁₀ aryl or 5-10 membered heteroaryl.

In another embodiment, R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 hydroxymethyl or 2-hydroxyethyl;

R ¹¹ and R ¹² are each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In some embodiments, the present invention relates to a compound that is a compound of formula (II), or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (II),

Wherein each R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、U、V and n have the meaning as described herein.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) as disclosed herein.

In one embodiment, the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In another aspect, the invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof as disclosed herein for the manufacture of a medicament for preventing, treating or alleviating a disease in a patient modulated by an MAO-B inhibitor.

In one embodiment, the disorder modulated by the MAO-B inhibitor is a neurodegenerative disorder, a psychotic disorder or a cancer.

In one embodiment, the neurodegenerative disease is parkinson's disease, cerebral ischemia, alzheimer's disease, amyotrophic lateral sclerosis, bovine spongiform encephalopathy, huntington's disease, creutzfeldt-jakob disease, ataxia telangiectasia, cerebellar atrophy, spinal muscular atrophy, primary lateral sclerosis, or multiple sclerosis.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).

Biological test results show that the compound has a good inhibition effect on the activity of MAO-B and can be used as a good medicament for treating parkinsonism.

Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. 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 application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be 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 sub-combination.

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, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, the general principles of organic chemistry may be found in the descriptions of "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 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" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, the articles refer to articles of manufacture that include one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The term "chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

The term "diastereoisomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definition 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. that many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. 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.

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

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

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2^nd Ed.Robert E.Gawley,Jeffrey Aube,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 be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion 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.

By "pharmaceutically acceptable" is meant those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with …" that is, the structure is unsubstituted or substituted with one or more substituents described herein including, but not limited to, D, F, cl, br, I, N ₃, -OH, oxo (=o), -NH ₂,NO₂, -CN, -SH, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at a reasonable position at which each of the groups may be substituted. When more than one position in a given formula can be substituted with one or more specific substituents selected from, then the substituents may be the same or different at each reasonable position in the formula.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

The term "unsaturated" or "unsaturated" means that the moiety contains one or more unsaturations.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C ₁-C₆ alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited 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 enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "D" represents a single deuterium atom.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of 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 representing a substituent as described in the present invention.

The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃), ethyl (Et, -CH ₂CH₃), n-propyl (n-Pr, -CH ₂CH₂CH₃), isopropyl (i-Pr, -CH (CH ₃)₂), n-butyl (n-Bu, -CH ₂CH₂CH₂CH₃), isobutyl (i-Bu, -CH ₂CH(CH₃)₂), sec-butyl (s-Bu, -CH (CH ₃)CH₂CH₃), tert-butyl (t-Bu, -C (CH ₃)₃), and the like.

The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples include methylene (-CH ₂ -), ethylene (-CH ₂CH₂ -), isopropylidene (-CH (CH ₃)CH₂ -), etc.. The alkylene group is optionally substituted with one or more substituents as described herein.

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 sp ² double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group comprises 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch ₂), allyl (-CH ₂CH＝CH₂), 1-propenyl (i.e., propenyl, -ch=ch-CH ₃), and the like.

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. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH ₃), and the like.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃), ethoxy (EtO, -OCH ₂CH₃), 1-propoxy (n-PrO, n-propoxy, -OCH ₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, -OCH (CH ₃)₂), 1-butoxy (n-BuO, n-butoxy, -OCH ₂CH₂CH₂CH₃), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂CH(CH₃)₂), 2-butoxy (s-BuO, s-butoxy, -OCH (CH ₃)CH₂CH₃), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH ₃)₃), and the like.

The term "alkylthio" means that the alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.

Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH ₃), ethylthio (ETS, -SCH ₂CH₃), 1-propylthio (n-PrS, n-propylthio, -SCH ₂CH₂CH₃), 2-propylthio (i-PrS, i-propylthio, -SCH (CH ₃)₂), 1-butylthio (n-BuS, n-butylthio, -SCH ₂CH₂CH₂CH₃), 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH ₂CH(CH₃)₂), 2-butylthio (s-BuS, s-butylthio, -SCH (CH ₃)CH₂CH₃), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC (CH ₃)₃), and the like.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups, where the alkyl groups have the meaning as described herein. Suitable alkylamino groups may be mono-or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、-CF₂CH₃、-CH₂CF₂CHF₂ and the like. In one embodiment, the C ₁-C₆ haloalkyl comprises a fluoro-substituted C ₁-C₆ alkyl; in another embodiment, the C ₁-C₄ haloalkyl comprises a fluoro-substituted C ₁-C₄ alkyl; in yet another embodiment, the C ₁-C₂ haloalkyl comprises a fluoro-substituted C ₁-C₂ alkyl.

The term "haloalkoxy" means that the alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCHFCH₃、-OCH₂CH₂F、-OCF₂CH₃、-OCH₂CF₂CHF₂ and the like. In one embodiment, the C ₁-C₆ haloalkoxy group comprises a fluoro-substituted C ₁-C₆ alkoxy group; in another embodiment, the C ₁-C₄ haloalkoxy group comprises a fluoro-substituted C ₁-C₄ alkoxy group; in yet another embodiment, the C ₁-C₂ haloalkoxy group comprises a fluoro-substituted C ₁-C₂ alkoxy group.

The term "j-k atoms" or "j-k elements" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or O, N, S, P or other heteroatoms; each of j and k is independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "3-8 atom" or "3-8 membered", "3-6 atom" or "3-6 membered", "5-10 atom" or "5-10 membered", "5-6 atom" or "5-6 membered" means that the cyclic group is composed of 3-8 (3, 4,5, 6, 7 or 8), 3-6 (3, 4,5 or 6), 5-10 (5, 6, 7, 8, 9 or 10) or 5-6 (5 or 6) ring atoms, which include heteroatoms such as carbon atoms and/or O, N, S, P. For another example, a piperidinyl group is a 6-ring-atom-composed heterocyclyl group or a 6-membered heterocyclyl group, and a pyridinyl group is a 6-ring-atom-composed heteroaryl group or a 6-membered heteroaryl group.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings, and spiro rings. In one embodiment, cycloalkyl groups contain 3 to 10 carbon atoms; in another embodiment, cycloalkyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms in which one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described herein, which rings may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In one embodiment, the heterocyclyl group is a monocyclic ring of 3-8 membered rings (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO ₂,PO,PO₂, when the ring is a three membered ring, only one of which is a heteroatom), or a bicyclic ring of 7-12 membered rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S where S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO ₂,PO,PO₂). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The ring atoms of the heterocyclic groups may be carbon groups or heteroatom groups. Wherein the-CH ₂ -group of the ring is optionally replaced by-C (=O) -and the sulfur atom of the ring is optionally oxidized to S-oxide and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxaalkyl, homopiperazinyl, homopiperidinyl, oxacycloheptyl, thietanyl, oxaazaRadical, diaza/>Radical, thiaza/>Radical, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, and the like. Examples of the substitution of the-CH ₂ -group in the heterocyclyl group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl, and the like. Examples of sulfur atoms in the heterocyclyl group that are oxidized include, but are not limited to, sulfolane, thiomorpholino 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system 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 rings of 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, indenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. Heteroaryl groups are typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "aromatic heterocycle" or "heteroaromatic. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5 to 10 atoms comprises 1,2,3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-thiotriazinyl, 1, 3-dithio-pyrazinyl, 1, 3-thiotriazinyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, 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, and the like.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I) or formula (II). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C _1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"Metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained with suitable bases include the alkali metal, alkaline earth metal, ammonium and N ⁺(C_1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may 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 counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C ₁-C₈ sulphonates and aromatic sulphonates.

"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that are water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in another embodiment, one molecule of the compounds of the present invention may be combined with more than one water molecule, such as dihydrate; in yet another embodiment, one molecule of the compounds of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.

The expression "compound of the present invention", "compound described in the present invention" or the like as used in the present invention refers to a compound represented by any one of the general structures described in the present invention, that is, a compound represented by the formula (I) or the formula (II) in the present invention.

The term "treating" any disease or disorder, in some embodiments refers to ameliorating the disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" 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" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

The term "preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., stopping the progression of at least one clinical symptom of a disease in a subject who may or may not have been predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

The alpha-amino amide derivative, the pharmaceutically acceptable salt, the pharmaceutical preparation and the pharmaceutical composition thereof can inhibit the activity of MAO-B and have potential application to the treatment of neurodegenerative diseases, in particular to the treatment of Parkinson's disease.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the invention are intended to be encompassed within the scope of the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.

Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I) or (II) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. 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. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying a compound of formula (I) or formula (II) and/or for isolating an enantiomer of a compound of formula (I) or formula (II).

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of other suitable salts can be found in the nature, selection and application (Handbook of Pharmaceutical Salts:Properties,Selection,and Use)",Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002).

Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and ¹²⁵ I.

In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or formula (II).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.

Description of the Compounds of the invention

The azetidine amide derivative, the pharmaceutically acceptable salt thereof, the pharmaceutical preparation and the pharmaceutical composition thereof have an inhibitory effect on the activity of MAO-B and have potential application to the treatment of neurodegenerative diseases, in particular to the treatment of parkinsonism. The invention further describes a method for synthesizing the compounds. The compounds of the present invention exhibit good biological activity.

In one embodiment, U is CR ^u or N; wherein R ^u has the meaning as described in the present invention.

In one embodiment, V is O, S or NH.

In one embodiment, R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, hydroxy-substituted C ₁-C₆ alkyl, C ₃-C₈ cycloalkyl, 3-8 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl.

In one embodiment, R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, or hydroxy substituted C ₁-C₆ alkyl.

In one embodiment, R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, or hydroxy substituted C ₁-C₆ alkyl.

In one embodiment, R ¹¹ and R ¹² are each independently H, D, C ₁-C₆ alkyl, C ₂-C₆ alkenyl, C ₂-C₆ alkynyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy, C ₁-C₆ haloalkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, hydroxy-substituted C ₁-C₆ alkyl, C ₃-C₈ cycloalkyl, 3-8 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl.

In one embodiment, n is 1 or 2.

In one embodiment, R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, C ₁-C₄ alkylthio, C ₁-C₄ alkylamino, hydroxy-substituted C ₁-C₄ alkyl, C ₃-C₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl.

In another embodiment, R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, or quinolinyl.

In one embodiment, R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, or hydroxy substituted C ₁-C₄ alkyl.

In another embodiment, R ⁵、R⁶、R⁷ and R ⁸ are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, or hydroxy substituted C ₁-C₄ alkyl.

In another embodiment, R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R ¹¹ and R ¹² are each independently H, D, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, C ₁-C₄ alkylthio, C ₁-C₄ alkylamino, hydroxy-substituted C ₁-C₄ alkyl, C ₃-C₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl.

In another embodiment, R ¹¹ and R ¹² are each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, or quinolinyl.

In one embodiment, the compound of the invention is a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, of a compound having one of the following structures or of a compound having one of the following structures, but in no way limited to:

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In another aspect, the invention relates to the use of a compound of formula (I) or formula (II) or a combination thereof or a pharmaceutical composition thereof as disclosed herein for the manufacture of a medicament for preventing, treating or alleviating a disease in a patient modulated by a MAO-B inhibitor.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or a formula (II) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C.et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia;Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia; and Rowe r.c., handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, chicago.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients may be selected that facilitate carrying or transporting the compounds of the present invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed in Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. It is within the scope of the present invention to contemplate its use in addition to any common carrier that is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the present invention, or metabolites or residues thereof, when administered to a patient in need thereof.

In one embodiment, the presently disclosed compounds may be formulated into oral dosage forms. In another embodiment, the presently disclosed compounds may be formulated into an inhalation dosage form. In another embodiment, the presently disclosed compounds may be formulated for nasal administration. In yet another embodiment, the presently disclosed compounds may be formulated into transdermal dosage forms. In yet another embodiment, the presently disclosed compounds may be formulated into topical dosage forms.

For example, a solid oral dosage form may comprise, in addition to the active ingredient: diluents such as lactose, dextrose, sucrose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; humectants such as lecithin, polysorbates, lauryl sulfate; and generally non-toxic and pharmaceutically inactive substances for pharmaceutical formulations. The pharmaceutical preparations can be prepared in a known manner, for example by mixing, granulating, tabletting, sugar-coating or film-coating processes.

Oral formulations include sustained release formulations which can be prepared in conventional manner, for example by enteric coating tablets and granules.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions.

The pharmaceutical compositions provided herein may be provided in compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, or enteric tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet and a compression coated or dry coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent nos.4,328,245;4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Emulsions and suspensions may contain as a carrier, for example, natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injection may contain a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, together with the active compound. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Solutions for intravenous or infusion may comprise, for example, sterile water as a carrier or preferably they may be in the form of sterile, aqueous isotonic saline solutions. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups may contain as carrier, for example, sucrose or an aqueous solution of sucrose with glycerol and/or mannitol and/or sorbitol, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration by inhalation to a patient, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions can be formulated into dosage forms suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound of the presently disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. The fine powder can be prepared by, for example, micronization and grinding. In general, reduced size (e.g., micronized) compounds may be defined by a D50 value (e.g., as measured by laser diffraction) of about 1 to 10 microns.

Pharmaceutical compositions suitable for transdermal administration may be formulated as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch by ion permeation, as generally described in Pharmaceutical Research,3 (6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base may include water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.

The compounds of the present invention may also be conjugated to soluble polymers as carriers for targeted drugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided herein may be administered parenterally, by injection, infusion or implantation, for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: THE SCIENCE and Practice of Pharmacy, supra).

Pharmaceutical compositions contemplated for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided by the present invention may be administered via rectal suppositories by mixing the drug with suitable non-irritating excipients such as cocoa butter, polyethylene glycol synthetic glycerides, which are solid at ordinary temperatures, and then liquefying or dissolving the drug in the rectal cavity. Because of individual differences, the severity of symptoms can vary considerably and each drug has its unique therapeutic properties, the dosage form and treatment regimen should be determined by the practitioner for each individual precise mode of administration.

The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure, or alleviate symptoms of the disease is administered or equilibrated in vivo. The effective amount required for a particular therapeutic regimen will depend upon a variety of factors including the disease being treated, the severity of the disease, the activity of the particular agent being used, the mode of administration, the rate of clearance of the particular agent, the duration of the treatment, the combination, the age, body weight, sex, diet and health of the patient, etc. Other factors considered in the art for "therapeutically effective amount" can be found in Gilman et al.,eds.,Goodman And Gilman's:The Pharmacological Bases of Therapeutics,8th ed.,Pergamon Press,1990;Remington's Pharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton,Pa.,1990. for a therapeutically effective amount of a compound of the invention, which has in vivo activity when administered orally, intraperitoneally, or intravenously at 0.1-200 mg/kg.

The optimal therapeutically effective amount to be administered can be readily determined by one skilled in the art and will vary substantially depending on the strength of the formulation, the mode of administration, and the advancement of the disease or condition being treated. In addition, factors related to the particular subject being treated include the subject's age, weight, diet, and time of administration, resulting in the need to adjust the dosage to an appropriate therapeutically effective level.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration form includes paste, lotion, tablet, capsule, pill, powder, granule, suppository, pellet, lozenge, injection, sterile solution or nonaqueous solution, suspension, emulsion, patch, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., dextrose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, and the dosage will vary depending on the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on the body weight, physiology and the chosen vaccination regimen. The weight of the compound per unit dose is the weight of the compound per administration and does not include the weight of the carrier (the carrier is contained in the drug). Pharmaceutical compositions comprising an alpha-aminoamide derivative of formula (I) or (II) as defined above contain from about 0.1mg to about 500mg, most preferably from 1 to 10mg, of one or more active ingredients per unit dose, e.g., capsule, tablet, powder injection, teaspoon capacity, suppository, etc.

The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered orally. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered by inhalation. In yet another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered intranasally.

In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention may be administered at once, or at several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for a compound of the invention or a pharmaceutical composition comprising a compound of the invention, including the duration of time for which the regimen is performed, will depend on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the appropriate dosing regimen may be required for the individual patient's response to the dosing regimen, or as the individual patient needs to change over time.

The compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or in the same pharmaceutical compositions as they are.

Furthermore, the compounds of the present invention may be administered in the form of prodrugs. In the present invention, a "prodrug" of a compound of the invention is a functional derivative that, when administered to a patient, ultimately releases the compound of the invention in vivo. When the compounds of the invention are administered in prodrug form, one skilled in the art can practice one or more of the following modes: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; (c) altering in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for the preparation of prodrugs include variants of compounds that cleave chemically or enzymatically in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the invention can be used for preparing medicines for preventing, treating or relieving diseases regulated by MAO-B inhibitors of patients, and also can be used for preparing medicines for preventing, treating or relieving neurodegenerative diseases, psychosis or cancers.

In particular, the amount of compound in the compositions of the present invention is effective to detectably selectively inhibit MAO-B activity.

The compounds of the present invention may be applied to, but are in no way limited to, the prevention, treatment, or alleviation of neurodegenerative diseases using an effective amount of a compound or composition of the present invention administered to a patient. The neurodegenerative disease further includes, but is not limited to, parkinson's disease, cerebral ischemia, alzheimer's disease, amyotrophic lateral sclerosis, hearing loss due to aging, dementia, retinal degeneration, macular degeneration, glaucoma, bovine spongiform encephalopathy, huntington's chorea, creutzfeldt-jakob disease, ataxia telangiectasia, cerebellar atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.

