CN109251155A

CN109251155A - Alpha-aminoamide derivatives and application thereof

Info

Publication number: CN109251155A
Application number: CN201810735283.2A
Authority: CN
Inventors: 陈康智; 金传飞; 张英俊
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2017-07-14
Filing date: 2018-07-06
Publication date: 2019-01-22

Abstract

The invention discloses alpha-aminoamide derivatives and application thereof, in particular it relates to a kind of novel alpha-aminoamide derivatives and the pharmaceutical composition comprising such compound.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they in preparation treatment by the disease that MAO-B inhibitor is adjusted include neurodegenerative disease, the especially purposes in the drug of Parkinson's disease.

Description

Alpha-aminoamide derivatives and application thereof

Technical field

The invention belongs to technical field of pharmaceuticals, and in particular to include the chemical combination for treating the compound of Parkinson's disease The pharmaceutical composition and its application method and purposes of object.Particularly, compound of the present invention is to can be used as MAO-B suppression The alpha-aminoamide derivatives of preparation.

Background technique

Parkinson's disease (Parkinson ' s disease, PD) is a kind of common nervous system chronic degenerative diseases, always Year, people was common, and average age of onset is 60 years old or so, and the young Parkinson's disease of 40 years old or less onset is more rare.China's over-65s The illness rate of crowd PD is about 1.7%.Most of Parkinsonian is Sporadic cases, and the only patient less than 10% has house Race's history.Parkinson's disease insidious onset, makes slow progress.Onset symptoms be usually side limbs tremble or activity is clumsy, and then it is tired And contralateral limbs.Clinically it is mainly shown as static tremor, bradykinesia, myotonia and posture gait disorder.In recent years messenger More and more notice that the non-motor symptoms such as depression, constipation and sleep disturbance are also the common main suit of Parkinsonian, Their influences to patients ' life quality are even more than motor symptoms.

The most important pathological change of Parkinson's disease is that the denaturation of substantia nigra of midbrain dopamine (dopamine, DA) serotonergic neuron is dead It dies, striatum DA level conspicuousness is caused to reduce and cause a disease therefrom.The definite cause of disease of this pathological change is not led at present still not Clear, the denaturation that inherent cause, environmental factor, age ageing, oxidative stress etc. may participate in PD dopaminergic neuron is dead Die process.

Most of case morbidities are likely to or environmental factor related with environmental factor and inherent cause interaction As a result.Site morbidity mechanism involve free radical, oxidative stress, glutamate excitotoxicity, lack neurotrophic agents, inflammation, Apoptosis and mitochondrial complex I missing, the interaction of these mechanism eventually leads to neuronal death in tandem type biochemical reaction (Teismann P,Schulz JB.Celluar pathology of Parkinson’s disease.:astrocytes, microglia and inflammation[J].CellTissue Res,2004,318:149-161).In some familial PD Inherent cause has played decisive role.Recent genetics research discovery, in the pathogenesis of most of PD, Ubiquitin-proteasome The abnormal aggregation of system function defect and albuminate has played important function.In addition, the formation of oxidative stress and free radical, Excitatory toxicity, mitochondria dysfunction, inflammation and the Ubiquitin-proteasome system damage that glutamic acid excessively discharges mediation are led The progress of the factors such as the Neuron Apoptosis of cause and disease is closely related.

Currently, the primary treatments of PD are the symptomatic treatments of dopamine substitution, levodopa (L-dopa) is still clinical Most effective drug (RASCO O, GOETZ C, KOLLERW, the et al.Treatment of upper control PD sings and symptoms interventions for Parkinson’s disease:an evidence based assessment[J].Lancet, 2002,359(9317):1589-1598).Although L-dopa be capable of it is temporary control PD symptom, long-term administration will lead to as Many adverse reactions such as unusual fluctuation disease, motor fluctuation and mental symptom.Although using lasting DA serotonergic neuron stimulation, surgical Deep brain stimulation (deep brain stimuli, DBS), long-acting dopamine-receptor stimulant can reduce to a certain extent Generation (SCHAPIRAAHV, EMREBM, JENNERP, et al.Levodopa in the treatment of these complication Of Parkinson ' s disease [J] .Eur J Neurol, 2009,16 (9): 982-989), but disease can not be delayed Progress.In addition, dopamine-receptor stimulant such as Cabergoline (cabergoline), catechol-oxygen position-transmethylase inhibits Agent (COMT) such as Entacapone (Comtan), glutamate receptor antagonists such as Memantine (memantine), cholinolytic preparation such as benzene Extra large rope (benzhexol, artane), has adverse reaction, but be used equally for the ancillary drug of levodopa, can pass through drug combination Different mechanism of action enhance levodopa drug effects, reduce levodopa dosage, reduce adverse reaction.Therefore, it researchs and develops The symptom of PD patient DA energy and non-DA energy system can be improved out and slowed down and even prevent progression of disease and play neuroprotection The new drug of effect, it is particularly important.

Monoamine oxidase (MAO, EC 1.4.3.4) is a kind of containing flavo-enzyme, for the enzyme for being catalyzed monoamine oxidative deamination, Be responsible for endogenous monoamine neurotransmitter carry out oxidative deamination, endogenous monoamine neurotransmitter include: dopamine, serotonin, Adrenaline or norepinephrine and trace amine such as phenylethylamine and many amine xenobiotics etc..Monoamine oxidase can be divided into Two hypotypes of MAO-A and MAO-B.Their gene coding it is different (A.W.Bach etc., Proc.Natl.Acad.Sci.USA1988,85,4934-4938), and in terms of structure, Tissue distribution and substrate specificity Also variant.MAO-A is present in liver, gastrointestinal mucosa more, can inactivate in catecholamine and diet in blood circulation system Vaso-active substance (such as tyrosine), to assist intracerebral neurotransmitter degradation；And MAO-B is primarily present in intracerebral and blood platelet In.MAO-A has higher compatibility to octopamine, serotonin, adrenaline and norepinephrine；And the day of MAO-B Right substrate is junket ammonia and phenylethylamine.The but oxidable dopamine of both isoforms.

Monoamine oxidase B (monoamine oxidase B, MAO-B) is one of the key enzyme of DA catabolism, passes through choosing Selecting property, specificity inhibit endogenous and exogenous dopamine to decompose, and extend the action time of dopamine, so as to improve clinical condition Shape can be used for P D early stage single therapy and the adjuvant treatment after motor fluctuations occurs.Mainly there are following 3 effects: (1) will be more Bar amine is decomposed into 3,4-Dihydroxyphenylacetic acid and homovanillic acid, while generating small molecule H₂O₂, toxicity is generated to nerve cell and is made With；(2) make to stimulate dopamine secretion, β-phenyl ethylamine deamination of dopamine reuptake is inhibited to lose activity；It (3) can also be by 1- first Base -4- phenyl -1,2,3,6- tetrahydropyrimidine (MPTP) is decomposed into the l- methyl 4-phenyl pyridinium ion (MPP with neurotoxicity⁺).Therefore, according to the physiological function of MAO-B, on the one hand, inhibit the activity of MAO-B that can reduce degradation and the reuptake of dopamine, Intracerebral dopamine concentration is improved, PD clinical symptoms can be improved；On the other hand, by reducing H₂O₂、MPP⁺Equal neurotoxin levels prolong Death process (HEIKKILARE, MANZINO L, CABBAT F S, et the al.Protection against of slow nigral cell the dopaminergic neurotoxiciy of 1-methyl-1,2,3,6-tetrahydropyridine(MPTP)by monoamine inhibitors[P].Nature,1984,311(5985):467-469；YOUDIM M BH,BAKHLE Y S.Monoamine oxidase isoforms and inhibitors in Parkinson’s diseaseand depressive illness[J].Br J Pharmacol,2006,147(S1):S287-S296；NAOI M,WAKAKO M.Monoamine oxidase inhibitors as neuroprotective agents in age-dependent Neurodegenerative disorders [J] .Curr PharmDes, 2010,16 (25): 2799-2817), PD can be changed Process.Since MAO-B inhibitor can not only improve PD symptom, and neuroprotection can also be played, therefore be that anti-pa is golden at present The hot spot of gloomy medicine research.

Currently, people have carried out some research MAO-B inhibitor:

2016052928 A1 of WO discloses the alpha-aminoamide derivatives as MAO-B inhibitor, with excellent steady Qualitative, compared to traditional invertibity MAO-B inhibitor, effect is more preferable.For treating neurodegenerative disease.

2011042217 A1 of WO discloses substituted aryl-cyclopropylamine second of alternatively property LSD1/MAO-B inhibitor Amide compound and substituted heteroaryl-cyclopropylamine acetamide compound are used for treating cancer and neurodegenerative disease.

2003106380 A2 of WO discloses the Fluorobenzoyl amine derivative of alternatively property MAO-B inhibitor, is used for Treat Alzheimer disease and senile dementia.

2003066596 A1 of WO discloses the picolinamide radical derivative of alternatively property MAO-B inhibitor, for controlling Treat neurological disease, including Alzheimer disease, senile dementia, Parkinson's disease and depression.

It remains desirable, however, that further studying to find more more preferable more effectively MAO-B inhibitor.

Summary of the invention

The present invention relates to a kind of novel alpha-aminoamide derivatives, there is preferable inhibition to make the activity of MAO-B With, so as to be used to prepare treatment neurodegenerative disease drug, be especially used to prepare treatment Parkinson's disease drug. The compounds of this invention property is stablized, good security, has good pharmacodynamics and pharmacokinetic property, such as good Brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., thus have compared with Good potential applicability in clinical practice.

Pharmaceutical composition the present invention also provides the method for preparing this kind of compound and containing such compound.

On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, can pharmaceutically connect geometric isomer The salt or its prodrug received,

Wherein:

X is CR²Or N；

R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Haloalkoxy Base, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base or C₆-C₁₀Virtue Base, wherein the C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkoxy, C₁-C₆Alkylthio group, C₁-C₆Alkylamino, The C that hydroxyl replaces₁-C₆Alkyl, C₃-C₈Naphthenic base and 3-8 circle heterocyclic ring base independently by 1,2,3,4 or 5 selected from D, F, Cl, Br, C₁-C₆Alkyl, C₂-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Alkylene Replaced the group of base-, the C₆-C₁₀Aryl is selected from D, F, Cl, Br, C by 1,2,3,4 or 5₁-C₆Alkyl, C₂-C₆It is halogenated Alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Replaced the group of alkylidene-；

R²For H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy or The C that hydroxyl replaces₁-C₆Alkyl；

R³、R⁴It is each independently H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆ The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl；

R⁵For H, D, C₂-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆It is halogenated The C that alkoxy, hydroxyl replace₁-C₆Alkyl or C₃-C₈Naphthenic base-C₀-C₆Alkylidene-；

R⁶、R⁷It is each independently H, D, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkane Oxygroup, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 Circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein the C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆ Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkane Base, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl and 5-10 unit's heteroaryl it is individually optional be selected from by 1,2,3,4 or 5 D, F, Cl, Br, I, OH, oxo (=O), NH₂、NO₂、CN、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogen For alkoxy, C₃-C₈Replaced the group of naphthenic base and 3-8 circle heterocyclic ring base；

R⁸For H；

M is 1 or 2；With

Condition is that formula (I) compound represented does not include following compound:

In one embodiment, R¹For C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alcoxyl Base, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 member Heterocycle or C₆-C₁₀Aryl, wherein the C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Alkoxy, C₁-C₄Alkane sulphur Base, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base and 3-6 circle heterocyclic ring base are independently by 1,2,3,4 or 5 Selected from D, F, Cl, Br, C₁-C₄Alkyl, C₂-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy and C₁-C₄Alkyl-S (=O)₂-C₁-C₄Replaced the group of alkylidene-, the C₆-C₁₀Aryl is selected from D, F, Cl, Br, C by 1,2,3,4 or 5₁- C₄Alkyl, C₂-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy and C₁-C₄Alkyl-S (=O)₂-C₁-C₄Alkylidene- Group replaced.

