CN111072604A

CN111072604A - α -aminoamide derivatives and uses thereof

Info

Publication number: CN111072604A
Application number: CN201811211693.3A
Authority: CN
Inventors: 金传飞; 陈康智; 易超
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2018-10-18
Filing date: 2018-10-18
Publication date: 2020-04-28
Anticipated expiration: 2038-10-18
Also published as: CN111072604B

Abstract

The invention discloses α -amino amide derivatives and application thereof, in particular to a novel α -amino amide derivative and a pharmaceutical composition containing the compound, and also relates to a method for preparing the compound and the pharmaceutical composition, and application thereof in preparing medicaments for treating diseases regulated by MAO-B inhibitors, including neurodegenerative diseases, especially Parkinson's disease.

Description

α -aminoamide derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound for treating Parkinson's disease, a pharmaceutical composition containing the compound, and a using method and application of the compound.

Background

Parkinson's Disease (PD) is a common chronic degenerative disease of the nervous system, and is common in the elderly, the average age of the disease is about 60 years, and the onset of juvenile Parkinson's disease below 40 years is rare. The prevalence rate 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 begins with an insidious course and progresses slowly. The first symptoms are often tremors or awkward movements in one limb and further involvement in the contralateral limb. Clinically, the symptoms are static tremor, bradykinesia, muscular rigidity and gait disorder. In recent years, people pay more attention to non-motor symptoms such as depression, constipation and sleep disorder, which are also common complaints of Parkinson patients, and the influence of the non-motor symptoms on the life quality of the patients even exceeds the motor symptoms.

The most prominent pathological change of parkinson's disease is the degenerative death of mesocerebral Dopaminergic (DA) neurons, which causes a marked reduction in striatal DA content and causes disease. The exact etiology of this pathological change is still unclear, and genetic factors, environmental factors, aging, oxidative stress, etc. may all be involved in the degenerative death process of PD dopaminergic neurons.

Most cases develop as a result of, or are likely to be associated with, environmental factors, or the interaction of environmental factors with genetic factors. Some of the pathogenesis involved in free radicals, oxidative stress, glutamate excitotoxicity, lack of neurotrophic agents, inflammation, apoptosis and loss of mitochondrial complex I, interaction of these mechanisms in a cascade biochemical reaction ultimately leads to neuronal death (Teismann P, Schulz jb. Cell pathology of Parkinson's disease: astrocytes, microria and inflammation [ J ]. Cell Tissue Res,2004,318: 149-. Genetic factors play a decisive role in part of familial PD. Recent genetic studies have found that defects in the functional capacity of the ubiquitin-proteasome system and abnormal aggregation of denatured proteins play a significant role in most pathogenesis of PD. In addition, factors such as oxidative stress and formation of free radicals, excitotoxicity mediated by excessive release of glutamate, mitochondrial dysfunction, inflammation, and neuronal apoptosis caused by damage to the ubiquitin-proteasome system are closely related to the progression of the disease.

Currently, the primary treatment for PD is dopamine-replacement symptomatic therapy, and levodopa (L-dopa) remains the most clinically effective drug for controlling symptoms and signs of PD (RASCO, GOETZ C, KOLLER W, et al. treatment interventions for Parkinson's disease: an evidence based assessment [ J ]. Lancet,2002,359(9317): 1589-. Although L-dopa can temporarily control the symptoms of PD, chronic administration can result in many adverse reactions such as dyskinesias, motor fluctuations, and psychiatric symptoms. Although the use of sustained DA-ergic neuronal stimulation, deep brain stimulation of the surgical pathway (DBS), long-acting dopamine receptor agonists can reduce the occurrence of these complications to some extent (SCHAPIRA AHV, EMREBM, JENNER P, et al, Levodopa in the effort of Parkinson's disease [ J ]. Eur J Neurol,2009,16(9): 982-. In addition, dopamine receptor agonists such as cabergoline (cabergoline), catechol-o-methyltransferase inhibitors (COMT) such as entacapone (comban), glutamate receptor antagonists such as memantine (memantine), and anticholinergics such as benzhexol (amban) all have adverse reactions, but can be used as auxiliary drugs for levodopa, and can enhance the drug effect of levodopa, reduce the dosage of levodopa, and reduce adverse reactions through different action mechanisms of combined drugs. Therefore, it is important to develop new drugs that can improve symptoms of DA-ergic and non-DA-ergic systems in PD patients, and can slow down or even stop disease progression to exert neuroprotective effect.

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme, an enzyme that catalyzes the oxidative deamination of monoamines, and is responsible for the oxidative deamination of endogenous monoamine neurotransmitters, including: dopamine, 5-hydroxytryptamine, epinephrine or norepinephrine, and trace amines such as phenylethylamine, and many aminoxenobiotics, and the like. Monoamine oxidases can be divided into two subtypes, MAO-A and MAO-B. Their genes encode differently (A.W.Bach et al, Proc.Natl.Acad.Sci.USA1988,85, 4934-. MAO-A is mostly present in liver, gastrointestinal mucosA, catecholamines in blood circulation system and vasoactive substances in diet (e.g. tyrosine) can be inactivated, thereby assisting neurotransmitter degradation in brain; whereas MAO-B is mainly present in the brain and in platelets. MAO-A has A higher affinity for octopamine, 5-hydroxytryptamine, epinephrine, and norepinephrine; while the natural substrates of MAO-B are tyrosine and phenylethylamine. Both isoforms, however, can oxidize dopamine.