The compounds of the present invention may be applied to, but are in no way limited to, the use of an effective amount of a compound or composition of the present invention for administration to a patient to prevent, treat or alleviate psychosis. The psychosis is schizophrenia and/or anxiety, wherein schizophrenia further includes but is not limited to brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophreniform disorder; wherein anxiety disorders further include, but are not limited to, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia or social anxiety disorder, specific phobia, and generalized anxiety disorder.

The compounds of the present invention may be applied to, but are in no way limited to, the use of an effective amount of a compound or composition of the present invention to be administered to a patient to prevent, treat or ameliorate cancer. The cancers further include, but are not limited to, prostate cancer, breast cancer, testicular cancer, colorectal cancer, lung cancer, brain tumor, kidney tumor, or blood cancer.

The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

General synthetic procedure for the Compounds of the invention

For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.

In general, the compounds of the 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 are provided to further illustrate the present invention.

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

The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as ALDRICH CHEMICAL Company, arco Chemical Company AND ALFA CHEMICAL Company and used without further purification unless otherwise indicated. General reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin good Chemies, tianjin Fuchen Chemies, wuhan Xinhua Yuan technology development Co., ltd., qingdao Teng Chemies Co., and Qingdao sea chemical Co.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.

The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. ¹ H NMR spectra were taken with CDC1 ₃、DMSO-d₆、CD₃ OD or acetone-d ₆ as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet, doublet), q (quartet ), m (multiplet, multiplet), br (broadened, broad), brs (broadened singlet, broad singlet), dd (doublet of doublets, doublet), ddd (doublet of doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), tt (triplet of triplets, triplet). Coupling constant J, expressed in hertz (Hz).

The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-M (column type: zorbax SB-C18, 2.1X130 mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid), electrospray ionization (ESI) was used, UV detection at 210nm/254 nm.

The pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following abbreviations are used throughout the present invention:

CH ₂Cl₂, DCM dichloromethane mmol

CDC1 ₃ deuterated chloroform g

DMSO-d ₆ deuterated dimethyl sulfoxide mg

DMSO dimethylsulfoxide μg micrograms

DMF N, N-dimethylformamide ng nanogram

EtOAc, EA ethyl acetate μL, and μL

CD ₃ OD deuterated methanol mL, mL milliliters

THF tetrahydrofuran HEPES 4-hydroxyethyl piperazine ethanesulfonic acid

SOCl ₂ sulfoxide chloride Glucan glucosamine

PE petroleum ether (60-90 ℃) Saline physiological Saline

RT, RT, r.t. room temperature min

NBS N-bromosuccinimide for h hours

The following synthetic schemes describe the steps for preparing the disclosed compounds of the present invention, wherein each R ¹、R²、R³、R⁴、R⁵ and U has the definition as described herein, unless otherwise indicated.

Intermediate Synthesis scheme 1

The compound represented by the formula (4) can be produced by the following process: the compound shown in the formula (1) reacts with NBS under the catalysis of silver nitrate to obtain the compound shown in the formula (2). The compound shown in the formula (2) and the compound shown in the formula (3) react under the catalysis of a base and a palladium catalyst to obtain the compound shown in the formula (4).

Intermediate Synthesis scheme 2

The compound represented by the formula (4) can be produced by the following process: the compound shown in the formula (1) and the compound shown in the formula (3') are reacted under the catalysis of CuI and a palladium catalyst to obtain the compound shown in the formula (4).

Synthesis scheme 1

The compound represented by the formula (7) can be produced by the following process: the compound shown in the formula (4) reacts under the action of a reducing agent (such as NaBH ₄) to obtain the compound shown in the formula (5). The compound represented by formula (5) is reacted with SOCl ₂ to obtain the compound represented by formula (6). The compound shown in the formula (6) reacts with (S) -azetidine-2-formamide 4-methylbenzenesulfonate under the action of alkali to obtain a target product shown in the formula (7).

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.

Examples

Example 1 Synthesis of (S) -1- ((2-phenylbenzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2-phenylbenzofuran-5-carbaldehyde

In a 50mL single-necked flask, 4-hydroxy-3-iodobenzaldehyde (2.00 g,8.06 mmol), cuI (0.046 mg,0.24 mmol), bis triphenylphosphine palladium dichloride (0.17 g,0.24 mmol), tetramethylguanidine (3.00 mL,24.18 mmol), phenylacetylene (1.23 g,12.09 mmol) and DMF (10 mL) were sequentially added, the mixture was evacuated, nitrogen protected, and the mixture was heated at 60℃for reaction for 55h. Cooling to room temperature, adding ethyl acetate (40 mL) and water (20 mL), extracting, separating, collecting ethyl acetate layer, washing with water (30 ml×3), collecting ethyl acetate layer, and separating and purifying by column chromatography with silica gel (petroleum ether/ethyl acetate (v/v) =50/1-15/1) to give the title compound as yellow solid (1.40 g, 78.1%).

MS(ESI,pos.ion)m/z:223.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.05(s,1H),8.10(s,1H),7.87–7.83(m,3H),7.61(d,J＝8.5Hz,1H),7.49–7.45(m,2H),7.41–7.38(m,1H),7.09(s,1H).

Step 2) (Synthesis of 2-phenylbenzofuran-5-yl) methanol

In a 100mL single-neck flask, 2-phenylbenzofuran-5-carbaldehyde (1.20 g,5.41 mmol) and DMF (10 mL) were sequentially added, the mixture was transferred to 0 ℃, sodium borohydride (0.41 g,10.82 mmol) was added, and the mixture was transferred to room temperature to react for 5h; water (50 mL) was added, stirred for 30min, filtered to give a solid, dichloromethane (60 mL) was added to the solid, stirred for 2h, dissolved, clarified, separated, and the organic phase was collected and purified by column chromatography over silica gel (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (0.74 g, 61.2%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.91(s,1H),7.90(s,1H),7.59(s,1H),7.56(d,J＝8.5Hz,1H),7.51–7.48(m,2H),7.44–7.37(m,2H),7.28(dd,J＝8.4,1.2Hz,1H),4.59(d,J＝5.7Hz,2H).

Step 3) Synthesis of 5-chloromethyl-2-phenylbenzofuran

(2-Phenyl benzofuran-5-yl) methanol (0.50 g,2.23 mmol) and DMF (4 mL) are sequentially added into a 100mL single-neck flask, the mixture is transferred to 0 ℃, thionyl chloride (0.18 mL,2.45 mmol) is slowly added, the mixture is transferred to room temperature for reaction for 38min after the addition is finished, water (30 mL) is added after the reaction is finished, the mixture is stirred for 30min, and a solid is obtained by filtration; the solid was dissolved in dichloromethane (20 mL), the organic phase was collected and concentrated to give a yellow solid (0.54 g, 99.1%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.88(d,J＝1.3Hz,1H),7.86(s,1H),7.60(d,J＝1.3Hz,1H),7.51(d,J＝8.4Hz,1H),7.48–7.45(m,2H),7.39–7.36(m,1H),7.32(dd,J＝8.4,1.7Hz,1H),7.00(s,1H),4.72(s,2H).

Step 4) (S) -1- ((2-phenylbenzofuran-5-yl) methyl) azetidine-2-carboxamide Synthesis

5-Chloromethyl-2-phenylbenzofuran (0.22 g,0.91 mmol), triethylamine (0.38 mL,2.73 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.30 g,1.09 mmol) and DMF (5 mL) are added sequentially to a 100mL flask, reacted at room temperature for 37h, water (30 mL) is added, stirred for 1h, filtered to give a solid which is dissolved in dichloromethane (30 mL), the organic phase is collected, and concentrated and purified by column chromatography (dichloromethane/methanol (v/v) =10/1) to give the title compound as an off-white solid (0.10 g, 40.4%).

MS(ESI,pos.ion)m/z:307.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.90(s,2H),7.59–7.50(m,4H),7.38–7.30(m,3H),7.10(s,2H),3.77(s,2H),3.13(s,2H),2.88(s,1H),2.21(s,1H),1.97(s,1H);

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)175.0,155.9,154.0,133.2,130.2,129.5,129.3,129.2,126.2,125.1,121.7,111.2,102.5,66.1,62.0,50.3,22.6.

Example 2 Synthesis of (S) -1- ((2- (2-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (2-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by reacting 4-hydroxy-3-iodobenzaldehyde (1.00 g,4.03 mmol), cuI (0.023 mg,0.12 mmol), bis triphenylphosphine palladium dichloride (0.085 mg,0.12 mmol), tetramethylguanidine (1.50 mL,12.09 mmol), 2-fluorophenylacetylene (0.73 g,6.05 mmol) and DMF (5 mL) followed by column chromatography separation and purification (petroleum ether/ethyl acetate (v/v) =100/1-15/1) to give the title compound as an off-white solid (0.89 g, 91.9%).