In another embodiment, R¹For methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, third Alkynyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, Isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, Methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azetidin Base, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, phenyl, indenyl or naphthalene, wherein the methyl, Ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl Base oxygroup, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl and morpholinyl independently by 1, 2,3,4 or 5 are selected from D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl ,-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、- CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、- OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、-CH₂- S (=O)₂-CH₃With-CH₂- S (=O)₂-CH₂CH₃Group replaced, Phenyl, indenyl and the naphthalene is independently selected from D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl by 1,2,3,4 or 5 Base ,-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,- OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、-CH₂- S (=O)₂-CH₃With-CH₂- S (= O)₂-CH₂CH₃Group replaced.

In one embodiment, R²For H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁- C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R²For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CHF₂、- CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,- OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methylol or 2- hydroxyethyl.

In one embodiment, R⁵For H, D, C₂-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄ Alkoxy, C₁-C₄The C that halogenated alkoxy, hydroxyl replace₁-C₄Alkyl or C₃-C₆Naphthenic base-C₀-C₄Alkylidene-.

In another embodiment, R⁵For H, D, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propine Base ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methylol, 2- hydroxyl second Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl ,-CH₂Cyclopropyl ,-CH₂Cyclobutyl ,-CH₂Cyclopenta or-CH₂Hexamethylene Base.

In one embodiment, R⁶、R⁷It is each independently H, D, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄ Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkane Base, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein the C₁-C₄Alkyl, C₂-C₄Alkene Base, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄Alkylamino, hydroxyl The C that base replaces₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl and 5-10 unit's heteroaryl individually optional ground quilt 1,2,3,4 or 5 are selected from D, F, Cl, Br, I, OH, oxo (=O), NH₂、NO₂、CN、C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁- C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₃-C₆Replaced the group of naphthenic base and 3-6 circle heterocyclic ring base.

In another embodiment, R⁶、R⁷Be each independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, Acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, second Oxygroup, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、- OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, phenyl, indenes Base, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, oxazolyl, pyrrole Piperidinyl, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl or quinolyl, wherein the methyl, ethyl, positive third Base, isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF₂、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、- CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCHFCH₂F、-OCF₂CHF₂、- OCH₂CF₃、-OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholine Base, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furyl, thienyl, thiazole Base, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl and quinolyl it is individually optional by 1, 2,3,4 or 5 are selected from D, F, Cl, Br, I, OH, oxo (=O), NH₂、NO₂, CN, methyl, ethyl, n-propyl, isopropyl ,- CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl Oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl and morpholinyl group replaced.

In some embodiments, the present invention relates to a kind of compounds, for such as formula (II) compound represented or formula (II) stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate of compound represented, Metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, R¹、R³、R⁴、R⁵、R⁶、R⁷, X and m all have meaning described in the invention.

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes formula disclosed by the invention (I) Or compound shown in formula (II).

In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.

On the other hand, the present invention relates to compound or its pharmaceutical compositions shown in formula disclosed by the invention (I) or formula (II) Purposes in medicine preparation, the drug is for preventing, treating or mitigating the disease that patient is adjusted by MAO-B inhibitor Disease.

In one embodiment, the disease being adjusted by MAO-B inhibitor is neurodegenerative disease, spirit Disease or cancer.

In one embodiment, the neurodegenerative disease is Parkinson's disease, cerebral ischemia, Alzheimer disease, muscle Atrophic lateral schlerosis, bovine spongiform encephalopathy, Huntington chorea, gram refined Er Shi disease, ataxia telangiectasia, Cerebral atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.

On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I) or formula (II).

Biological results show that the compounds of this invention has good inhibiting effect to the activity of MAO-B, and can be used as The drug of preferable treatment Parkinson's disease.

Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.

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

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March ' s Advanced Organic Chemistry " by MichaelB.Smith and Jerry March, Description in John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.

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

Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans isomers), atropisomer, etc..

Term " chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be with its mirror image The molecule of overlapping.

Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

Term " racemate " or " racemic mixture " be optically active two enantiomters of hypodactylia etc. rub That mixture.

Term " diastereoisomer " refer to there are two or multiple chiral centres and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw- HillDictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(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.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；ChiralSeparation Techniques:APracticalApproach (Subramanian,G.Ed.,Wiley-VCHVerlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

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

" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.

Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N₃,-OH, oxo (=O) ,-NH₂, NO₂,-CN ,-SH, alkyl, alkenyl, alkynyl, alcoxyl Base, alkylthio group, alkylamino, halogenated alkyl, halogenated alkoxy, the alkyl that hydroxyl replaces, alkyl-S (=O)₂Alkylidene-, cycloalkanes Base-alkylidene-, naphthenic base, heterocycle, aryl, heteroaryl etc..

In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

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

One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C₁-C₆Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Term " D " indicates single D-atom.

Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。

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

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,-CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃), etc..

Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from the linear chain or branched chain alkyl of saturation Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment party In case, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.This The example of sample includes methylene (- CH₂), ethylidene (- CH₂CH₂), isopropylidene (- CH (CH₃)CH₂), etc..The alkylene Base group is optionally replaced one or more substituent groups described in the invention.

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In an embodiment In, alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another reality It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH₂), allyl (- CH₂CH=CH₂), 1- acrylic is (that is, acrylic ,-CH=CH-CH₃), etc..

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl is (that is, propinyl ,-C ≡ C-CH₃), Etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), etc..

Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.

The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH₃), ethylmercapto group (EtS ,- SCH₂CH₃), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH₂CH₂CH₃), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH (CH₃)₂), 1- butylthio (n-BuS, n- butylthio ,-SCH₂CH₂CH₂CH₃), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur Base ,-SCH₂CH(CH₃)₂), 2- butylthio (s-BuS, s- butylthio ,-SCH (CH₃)CH₂CH₃), 2- methyl -2- rosickyite base (t- BuS, t- butylthio ,-SC (CH₃)₃), etc..

Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets It invents replaced described substituent group.

Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..

Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、- CH₂CF₃、-CHFCH₃、-CH₂CH₂F、-CF₂CH₃Deng.In one embodiment, C₁-C₆Halogenated alkyl includes fluorine-substituted C₁-C₆Alkane Base；In another embodiment, C₁-C₄Halogenated alkyl includes fluorine-substituted C₁-C₄Alkyl；In yet another embodiment, C₁-C₂Halogen Substituted alkyl includes fluorine-substituted C₁-C₂Alkyl.

Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCHF₂、-OCF₃、-OCHFCH₂F、- OCF₂CHF₂、-OCH₂CF₃、-OCHFCH₃、-OCH₂CH₂F、-OCF₂CH₃、-OCH₂CF₂CHF₂Deng.In one embodiment, C₁-C₆ Halogenated alkoxy includes fluorine-substituted C₁-C₆Alkoxy；In another embodiment, C₁-C₄Halogenated alkoxy includes fluorine-substituted C₁-C₄Alkoxy；In yet another embodiment, C₁-C₂Halogenated alkoxy includes fluorine-substituted C₁-C₂Alkoxy.

Term " n former molecular " or " n member ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule Mesh, the number of ring member nitrogen atoms is n in the molecule.For example, piperidyl is the molecular heterocycle of 6 originals or 6 circle heterocyclic ring bases, And 1,2,3,4- naphthane is the molecular aryl of 10 originals or 10 yuan of aryl.

Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.The example of carbocylic radical group further comprises ring Propyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- Cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, ring nonyl Base, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group is optionally by one or more institutes of the present invention Replaced the substituent group of description.

Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon Atom.The group of naphthene base is optionally replaced one or more substituent groups described in the invention.

Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the monocycle comprising 3-12 annular atom, double Ring or three-ring system, one or more atoms are independently replaced by hetero atom in middle ring, and the hetero atom has such as this hair The bright meaning, ring can be fully saturated or comprising one or more degrees of unsaturation, but an aromatic rings cannot all have. In one embodiment, heterocyclyl groups are monocycle (2-6 carbon atom and selected from N, O, P, the 1-3 miscellaneous originals of S of 3-8 member ring Son optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO₂, PO, PO₂Group, when the ring When for three-membered ring, only one of them hetero atom) or the bicyclic of 7-12 member (4-9 carbon atom and be selected from N, O, P, the 1-3 of S is a Hetero atom optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO₂, PO, PO₂Group).It is described miscellaneous Cyclic groups are optionally replaced one or more substituent groups described in the invention.

The annular atom of heterocycle can be carbon-based or heteroatom group.Wherein ,-the CH of ring₂Group is optionally by-C (=O)- Substitution, the sulphur atom of ring are optionally oxidized to S- oxide, and the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.Heterocycle The example of base includes, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- Pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran Base, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- Pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithiane Base, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, Sulphur azepineBase, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base, etc..- CH in heterocycle₂Group quilt-C (=O)-it takes The example in generation includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidone base, 3,5- dioxo Piperidyl, hybar X base, etc..The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base, thio Morpholinyl 1,1- dioxide, etc..The heterocyclyl groups are optionally by one or more substitutions described in the invention Replaced base.

Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term " aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group may include phenyl, indenyl, naphthalene And anthryl.The aryl group is optionally replaced one or more substituent groups described in the invention.

Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous Atom, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are in general, but unnecessarily pass through heteroaryl The armaticity ring of base group is connect with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl Compounds of group " is used interchangeably.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention. In one embodiment, 5-10 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.

The example of heteroaryl groups includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazole Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazole Base (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3- Oxadiazoles base, 1,2,5- oxadiazoles bases, 1,2,4- oxadiazoles bases, 1,2,3-triazoles base, 1,2,3- thio biphosphole bases, 1,3,4- sulphur For di azoly, 1,2,5- thio biphosphole bases, pyrazinyl, 1,3,5-triazines base；Also include below bicyclic, but be not limited to these It is bicyclic: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinoline Quinoline base, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1, 2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine Base, etc..