Monoamine oxidase B (MAO-B) is one of the key enzymes of DA catabolism, and can be used for improving clinical symptoms by selectively and specifically inhibiting endogenous and exogenous dopamine decomposition and prolonging the action time of dopamine, and can be used for early-stage single-drug therapy of PD and adjuvant therapy after symptom fluctuation. The following 3 functions are mainly realized: (1) decomposing dopamine into 3, 4-dihydroxyphenylacetic acid and homovanillic acid, and simultaneously generating small molecular H₂O₂The compound has toxic effect on nerve cells, (2) β -phenethylamine deamination inactivation capable of stimulating dopamine secretion and inhibiting dopamine reuptake, (3) 1-methyl-4-phenyl-1, 2,3, 6-tetrahydropyrimidine (MPTP) can be decomposed into neurotoxic l-methyl-4-phenylpyridine ion (MPP)⁺). Therefore, 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, improve the dopamine concentration in brain and improve the clinical symptoms of PD; on the other hand, by lowering H₂O₂、MPP⁺Isoneurotoxin levels retard the process of nigral cell death (HEIKKILA RE, MANZINO L, CABAT F S, et al. protection against the protein kinase of 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) bmonoamine inhibitors P].Nature,1984,311(5985):467-469；YOUDIM M BH,BAKHLE YS.Monoamine oxidase isoforms and inhibitors in Parkinson’s disease anddepressive illness[J].Br J Pharmacol,2006,147(S1):S287-S296；NAOI M,WAKAKOM.Monoamine oxidase inhibitors as neuroprotective agents in age-dependentneurodegenerative disorders[J]Curr Pharm Des,2010,16(25):2799-2817), the PD process may be altered. Because the MAO-B inhibitor not only can improve PD symptoms, but also can play a role in neuroprotection, the MAO-B inhibitor is a hotspot of the research of the current anti-Parkinson disease drugs.

Currently, some studies on MAO-B inhibitors have been carried out:

WO 2016052928 a1 discloses α -aminoamide derivatives as MAO-B inhibitors, having excellent stability and better efficacy compared to traditional reversible MAO-B inhibitors, for the treatment of neurodegenerative diseases.

WO 2011042217 a1 discloses substituted aryl-and heteroaryl-cyclopropylamine acetamide 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 2003066596 a1 discloses pyridylamide derivatives as selective MAO-B inhibitors for the treatment of neurological diseases including alzheimer's disease, senile dementia, parkinson's disease and depression.

However, further research is still needed to find more better and more potent MAO-B inhibitors.

Disclosure of Invention

The compound has stable property, good safety, and good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability, and the like, thereby having good clinical application prospect.

The invention also provides processes for the preparation of such compounds and pharmaceutical compositions containing them.

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

wherein:

x is CR^xOr N;

y is O, S or NH;

R^1a、R^1b、R^1c、R^1dand R^xEach independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group;

R³、R⁴each independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group;

R⁵is H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group;

R⁶、R⁷each independently is H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; and

m is 1 or 2.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl;

R^2a、R^2b、R^2cand R^2dEach independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxyN-propyloxy, i-propyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl;

R^2a、R^2b、R^2cand R^2dEach independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R³、R⁴Each independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group;

R⁵is H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Alkyl halidesOxy or hydroxy substituted C₁-C₄An alkyl group;

R⁶、R⁷each independently is H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R³、R⁴Each independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl;

R⁵h, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl;

R⁶、R⁷each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, and propylAlkynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

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

wherein R is^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c、R^2d、R³、R⁴、R⁶、R⁷X, Y and m all have the meanings as described in the present invention.

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 pharmaceutical composition of the present invention further comprises 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 preparation of a medicament for preventing, treating or ameliorating a disease mediated by a MAO-B inhibitor in a patient.

In one embodiment, the disease modulated by MAO-B inhibitors is a neurodegenerative disease, a psychiatric disease, 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 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 better inhibition effect on the activity of MAO-B, and can be used as a better medicament for treating Parkinson's disease.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, 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 invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

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

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

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

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

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

The term "chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that are not overlapping 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 "diastereomer" 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 points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an 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 denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as 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 exist as one of the possible isomers or as mixtures thereof, for example as 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 substituents 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.

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

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

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

"pharmaceutically acceptable" refers to 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 which are effective for their intended use.

The term "optionally substituted with … ….," is used interchangeably with the term "unsubstituted or substituted with ….," i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃-OH, oxo (═ O), -NH₂，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 any reasonable position in the group that it may be substituted for. When more than one position in a given formula can be substituted with one or more particular substituents selected from the group, then the substituents may be substituted identically or differently at each of the possible positions in the formula.