MS(ESI,pos.ion)m/z:241.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)10.08(s,1H),8.16(s,1H),8.04(t,J＝7.2Hz,1H),7.90(d,J＝7.9Hz,1H),7.65(d,J＝8.4Hz,1H),7.40–7.37(m,1H),7.33(d,J＝2.9Hz,1H),7.32–7.28(m,1H),7.24–7.20(m,1H).

Step 2) (Synthesis of 2- (2-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (2-fluorophenyl) benzofuran-5-carbaldehyde (0.45 g,1.87 mmol), THF (4 mL), methanol (10 mL) and sodium borohydride (0.14 g,3.74 mmol) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a white solid (0.15 g, 45.4%).

¹H NMR(400MHz,CDCl₃)δ(ppm)8.05(td,J＝7.7,1.7Hz,1H),7.62(s,1H),7.53(d,J＝8.4Hz,1H),7.35–7.32(m,2H),7.30–7.28(dd,J＝7.5,1.2Hz,1H),7.24(d,J＝3.0Hz,1H),7.23–7.16(m,1H),4.79(s,2H).

Step 3) Synthesis of 5-chloromethyl-2- (2-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (2- (2-fluorophenyl) benzofuran-5-yl) methanol (0.13 g,0.54 mmol), DMF (4 mL) and thionyl chloride (0.071 g,0.59 mmol) sequentially to a 100mL single neck round bottom flask and reacting to give the title compound as a white solid (0.12 g, 85.8%).

¹H NMR(600MHz,CDCl₃)δ(ppm)8.05(td,J＝7.6,1.3Hz,1H),7.65(s,1H),7.53(d,J＝8.4Hz,1H),7.37(dd,J＝13.7,6.8Hz,2H),7.29(t,J＝7.3Hz,1H),7.24(d,J＝3.2Hz,1H),7.21(dd,J＝11.0,8.5Hz,1H),4.74(s,2H).

Step 4) (S) -1- ((2- (2-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (2-fluorophenyl) benzofuran (0.10 g,0.38 mmol), triethylamine (0.16 mL,1.14 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.12 g,0.46 mmol) and DMF (5 mL) sequentially to a 100mL single neck round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1-dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (0.05 g, 67.5%).

MS(ESI,pos.ion)m/z:325.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.97–7.93(m,1H),7.44–7.39(m,2H),7.29–7.25(m,1H),7.21–7.18(m,1H),7.14–7.09(m,3H),3.72(dd,J＝12.4,5.2Hz,1H),3.62–3.59(m,2H),3.29–3.28(m,1H),3.02–2.97(m,1H),2.39–2.35(m,1H),2.14–2.09(m,1H);

¹³C NMR(151MHz,CD₃OD)δ(ppm)177.1,159.5(d,J＝252.1Hz),153.6,150.4(d,J＝3.4Hz),131.9,129.7(d,J＝8.6Hz),129.5,126.9(d,J＝2.6Hz),125.6,124.4(d,J＝3.4Hz),121.3,118.6(d,J＝11.7Hz),116.0(d,J＝21.5Hz),111.0,106.3(d,J＝12.9Hz),65.7,62.2,50.5,22.8.

Example 3 Synthesis of (S) -1- ((7-fluoro-2- (2-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 1-bromoethynyl-2-fluorobenzene

1-Ethynyl-4-fluorobenzene (2.00 g,16.67 mmol), NBS (3.56 g,20.00 mmol), silver nitrate (0.28 g,1.67 mmol) and acetone (20 mL) were added sequentially to a 100mL single-neck round bottom flask, reacted at room temperature for 4.5h, petroleum ether (30 mL) was added and stirred for 20min, filtered to give filtrate, and the filtrate was collected and concentrated to give yellow oil (3.30 g, 100.0%).

Step 2) Synthesis of 7-fluoro-2- (2-fluorophenyl) benzofuran-5-carbaldehyde

1-Bromoethynyl-2-fluorobenzene (3.30 g,16.58 mmol), 3-fluoro-4-hydroxybenzaldehyde (2.37 g,16.91 mmol), potassium carbonate (4.58 g,33.16 mmol) and DMF (20 mL) were sequentially added to a 100mL single-port round bottom flask, the reaction was closed at 110℃for 17h, palladium chloride (0.15 g,0.83 mmol) was added, then the reaction was warmed to 130℃for 9h, after the reaction was completed, cooled to room temperature and diluted with ethyl acetate (50 mL), washed with water (30 mL) for 2 times, the organic phase was collected, and concentrated and stirred column chromatography was performed to purify (petroleum ether/ethyl acetate (v/v) =30/1) to give the title compound as a brown solid (0.43 g, 10.0%).

MS(ESI,pos.ion)m/z:259.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.03(d,J＝1.9Hz,1H),8.10–8.03(m,1H),7.93(s,1H),7.61(d,J＝10.3Hz,1H),7.43–7.39(m,1H),7.35(t,J＝2.8Hz,1H),7.33–7.27(m,1H),7.24–7.19(m,1H).

Step 3) (Synthesis of 7-fluoro-2- (2-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 7-fluoro-2- (2-fluorophenyl) benzofuran-5-carbaldehyde (1.22 g,4.73 mmol), THF (14 mL) and sodium borohydride (0.36 g,9.46 mmol) sequentially to a 100mL single neck round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =5/1) to give the title compound as a white solid (1.03 g, 83.8%).

¹H NMR(600MHz,CD₃OD)δ(ppm)8.00(td,J＝7.7,1.3Hz,1H),7.33–7.29(m,2H),7.23(t,J＝7.5Hz,1H),7.17(t,J＝3.0Hz,1H),7.14(dd,J＝11.1,8.5Hz,1H),7.04(d,J＝11.4Hz,1H),3.72(s,2H).

Step 4) Synthesis of 5-chloromethyl-7-fluoro-2- (2-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (7-fluoro-2- (2-fluorophenyl) benzofuran-5-yl) methanol (0.70 g,2.69 mmol), DMF (4 mL) and thionyl chloride (0.21 g,2.96 mmol) sequentially to a 100mL single neck round bottom flask and reacting and concentrating to give the title compound as a white solid (0.74 g, 98.2%).

¹H NMR(400MHz,CDCl₃)δ(ppm)8.06(td,J＝7.7,1.4Hz,1H),7.38–7.34(m,2H),7.30–7.28(m,1H),7.22(t,J＝3.0Hz,1H),7.20–7.17(m,1H),7.13–7.10(m,1H),4.67(s,2H).

Step 5) (S) -1- ((7-fluoro-2- (2-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-7-fluoro-2- (2-fluorophenyl) benzofuran (0.20 g,0.72 mmol), triethylamine (0.30 mL,2.16 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.23 g,0.86 mmol) and DMF (5 mL) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1-1/1) to give the title compound as an off-white solid (0.15 g, 61.0%).

MS(ESI,pos.ion)m/z:343.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.96(t,J＝7.8Hz,1H),7.52–7.47(m,1H),7.46(s,1H),7.42–7.39(m,1H),7.37–7.33(m,2H),7.32(d,J＝4.8Hz,1H),7.19(s,1H),7.13(s,1H),3.78(d,J＝12.7Hz,1H),3.55–3.50(m,2H),3.14(t,J＝6.5Hz,1H),2.90–2.84(m,1H),2.25–2.19(m,1H),2.01–1.96(m,1H);

¹³C NMR(101MHz,DMSO-d₆)δ(ppm)174.9,159.2(d,J＝251.1Hz),151.0(d,J＝2.7Hz),147.1(d,J＝247.0Hz),140.0(d,J＝11.3Hz),135.1(d,J＝5.1Hz),132.4(d,J＝2.0Hz),131.5(d,J＝8.6Hz),127.4(d,J＝2.1Hz),125.7(d,J＝3.3Hz),117.9(d,J＝3.3Hz),117.6(d,J＝11.6Hz),116.9(d,J＝21.1Hz),112.6(d,J＝16.1Hz),107.2(d,J＝9.9Hz),66.2,61.6,50.4,22.6.