Term " prodrug " used in the present invention represents a compound and is converted into shown in formula (I) or formula (II) in vivo Compound.Such conversion is hydrolyzed in blood by pro-drug or is precursor structure through enzymatic conversion in blood or tissue It influences.Pro-drug compounds of the present invention can be ester, and what ester can be used as pro-drug in existing invention has phenyl ester Class, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as the present invention In a compound include hydroxyl, it can be acylated to obtain the compound of prodrug form.Other pro-drugs Form includes phosphate, if these phosphate compounds are obtaining through the di on parent.

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe Pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, Documented by 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C₁-C₈Sulphonic acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate；In yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.

" the compound of the present invention " used in the present invention, " compound described in the invention ", " of the present inventionization Close object " or similar statement, compound representated by any one general formula structure of the present invention is all referred to, that is, refers to this hair Compound representated by bright middle formula (I) or formula (II).

Any disease of term " treatment " or illness refer to that improving disease or illness (slows down in some of these embodiments Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls Treat " refer in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable body) or above-mentioned two Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness Change.

Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).

Alpha-aminoamide derivatives of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and its pharmaceutical composition Object can inhibit the activity of MAO-B, have potential purposes to the treatment of neurodegenerative disease, especially Parkinson's disease.

Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, geometrical isomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt and its prodrug are all Comprising within the scope of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.

Compound shown in formula (I) or formula (II) can exist in a salt form.In one embodiment, the salt refers to medicine Acceptable salt on.Term " pharmaceutically acceptable " refers to that substance or composition must be with other ingredients comprising preparation And/or it is compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment, the salt is not necessarily It is pharmaceutically acceptable salt, can be and be used to prepare and/or purify compound shown in formula (I) or formula (II) and/or for dividing The intermediate of enantiomer from compound shown in this formula (I) or formula (II).

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

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, the present invention relates to the intermediates of compound shown in preparation formula (I) or formula (II).

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.

The description of the compounds of this invention

Alpha-aminoamide derivatives, its pharmaceutically acceptable salt, its pharmaceutical preparation and its medicine group of the present invention Object is closed, it is inhibited to the activity of MAO-B, to neurodegenerative disease, especially have potentially to the treatment of Parkinson's disease Purposes.The present invention further describes the method for synthesizing the compound.The compound of the present invention shows good biology Activity.

Wherein, each R¹、R³、R⁴、R⁵、R⁶、R⁷、R⁸, X and m there is meaning as described in the present invention；

In one embodiment, X CR²Or N.

In one embodiment, R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alcoxyl Base, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 member Heterocycle or C₆-C₁₀Aryl, wherein the C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkoxy, C₁-C₆Alkane sulphur Base, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base and 3-8 circle heterocyclic ring base are independently by 1,2,3,4 or 5 Selected from D, F, Cl, Br, C₁-C₆Alkyl, C₂-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Replaced the group of alkylidene-, the C₆-C₁₀Aryl is selected from D, F, Cl, Br, C by 1,2,3,4 or 5₁- C₆Alkyl, C₂-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Alkylidene- Group replaced.

In one embodiment, R²For H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁- C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R³、R⁴It is each independently H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R⁵For H, D, C₂-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆ Alkoxy, C₁-C₆The C that halogenated alkoxy, hydroxyl replace₁-C₆Alkyl or C₃-C₈Naphthenic base-C₀-C₆Alkylidene-.

In one embodiment, R⁶、R⁷It is each independently H, D, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆ Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkane Base, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein the C₁-C₆Alkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆Alkylamino, hydroxyl The C that base replaces₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl and 5-10 unit's heteroaryl individually optional ground quilt 1,2,3,4 or 5 are selected from D, F, Cl, Br, I, OH, oxo (=O), NH₂、NO₂、CN、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁- C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₃-C₈Replaced the group of naphthenic base and 3-8 circle heterocyclic ring base.

In one embodiment, R⁸For H.

In one embodiment, m is 1 or 2.

In one embodiment, R³、R⁴It is each independently H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R³、R⁴It is each independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl Base ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methylol or 2- hydroxyl second Base.

In one embodiment, compound of the present invention for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, geometric isomer, tautomer, nitrogen oxides, hydrate, solvation Object, metabolite, pharmaceutically acceptable salt or its prodrug, but be not limited to:

On the other hand, the present invention relates to compound shown in formula disclosed by the invention (I) or formula (II) or combinations thereof or its medicines The purposes of compositions in medicine preparation, the drug are carried out for preventing, treating or mitigating patient by MAO-B inhibitor The disease of adjusting.

Pharmaceutical composition, preparation and the administration of the compounds of this invention

The present invention provides a kind of pharmaceutical composition, including compound shown in formula (I) or formula (II) or it is individually three-dimensional different Structure body, the racemic or non-racemic mixture of isomers or its pharmaceutically acceptable salt or solvate.Of the invention In one embodiment, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or figuration Agent, and optionally, others treatment and/or prevention ingredient.

It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example AnselH.C.et al.,Ansel’s PharmaceuticalDosage Forms and Drug Delivery Systems (2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington: The Science and Practiceof Pharmacy(2000)Lippincott,Williams&Wilkins, Philadelphia；With Rowe R.C., Handbook of PharmaceuticalExcipients (2005) In PharmaceuticalPress, Chicago.

" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.

Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, adhesive, Disintegrating agent, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.

Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's PharmaceuticalSciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),andTheHandbook ofPharmaceutical Excipients(the American PharmaceuticalAssociation and the PharmaceuticalPress)。

In Remington:The Science and Practice of Pharmacy, 21stedition, 2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of PharmaceuticalTechnology,eds.J.Swarbrickand J.C.Boylan,1988-1999, The various carriers for configuring pharmaceutically acceptable composition are disclosed in MarcelDekker, New York, and are used for it The well-known technique of preparation, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any not phase The biological effect of prestige, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with Outside the incompatible any commonly employed carrier of the compounds of this invention, pays close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's PharmaceuticalSciences (Mack Publishing Company)。

Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.

Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.

It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.

In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.

For example, solid oral dosage form in addition to comprising active constituent, can also include: diluent such as lactose, glucose, sugarcane Sugar, cornstarch or potato starch；Lubricant such as silica, talcum powder, stearic acid, magnesium stearate or calcium stearate And/or polyethylene glycols；Adhesive such as starch, gum arabic, gelatin, methylcellulose, carboxymethyl cellulose or poly- second Alkene pyrrolidone；Disintegrating agent such as starch, alginic acid, alginates or sodium starch glycollate；Effervescent mixture；Dyestuff；Sweetener； Wetting agent such as lecithin, polysorbate esters, lauryl sulfate；Drug is used for general non-toxic and inactive pharmacy The substance of preparation.Institute can be prepared according to known manner, such as by mixing, granulation, tabletting, sugar coating or film coating process State pharmaceutical preparation.

Oral preparation includes can be in a conventional manner for example by the sustained release system to tablet and the enteric coated preparation of particle Agent.

Liquid dispersion for oral administration can be syrup, emulsion and suspension.

Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to gastric acid effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to fatty acid, rouge Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by preparing more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.

Tabules can be by one kind that powder, crystallization or granular active constituent are individual or describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.

Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, and one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.

Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Emulsion and suspension may include as load Such as natural gum, agar, mosanom, pectin, methylcellulose, carboxymethyl cellulose or the polyvinyl alcohol of body.For muscle The suspension or solution of injection may include pharmaceutically acceptable carrier and reactive compound, the pharmaceutically acceptable carrier example Such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol.Aqueous alcohol solutions may include pharmaceutically acceptable contracting Aldehyde, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there are one or more hydroxyls Water-soluble solvent, such as propylene glycol and ethyl alcohol.It may include for intravenous or infusion solution as for example sterile of carrier Water or preferably they can be the form of sterile, aqueous isotonic salting liquid.Elixir is transparent, sweet taste water-alcohol solution.Syrup Agent may include such as sucrose or sucrose and glycerol and/or mannitol and/or sorbierite as carrier, such as the water of sucrose Solution, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol can use enough medicines Acceptable liquid-carrier such as water dilutes on, to be accurately, conveniently administered.

Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared At be suitable for dry powder doses to the dosage form of patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Include fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising cream Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next It says, (such as micronization) compound that size reduces can be by about 1 to 10 micron of D50 value (for example, being surveyed with laser diffractometry Amount) it defines.

The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as PharmaceuticalResearch, 3 (6), the general description in 318 (1986).

Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

The compounds of this invention can also be in conjunction with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine that palmitoyl residues replace.In addition, compound disclosed in this invention can with realizing drug Control release used in one kind Biodegradable polymeric combination, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel crosslinking or amphiphilic block copolymer.

Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for parenteral administration pharmaceutical composition may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.

Pharmaceutical composition provided by the invention can be administered by rectal suppository, by by drug with it is suitable nonirritant Excipient (such as cupu oil, the glyceride of polyethylene glycol synthesis) mixing, be solid under room temperature, then in rectum intraluminal fluid Change or dissolution discharges drug.Due to individual difference, bigger variation can be presented in the severity of symptom, and every kind of medicine has Its unique treatment characteristic, therefore, for the accurate administration mode of each individual, dosage form and therapeutic scheme all should be by operation Doctor determines.

Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

Term as used herein " therapeutically effective amount " refers to each active component for being enough to show beneficial therapeutic effect Total amount.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special controls Effective quantity needed for treatment scheme depends on many factors, the disease including treatment, the severity of disease, the certain drug used Activity, administration mode, the clearance rate of certain drug, duration for the treatment of, drug combination, the age, weight, gender, diet and The health etc. of patient.This field description as described in " therapeutically effective amount " other factors in need of consideration can be found in Gilman et al.,eds.,Goodman And Gilman’s:The PharmacologicalBases of Therapeutics,8th ed.,Pergamon Press,1990；Remington's PharmaceuticalSciences,17th ed., MackPublishing Company,Easton,Pa.,1990.The therapeutically effective amount of the compounds of this invention, take orally, in peritonaeum or When intravenous administration 0.1-200mg/kg, the compound of the present invention has activity in vivo.

The optimal treatment effective quantity to be given can be readily determined by those skilled in the art, and essentially according to preparation The different of the progress of intensity, administration mode and treated disease or illness change.In addition, with treated particular subject phase The factor of pass includes that subject age, weight, diet and administration time cause to adjust dosage to suitable treatment effective level Demand.

Term " administration " shows individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose, Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch, Urea, dextran etc.) it is compound.

Preferred administration route can change with Clinical symptoms, and the variation of dosage is necessarily dependent upon patient being treated The case where, doctor can determine suitable dosage according to individual patient.The therapeutically effective amount of per unit dose depends on weight, raw Manage the vaccination regimen of function and selection.The weight of compound when the compound of per unit dose refers to each administration does not include carrying The weight (containing carrier in drug) of body.The medicine of alpha-aminoamide derivatives comprising formula as defined above (I) or formula (II) Compositions include the one of per unit metering about 0.1mg- about 500mg such as capsule, tablet, powder needle, teaspoonful, suppository Kind or a variety of active ingredients, most preferably 1-10mg.

Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.

Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.

In one embodiment, treatment method of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.

In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administration.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administration.