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

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

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

The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

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

The term "D" denotes 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 amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R representing a substituent as described herein).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, 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 group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (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 so on.

The term "alkylene" denotes a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon radicalAnd (4) clustering. Unless otherwise specified, the alkylene group contains 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 of this include methylene (-CH)₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like. The alkylene group is optionally substituted with one or more substituents 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 sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents 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 contains 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 so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 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 so on.

The term "alkylthio" means an alkyl group attached to the rest 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 so on.

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

The term "hydroxy-substituted alkyl" denotes an alkyl group 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" denotes 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、-CH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in another embodiment, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in yet another embodiment, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The term "haloalkoxy" denotes an alkoxy group 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、-OCH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆Haloalkoxy comprises fluorine substituted C₁-C₆An alkoxy group; in another embodiment, C₁-C₄Haloalkoxy comprises fluorine substituted C₁-C₄An alkoxy group; in yet another embodiment, C₁-C₂Haloalkoxy comprises fluorine substituted C₁-C₂An alkoxy group.

The term "n-member" or "n-member" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is 6-atom heterocyclyl or 6-membered heterocyclyl, while indolyl is 9-atom heteroaryl or 9-membered heteroaryl.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 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 and refer to a monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms in which one or more of the ring atoms is independently replaced by a heteroatom having the meaning described herein, which ring may be fully saturatedAnd or contain one or more unsaturations, but none of the aromatic rings. In one embodiment, the heterocyclyl group is a 3-8 membered ring monocyclic (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 ring system like SO, SO₂，PO，PO₂When said ring is a three-membered ring, in which there is only one heteroatom), or 7-12 membered bicyclic rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give the group like SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Wherein, is cyclic-CH₂The group is optionally replaced by-C (═ O) -, 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-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂The radical being-C (═ O) -Examples of substitutions include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 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 terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes 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. The heteroaryl group is 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 "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 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), and the like, 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, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] 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 ] pyridyl, and the like.

The term "prodrug", as used herein, represents 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 by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

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

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. The water-soluble or oil-soluble or dispersible products can be obtained byQuaternization is achieved. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C₁-C₈Sulfonates and aromatic sulfonates.

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

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

As used herein, the terms "compound of the present invention", "compound described herein" or similar terms refer to a compound represented by any one of the general structures described herein, i.e., to a compound represented by formula (I) or formula (II) herein.

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

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

The α -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, particularly Parkinson's disease.

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

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

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I) or formula (II) may be present in the form of a salt. 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 need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) or formula (II) and/or in the isolation of an enantiomer of a compound of formula (I) or formula (II).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate 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 the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I) or formula (II).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present 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 dosage form.

Description of the Compounds of the invention

The α -amino amide derivative, its pharmaceutically acceptable salt, its medicinal preparation and its medicinal composition have inhibiting effect on MAO-B activity and latent application in treating neurodegenerative diseases, especially Parkinson's disease.

wherein each R is^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c、R^2d、R³、R⁴、R⁵、R⁶、R⁷X, Y and m all have the meanings as described in the present invention.

In one embodiment, X is CR^xOr N.

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

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, R^2a、R^2b、R^2cAnd R^2dEach independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R³、R⁴Each independently is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁵Is H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁶、R⁷Each independently is H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, m is 1 or 2.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrazoylPyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, R^2a、R^2b、R^2cAnd R^2dEach independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R^2a、R^2b、R^2cAnd R^2dEach independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R³、R⁴Each independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R³、R⁴Each independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R⁵Is H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R⁵H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl.

In one embodiment, R⁶、R⁷Each independently is H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R⁶、R⁷Each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propyneRadical, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

wherein each R is^1a、R^1b、R^1c、R^1d、R^2a、R^2b、R^2c、R^2d、R³、R⁴、R⁶、R⁷X, Y and m all have the meanings as described in the present invention.

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound having one of the following structures, but is by no means limited thereto:

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 preparation of a medicament for preventing, treating or ameliorating a disease mediated by a MAO-B inhibitor in a patient.

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 an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, 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, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug delivery systems (2004) Lippincott, Williams & Wilkins, philidelphia; 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, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which 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 on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting a compound of the 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 may be selected that enhance patient compliance.

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, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. 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. sup. 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

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

Thus, in another aspect, the 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 admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds 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 a 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 patches; (4) rectal administration, e.g., suppositories; (5) inhalation, 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 be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

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

For example, a solid oral dosage form may comprise, in addition to the active ingredient: diluents such as lactose, glucose, sucrose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; a binder such as starch, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; wetting agents such as lecithin, polysorbates, lauryl sulfate; and generally non-toxic and pharmaceutically inactive materials used in pharmaceutical formulations. The pharmaceutical preparations may be manufactured in a known manner, for example, by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.