Example 4 Synthesis of (S) -1- ((2- (3-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (3-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by adding 4-hydroxy-3-iodobenzaldehyde (1.00 g,4.03 mmol), cuI (0.023 mg,0.12 mmol), bis triphenylphosphine palladium dichloride (0.085 mg,0.12 mmol), tetramethylguanidine (1.50 mL,12.09 mmol), 3-fluorophenylacetylene (0.73 g,6.05 mmol) and DMF (10 mL) sequentially to a 100mL single port round bottom flask and then column chromatography isolation and purification (petroleum ether/ethyl acetate (v/v) =100/1-15/1) to give the title compound as a yellow solid (0.96 g, 99.2%). MS (ESI, pos.ion) m/z 241.1[ M+H ] ⁺;

¹H NMR(400MHz,CDCl₃)δ(ppm)10.07(s,1H),8.13(s,1H),7.88(d,J＝8.5Hz,1H),7.66–7.63(m,2H),7.57(d,J＝9.7Hz,1H),7.44(dd,J＝13.9,8.0Hz,1H),7.14(s,1H),7.09(td,J＝8.4,1.9Hz,1H).

step 2) (Synthesis of 2- (3-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (3-fluorophenyl) benzofuran-5-carbaldehyde (0.30 g,1.25 mmol), DMF (2 mL), methanol (8 mL) and sodium borohydride (0.095 g,2.51 mmol) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =3/1) in concentrated preshrunk to give the title compound as a yellow solid (0.25 g, 82.7%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.76–7.72(m,2H),7.61(s,1H),7.58(d,J＝8.4Hz,1H),7.55–7.53(m,2H),7.31(d,J＝8.3Hz,1H),7.24(t,J＝7.7Hz,1H),4.60(d,J＝5.5Hz,2H).

Step 3) Synthesis of 5-chloromethyl-2- (3-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (2- (3-fluorophenyl) benzofuran-5-yl) methanol (0.22 g,0.91 mmol), DMF (4 mL) and thionyl chloride (0.12 g,0.99 mmol) sequentially to a 100mL single neck round bottom flask and reacting and concentrating to give the title compound as a white solid (0.23 g, 97.1%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.63–7.61(m,2H),7.56–7.53(m,1H),7.50(d,J＝8.5Hz,1H),7.41(td,J＝8.0,6.0Hz,1H),7.34(dd,J＝8.5,1.7Hz,1H),7.06(td,J＝8.4,1.8Hz,1H),7.01(s,1H),4.71(s,2H).

Step 4) (S) -1- ((2- (3-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (3-fluorophenyl) benzofuran (0.20 g,0.77 mmol), triethylamine (0.32 mL,2.31 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.25 g,0.92 mmol) and DMF (4 mL) sequentially to a 100mL single neck round bottom flask and reacting, concentrating and column chromatography separating and purifying (petroleum ether/ethyl acetate (v/v) =1/1-dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (0.12 g, 48.2%).

MS(ESI,pos.ion)m/z:325.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.61(d,J＝7.7Hz,1H),7.53(d,J＝9.7Hz,1H),7.46–7.45(m,2H),7.42–7.37(m,1H),7.20(d,J＝8.4Hz,1H),7.06–7.01(m,1H),6.99(s,1H),3.78(d,J＝12.6Hz,1H),3.70(t,J＝8.5Hz,1H),3.64(d,J＝12.6Hz,1H),3.35(t,J＝6.6Hz,1H),3.06–3.00(m,1H),2.45–2.38(m,1H),2.23–2.11(m,1H);

¹³C NMR(151MHz,CDCl₃)δ(ppm)176.2,163.1(d,J＝245.7Hz),155.1(d,J＝3.0Hz),154.4,132.4(d,J＝8.4Hz),132.3,130.4(d,J＝8.4Hz),129.2,125.6,121.1,120.6(d,J＝2.8Hz),115.5(d,J＝21.3Hz),111.8(d,J＝23.6Hz),111.3,102.3,66.1,62.3,50.7,23.0.

Example 5 Synthesis of (S) -1- ((7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 1- (bromoethynyl) -3-fluorobenzene

The title compound was prepared as described in example 3, step 1 by adding 1-ethynyl-3-fluorobenzene (3.00 g,24.96 mmol), NBS (4.86 g,27.42 mmol), silver nitrate (0.42 g,2.52 mmol) and acetone (30 mL) sequentially to a 100mL single port round bottom flask and then column chromatography to isolate and purify (petroleum ether) to give the title compound as a pale yellow oil (3.78 g, 75.8%).

Step 2) Synthesis of 7-fluoro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 3, step 2 by adding 1-bromoethynyl-3-fluorobenzene (3.00 g,15.08 mmol), 3-fluoro-4-hydroxybenzaldehyde (2.16 g,15.38 mmol), potassium carbonate (4.16 g,30.16 mmol), DMF (20 mL) and palladium chloride (0.13 g,0.76 mmol) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a brown solid (0.53 g, 13.6%).

MS(ESI,pos.ion)m/z:259.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.04(d,J＝2.0Hz,1H),7.93(d,J＝1.2Hz,1H),7.69(d,J＝7.8Hz,1H),7.63–7.58(m,2H),7.47(td,J＝8.0,5.9Hz,1H),7.18(d,J＝2.7Hz,1H),7.14(td,J＝8.4,2.1Hz,1H).

Step 3) (Synthesis of 7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 7-fluoro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde (0.50 g,1.94 mmol), DMF (6 mL) and sodium borohydride (0.15 g,3.88 mmol) sequentially to a 100mL single neck round bottom flask and then concentrating preshrunk-column chromatography for purification (petroleum ether/ethyl acetate (v/v) =3/1) to give the title compound as a yellow solid (0.44 g, 50.4%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.62(d,J＝7.8Hz,1H),7.54(dd,J＝9.7,1.8Hz,1H),7.40(td,J＝8.0,6.0Hz,1H),7.31(s,1H),7.09–7.02(m,2H),7.00(d,J＝2.8Hz,1H),4.73(s,2H).

Step 4) Synthesis of 5-chloromethyl-7-fluoro-2- (3-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methanol (0.40 g,1.54 mmol), DMF (4 mL) and thionyl chloride (0.12 g,1.69 mmol) sequentially to a 100mL single neck round bottom flask and reacting and concentrating to give the title compound as a brown solid (0.35 g, 81.7%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.64(d,J＝7.8Hz,1H),7.55(dd,J＝9.7,1.7Hz,1H),7.42(td,J＝8.0,5.9Hz,1H),7.37(s,1H),7.11–7.05(m,2H),7.02(d,J＝2.8Hz,1H),4.65(s,2H).

Step 5) (S) -1- ((7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-7-fluoro-2- (3-fluorophenyl) benzofuran (0.15 g,0.54 mmol), triethylamine (0.23 mL,1.62 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.18 g,0.65 mmol) and DMF (5 mL) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1-1/1) to give the title compound as a yellow solid (0.60 g, 32.6%).

MS(ESI,pos.ion)m/z:343.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.76–7.72(m,2H),7.58–7.52(m,2H),7.44(s,1H),7.32(d,J＝12.0Hz,1H),7.26(td,J＝8.6,2.0Hz,1H),7.19(s,1H),7.12(s,1H),3.78(d,J＝12.7Hz,1H),3.55–3.50(m,2H),3.16–3.12(m,1H),2.90–2.84(m,1H),2.26–2.18(m,1H),2.03–1.94(m,1H);

¹³C NMR(101MHz,DMSO-d₆)δ(ppm)174.9,163.0(d,J＝243.9Hz),155.6(d,J＝2.7Hz),147.1(d,J＝247.0Hz),140.5(d,J＝11.3Hz),135.1(d,J＝5.2Hz),132.3(d,J＝3.2Hz),131.8(d,J＝6.9Hz),131.8(d,J＝6.8Hz),121.4(d,J＝2.7Hz),117.8(d,J＝3.2Hz),116.5(d,J＝21.2Hz),112.5(d,J＝16.0Hz),112.0(d,J＝23.8Hz),104.3(d,J＝1.9Hz),66.2,61.6,50.4,22.6.

Example 6 Synthesis of (S) -1- ((2- (4-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (4-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by adding 4-hydroxy-3-iodobenzaldehyde (3.00 g,12.09 mmol), cuI (0.069 mg,0.36 mmol), bis triphenylphosphine palladium dichloride (0.26 mg,0.36 mmol), tetramethylguanidine (4.50 mL,36.27 mmol), 4-fluorophenylacetylene (2.19 g,18.15 mmol) and DMF (30 mL) sequentially to a 100mL single neck round bottom flask and then column chromatography isolation and purification (petroleum ether/ethyl acetate (v/v) =100/1-15/1) to give the title compound as a yellow solid (2.62 g, 90.2%). MS (ESI, pos.ion) m/z 241.1[ M+H ] ⁺;

¹H NMR(400MHz,CDCl₃)δ(ppm)10.05(s,1H),8.10(s,1H),7.86–7.82(m,3H),7.60(d,J＝8.5Hz,1H),7.16(t,J＝8.6Hz,2H),7.02(s,1H).

step 2) (Synthesis of 2- (4-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (4-fluorophenyl) benzofuran-5-carbaldehyde (1.90 g,7.91 mmol), THF (30 mL), methanol (40 mL) and sodium borohydride (0.60 g,15.86 mmol) sequentially to a 250mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =3/1) using concentrated preshrunk to give the title compound as a yellow solid (1.50 g, 78.0%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.95(dd,J＝8.7,5.5Hz,2H),7.59(s,1H),7.56(d,J＝8.4Hz,1H),7.38(s,1H),7.34(t,J＝8.9Hz,2H),7.28(d,J＝8.4Hz,1H),4.60(d,J＝5.7Hz,2H).