In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, the duration including implementing the program are treated disease depending on treated disease The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs to change as time goes by it may require that adjust it is suitable to Prescription case.

The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.

In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.

The purposes of the compounds of this invention and pharmaceutical composition

Compound provided by the invention and pharmaceutical composition can be used for preparing to be passed through for preventing, treating or mitigating patient The drug for the disease that MAO-B inhibitor is adjusted can be used for preparation for preventing, treating or mitigating nervus retrogression disease The drug of disease, mental disease or cancer.

Specifically, the amount of compound effectively detectably can selectively inhibit MAO- in composition of the invention The activity of B.

The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate neurodegenerative disease.The neurodegenerative disease further comprises but simultaneously It is not limited to, hearing disability caused by Parkinson's disease, cerebral ischemia, Alzheimer disease, amyotrophic lateral sclerosis, aging, Dementia, retinosis, macular degeneration, glaucoma, bovine spongiform encephalopathy, Huntington chorea, gram refined Er Shi disease, incoordination Telangiectasia, cerebral atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.

The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate mental disease.The mental disease is schizophrenia and/or anxiety disorder, wherein essence Refreshing Split disease further comprises but is not limited to, brief psychotic disorder, paranoea, schizoaffective disorders and Schizophreniform Phrenoblabia；Wherein anxiety disorder further comprises but is not limited to, panic disorder, compulsive disorder, posttraumatic stress disorder, Social phobia or social anxiety disorder, specific phobia and general anxiety disease.

The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate cancer.The cancer further comprises but is not limited to, prostate cancer, mammary gland Cancer, carcinoma of testis, colorectal cancer, lung cancer, brain tumor, kidney neoplasms or leukemia.

The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.

The general synthesis step of the compounds of this invention

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

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

The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich ChemicalCompany, Arco ChemicalCompany and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.

¹H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.¹H H NMR spectroscopy is with CDC1₃、 DMSO-d₆、CD₃OD or acetone-d₆For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet of Doublet of doublets, in pairs doublet), dt (doublet of triplets, double triplets), td (triplet Of doublets, three doublets), tt (triplet of triplets, three triplets).Coupling constant J, with hertz (Hz) table Show.

The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.

Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.

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

CH₂Cl₂, DCM methylene chloride PBr₃Phosphorus tribromide

CDC1₃Mmol mMs of deuterated chloroform

DMSO-d₆G grams of deuterated dimethyl sulfoxide

Mg milligrams of DMF N,N-dimethylformamide

EtOAc, EA ethyl acetate μ g microgram

CH₃OH, MeOH methanol ng nanogram

CH₃CH₂OH, EtOH ethyl alcohol Pd/C palladium/carbon

Acetone acetone NaHCO₃Sodium bicarbonate

H₂O water K₂CO₃Potassium carbonate

CH₃COOH acetic acid NaCl sodium chloride

Et₃N triethylamine KCl potassium chloride

Et₂NH diethylamine Na₂HPO₄·2H₂O phosphate dihydrate disodium hydrogen

DIPEA N, N- diisopropylethylamine PE petroleum ether (60-90 DEG C)

DMAP 4-dimethylaminopyridine RT, rt, r.t. room temperature

DCC dicyclohexylcarbodiimide HEPES 4- hydroxyethyl piperazineethanesulfonic acid

HOBt I-hydroxybenzotriazole Glucan aminoglucose

NaBH₃CN sodium cyanoborohydride Saline physiological saline

KBH₄Potassium borohydride min minutes

MTBE methyl tertiary butyl ether(MTBE) h hours

LiCl lithium chloride μ L, μ l microlitres

H₂ML, ml milliliters of hydrogen

Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R¹、R⁶、 R⁷There is definition as described in the present invention with X.

Synthetic schemes 1

Wherein, L is leaving group, including but not limited to halogen atom, mesyl oxygroup, to Methyl benzenesulfonyl base oxygroup Deng.

Formula (4) compound represented can be prepared by following process: formula (1) compound represented and compoundCoupling obtain formula (2) compound represented.Formula (2) compound represented and L- alanimamides hydrochloride or L- alanyl Amine derivative react to obtain formula (3) compound represented.Formula (3) compound represented reacts in the presence of alkali with 3- propargyl bromide Obtain formula (4) compound represented.

Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.

Embodiment

The synthesis of embodiment 1 (S) -2- ((4- (4- (methyl sulphonyl) methyl) benzyloxy) benzyl amino) propionamide

The synthesis of step 1) 4- (4- (bromomethyl) benzyloxy) benzaldehyde

By 4- hydroxy benzaldehyde (1.0g, 8.19mmol), Isosorbide-5-Nitrae-two (bromomethyl) benzene (4.3g, 16.38mmol), potassium carbonate (4.5g, 32.76mmol) and acetone (50mL) are added sequentially in 100mL single necked round bottom flask, are reacted 5h at 60 DEG C, are cooled to Room temperature, filtering collect filtrate, then directly mix sample column chromatographic purifying (petrol ether/ethyl acetate (v/v)=5/1) and obtain title Compound is white solid (1.35g, 54.0%).

MS(ESI,pos.ion)m/z:305.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)9.89(s,1H),7.92-7.75(m,2H),7.46-7.39(m,4H), 7.07 (d, J=8.7Hz, 2H), 5.15-5.14 (m, 2H), 4.50 (s, 2H)

The synthesis of step 2) 4- (4- ((mesyl) methyl) benzyloxy) benzaldehyde

By 4- (4- (bromomethyl) benzyloxy) benzaldehyde (0.78g, 2.54mmol), methane sulfinic acid sodium (0.28g, It 2.79mmol) is added sequentially in 100mL single necked round bottom flask with ethyl alcohol (20mL), reacts 3h at 100 DEG C, be cooled to room temperature, Then directly mixing sample column chromatographic purifying (petrol ether/ethyl acetate (v/v)=1/1) and obtaining title compound is white solid (0.67g, 86.7%).

MS(ESI,pos.ion)m/z:305.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 9.87 (s, 1H), 7.88 (d, J=8.7Hz, 2H), 7.50 (d, J= 8.0Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 7.21 (d, J=8.7Hz, 2H), 5.25 (s, 2H), 4.50 (s, 2H), 2.91 (s,3H).

The synthesis of step 3) (S) -2- ((4- (4- (methyl sulphonyl) methyl) benzyloxy) benzyl amino) propionamide

By L- alanimamides hydrochloride (0.27g, 2.20mmol), 4- (4- ((mesyl) methyl) benzyloxy) benzaldehyde (0.67g, 2.20mmol), triethylamine (0.2mL, 2.20mmol), acetic acid (0.25mL, 4.40mmol) and methanol (20mL) are successively Be added in 100mL single necked round bottom flask, react 3h at room temperature, be transferred to 0 DEG C, be added sodium cyanoborohydride (0.21g, 3.29mmol), it after adding, is transferred to and reacts 19h at room temperature, be concentrated, add methylene chloride (50mL), uses saturated sodium bicarbonate solution (10mL) neutralizes acetic acid, and liquid separation collects dichloromethane layer, then evaporating column chromatographic purifying (methylene chloride/methanol (v/v)=10/ 1) obtaining title compound is white solid (0.30g, 36.2%).

MS(ESI,pos.ion)m/z:377.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 7.44 (dd, J=19.9,8.1Hz, 4H), 7.23 (d, J=8.5Hz, 2H), 6.95 (d, J=8.6Hz, 2H), 5.10 (s, 2H), 4.48 (s, 2H), 3.49 (s, 2H), 2.90 (s, 3H), 1.12 (d, J =6.9Hz, 3H)；

¹³C NMR(101MHz,DMSO-d₆)δ(ppm)177.5,162.9,157.6,138.0,133.2,131.5, 129.6,129.0,128.6,128.2,115.0,69.3,59.6,56.9,55.3,50.9,19.7.

Embodiment 2 (S) -2- (4- (4- ((mesyl) methyl) benzyloxy) benzyl) (propyl -2- alkynes -1- base) amino) The synthesis of propionamide

By (S) -2- ((4- (4- (methyl sulphonyl) methyl) benzyloxy) benzyl amino) propionamide (0.16g, 0.43mmol), DIPEA (0.34mL, 2.04mmol), DMF (5mL) and 3- propargyl bromide (0.29mL, 3.44mmol) are added sequentially to 100mL single port In round-bottomed flask, it is heated to 80 DEG C of reaction 15h, stops reaction, be cooled to room temperature, adds water (20mL) and with ethyl acetate (20mL × 2) it extracts, washes (20mL × 3), collect ethyl acetate layer, then evaporating column chromatographic purifying (petrol ether/ethyl acetate (v/v) =1/5) obtaining title compound is white solid (0.05g, 28.4%).

MS(ESI,pos.ion)m/z:415.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.45 (dd, J=19.4,7.8Hz, 4H), 7.24 (d, J=8.2Hz, 2H), 6.93 (d, J=8.3Hz, 2H), 5.07 (s, 2H), 4.26 (s, 2H), 3.63 (dd, J=75.3,13.1Hz, 2H), 3.42 (dd, J=13.7,6.8Hz, 1H), 3.33-3.24 (m, 2H), 2.77 (s, 3H), 2.26 (s, 1H), 1.36 (d, J=6.9Hz, 3H)；

¹³C NMR(101MHz,CDCl₃)δ(ppm)177.1,158.0,138.2,130.7,130.3,130.1,128.0, 127.9,114.9,78.9,73.4,69.4,61.0,60.9,54.3,39.1,38.7,12.7.

The synthesis of embodiment 3 (S) -2- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyl amino) propionamide

The synthesis of step 1) 4- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde

By 4- toluenesulfonic acid tetrafluoro propyl ester (4.0g, 13.97mmol), 4- hydroxy benzaldehyde (3.4g, 27.95mmol), Potassium carbonate (3.86g, 27.95mmol) and DMF (20mL) are added sequentially in 100mL single necked round bottom flask, are heated to 100 DEG C instead 13h is answered, stops reaction, is cooled to room temperature, add water (40mL) and is extracted with ethyl acetate (50mL × 2), is washed (50mL × 3), Ethyl acetate layer is collected, then evaporating column chromatographic purifying (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound and is Light yellow oil (3.10g, 94.0%).

MS(ESI,pos.ion)m/z:237.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.92 (s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.05 (d, J= 8.7Hz, 2H), 6.06 (tt, J=53.1,4.6Hz, 1H), 4.44 (t, J=11.8Hz, 2H)

The synthesis of step 2) (S) -2- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyl amino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.32g, 2.54mmol), 4- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (0.50g, 2.12mmol), triethylamine (0.44mL, 3.20mmol), acetic acid (0.29mL, 5.08mmol), methanol (20mL) and sodium cyanoborohydride (0.20g, It 3.18mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (EA) obtains title compound Object is white solid (0.37g, 56.7%).