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

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

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to 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, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets 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. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular 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 present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted 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 as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be 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 dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. Emulsions and suspensions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, with the active compound. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. 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 contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous isotonic salt solutions. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups may contain as carrier, for example, sucrose or an aqueous solution of sucrose and 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 precise and convenient administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are 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. Fine powders may be prepared, for example, by micronization and milling. In general, a size-reduced (e.g., micronized) compound 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 prepared 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 agent by iontophoresis, 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 a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases 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. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

The compounds of the invention may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

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

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

Pharmaceutical compositions intended 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 agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided herein can be administered by rectal suppository by mixing the drug with a suitable non-irritating excipient (e.g., cocoa butter, glycerol esters synthesized with polyethylene glycol), which is solid at ordinary temperatures, and then liquefying or dissolving in the rectal cavity to release the drug. Because of individual variation, the severity of symptoms can vary widely, and each drug has its unique therapeutic properties, the precise mode of administration, dosage form and treatment regimen for each individual should be determined by the practitioner.

The pharmaceutical compositions provided by the present invention may be formulated into 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 allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Other factors that need to be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's The Pharmacological Bases of Therapeutics,8The d., Pergamon Press, 1990; remington's Pharmaceutical Sciences,17th ed., MackPublishing Company, Easton, Pa., 1990. Therapeutically effective amounts of the compounds of the invention are such that the compounds of the invention are active in vivo when administered from 0.1 to 200mg/kg orally, intraperitoneally or intravenously.

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 disorder being treated. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, result 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 forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, the dosage will necessarily vary depending upon the condition of the patient being treated, and the appropriate dosage will be determined by the physician according to the individual patient, the therapeutically effective amount per unit dose will depend upon body weight, physiology and the selected vaccination regimen, the weight of the compound per unit dose, excluding the weight of the carrier in which it is administered (the carrier being present in the medicament), pharmaceutical compositions comprising the α -aminoamide derivative of formula (I) or formula (II) as defined above will 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, teaspoonful, suppository, etc.

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

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

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a 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 carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds 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 person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition 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 other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

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

In addition, the compounds of the present invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, is ultimately released in vivo from the compound of the present invention. When administering the compounds of the present invention in prodrug form, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the 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 preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve 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 compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for preventing, treating or relieving the diseases of patients regulated by MAO-B inhibitors, and also can be used for preparing medicines for preventing, treating or relieving neurodegenerative diseases, psychosis or cancer.

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

The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of psychosis by administering to a patient an effective amount of a compound or composition of the present invention. The psychosis is schizophrenia and/or anxiety, wherein schizophrenia, further including but not limited to brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophreniform disorder; wherein anxiety disorders further include, but are not limited to, panic disorders, obsessive compulsive disorders, post-traumatic stress disorders, social phobia or social anxiety disorders, specific phobias, and generalized anxiety disorders.

The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of cancer by administering to a patient an effective amount of a compound or composition of the present invention. The cancer further includes, but is not limited to, prostate cancer, breast cancer, testicular cancer, colorectal cancer, lung cancer, brain tumor, kidney tumor, or blood cancer.

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

General synthetic procedures for Compounds of the invention

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

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

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

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), q (quatets, quartets), m (multiplets ), br (broadpededwideams), brs (broadpedsinglets, wideadlets), dd (doublets ), ddd (doublets of doublets, doublets), dt (doublets of triplets), td (triplet of triplets ). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

CH₂Cl₂DCM dichloromethane mmol

CDC1₃G of deuterated chloroform

DMSO-d₆Deuterated dimethyl sulfoxide mg

DMSO. mu.g of dimethyl sulfoxide

DMF N, N-dimethylformamide ng g N g

EtOAc, EA ethyl acetate μ L, μ L

NaCl sodium chloride mL, mL mL

KCl potassium chloride HEPES 4-hydroxyethyl piperazine ethanesulfonic acid

Na₂HPO₄·2H₂Glucan glucosamine disodium hydrogen phosphate O dihydrate

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

RT, RT, r.t. Room temperature min

NBS N-bromosuccinimide h hour

The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicated^1c、R^2b、R⁶And R⁷All have the definitions as described in the present invention.

Synthesis scheme 1

Wherein NBS refers to N-bromosuccinimide.

The compound represented by the formula (4) can be prepared by the following process: phenylacetylene containing different substituents shown in the formula (1) reacts with NBS under the catalysis of silver nitrate to obtain a compound shown in the formula (2). Reacting the compound shown in the formula (2) with p-hydroxybenzaldehyde containing different substituents under the action of alkali to obtain the compound shown in the formula (3). Reacting the compound shown in the formula (3) with L-alaninamide hydrochloride or L-alaninamide derivative to obtain the compound shown in the formula (4).