Step 3) Synthesis of 5-chloromethyl-2- (4-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (2- (4-fluorophenyl) benzofuran-5-yl) methanol (1.50 g,6.20 mmol), DMF (4 mL) and thionyl chloride (0.82 g,6.82 mmol) sequentially to a 100mL single neck round bottom flask and reacting, concentrating to give the title compound as a brown solid (1.39 g, 86.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.84–7.80(m,2H),7.59(s,1H),7.48(d,J＝8.4Hz,1H),7.33–7.26(m,1H),7.14(t,J＝8.7Hz,2H),6.91(s,1H),4.71(s,2H).

Step 4) (S) -1- ((2- (4-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (4-fluorophenyl) benzofuran (0.25 g,0.96 mmol), triethylamine (0.40 mL,2.88 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.31 g,1.15 mmol) and DMF (4 mL) in sequence to a 100mL single neck round bottom flask and then separating and purifying by column chromatography (ethyl acetate-dichloromethane/methanol (v/v) =10/1) to give the title compound as a white solid (0.21 g, 67.5%).

MS(ESI,pos.ion)m/z:325.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.98–7.95(m,2H),7.61(s,1H),7.54(d,J＝8.3Hz,1H),7.38–7.30(m,4H),7.10(d,J＝6.8Hz,2H),3.80(d,J＝12.4Hz,1H),3.57–3.49(m,2H),3.14(s,1H),2.90–2.88(m,1H),2.23–2.21(m,1H),1.99–1.96(m,1H);

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)174.9,162.7(d,J＝246.7Hz),155.0,154.0,133.2,129.2,127.3(d,J＝8.4Hz),126.9(d,J＝3.0Hz),126.2,121.7,116.6(d,J＝22.0Hz),111.2,102.4,66.1,62.0,50.3,22.6.

Example 7 Synthesis of (S) -1- ((7-fluoro-2- (4-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 1- (bromoethynyl) -4-fluorobenzene

The title compound was prepared as described in example 3, step 1 by adding 1-ethynyl-4-fluorobenzene (4.00 g,33.33 mmol), NBS (6.53 g,36.66 mmol), silver nitrate (0.57 g,3.33 mmol) and acetone (40 mL) sequentially to a 100mL single port round bottom flask and then column chromatography to isolate and purify (petroleum ether) to give the title compound as a pale yellow oil (4.76 g, 71.8%).

Step 2) Synthesis of 7-fluoro-2- (4-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 3, step 2 by adding 1- (bromoethynyl) -4-fluorobenzene (4.76 g,23.92 mmol), 3-fluoro-4-hydroxybenzaldehyde (3.42 g,24.40 mmol), potassium carbonate (6.60 g,47.84 mmol), DMF (20 mL) and palladium chloride (0.21 g,0.76 mmol) sequentially to a 100mL single port round bottom flask and separating and purifying by column chromatography (ethyl acetate-dichloromethane/methanol (v/v) =10/1) to give the title compound as a brown solid (1.05 g, 17.0%).

MS(ESI,pos.ion)m/z:259.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.01(d,J＝1.9Hz,1H),7.89–7.85(m,3H),7.57(dd,J＝10.4,1.0Hz,1H),7.17(t,J＝8.6Hz,2H),7.07(d,J＝2.7Hz,1H).

Step 3) (Synthesis of 7-fluoro-2- (4-fluorophenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 7-fluoro-2- (4-fluorophenyl) benzofuran-5-carbaldehyde (0.60 g,2.32 mmol), DMF (2 mL), methanol (10 mL) and sodium borohydride (0.18 g,4.65 mmol) sequentially to a 100mL single neck round bottom flask and then separating and purifying (petroleum ether/ethyl acetate (v/v) =3/1) by column chromatography over preshrunk volumes to give the title compound as a yellow solid (0.57 g, 94.3%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.94–7.91(m,2H),7.42(d,J＝2.8Hz,1H),7.39(s,1H),7.32(t,J＝8.8Hz,2H),7.13(d,J＝11.9Hz,1H),4.56(d,J＝4.7Hz,2H).

Step 4) Synthesis of 5-chloromethyl-7-fluoro-2- (4-fluorophenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (7-fluoro-2- (4-fluorophenyl) benzofuran-5-yl) methanol (0.52 g,2.00 mmol), DMF (4 mL) and thionyl chloride (0.26 g,2.20 mmol) sequentially to a 100mL single neck round bottom flask and reacting and concentrating to give the title compound as a brown solid (0.53 g, 95.2%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.86–7.82(m,2H),7.35(s,1H),7.15(t,J＝8.7Hz,2H),7.08(dd,J＝11.1,1.1Hz,1H),6.93(d,J＝2.7Hz,1H),4.65(s,2H).

Step 5) (S) -1- ((7-fluoro-2- (4-fluorophenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared by the method described in example 1, step 4 by adding 5-chloromethyl-7-fluoro-2- (4-fluorophenyl) benzofuran (0.16 g,0.57 mmol), triethylamine (0.24 g, 1.71 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.19 g,0.68 mmol) and DMF (3 mL) sequentially to a 100mL single-neck round bottom flask and then reacting them, concentrating and column chromatography separating and purifying (petroleum ether/ethyl acetate (v/v) =1/1 to dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (0.14 g, 70.5%). MS (ESI, pos.ion) m/z 343.2[ M+H ] ⁺;

¹H NMR(400MHz,CDCl₃)δ(ppm)7.78–7.74(m,2H),7.15(s,1H),7.06(t,J＝8.5Hz,2H),6.89(d,J＝11.8Hz,1H),6.87(d,J＝2.6Hz,1H),3.69(d,J＝12.7Hz,1H),3.61(t,J＝8.5Hz,1H),3.54(d,J＝12.8Hz,1H),3.28(t,J＝6.1Hz,1H),2.95(dd,J＝16.2,8.2Hz,1H),2.35(d,J＝8.5Hz,1H),2.17–2.03(m,1H).

¹³C NMR(151MHz,CD₃OD)δ(ppm)176.8,163.1(d,J＝249.5Hz),156.5,147.6(d,J＝249.8Hz),141.0(d,J＝11.3Hz),133.3(d,J＝4.9Hz),132.7(d,J＝3.5Hz),127.0(d,J＝8.3Hz),126.0(d,J＝3.3Hz),116.3(d,J＝3.3Hz),115.9(d,J＝22.1Hz),111.1(d,J＝16.4Hz),101.2,65.8,61.9,50.6,22.8.

example 8 Synthesis of (S) -1- ((2- (2-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (2-methoxyphenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by adding 4-hydroxy-3-iodobenzaldehyde (2.00 g,8.06 mmol), cuI (0.046 mg,0.24 mmol), bis triphenylphosphine palladium dichloride (0.17 mg,0.24 mmol), tetramethylguanidine (3.00 mL,24.18 mmol), 2-ethynylanisole (1.60 g,12.09 mmol) and DMF (20 mL) sequentially to a 100mL single port round bottom flask and then column chromatography isolation and purification (petroleum ether/ethyl acetate (v/v) =100/1-15/1) to give the title compound as a yellow solid (1.65 g, 81.3%).

MS(ESI,pos.ion)m/z:253.1[M+H]⁺；

1H NMR(400MHz,CDCl₃)δ(ppm)10.05(s,1H),8.11(d,J＝1.2Hz,1H),8.05(dd,J＝7.8,1.6Hz,1H),7.83(dd,J＝8.5,1.6Hz,1H),7.59(d,J＝8.5Hz,1H),7.42(s,1H),7.39–7.34(m,1H),7.11–7.07(m,1H),7.02(d,J＝8.3Hz,1H),4.01(s,3H).

Step 2) (Synthesis of 2- (2-methoxyphenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (2-methoxyphenyl) benzofuran-5-carbaldehyde (0.50 g,1.98 mmol), THF (10 mL) and sodium borohydride (0.15 g,3.96 mmol) sequentially to a 100mL single port round bottom flask and then column chromatography to isolate and purify (petroleum ether/dichloromethane (v/v) =1/2) to give the title compound as a yellow solid (0.48 g, 96.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm)8.09(dd,J＝7.8,1.6Hz,1H),7.60(s,1H),7.51(d,J＝8.4Hz,1H),7.38–7.34(m,2H),7.31–7.28(m,1H),7.13–7.09(m,1H),7.04(d,J＝8.3Hz,1H),4.78(s,2H),4.02(s,3H).