MS(ESI,pos.ion)m/z:309.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.27 (d, J=8.5Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 6.06 (tt, J=53.1,4.9Hz, 1H), 4.32 (t, J=11.9Hz, 2H), 3.74 (q, J=13.1Hz, 2H), 3.31 (q, J= 6.9Hz, 1H), 1.34 (d, J=6.9Hz, 3H)；

¹³C NMR(101MHz,CDCl₃) δ (ppm) 177.7,156.8,132.5,129.7,117.1 (t, J=13.1Hz), 114.9,114.5 (t, J=27.2Hz), 112.0 (t, J=26.9Hz), 109.0 (tt, J=34.3,250.9Hz), 65.3 (t, ), J=29.9Hz 57.2,51.4,19.1.

The synthesis of embodiment 4 (S) -2- (4- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyloxy) benzyl amino) propionamide

The synthesis of step 1) (4- (2,2,3,3- tetrafluoro propoxyl group) phenyl) methanol

4- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (1.0g, 4.23mmol) and methanol (10mL) are added sequentially to In 100mL single necked round bottom flask, it is transferred to 0 DEG C, is added sodium borohydride (0.32g, 8.46mmol), and react 1h, reaction stops Afterwards, methanol is concentrated, add methylene chloride (30mL) dissolution, is washed, liquid separation with water (20mL), collects dichloromethane layer, is directly concentrated Obtaining title compound is colorless oil (0.94g, 93.2%).

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 7.26 (d, J=8.4Hz, 2H), 7.00 (d, J=8.5Hz, 2H), 6.67 (tt, J=51.9,5.4Hz, 1H), 4.55 (t, J=13.4Hz, 2H), 4.43 (s, 2H)

The synthesis of step 2) 1- (bromomethyl) -4- (2,2,3,3- tetrafluoro propoxyl group) benzene

By (4- (2,2,3,3- tetrafluoro propoxyl group) phenyl) methanol (0.92g, 3.86mmol) and methylene chloride (20mL) according to It is secondary to be added in 100mL single necked round bottom flask, it is added phosphorus tribromide (0.40mL, 4.25mmol), reacts 7h at room temperature, add water Dichloromethane layer is collected in (20mL), liquid separation, and then evaporating column chromatographic purifying (petrol ether/ethyl acetate (v/v)=10/1) obtains Title compound is colorless oil (0.91g, 77.8%).

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.37-7.34 (m, 2H), 6.97-6.85 (m, 2H), 6.06 (tt, J= 53.1,4.9Hz, 1H), 4.49 (s, 2H), 4.35 (t, J=11.8Hz, 2H)

The synthesis of step 3) 4- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyloxy) benzaldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 4- hydroxy benzaldehyde (0.34g, 2.78mmol), 1- (bromomethyl) -4- (2,2,3,3- tetrafluoro propoxyl group) benzene (0.88g, 2.92mmol), potassium carbonate (1.53g, 11.10mmol) is added to reaction in acetone (30mL) and prepares, column chromatographic purifying (petrol ether/ethyl acetate (v/v)= 10/1) obtaining title compound is white solid (0.78g, 82.6%).

MS(ESI,pos.ion)m/z:343.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.89 (s, 1H), 7.84 (d, J=8.7Hz, 2H), 7.40 (d, J= 8.6Hz, 2H), 7.07 (d, J=8.7Hz, 2H), 6.96 (d, J=8.6Hz, 2H), 6.07 (tt, J=53.1,4.9Hz, 1H), 5.09 (s, 2H), 4.36 (t, J=11.8Hz, 2H)

The synthesis of step 4) (S) -2- (4- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyloxy) benzyl amino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.34g, 2.70mmol), 4- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyloxy) benzaldehyde (0.77g, 2.25mmol), Triethylamine (0.38mL, 2.70mmol), acetic acid (0.31mL, 5.40mmol), methanol (20mL) and sodium cyanoborohydride (0.21g, It 3.37mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (EA) obtains title compound Object is white solid (0.41g, 44.0%).

MS(ESI,pos.ion)m/z:415.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.48 (d, J=7.4Hz, 2H), 7.33 (d, J=7.0Hz, 2H), 7.04 (s, 4H), 6.07 (tt, J=53.1,4.9Hz, 1H), 5.09 (s, 2H), 4.45 (t, J=11.4Hz, 2H), 3.84 (s, 2H), 3.43 (brs, 1H), 1.45 (d, J=4.6Hz, 3H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm)177.7,158.1,157.1,130.9,129.5,129.2,116.1 (t, J=26.9Hz), 114.9,114.8,114.5 (t, J=27.0Hz), 112.8 (t, J=27.0Hz), 109.0 (tt, J= ), 249.8,34.2Hz 69.4,65.3 (t, J=29.8Hz), 57.3,51.6,19.2.

The synthesis of embodiment 5 (S) -2- (4- ((3- fluorine benzyloxy) benzyl) (propyl -2- alkynes -1- base) amino) propionamide

The synthesis of step 1) 4- (3- fluorine benzyloxy) benzaldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 3- fluorobenzyl bromide (1.06mL, 8.64mmol), 4- hydroxy benzaldehyde (1.0g, 8.19mmol), potassium carbonate (4.3g, 32.76mmol) are added to third Reaction preparation in ketone (50mL), then column chromatographic purifying (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound and is White solid (1.78g, 94.4%).

MS(ESI,pos.ion)m/z:231.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.89 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.37 (td, J= 7.9,6.0Hz, 1H), 7.20 (d, J=7.7Hz, 1H), 7.15 (d, J=9.4Hz, 1H), 7.08 (s, 1H), 7.06 (s, 1H), 7.03 (dd, J=8.4,2.2Hz, 1H), 5.15 (s, 2H)

Step 2) (S) -2- ((synthesis of 4- ((3- fluorine benzyloxy) benzyl amino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.51g, 4.06mmol), triethylamine (0.71mL, 5.08mmol), acetic acid (0.46mL, 8.12mmol), methanol (20mL), 4- (3- fluorine benzyloxy) benzaldehyde (0.78g, 3.39mmol) and sodium cyanoborohydride (0.21g, 3.37mmol) are successively It is added in 100mL single necked round bottom flask and reacts preparation, it is white solid that then column chromatographic purifying (EA), which obtains title compound, (0.53g, 51.7%).

MS(ESI,pos.ion)m/z:303.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.34 (td, J=7.9,6.0Hz, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 7.18 (d, J=7.8Hz, 1H), 7.14 (d, J=9.6Hz, 1H), 7.00 (td, J=8.4,2.2Hz, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 5.04 (s, 2H), 3.71 (q, J=12.9Hz, 2H), 3.26 (q, J=7.0Hz, 1H), 1.33 (d, J= 7.0Hz,3H).

The synthesis of step 3) (S) -2- (4- ((3- fluorine benzyloxy) benzyl) (propyl -2- alkynes -1- base) amino) propionamide

This step title compound method referring to described in embodiment 2 is prepared, i.e., by (S) -2- ((4- ((3- fluorine Benzyloxy) benzyl amino) propionamide (0.20g, 0.66mmol), DMF (20mL), DIPEA (0.53mL, 3.18mmol) and 3- bromine third Alkynes (0.45mL, 5.30mmol), which is added in 100mL single necked round bottom flask, reacts preparation, then column chromatographic purifying (petroleum ether/second Acetoacetic ester (v/v)=1/1) title compound is obtained as white solid (0.09g, 40.0%).

MS(ESI,pos.ion)m/z:341.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.28-7.09(m,4H),7.04-6.84(m,4H),5.03(s,2H), 3.62 (dd, J=69.4,12.4Hz, 2H), 3.46-3.41 (m, 1H), 3.28 (s, 2H), 2.26 (s, 1H), 1.36 (d, J= 5.2Hz,3H)；

¹³C NMR(101MHz,CDCl₃) δ (ppm) 177.3,162.9 (d, J=246.2Hz), 157.9,139.5 (d, J= 7.3Hz), 130.2,130.1 (d, J=8.1Hz), 130.0,122.6 (d, J=2.9Hz), 114.9,114.8,114.6, 114.2,114.0,78.7 (d, J=15.1Hz), 73.4 (d, J=16.8Hz), 69.2 (d, J=1.6Hz), 60.9,54.3, 38.6,12.8.

The synthesis of embodiment 6 (S) -2- (4- (3- fluorine benzyloxy) -2- methylbenzylamino) propionamide

The synthesis of step 1) 4- (3- fluorine benzyloxy) -2- tolyl aldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 3- fluorobenzyl bromide (0.48mL, 3.90mmol), 4- hydroxy-2-methyl benzaldehyde (0.50g, 3.67mmol), potassium carbonate (2.03g, 14.70mmol) It is added in 100mL single necked round bottom flask with acetone (35mL) and reacts preparation, then column chromatographic purifying (petrol ether/ethyl acetate (v/v)=9/1) obtaining title compound is white solid (0.78g, 87.0%).

MS (ESI, pos.ion) m/z:245.1 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 10.14 (s, 1H), 7.77 (d, J=8.6Hz, 1H), 7.37 (tt, J= 13.3,6.7Hz, 1H), 7.19 (dd, J=18.1,8.6Hz, 2H), 7.05 (td, J=8.4,2.2Hz, 1H), 6.96-6.87 (m, 1H), 6.87-6.80 (m, 1H), 5.13 (d, J=7.8Hz, 2H), 2.67 (s, 3H)

The synthesis of step 2) (S) -2- (4- (3- fluorine benzyloxy) -2- methylbenzylamino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.48g, 2.84mmol), triethylamine (0.67mL, 4.80mmol), acetic acid (0.32mL, 5.68mmol), methanol (10mL), 4- (3- fluorine benzyloxy) -2- tolyl aldehyde (0.78g, 3.19mmol) and sodium cyanoborohydride (0.31g, It 4.77mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (EA) obtains title compound Object is white solid (0.48g, 48.0%).

MS (ESI, pos.ion) m/z:317.2 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 7.33 (dd, J=13.8,7.7Hz, 1H), 7.18 (s, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 7.01-6.97 (m, 1H), 6.80 (s, 1H), 6.75 (d, J=8.3Hz, 1H), 5.02 (s, 2H), 3.78-3.57 (m, 2H), 3.25 (q, J=6.9Hz, 1H), 2.32 (s, 3H), 1.34 (d, J=6.9Hz, 3H)；

¹³C NMR (101MHz, CDCl₃) δ (ppm) 178.4,163.0 (d, J=246.1Hz), 157.7,139.8 (d, J= 7.3Hz), 137.8,130.4,130.1 (d, J=8.2Hz), 129.8,122.7 (d, J=2.9Hz), 117.2,114.7 (d, J =21.2Hz), 114.2 (d, J=22.0Hz), 111.9,69.1 (d, J=1.7Hz), 58.1,49.9,19.7,19.2.