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

Examples

EXAMPLE 1 Synthesis of (S) -2- (((2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propanamide

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

1-ethynyl-3-fluorobenzene (1.0g,8.32mmol), NBS (1.62g,9.14mmol), silver nitrate (0.14g,0.84mmol) and acetone (10mL) were added sequentially to a 100mL single-neck round-bottom flask, reacted at room temperature for 2.5 hours, filtered, the filtrate collected, and then purified by direct column chromatography (petroleum ether) to give the title compound as a pale yellow oil (1.26g, 75.8%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.31-7.27(m,1H),7.25-7.23(m,1H),7.15(d,J＝9.4 Hz,1H),7.06(t,J＝9.1Hz,1H).

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

1- (bromoethynyl) -3-fluorobenzene (0.5g,2.51mmol), 4-hydroxybenzaldehyde (0.34g,2.76mmol), potassium carbonate (0.69g,5.02mmol) and N, N-dimethylformamide (5mL) were added to a 100mL single-neck round-bottom flask, heated to 110 ℃ for 13 hours, followed by palladium dichloride (0.022g,0.12mmol), heated to 130 ℃ for 12 hours, after completion of the reaction, cooled to room temperature, and concentrated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a yellow solid (0.21g, 34.8%).

MS(ESI,pos.ion)m/z:241.2[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 3) Synthesis of (S) -2- (((2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propionamide

L-alaninamide hydrochloride (0.34g,2.75mmol), triethylamine (0.96mL,6.87mmol) and methanol (10mL) were sequentially added to a 100mL single-neck round-bottom flask, reacted at room temperature for 30 minutes, then 2- (3-fluorophenyl) benzofuran-5-carbaldehyde (0.55g,2.29mmol) was added, reacted at room temperature for 3.5 hours, transferred to a 0 ℃ cold bath, potassium borohydride (0.74g,13.74mmol) was slowly added until no bubble was generated, transferred to 65 ℃ for 3 hours, reacted, and then concentrated and sample-stirred column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 1/5) gave the title compound as a white solid (0.33g, 46.1%).

MS(ESI,pos.ion)m/z:313.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.76-7.71(m,2H),7.61(s,1H),7.57-7.54(m,2H),7.51(s,1H),7.39-7.29(m,2H),7.24(dd,J＝11.8,5.1Hz,1H),7.00(s,1H),3.71(dd,J＝53.3,13.3Hz,2H),3.05(q,J＝6.8Hz,1H),1.16(d,J＝6.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)177.5,163.1(d,J＝243.5Hz),154.5(d,J＝3.0Hz),154.0,136.3,132.6(d,J＝8.7Hz),131.7(d,J＝8.5Hz),129.0,125.9,121.1(d,J＝2.4Hz),121.0,116.0(d,J＝21.2Hz),111.7(d,J＝23.6Hz),111.3,103.9,56.9,51.5,19.9.

EXAMPLE 2 Synthesis of (S) -2- (((7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propanamide

Step 1) Synthesis of 7-fluoro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 2 by adding 1- (bromoethynyl) -3-fluorobenzene (1.2g,6.03mmol), 3-fluoro-4-hydroxybenzaldehyde (0.93g,6.63mmol), potassium carbonate (1.66g,12.06mmol), N-dimethylformamide (10mL) and palladium dichloride (0.053g,0.30mmol) in that order to a 100mL single neck round bottom flask and then purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a yellow solid (0.39g, 25.0%).

MS(ESI,pos.ion)m/z:259.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.02(d,J＝1.9Hz,1H),7.92(d,J＝0.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.62-7.57(m,2H),7.46(dt,J＝13.8,6.9Hz,1H),7.17(d,J＝2.7Hz,1H),7.12(td,J＝8.3,2.0Hz,1H).

Step 2 Synthesis of) (S) -2- (((7-fluoro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propionamide

The title compound was prepared as described in example 1, step 3 by adding L-alaninamide hydrochloride (0.20g,1.62mmol), triethylamine (0.56mL,4.05mmol), methanol (10mL), 7-fluoro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde (0.35g,1.35mmol) and potassium borohydride (0.44g,8.10mmol) in that order to a 100mL single neck round bottom flask and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (0.30g, 67.1%).

MS(ESI,pos.ion)m/z:331.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.79-7.75(m,2H),7.62(d,J＝2.8Hz,1H),7.57(dd,J＝14.2,8.0Hz,1H),7.44(s,1H),7.34(s,1H),7.30-7.25(m,2H),6.98(s,1H),3.71(dd,J＝54.4,13.7Hz,2H),3.03(q,J＝6.8Hz,1H),1.15(d,J＝6.8Hz,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ(ppm)177.3,163.0(d,J＝243.8Hz),155.6(d,J＝2.6Hz),148.4,145.9,140.3(d,J＝11.3Hz),138.2(d,J＝4.9Hz),132.4(d,J＝3.3Hz),131.8(d,J＝8.6Hz),121.4(d,J＝2.7Hz),116.7(d,J＝3.2Hz),116.5(d,J＝21.3Hz),112.0(d,J＝23.8Hz),111.6(d,J＝16.0Hz),104.3,56.9,51.1,19.8.