Step 3) Synthesis of 5-chloromethyl-2- (2-methoxyphenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (2- (2-methoxyphenyl) benzofuran-5-yl) methanol (0.45 g,1.77 mmol), DMF (4 mL) and thionyl chloride (0.14 mL,1.95 mmol) sequentially to a 100mL single neck round bottom flask and reacting followed by concentration to give a yellow solid (0.47 g, 97.0%).

¹H NMR(400MHz,CDCl₃)δ(ppm)8.08–8.06(m,1H),7.62(s,1H),7.49(d,J＝8.4Hz,1H),7.37–7.26(m,3H),7.10(t,J＝7.5Hz,1H),7.02(d,J＝8.3Hz,1H),4.73(s,2H),4.00(s,3H).

Step 4) (S) -1- ((2- (2-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (2-methoxyphenyl) benzofuran (0.16 g,0.59 mmol), triethylamine (0.25 g, 1.77 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.19 g,0.71 mmol) and DMF (2 mL) in sequence to a 100mL single neck round bottom flask and then separating and purifying by column chromatography (dichloromethane/methanol (v/v) =150/1-10/1) to give the title compound as a white solid (0.15 g, 77.3%).

MS(ESI,pos.ion)m/z:337.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.05(d,J＝7.4Hz,1H),7.46–7.43(m,2H),7.32(s,1H),7.16(d,J＝8.1Hz,1H),7.08(t,J＝7.5Hz,1H),7.00(d,J＝7.9Hz,2H),3.99(s,3H),3.78(d,J＝12.5Hz,1H),3.70(t,J＝8.5Hz,1H),3.64(d,J＝12.5Hz,1H),3.34(t,J＝6.6Hz,1H),3.02(dd,J＝16.2,8.2Hz,1H),2.41(dd,J＝17.0,8.4Hz,1H),2.17(dd,J＝18.4,9.1Hz,1H);

¹³C NMR(101MHz,CDCl₃)δ(ppm)176.2,156.6,153.4,152.8,131.7,130.1,129.4,127.7,125.0,121.0,120.8,119.3,111.1,110.8,106.2,66.1,62.4,55.5,50.6,23.0.

Example 9 Synthesis of (S) -1- ((2- (3-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (3-methoxyphenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by adding 4-hydroxy-3-iodobenzaldehyde (1.00 g,4.03 mmol), cuI (0.023 mg,0.12 mmol), bis triphenylphosphine palladium dichloride (0.084 g,0.12 mmol), tetramethylguanidine (1.50 mL,12.09 mmol), 3-ethynylanisole (0.80 g,6.05 mmol) and DMF (10 mL) sequentially to a 100mL single port round bottom flask for reaction, followed by column chromatography isolation and purification (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a yellow solid (1.01 g, 99.0%). MS (ESI, pos, ion) m/z 253.1[ M+H ] ⁺;

¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.06(s,1H),8.23(d,J＝0.9Hz,1H),7.88(dd,J＝8.5,1.5Hz,1H),7.81(d,J＝8.5Hz,1H),7.62(s,1H),7.52(d,J＝7.7Hz,1H),7.47(s,1H),7.43(t,J＝7.9Hz,1H),7.02(dd,J＝8.1,1.8Hz,1H),3.85(s,3H).

step 2) (Synthesis of 2- (3-methoxyphenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (3-methoxyphenyl) benzofuran-5-carbaldehyde (0.35 g,1.39 mmol), DMF (2 mL), methanol (8 mL) and sodium borohydride (0.11 g,2.78 mmol) sequentially to a 100mL single port round bottom flask and reacting, concentrating and column chromatography to isolate and purify (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (0.34 g, 96.4%).

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.60–7.57(m,2H),7.50(d,J＝7.7Hz,1H),7.46(s,2H),7.42(t,J＝8.0Hz,1H),7.29(d,J＝8.3Hz,1H),6.98(dd,J＝8.0,1.8Hz,1H),4.60(d,J＝5.6Hz,2H),3.85(s,3H).

Step 3) Synthesis of 5-chloromethyl-2- (3-methoxyphenyl) benzofuran

The title compound was obtained by the method described in example 1, step 3 by adding (2- (3-methoxyphenyl) benzofuran-5-yl) methanol (0.30 g,1.18 mmol), DMF (4 mL) and thionyl chloride (0.15 g,1.30 mmol) sequentially to a 100mL single neck round bottom flask and reacting and concentrating to give the title compound as a yellow solid (0.30 g, 93.3%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.59(d,J＝1.2Hz,1H),7.50(d,J＝8.4Hz,1H),7.45(d,J＝7.7Hz,1H),7.41–7.40(m,1H),7.37(t,J＝7.9Hz,1H),7.32(dd,J＝8.4,1.7Hz,1H),6.99(s,1H),6.93(dd,J＝8.1,1.8Hz,1H),4.71(s,2H),3.90(s,3H).

Step 4) (S) -1- ((2- (3-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (3-methoxyphenyl) benzofuran (0.27 g,0.99 mmol), triethylamine (0.41 mL,2.97 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.32 g,1.19 mmol) and DMF (4 mL) in sequence to a 100mL single neck round bottom flask and then reacting them, concentrating and column chromatography separating the purified (petroleum ether/ethyl acetate (v/v) =1/1-dichloromethane/methanol (v/v) =20/1) to give the title compound as a white solid (0.22 g, 66.7%). MS (ESI, pos.ion) m/z 337.2[ M+H ] ⁺;

¹H NMR(400MHz,CDCl₃)δ(ppm)7.44(s,2H),7.39(s,1H),7.34(t,J＝7.9Hz,1H),7.17(d,J＝8.2Hz,1H),7.00(s,1H),6.97(s,1H),6.90(d,J＝7.4Hz,1H),3.87(s,3H),3.77(d,J＝12.5Hz,1H),3.69(t,J＝8.5Hz,1H),3.62(d,J＝12.6Hz,1H),3.33(t,J＝6.5Hz,1H),3.01(dd,J＝16.2,8.2Hz,1H),2.40(dd,J＝17.0,8.4Hz,1H),2.17(dd,J＝18.3,9.2Hz,1H);

¹³C NMR(151MHz,CDCl₃)δ(ppm)176.3,160.0,156.3,154.3,132.1,131.7,129.9,129.4,125.2,120.92,117.5,114.5,111.2,110.2,101.6,66.1,62.3,55.4,50.6,23.0.

Example 10 Synthesis of (S) -1- ((2- (4-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide

Step 1) Synthesis of 2- (4-methoxyphenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 1 by adding 4-hydroxy-3-iodobenzaldehyde (1.00 g,4.03 mmol), cuI (0.023 mg,0.12 mmol), bis triphenylphosphine palladium dichloride (0.084 g,0.12 mmol), tetramethylguanidine (1.50 mL,12.09 mmol), 4-ethynylanisole (0.80 g,6.05 mmol) and DMF (10 mL) sequentially to a 100mL single port round bottom flask for reaction, followed by column chromatography isolation and purification (petroleum ether/ethyl acetate (v/v) =100/1) to give the title compound as a yellow solid (0.85 g, 83.3%). MS (ESI, pos.ion) m/z 253.1[ M+H ] ⁺;

¹H NMR(400MHz,CDCl₃)δ(ppm)9.97(s,1H),8.03(d,J＝1.2Hz,1H),7.77–7.74(m,3H),7.55(d,J＝8.5Hz,1H),6.95–6.91(m,3H),3.81(s,3H).

Step 2) (Synthesis of 2- (4-methoxyphenyl) benzofuran-5-yl) methanol

The title compound was prepared as described in example 1, step 2 by adding 2- (4-methoxyphenyl) benzofuran-5-carbaldehyde (0.50 g,1.98 mmol), DMF (10 mL), methanol (20 mL) and sodium borohydride (0.15 g,3.97 mmol) sequentially to a 100mL single port round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give the title compound as a yellow solid (0.26 g, 51.6%).

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.85–7.84(m,2H),7.55–7.53(m,2H),7.25–7.23(m,2H),7.06–7.05(m,2H),4.59(s,2H),3.82(s,3H).

Step 3) Synthesis of 5-chloromethyl-2- (4-methoxyphenyl) benzofuran

The title compound was prepared as described in example 1, step 3 by adding (2- (4-methoxyphenyl) benzofuran-5-yl) methanol (0.24 g,0.94 mmol), DMF (4 mL) and thionyl chloride (0.12 g,1.03 mmol) sequentially to a 100mL single neck round bottom flask and reacting and then concentrating to give the title compound as a tan solid (0.23 g, 89.4%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.80(s,1H),7.78(s,1H),7.56(d,J＝1.2Hz,1H),7.47(d,J＝8.4Hz,1H),7.28(dd,J＝8.4,1.7Hz,1H),6.99(s,1H),6.97(s,1H),6.85(s,1H),4.71(s,2H),3.86(s,3H).