Embodiment 7 (S) -2- (4- ((3- fluorine benzyloxy) -2- methylbenzyl) (propyl -2- alkynes -1- base) amino) propionamide Synthesis

By (S) -2- (4- (3- fluorine benzyloxy) -2- methylbenzylamino) propionamide (0.18g, 0.57mmol), potassium carbonate (0.94g, 6.84mmol), DMF (10mL) and 3- propargyl bromide (0.06mL, 0.70mmol) are added sequentially to 100mL single neck round bottom In flask, 12h is reacted at room temperature, add water (30mL) and is extracted with ethyl acetate (30mL × 2), is washed (20mL × 3), is collected second Ethyl acetate layer, then it is solid for white to obtain title compound for evaporating column chromatographic purifying (petrol ether/ethyl acetate (v/v)=2/1) Body (0.20g, 99.2%).

MS (ESI, pos.ion) m/z:355.0 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 7.37 (dd, J=13.8,7.5Hz, 1H), 7.23 (d, J=5.7Hz, 1H), 7.21-7.14 (m, 1H), 7.03 (t, J=7.7Hz, 1H), 6.86-6.78 (m, 3H), 5.06 (s, 2H), 3.71 (dd, J =126.9,13.3Hz, 2H), 3.44 (dd, J=13.3,6.5Hz, 1H), 3.32 (s, 2H), 2.39 (s, 3H), 1.40 (d, J= 6.8Hz, 3H)；

¹³C NMR (151MHz, CDCl₃) δ (ppm) 177.3,162.9 (d, J=246.0Hz), 157.7,139.6 (d, J= 7.3Hz), 138.7,130.7,130.0 (d, J=8.2Hz), 128.2,122.6,117.1,114.7,114.1,111.7, 79.1,73.4,69.0,60.3,52.2,38.9,19.5,12.2.

The synthesis of embodiment 8 (S) -2- (the fluoro- 4- of 2- (3- fluorine benzyloxy) benzyl amino) propionamide

The synthesis of the fluoro- 4- of step 1) 2- (3- fluorine benzyloxy) benzaldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 3- fluorobenzyl bromide (0.46mL, 3.75mmol), the fluoro- 4- hydroxy benzaldehyde (0.50g, 3.57mmol) of 2-, potassium carbonate (1.97g, 14.28mmol) and Acetone (25mL), which is added in 100mL single necked round bottom flask, reacts preparation, then column chromatographic purifying (petrol ether/ethyl acetate (v/ V)=10/1) obtaining title compound is white solid (0.73g, 81.8%).

MS(ESI,pos.ion)m/z:249.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.20 (s, 1H), 7.83 (t, J=8.4Hz, 1H), 7.37 (td, J= 7.9,5.9Hz, 1H), 7.18 (d, J=7.6Hz, 1H), 7.13 (d, J=9.4Hz, 1H), 7.05 (td, J=8.4,2.2Hz, 1H), 6.84 (dd, J=8.8,2.2Hz, 1H), 6.70 (dd, J=12.2,2.3Hz, 1H), 5.12 (s, 2H)

The synthesis of step 2) (S) -2- (the fluoro- 4- of 2- (3- fluorine benzyloxy) benzyl amino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.42g, 3.38mmol), triethylamine (0.59mL, 4.23mmol), acetic acid (0.38mL, 6.76mmol), methanol (20mL), the fluoro- 4- of 2- (3- fluorine benzyloxy) benzaldehyde (0.70g, 2.82mmol) and sodium cyanoborohydride (0.27g, It 4.23mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (methylene chloride/methanol (v/v)=50/1) obtaining title compound is white solid (0.31g, 34.3%).

MS(ESI,pos.ion)m/z:321.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.38-7.30 (m, 1H), 7.17 (d, J=5.3Hz, 2H), 7.13 (d, J =12.1Hz, 1H), 7.01 (td, J=8.4,2.0Hz, 1H), 6.73-6.64 (m, 2H), 5.03 (s, 2H), 3.73 (dd, J= 38.7,13.1Hz, 2H), 3.21 (q, J=6.9Hz, 1H), 1.31 (d, J=6.9Hz, 3H)；

¹³C NMR(151MHz,CDCl₃) δ (ppm) 178.1,163.2 (d, J=179.3Hz), 161.5 (d, J= 178.9Hz), 159.1 (d, J=11.1Hz), 138.9 (d, J=7.3Hz), 131.0 (d, J=6.6Hz), 130.2 (d, J= 8.2Hz), 122.6 (d, J=2.9Hz), 118.9 (d, J=15.6Hz), 115.0 (d, J=21.1Hz), 114.1 (d, J= 22.1Hz), 110.4 (d, J=3.0Hz), 102.8 (d, J=25.5Hz), 69.4 (d, J=1.6Hz), 57.5,46.1 (d, J= 1.5Hz),19.7.

Embodiment 9 (S) -2- (the fluoro- 4- of 2- ((3- fluorine benzyloxy) benzyl) (propyl -2- alkynes -1- base) amino) propionamide Synthesis

This step title compound method referring to described in embodiment 7 is prepared, i.e., by (S) -2- (fluoro- 4- (3- of 2- Fluorine benzyloxy) benzyl amino) propionamide (0.20g, 0.62mmol), 3- propargyl bromide (0.06mL, 0.74mmol), potassium carbonate (1.04g, 7.44mmol) and DMF (10mL) are added sequentially to react preparation in 100mL single necked round bottom flask, and then column chromatography is pure Changing (petrol ether/ethyl acetate (v/v)=2/1) to obtain title compound is white solid (0.16g, 71.5%).

MS(ESI,pos.ion)m/z:359.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.42-7.33(m,1H),7.28(s,1H),7.21-7.15(m,2H), 7.06-7.05(m,1H),6.76-6.89(m,2H),5.06(s,2H),3.72(s,2H),3.46-3.16(m,3H),2.31(s, 1H), 1.42 (d, J=5.9Hz, 3H)；

¹³C NMR(151MHz,CDCl₃) δ (ppm) 177.1,162.9 (d, J=246.8Hz), 162.2 (d, J= 247.4Hz), 159.4 (d, J=10.4Hz), 138.9 (d, J=7.3Hz), 132.2,130.2 (d, J=8.2Hz), 122.7 (d, J=2.7Hz), 116.8,115.0 (d, J=21.1Hz), 114.2 (d, J=22.1Hz), 110.5,102.9 (d, J= 25.8Hz), 78.5,73.7,69.4,61.3,48.9,38.6,13.4.

The synthesis of embodiment 10 (S) -2- (the chloro- 4- of 2- (3- fluorine benzyloxy) benzyl amino) propionamide

The synthesis of the chloro- 4- of step 1) 2- (3- fluorine benzyloxy) benzaldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 3- fluorobenzyl bromide (0.42mL, 3.40mmol), 2- chloro-4-hydroxyl benzaldehyde (0.50g, 3.19mmol), potassium carbonate (1.77g, 12.78mmol) and Acetone (35mL) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (petroleum ether/acetic acid second Ester (v/v)=9/1) title compound is obtained as white solid (0.52g, 61.9%).

MS (ESI, pos.ion) m/z:265.1 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 10.36 (d, J=0.6Hz, 1H), 7.92 (t, J=7.1Hz, 1H), 7.40 (td, J=7.9,5.9Hz, 1H), 7.22 (t, J=8.3Hz, 1H), 7.16 (d, J=9.4Hz, 1H), 7.08 (td, J= 8.4,2.2Hz, 1H), 7.03 (d, J=2.4Hz, 1H), 6.98 (dd, J=8.7,1.8Hz, 1H), 5.15 (s, 2H)

The synthesis of step 2) (S) -2- (the chloro- 4- of 2- (3- fluorine benzyloxy) benzyl amino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.30g, 2.37mmol), triethylamine (0.42mL, 3.00mmol), acetic acid (0.27mL, 4.74mmol), methanol (20mL), the chloro- 4- of 2- (3- fluorine benzyloxy) benzaldehyde (0.52g, 1.96mmol) and sodium cyanoborohydride (0.19g, It 2.95mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (EA) obtains title compound Object is white solid (0.36g, 54.0%).

MS (ESI, pos.ion) m/z:337.1 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 7.44-7.33 (m, 1H), 7.27-7.11 (m, 4H), 7.08-6.99 (m, 2H), 6.85 (dd, J=8.4,2.5Hz, 1H), 5.59 (s, 1H), 5.06 (s, 2H), 3.81 (dd, J=39.2,13.2Hz, 2H), 3.24 (q, J=7.0Hz, 1H), 1.35 (d, J=7.0Hz, 3H)

¹³C NMR (101MHz, CDCl₃) δ (ppm) 178.0,163.0 (d, J=246.5Hz), 158.4,139.0 (d, J= 7.3Hz), 134.5,131.3,130.2 (d, J=8.2Hz), 129.4,122.7 (d, J=3.0Hz), 116.3,115.0 (d, J =21.1Hz), 114.2 (d, J=22.2Hz), 113.5,69.5 (d, J=1.8Hz), 57.5,49.9,19.8.

Embodiment 11 (S) -2- (the chloro- 4- of 2- ((3- fluorine benzyloxy) benzyl) (propyl -2- alkynes -1- base) amino) propionamide Synthesis

This step title compound method referring to described in embodiment 7 is prepared, i.e., by (S) -2- (chloro- 4- (3- of 2- Fluorine benzyloxy) benzyl amino) propionamide (0.50g, 1.48mmol), 3- propargyl bromide (0.15mL, 1.77mmol), potassium carbonate (2.46g, 17.76mmol) and DMF (10mL) are added sequentially to react preparation in 100mL single necked round bottom flask, and then column chromatographs It is white solid (0.37g, 67.4%) that purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.

MS (ESI, pos.ion) m/z:374.9 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 7.38-7.30 (m, 2H), 7.17 (d, J=7.7Hz, 1H), 7.13 (d, J =9.4Hz, 1H), 7.03-6.98 (m, 2H), 6.85 (d, J=2.5Hz, 1H), 5.03 (s, 2H), 3.78 (dd, J=72.1, 13.3Hz, 2H), 3.43 (q, J=7.0Hz, 1H), 3.35-3.19 (m, 2H), 1.39 (d, J=7.0Hz, 3H)；

¹³C NMR (101MHz, CDCl₃) δ (ppm) 176.9,163.0 (d, J=246.5Hz), 158.5,138.9 (d, J= 7.3Hz), 135.2,132.0,130.2 (d, J=8.2Hz), 127.7,122.7 (d, J=2.9Hz), 116.4,115.0 (d, J =21.1Hz), 114.2 (d, J=22.1Hz), 113.6,79.1,73.7,69.5 (d, J=1.7Hz), 60.7,52.2,39.1, 12.4.

The synthesis of embodiment 12 (S) -2- (((5- (3- fluorine benzyloxy) pyridine -2- base) methyl) amino) propionamide

The synthesis of step 1) 5- (3- fluorine benzyloxy) pyridine carboxaldehyde

This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 3- fluorobenzyl bromide (0.53mL, 4.30mmol), 5- Hydroxy-pyridine -2- formaldehyde (0.50g, 4.06mmol), potassium carbonate (0.85g, 6.20mmol) and Acetone (10mL) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (petroleum ether/acetic acid second Ester (v/v)=5/1) title compound is obtained as white solid (0.75g, 80.0%).