EXAMPLE 3 Synthesis of (S) -2- (((7-chloro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propionamide

Step 1) Synthesis of 7-chloro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 2 by adding 1- (bromoethynyl) -3-fluorobenzene (1.0g,5.02mmol), 3-chloro-4-hydroxybenzaldehyde (0.86g,5.52mmol), potassium carbonate (1.38g,10.04mmol), N-dimethylformamide (10mL) and palladium dichloride (0.044g,0.25mmol) sequentially to a 100mL single neck round bottom flask and then purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a yellow solid (0.41g, 30.0%).

MS(ESI,pos.ion)m/z:275.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.04(s,1H),8.10(s,1H),7.72(d,J＝8.0Hz,1H),7.61-7.59(m,2H),7.50(d,J＝8.5Hz,1H),7.17(s,1H),7.10(td,J＝8.2,2.1Hz,1H).

Step 2 Synthesis of (S) -2- (((7-chloro-2- (3-fluorophenyl) benzofuran-5-yl) methyl) amino) propionamide

The title compound was prepared as described in example 1, step 3 by adding L-alaninamide hydrochloride (0.21g,1.66mmol), triethylamine (0.57mL,4.14mmol), methanol (10mL), 7-chloro-2- (3-fluorophenyl) benzofuran-5-carbaldehyde (0.38g,1.38mmol) and potassium borohydride (0.45g,8.28mmol) in that order to a 100mL single neck round bottom flask and purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (0.28g, 58.3%).

MS(ESI,pos.ion)m/z:347.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.78-7.73(m,2H),7.61(s,1H),7.58-7.53(m,1H),7.49(s,1H),7.40-7.32(m,1H),7.25-7.10(m,2H),7.00(s,1H),3.71(dd,J＝54.0,13.2Hz,2H),3.04(q,J＝6.8Hz,1H),1.15(d,J＝6.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)177.6,163.2(d,J＝243.5Hz),154.7(d,J＝2.7Hz),154.2,136.6,132.5(d,J＝8.5Hz),131.5(d,J＝8.3Hz),128.9,126.1,121.0(d,J＝2.6Hz),120.8,116.2(d,J＝21.2Hz),111.6(d,J＝20.1Hz),111.0,104.0,56.9,51.2,19.8.

EXAMPLE 4 Synthesis of (S) -2- (((2- (3-chlorophenyl) benzofuran-5-yl) methyl) amino) propanamide

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

This step was prepared by the method described in example 1, step 1, i.e., 3-chlorophenylacetylene (1.0g,7.35mmol), NBS (1.44g,8.09mmol), silver nitrate (0.13g,0.74mmol) and acetone (20mL) were added sequentially to a 100mL single-neck round-bottom flask for reaction, followed by concentrated pad-batch column chromatography purification (petroleum ether) to give the title compound as a pale yellow oil (1.18g, 75.0%).

¹H NMR(400MHz,DMSO-d₆)δ7.34-7.31(m,1H),7.25(d,J＝10.2Hz,1H),7.20(d,J＝9.2Hz,1H),7.12(s,1H).

Step 2) Synthesis of 2- (3-chlorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 2 by adding 1- (bromoethynyl) -3-chlorobenzene (1.0g,4.67mmol), 4-hydroxybenzaldehyde (0.63g,5.14mmol), potassium carbonate (1.29g,9.34mmol), N-dimethylformamide (10mL) and palladium dichloride (0.041g,0.23mmol) in that order to a 100mL single neck round bottom flask and then purifying by concentrated pad-batch column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a yellow solid (0.38g, 32.1%).

MS(ESI,pos.ion)m/z:257.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.03(s,1H),8.20(s,1H),7.85(d,J＝8.3Hz,1H),7.64-7.61(m,2H),7.55(d,J＝8.9Hz,1H),7.45(d,J＝8.0Hz,1H),7.20(s,1H),7.09(t,J＝1.9Hz,1H).

Step 3 Synthesis of (S) -2- (((2- (3-chlorophenyl) benzofuran-5-yl) methyl) amino) propanamide

The title compound of this step was prepared by the method described in example 1, step 3, i.e. L-alaninamide hydrochloride (0.21g,1.69mmol), triethylamine (0.59mL,4.23mmol), methanol (10mL), 2- (3-chlorophenyl) benzofuran-5-carbaldehyde (0.36g,1.41mmol) and potassium borohydride (0.46g,8.46mmol) were added sequentially to a 100mL single neck round bottom flask for reaction, followed by concentrated pad-batch column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (0.32g, 70.1%).

MS(ESI,pos.ion)m/z:329.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.78-7.72(m,2H),7.65(s,1H),7.56-7.52(m,2H),7.50(s,1H),7.44-7.30(m,2H),7.26(d,J＝5.6Hz,1H),6.99(s,1H),3.72(dd,J＝53.3,13.2Hz,2H),3.04(q,J＝6.8Hz,1H),1.15(d,J＝6.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)177.3,164.1,155.5,154.5,136.6,132.4,131.4,130.0,126.1,122.0,121.2,117.0,112.6,111.5,105.0,56.9,51.5,19.9.