Step 4) (S) -1- ((2- (4-methoxyphenyl) benzofuran-5-yl) methyl) azetidine-2-carboxamide synthesis

The title compound was prepared as described in example 1, step 4 by adding 5-chloromethyl-2- (4-methoxyphenyl) benzofuran (0.20 g,0.73 mmol), triethylamine (0.30 mL,2.19 mmol), (S) -azetidine-2-carboxamide 4-methylbenzenesulfonate (0.24 g,0.88 mmol) and DMF (4 mL) sequentially to a 100mL single neck round bottom flask and then separating and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) =1/1-dichloromethane/methanol (v/v) =10/1) to give the title compound as a white solid (0.17 g, 70.4%).

MS(ESI,pos.ion)m/z:337.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.82–7.80(m,3H),7.68(s,1H),7.56(d,J＝8.4Hz,1H),7.43(s,1H),7.32(dd,J＝8.5,1.4Hz,1H),7.20(s,1H),7.03(d,J＝8.9Hz,2H),4.98(t,J＝9.1Hz,1H),4.06(q,J＝9.4Hz,1H),3.94–3.81(m,1H),3.77(s,3H),3.15(s,2H),2.69–2.54(m,1H),2.42–2.26(m,1H);

¹³C NMR(151MHz,CDCl₃)δ(ppm)168.4,160.4,156.9,154.8,130.0,126.8,126.7,124.9,123.5,122.4,118.7,116.8,113.0,111.6,100.4,64.5,57.7,55.6,48.9,27.0.

Biological assay

Example a: evaluation of the Activity inhibitory Effect of the Compounds of the invention on monoamine oxidase B

The experimental method comprises the following steps:

The experimental system adopts human recombinant monoamine oxidase B, expressed in Sf9 cells. In the experimental procedure, recombinant monoamine oxidase B was first dissolved in HEPES buffer (0.8% NaCl,0.037% KCl,0.0135% Na ₂HPO₄·2H₂ O,0.1% Glucan,0.5% HEPES, ph=7.0) prepared in advance at a concentration of 0.3 μg/μl. 10 μl of monoamine oxidase B solution was placed in 384 well plates, 10 concentration gradients of test compound (DMSO final concentration 1%) were added to each well, and positive drug selected from R- (-) -Deprenyl (selegiline) or Clorgyline (chloregiline) and incubated at room temperature for 15min. Then 10. Mu.l of substrate solution was added to each well and incubated at room temperature for 60min. Then 20 μl of fluorescein detection reagent was added to each well again, mixed well, incubated at room temperature for 20min to generate a stable fluorescent signal, and the fluorescent signal was read using a fluorescent microplate reader, the values being expressed in terms of relative light intensity (RLU). And calculating the enzyme activity inhibition rate according to the experimental result, wherein the calculation formula is as follows: inh% = (Max-Signal)/(Max-Min) 100, where Max is the value detected at the maximum concentration of the sample, min is the value detected at the minimum concentration of the sample, and Signal is the value detected at the current concentration of the sample.

The IC ₅₀ was calculated by obtaining a standard curve through experimental testing of the series of concentrations. The results are shown in Table A.

TABLE A test results of the Activity inhibition of the inventive Compounds on monoamine oxidase B

Example number	IC₅₀(μM)	Example number	IC₅₀(μM)
				Example 1	0.112	Example 5	0.074
Example 2	0.073	Example 6	0.038
				Example 3	0.069	Example 7	0.035
Example 4	0.086	Example 9	0.103

Experimental results show that the compound has a good inhibition effect on the activity of monoamine oxidase B.

Example B: pharmacokinetic evaluation of rats after intravenous injection or gavage quantification of the compounds of the invention

1) Test animals: the test animals were rats, and the specific cases are shown in table 1:

TABLE 1

Germ line

Grade

Sex (sex)

Quantity of

Weight of body

Week age

Source(s)

SD rat

Cleaning stage

Male male

6 Pieces of

180-220g

8 Weeks of

Changzhou Kavesi

2) The analysis method comprises the following steps:

The LC-MS/MS system for analysis comprises an Agilent 1200 series vacuum degasser, a quaternary pump, an orifice plate automatic sampler, a constant temperature column incubator and an API4000Qtrap triple quadrupole mass spectrometer of an electrified spray ionization source (ESI). Quantitative analysis was performed in MRM mode, where the source parameters of the MRM transitions are shown in table 2:

TABLE 2

Curtain gas/CUR	20psi
		Atomizing gas/GS 1	550psi
Auxiliary heating gas/GS 2	55psi
		Ion transmission voltage IS (V)/NC (mA)	5500
Atomization temperature/TEM	550℃
		Fracture voltage	30V
Capillary voltage	140V
		Dryer temperature	350℃
Atomizer	40psi
		Dryer flow rate	9L/min

Analysis was performed using waters xbridge C < 18 > (2.1X105 mm, 3.5. Mu.M column, 0.5. Mu.L sample injected) under the following conditions: the mobile phases were water+2 mM ammonium formate+0.1% formic acid (mobile phase A) and methanol+2 mM ammonium formate+0.1% formic acid (mobile phase B). The flow rate was 0.4mL/min. The mobile phase gradient is shown in table 3:

TABLE 3 Table 3

Time of	Gradient of mobile phase B
		0.5min	20％
1.2min	90％
		2.7min	90％
2.81min	20％
		4.0min	Termination of

3) The test method comprises the following steps:

the compounds of the invention were evaluated for pharmacokinetics in rats as follows:

The experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric administration. The compounds of the invention were administered to the test animals as 5% dmso+5%Kolliphor HS15+90% Saline solution. For the intravenous administration group, the administration dose was 1mg/kg, and then blood (0.3 mL) was intravenously taken at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20℃or-70 ℃. For the gavage administration group, the administration dose was 5mg/kg, and then blood (0.3 mL) was intravenously taken at the time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20℃or-70 ℃.

Mu.l of plasma was taken, 120. Mu.l of 50ng/ml of internal standard aqueous propranolol solution was added, after mixing well, extracted with 0.9ml of methyl tert-butyl ether (MTBE), 0.8ml of supernatant was dried with nitrogen and redissolved with 200. Mu.l of methanol water (methanol/water (v/v) =1/1).

The concentration of the target compound was detected by LC-MS/MS method and pharmacokinetic parameters were calculated using non-compartmental model. The analysis result shows that the compound has better pharmacokinetic property in the rat body.

In the description of the present specification, reference to the terms "one embodiment," "an embodiment," "some embodiments," "examples," "a particular example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, implementation, or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily for the same examples, implementations or illustrations. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A compound which is a compound represented by the formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

Wherein:

U is CR ^u or N;

V is O, S or NH;

N is 1 or 2.

2. The compound of claim 1, wherein R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, C ₁-C₄ alkylthio, C ₁-C₄ alkylamino, hydroxy-substituted C ₁-C₄ alkyl, C ₃-C₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆-C₁₀ aryl, or 5-10 membered heteroaryl;

3. The compound of claim 1 or 2, wherein R ¹、R²、R³、R⁴ and R ^u are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl, or quinolinyl;

4. The compound of claim 1, wherein R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, C ₁-C₄ alkyl, C ₂-C₄ alkenyl, C ₂-C₄ alkynyl, C ₁-C₄ haloalkyl, C ₁-C₄ alkoxy, C ₁-C₄ haloalkoxy, or hydroxy substituted C ₁-C₄ alkyl;

5. The compound of claim 1 or 4, wherein R ⁹ and R ¹⁰ are each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl 、-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、 methoxy, ethoxy, n-propyloxy, isopropyloxy 、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、 hydroxymethyl or 2-hydroxyethyl;

6. The compound according to claim 1, which is a compound represented by the formula (II), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound represented by the formula (II),

Wherein each R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、U、V and n have the meaning as described in claim 1.

7. The compound of claim 1 or 6, which is a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, of a compound having one of the following structures:

8. A pharmaceutical composition comprising a compound according to any one of claims 1-7; and

The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for preventing, treating or alleviating a disease in a patient mediated by a MAO-B inhibitor.

10. The use according to claim 9, wherein the disorder modulated by MAO-B inhibitors is a neurodegenerative disorder, a psychotic disorder or cancer;

Wherein the neurodegenerative disease is Parkinson's disease, cerebral ischemia, alzheimer's disease, amyotrophic lateral sclerosis, bovine spongiform encephalopathy, huntington's chorea, creutzfeldt-Jakob disease, ataxia telangiectasia, cerebellar atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.