MS (ESI, pos.ion) m/z:232.2 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 10.01 (d, J=10.6Hz, 1H), 8.51 (d, J=2.7Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.38 (ddd, J=11.6,8.0,4.3Hz, 2H), 7.19 (dd, J=21.0,8.5Hz, 2H), 7.07 (td, J=8.4,2.1Hz, 1H), 5.21 (s, 2H)

The synthesis of step 2) (S) -2- ((5- (3- fluorine benzyloxy) pyridine -2- base) methylamino) propionamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by L- alanyl amine salt Hydrochlorate (0.48g, 3.89mmol), triethylamine (1.02mL, 5.84mmol), acetic acid (0.44mL, 7.78mmol), methanol (10mL), 5- (3- fluorine benzyloxy) pyridine carboxaldehyde (0.75g, 3.24mmol) and sodium cyanoborohydride (0.31g, 4.86mmol) according to Secondary be added in 100mL single necked round bottom flask reacts preparation, and then it is solid for white to obtain title compound for column chromatographic purifying (EA) Body (0.82g, 83.0%).

MS (ESI, pos.ion) m/z:304.0 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 8.33 (d, J=2.6Hz, 1H), 7.42-7.33 (m, 1H), 7.25- 7.12 (m, 4H), 7.04 (td, J=8.4,2.0Hz, 1H), 5.64 (d, J=29.4Hz, 1H), 5.16 (s, 2H), 5.10 (d, J =10.6Hz, 2H), 3.24 (q, J=6.9Hz, 1H), 1.37 (d, J=6.9Hz, 3H)

Embodiment 13 (S) -2- (4- (3- fluorine benzyloxy) benzyl amino)-N- methyl-N- (propyl -2- alkynes -1- base) propionamide Synthesis

Step 1) (S)-(9H- fluorenes -9- base) methyl (1- (methyl (propyl -2- alkynes -1- base) amino) -1- oxopropan -2- Base) carbamate synthesis

By N- fluorenylmethyloxycarbonyl-l-Alanine (3.00g, 9.64mmol), N- methyl-propargyl amine (1.20mL, 14.47mmol), DMAP (0.12g, 0.96mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (3.17g, 16.39mmol) and methylene chloride (40mL) are added sequentially in 100mL single necked round bottom flask, are reacted at room temperature 13.5h adds water (20mL), liquid separation, collects organic phase, and then sample column chromatographic purifying (petrol ether/ethyl acetate (v/v) is mixed in concentration =2/1) obtaining title compound is white solid (2.28g, 65.3%).

MS (ESI, pos.ion) m/z:336.3 [M+H]⁺；

¹H NMR (400MHz, CDCl₃) δ (ppm) 7.79-7.77 (m, 3H), 7.63-7.61 (m, 2H), 7.36-7.32 (m, 3H), 4.72 (s, 2H), 4.31-4.29 (m, 1H), 3.95-3.93 (m, 2H), 3.82-3.75 (m, 1H), 3.09 (s, 3H), 2.97 (s, 1H), 1.23 (d, J=6.8Hz, 3H)

The synthesis of step 2) (S) -2- Amino-N-methyl-N- (propyl -2- alkynes -1- base) propionamide

By (S)-(9H- fluorenes -9- base) methyl (1- (methyl (propyl -2- alkynes -1- base) amino) -1- oxopropan -2- base) Carbamate (2.28g, 6.29mmol), methylene chloride (40mL) and diethylamine (20.8mL, 201.55mmol) sequentially add Into 100mL single necked round bottom flask, 3.5h is reacted at room temperature, then directly mixes sample column chromatographic purifying (petrol ether/ethyl acetate (v/v)=1/1) obtaining title compound is white solid (0.76g, 86.2%).

MS(ESI,pos.ion)m/z:141.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)4.72(s,2H),3.80-3.73(m,1H),3.07(s,3H),2.99 (s, 1H), 1.23 (d, J=6.8Hz, 3H)

Step 3) (S) -2- (4- (3- fluorine benzyloxy) benzyl amino)-N- methyl-N- (propyl -2- alkynes -1- base) propionamide Synthesis

By (S) -2- Amino-N-methyl-N- (propyl -2- alkynes -1- base) propionamide (0.25g, 1.78mmol), methanol (10mL), DIPEA (0.15mL, 0.89mmol), LiCl (0.038g, 0.89mmol) and 4- (3- fluorine benzyloxy) benzaldehyde (0.41g, 1.78mmol) is added sequentially in 100mL single necked round bottom flask, reacts 15h at room temperature, is transferred to 0 DEG C, and boron is added Hydrofining (0.096g, 1.78mmol), the reaction was continued, and 2h directly mixes sample column chromatographic purifying (methylene chloride/first after reaction Alcohol (v/v)=30/1) title compound is obtained as colorless oil (0.46g, 72.9%).

MS(ESI,pos.ion)m/z:355.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.38-7.32(m,1H),7.28(s,1H),7.26(s,1H),7.20 (d, J=7.8Hz, 1H), 7.16 (d, J=9.6Hz, 1H), 7.01 (td, J=8.4,2.1Hz, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 5.06 (s, 2H), 4.33-4.21 (m, 1H), 3.72 (dd, J=12.6,7.7Hz, 1H), 3.65-3.50 (m, 2H), 3.05-3.01(m,3H),2.19(s,2H),1.29-1.21(m,3H)；

¹³C NMR(101MHz,CDCl₃) δ 175.2,163.0 (d, J=246.2Hz), 157.6,139.8 (d, J= 7.3Hz), 132.5,130.1,130.0,129.7,122.7 (d, J=2.9Hz), 114.8,114.6,114.3,114.1, (78.6,72.0,69.2 d, J=1.8Hz), 52.2,51.3,36.6,33.8,18.8.

Embodiment 14 (S)-N- methyl-N- (propyl -2- alkynes -1- base) -2- (4- (2,2,3,3- tetrafluoro propoxyl group) benzyl ammonia Base) propionamide synthesis

This step title compound method referring to described in 13 step 3 of embodiment is prepared, i.e., by (S) -2- amino - N- methyl-N- (propyl -2- alkynes -1- base) propionamide (0.28g, 2.00mmol), methanol (10mL), DIPEA (0.17mL, 1.00mmol), LiCl (0.043g, 1.00mmol), 4- (2,2,3,3- tetrafluoro propoxyl group) benzaldehyde (0.47g, 2.00mmol) It is added sequentially to react preparation in 100mL single necked round bottom flask with potassium borohydride (0.11g, 2.00mmol), then column chromatography is pure Changing (EA) to obtain title compound is colorless oil (0.38g, 52.4%).

MS(ESI,pos.ion)m/z:361.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.29-7.27 (m, 2H), 6.86 (d, J=8.5Hz, 2H), 6.05 (tt, J=53.1,5.0Hz, 1H), 4.31 (t, J=11.9Hz, 2H), 4.28-4.16 (m, 1H), 3.72-3.67 (m, 1H), 3.64- 3.46(m,2H),3.03-3.00(m,3H),2.18(s,2H),1.27-1.20(m,3H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm)175.1,156.5,134.0,133.9,129.8,129.8,114.6, 114.5 (tt, J=259.3,26.9Hz), 109.0 (tt, J=249.8,34.2Hz), 78.6,72.0,65.4 (t, J= 29.9Hz),52.3,51.2,36.6,33.8,18.8.

The synthesis of embodiment 15 (S) -2- (4- (3- fluorine benzyloxy) benzyl amino)-N- (2- morpholine ethyl) propionamide

(the synthesis of 1- ((2- morpholine ethylamino) -1- oxopropan -2- base) carbamate of step 1) (S)-benzyl

It is mono- that carbobenzyloxy-L-alanine (0.50g, 2.24mmol) and methylene chloride (10mL) are added sequentially to 100mL In mouthful round-bottomed flask, be transferred at 0 DEG C, be added dicyclohexylcarbodiimide (0.57g, 2.68mmol) and HOBt (0.37g, 2.68mmol) and 1h is reacted, be then transferred to room temperature, adds N- (2- amino-ethyl) morpholine (0.88mL, 6.72mmol), room Temperature is lower to react 16.5h, and filtrate is collected in filtering, and filtrate washes (50mL × 2), and organic phase is collected in liquid separation, and then sample column is mixed in concentration It is white solid (0.60g, 75.1%) that chromatographic purifying (methylene chloride/methanol (v/v)=30/1), which obtains title compound,.

MS(ESI,pos.ion)m/z:336.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.37-7.31(m,5H),5.10(s,2H),4.23-4.20(m,1H), 3.68 (s, 4H), 3.34 (d, J=5.3Hz, 2H), 2.46-2.43 (m, 6H), 1.38 (d, J=7.0Hz, 3H)

The synthesis of step 2) (S) -2- amino-N- (2- morpholine ethyl) propionamide

By (S)-benzyl (1- ((2- morpholine ethylamino) -1- oxopropan -2- base) carbamate (0.50g, It 1.49mmol) is added sequentially in 100mL single necked round bottom flask with ethyl alcohol (15mL), 10%Pd/C (100mg) and hydrogen is added, 19h is reacted at room temperature, and after reaction, the diatomite of suction funnel place mat 5cm thickness filters Pd/C, collects filtrate, is concentrated to get Title compound is colorless oil (0.30g, 99.9%).

MS(ESI,pos.ion)m/z:202.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 3.78-3.61 (m, 4H), 3.47 (q, J=6.9Hz, 1H), 3.35 (dd, J=11.9,6.0Hz, 2H), 2.52-2.39 (m, 6H), 1.31 (d, J=6.9Hz, 3H)

The synthesis of step 3) (S) -2- (4- (3- fluorine benzyloxy) benzyl amino)-N- (2- morpholine ethyl) propionamide

This step title compound method referring to described in 13 step 3 of embodiment is prepared, i.e., by (S) -2- amino - N- (2- morpholine ethyl) propionamide (0.30g, 1.49mmol), methanol (10mL), DIPEA (0.12mL, 0.74mmol), LiCl (0.031g, 0.74mmol), 4- (3- fluorine benzyloxy) benzaldehyde (0.38g, 1.64mmol) and potassium borohydride (0.08g, It 1.49mmol) is added sequentially to react preparation in 100mL single necked round bottom flask, then column chromatographic purifying (methylene chloride/methanol (v/v)=10/1) obtaining title compound is white solid (0.35g, 56.5%).

MS(ESI,pos.ion)m/z:416.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 7.35 (td, J=7.9,6.0Hz, 1H), 7.27 (d, J=8.7Hz, 2H), 7.20 (d, J=7.7Hz, 1H), 7.16 (d, J=9.5Hz, 1H), 7.02 (td, J=8.4,2.2Hz, 1H), 6.93 (d, J =8.6Hz, 2H), 5.07 (s, 2H), 3.79-3.59 (m, 6H), 3.49-3.41 (m, 1H), 3.37-3.20 (m, 2H), 2.69- 2.33 (m, 6H), 1.33 (d, J=6.9Hz, 3H)；

¹³C NMR(101MHz,CDCl₃) δ (ppm) 174.8,162.9 (d, J=246.3Hz), 157.7,139.6 (d, J= 7.3Hz), 132.3,130.1,130.0,129.2,122.6 (d, J=2.9Hz), 114.8,114.6,114.2,114.0,69.2 (d, J=1.8Hz), 66.9,57.9,57.4,53.4,51.9,35.2,19.8.