EXAMPLE 5 Synthesis of (S) -2- (((2- (3-chlorophenyl) -7-fluorobenzofuran-5-yl) methyl) amino) propionamide

Step 1) Synthesis of 2- (3-chlorophenyl) -7-fluorobenzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 2 by adding 1- (bromoethynyl) -3-chlorobenzene (1.1g,5.14mmol), 3-fluoro-4-hydroxybenzaldehyde (0.79g,5.65mmol), potassium carbonate (1.42g,10.28mmol), N-dimethylformamide (10mL) and palladium dichloride (0.045g,0.26mmol) in that order to a 100mL single neck round bottom flask for reaction, followed by concentrated pad column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a pale yellow solid (0.47g, 33.0%).

MS(ESI,pos.ion)m/z:275.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.05(s,1H),8.12(s,1H),7.76(d,J＝8.2Hz,1H),7.64-7.60(m,2H),7.52(d,J＝8.1Hz,1H),7.20(s,1H),7.15(t,J＝2.3Hz,1H).

Step 2 Synthesis of (S) -2- (((2- (3-chlorophenyl) -7-fluorobenzofuran-5-yl) methyl) amino) propionamide

The title compound of this step was prepared by the method described in example 1, step 3, i.e. L-alaninamide hydrochloride (0.24g,1.93mmol), triethylamine (0.67mL,4.83mmol), methanol (10mL), 2- (3-chlorophenyl) -7-fluorobenzofuran-5-carbaldehyde (0.44g,1.61mmol) and potassium borohydride (0.52g,9.66mmol) were added sequentially to a 100mL single neck round bottom flask for reaction, followed by concentrated pad-batch column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 1/6) to give the title compound as a yellow solid (0.33g, 60.1%).

MS(ESI,pos.ion)m/z:347.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.79-7.75(m,2H),7.59(s,1H),7.56-7.52(m,1H),7.50(s,1H),7.42-7.33(m,1H),7.26-7.11(m,2H),6.98(s,1H),3.72(dd,J＝54.2,13.3Hz,2H),3.03(q,J＝6.8Hz,1H),1.14(d,J＝6.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)177.3,163.0(d,J＝244.0Hz),155.5(d,J＝3.0Hz),154.6,140.5,133.4(d,J＝8.7Hz),132.0(d,J＝8.1Hz),129.0,127.0,122.1(d,J＝3.2Hz),120.2,117.6(d,J＝22.1Hz),112.6(d,J＝20.3Hz),112.0,105.1,57.0,51.3,19.8.

EXAMPLE 6 Synthesis of (S) -2- (((7-chloro-2- (3-chlorophenyl) benzofuran-5-yl) methyl) amino) propionamide

Step 1) Synthesis of 7-chloro-2- (3-chlorophenyl) benzofuran-5-carbaldehyde

The title compound was prepared as described in example 1, step 2 by adding 1- (bromoethynyl) -3-chlorobenzene (1.0g,4.67mmol), 3-chloro-4-hydroxybenzaldehyde (0.80g,5.14mmol), potassium carbonate (1.29g,9.34mmol), N-dimethylformamide (10mL) and palladium dichloride (0.041g,0.23mmol) in that order to a 100mL single neck round bottom flask and then purifying by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 15/1) to give the title compound as a brown solid (0.42g, 31.2%).

MS(ESI,pos.ion)m/z:291.2[M+H]⁺；

¹HNMR(400MHz,CDCl₃)δ(ppm)10.07(s,1H),8.22(s,1H),7.84(d,J＝8.7Hz,1H),7.67-7.60(m,2H),7.50(d,J＝8.2Hz,1H),7.22(s,1H),7.10(t,J＝2.1Hz,1H).

Step 2 Synthesis of (S) -2- (((7-chloro-2- (3-chlorophenyl) benzofuran-5-yl) methyl) amino) propionamide

The title compound of this step was prepared by the method described in example 1, step 3, i.e. L-alaninamide hydrochloride (0.21g,1.66mmol), triethylamine (0.57mL,4.14mmol), methanol (10mL), 7-chloro-2- (3-chlorophenyl) benzofuran-5-carbaldehyde (0.40g,1.38mmol) and potassium borohydride (0.45g,8.28mmol) were added sequentially to a 100mL single neck round bottom flask for reaction, followed by concentrated pad column chromatography purification (petroleum ether/ethyl acetate (v/v) ═ 1/5) to give the title compound as a white solid (0.29g, 58.8%).

MS(ESI,pos.ion)m/z:363.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.79-7.73(m,2H),7.66(s,1H),7.55-7.51(m,2H),7.52(s,1H),7.46-7.32(m,2H),7.00(s,1H),3.72(dd,J＝54.3,13.5Hz,2H),3.02(q,J＝6.8Hz,1H),1.16(d,J＝6.8Hz,3H)；

¹³C NMR(151MHz,DMSO-d₆)δ(ppm)177.4,164.2,155.6,154.3,136.7,132.2,131.2,130.1,126.0,123.0,122.0,118.0,112.1,111.6,105.1,56.9,51.5,19.9.

Biological assay

Example A: evaluation of inhibitory Effect of the Compound of the present invention on monoamine oxidase B Activity

Experimental methods：

The experimental system adopts human recombinant monoamine oxidase B and is expressed in Sf9 cells. In the experimental process, firstly, the recombinant monoamine oxidase B is dissolved in a prepared HEPES buffer solution (0.8% NaCl, 0.037% KCl and 0.0135% Na)₂HPO₄·2H₂O, 0.1% Glucan, 0.5% HEPES, pH 7.0), and the formulation concentration was 0.3 μ g/μ l. Mu.l of monoamine oxidase B solution was placed in 384-well plates, 10 concentration gradients of the test compound (final DMSO concentration: 1%) were added to each well, and R- (-) -Deprenyl (selegiline) or Clorgyline (Clogylan) was used as a positive drug and incubated at room temperature for 15 min. Then 10. mu.l of substrate solution was added to each well and incubated for 60min at room temperature. Then 20. mu.l of fluorescein detection reagent was added to each well againAnd (3) fully and uniformly mixing the reagents, incubating for 20min at room temperature to generate a stable fluorescent signal, reading the fluorescent signal by using a fluorescence microplate reader, and expressing the numerical value by relative light intensity (RLU). And (3) calculating the enzyme activity inhibition rate according to the experimental result, wherein the calculation formula is as follows: and Inh% (Max-Signal)/(Max-Min) × 100, wherein Max is the value detected when the sample is at the maximum concentration, Min is the value detected when the sample is at the minimum concentration, and Signal is the value detected when the sample is at the current concentration.

Obtaining a standard curve through a series of experimental tests of concentration, and calculating IC₅₀. The results are shown in Table A.

Table a test results for the inhibition of monoamine oxidase B activity by the compounds of the invention

Example No. 2	IC₅₀(μM)
		Example 1	0.67
Example 2	0.72

The experimental result shows that the compound has better inhibition effect on the activity of monoamine oxidase B.

Example B: pharmacokinetic evaluation of rats after intravenous injection or gavage of a quantitative Compound of the invention

1) Test animal: the test animals are rats, and the specific conditions are shown in table 1:

TABLE 1

Germling

Grade

Sex

Number of

Body weight

The week of the year

Origin of origin

SD rat

Cleaning stage

Male sex

6 are

180-220g

8 weeks

Changzhou Kavens

2) Analytical method：

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 with an electric spray ionization source (ESI). The quantitative analysis was performed in MRM mode, where the source parameters of the MRM transitions are shown in table 2:

TABLE 2

Air curtain air/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℃
		Fragmentation voltage	30V
Capillary voltage	140V
		Dryer temperature	350℃
Atomizer	40psi
		Flow rate of dryer	9L/min

Analysis was performed using waters xbridge C18 (2.1X 50mm, 3.5. mu.M column, 0.5. mu.L sample injection) under the following conditions: the mobile phases were water +2mM ammonium formate + 0.1% formic acid (mobile phase a) and methanol +2mM ammonium formate + 0.1% formic acid (mobile phase B). The flow rate was 0.4 mL/min. The mobile phase gradients are shown in table 3:

TABLE 3

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

3) Test method：

The compound of the invention is evaluated by pharmacokinetics in rats, and the specific steps are as follows:

the experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric gavage. The compounds of the invention were administered to the test animals as a solution of 5% DMSO + 5% Kolliphor HS15+ 90% Saline. For the group administered by intravenous injection, the dose was 1mg/kg, followed by intravenous blood (0.3mL) 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 centrifugation 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 dose was 5mg/kg, and then blood (0.3mL) was taken intravenously at time points of 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 and added with 120. mu.l of 50ng/ml aqueous propranolol internal standard solution, mixed well and 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 is detected by an LC-MS/MS method, and pharmacokinetic parameters are calculated by a non-compartmental model. The analysis result shows that the compound of the invention has better pharmacokinetic property in rats.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. 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 various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

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

Claims

1. A compound which is a compound represented by formula (I) 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,

wherein:

x is CR^xOr N;

y is O, S or NH;

m is 1 or 2.

2. The compound of claim 1, wherein R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl;

3. The compound of claim 1 or 2, wherein R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl;

4. The compound of claim 1, wherein R³、R⁴Each independently is H, D, F, Cl, Br, I, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group;

R⁵is H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group;

5. The compound of claim 1 or 4, wherein R³、R⁴Each independently is H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Hydroxymethyl or 2-hydroxyethyl;

R⁶、R⁷each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

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

7. the compound according to claim 1 or 6, which is a compound having one of the following structures 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 having one of the following structures:

8. a pharmaceutical composition comprising a compound of 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 of any one of claims 1-7 or a pharmaceutical composition of claim 8 in the preparation of a medicament for preventing, treating or ameliorating a disease mediated by MAO-B inhibitors in a patient.

10. The use of claim 9, wherein the disease modulated by MAO-B inhibitors is a neurodegenerative disease, a psychiatric disease 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.