Biologic test

Embodiment A: activity inhibition of the evaluation the compounds of this invention to monoamine oxidase B

Experimental method:

Experimental system recombinates monoamine oxidase B using people, is expressed in Sf9 cell.Monoamine will be recombinated in experimentation first Oxidase B is dissolved in (0.8%NaCl, 0.037%KCl, 0.0135%Na2HPO in configured HEPES buffer solution in advance₄· 2H₂O, 0.1%Glucan, 0.5%HEPES, pH=7.0), configuration concentration is 0.3 μ g/ μ l.Take 10 μ l monoamine oxidase B solution In test compound is added in 384 orifice plates, in every hole, (DMSO 10 concentration gradients of final concentration of 1%), positive drug select R- (-)-Deprenyl (selegiline) or Clorgyline (clorgiline) is incubated at room temperature 15min.Then 10 μ l substrates are added in every hole Solution is incubated at room temperature 60min.Then the fluorescein detection reagent of 20 μ l is added in every hole again, mixes well, in incubation at room temperature 20min is allowed to generate stable fluorescence signal, reads fluorescence signal using fluorescence microplate reader, numerical value is with relative light intensity (RLU) It indicates.Inhibition of enzyme activity rate is calculated according to experimental result, calculation formula is as follows: Inh%=(Max-Signal)/(Max-Min) * 100, wherein value detected when Max is sample maximum concentration, Min when being sample Cmin value detected, Signal be Value detected when sample existing concentration.

Standard curve is obtained by the experiment test of series of concentrations, to calculate IC₅₀.It the results are shown in Table A.

Activity inhibition test result of the Table A the compounds of this invention to monoamine oxidase B

Example No.	IC₅₀(μM)
		Embodiment 6	0.071
Embodiment 8	0.061
		Embodiment 9	0.094
Embodiment 10	0.014
		Embodiment 11	0.068

Experimental result shows that the compounds of this invention has good inhibiting effect to the activity of monoamine oxidase B.

Embodiment B: Pharmacokinetic Evaluation of the rat after intravenous or stomach-filling quantify the compounds of this invention

1) animal subject: animal subject is rat, and concrete condition is as shown in table 1:

Table 1

Germline

Grade

Gender

Quantity

Weight

Week old

Source

SD rat

Cleaning grade

Male

6

180-220g

8 weeks

Changzhou Cavan this

2) analysis method:

The LC-MS/MS system of analysis includes the serial vacuum degassing machine of Agilent 1200, quaternary pump, and orifice plate is adopted automatically Sample device, thermostatted column compartment, the triple level four bars mass spectrographs of the API4000Qtrap of charged spray ionization source (ESI).Quantitative analysis exists It is carried out under MRM mode, wherein the source parameter of MRM conversion is as shown in table 2:

Table 2

Gas curtain gas/CUR:	20psi
		Atomization gas/GS1:	550psi
Auxiliary heating gas/GS2:	55psi
		Ion transmits voltage IS (V)/NC (mA)	5500
Atomization temperature/TEM:	550℃
		Fragmentation voltage	30V
Capillary voltage	140V
		Dryer temperature	350℃
Atomizer	40psi
		Drier flow velocity	9L/min

It is analyzed, is analyzed using waters xbridge C18 (2.1 × 50mm, 3.5 μM of columns inject 0.5 μ L sample) Condition are as follows: mobile phase is+0.1% formic acid (mobile phase A) of water+2mM ammonium formate and the (flowing of+0.1% formic acid of methanol+2mM ammonium formate Phase B).Flow velocity is 0.4mL/min.Eluent gradient is as shown in table 3:

Table 3

Time	The gradient of Mobile phase B
		0.5min	20%
1.2min	90%
		2.7min	90%
2.81min	20%
		4.0min	It terminates

3) test method:

The intracorporal pharmcokinetic evaluation of rat is carried out to the compounds of this invention, the specific steps are as follows:

Experiment is divided into two groups: one groups by intravenous injection administration, and one group passes through gastric infusion.By the compounds of this invention with The form of 5%DMSO+5%Kolliphor HS15+90%Saline solution is administered animal subject.For intravenous injection Administration group, dosage 1mg/kg, then time point upon administration be 0.083,0.25,0.5,1.0,2.0,4.0,6.0, Venous blood sampling (0.3mL) at 8.0 and 24 hours, and be centrifuged 10 minutes at 3,000 or 4,000rpm, plasma solutions are collected, and It is saved at -20 DEG C or -70 DEG C.For gastric infusion group, dosage 5mg/kg, then time point upon administration be 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm from The heart 10 minutes, plasma solutions are collected, and save at -20 DEG C or -70 DEG C.

20 μ l blood plasma are taken, the Propranolol internal standard aqueous solution of 120 μ l50ng/ml is added, 0.9ml methyl- tert fourth is used after mixing Base ether (MTBE) extraction, with 200 μ l methanol-waters (methanol: water=1: 1) again molten after taking 0.8ml supernatant use to be dried with nitrogen Solution.

Pharmacokinetics ginseng is calculated using the concentration of LC-MS/MS method detection target compound, and using non-compartment model Number.The compounds of this invention has preferable pharmacokinetic property in rat body as the result is shown for analysis.

In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.

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

Claims

1. a kind of compound is stereoisomer, the geometrical isomerism of compound shown in formula (I) compound represented or formula (I) Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein:

X is CR²Or N；

R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base or C₆-C₁₀Aryl, Wherein, the C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkoxy, C₁-C₆Alkylthio group, C₁-C₆Alkylamino, hydroxyl Substituted C₁-C₆Alkyl, C₃-C₈Naphthenic base and 3-8 circle heterocyclic ring base are independently selected from D, F, Cl, Br, C by 1,2,3,4 or 5₁-C₆ Alkyl, C₂-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Alkylidene- Replaced group, the C₆-C₁₀Aryl is selected from D, F, Cl, Br, C by 1,2,3,4 or 5₁-C₆Alkyl, C₂-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy and C₁-C₆Alkyl-S (=O)₂-C₁-C₆Replaced the group of alkylidene-；

R²For H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy or hydroxyl Substituted C₁-C₆Alkyl；

R³、R⁴It is each independently H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆It is halogenated The C that alkoxy or hydroxyl replace₁-C₆Alkyl；

R⁵For H, D, C₂-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Haloalkoxy The C that base, hydroxyl replace₁-C₆Alkyl or C₃-C₈Naphthenic base-C₀-C₆Alkylidene-；

R⁶、R⁷It is each independently H, D, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 member are miscellaneous Ring group, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein the C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆It is halogenated Alkyl, C₁-C₆Alkoxy, C₁-C₆Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃- C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl and 5-10 unit's heteroaryl it is individually optional by 1,2,3,4 or 5 selected from D, F, Cl, Br, I, OH, oxo (=O), NH₂、NO₂、CN、C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Alkyl halide Oxygroup, C₃-C₈Replaced the group of naphthenic base and 3-8 circle heterocyclic ring base；

R⁸For H；

M is 1 or 2；With

2. compound according to claim 1, wherein R¹For C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃- C₆Naphthenic base, 3-6 circle heterocyclic ring base or C₆-C₁₀Aryl, wherein the C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Alkane Oxygroup, C₁-C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base and 3-6 circle heterocyclic ring base are independently D, F, Cl, Br, C are selected from by 1,2,3,4 or 5₁-C₄Alkyl, C₂-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy And C₁-C₄Alkyl-S (=O)₂-C₁-C₄Replaced the group of alkylidene-, the C₆-C₁₀Aryl is selected from by 1,2,3,4 or 5 D、F、Cl、Br、C₁-C₄Alkyl, C₂-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy and C₁-C₄Alkyl-S (=O)₂- C₁-C₄Replaced the group of alkylidene-.

3. compound according to claim 1 or 2, wherein R¹For methyl, ethyl, n-propyl, isopropyl, allyl, propylene Base, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, N-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, first Sulfenyl, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, phenyl, indenyl or naphthalene, In, the methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl, methoxyl group, ethyoxyl, just Propyl oxygroup, isopropyl oxygroup, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyethyl, ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl and morpholine Base is independently selected from D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl ,-CHFCH by 1,2,3,4 or 5₂F、- CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、- OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、-CH₂- S (=O)₂-CH₃With-CH₂- S (=O)₂-CH₂CH₃Base Replaced group, the phenyl, indenyl and naphthalene are independently by 1,2,3,4 or 5 selected from D, F, Cl, Br, methyl, ethyl, just Propyl, isopropyl ,-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl Base oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂、-CH₂- S (=O)₂-CH₃With- CH₂- S (=O)₂-CH₂CH₃Group replaced.

4. compound according to claim 1, wherein R²For H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

5. compound according to claim 1 or 4, wherein R²For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl Base ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, it is methoxyl group, ethyoxyl, n-propyl oxygroup, different Propyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methylol or 2- hydroxyl second Base.

6. compound according to claim 1, wherein R⁵For H, D, C₂-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄ Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy, hydroxyl replace₁-C₄Alkyl or C₃-C₆Naphthenic base-C₀-C₄Alkylene Base-.

7. compound according to claim 1 or 6, wherein R⁵For H, D, ethyl, n-propyl, isopropyl, allyl, propylene Base, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, N-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, hydroxyl Methyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl ,-CH₂Cyclopropyl ,-CH₂Cyclobutyl ,-CH₂Ring penta Base or-CH₂Cyclohexyl.

8. compound according to claim 1, wherein R⁶、R⁷It is each independently H, D, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂- C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄Alkylamino, hydroxyl replace C₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein the C₁-C₄Alkane Base, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄ The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl and 5-10 unit's heteroaryl are independent Optionally D, F, Cl, Br, I, OH, oxo (=O), NH are selected from by 1,2,3,4 or 5₂、NO₂、CN、C₁-C₄Alkyl, C₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₃-C₆Replaced the group of naphthenic base and 3-6 circle heterocyclic ring base.

9. compound according to claim 1 or 8, wherein R⁶、R⁷Be each independently H, D, methyl, ethyl, n-propyl, Isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、- CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、- OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol, 2- hydroxyl Base ethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazine Base, morpholinyl, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furyl, thiophene Base, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl or quinolyl, wherein The methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF₂、-CHFCH₂F、- CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、- OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, hydroxyl Methyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperazine Piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furans Base, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl and quinolyl D, F, Cl, Br, I, OH, oxo (=O), NH are selected from by 1,2,3,4 or 5 individually optionally₂、NO₂, CN, methyl, ethyl, positive third Base, isopropyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl Oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl and morpholinyl group It is replaced.

10. compound according to claim 1 is the chemical combination as shown in formula (II) compound represented or formula (II) The stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug,

11. compound according to claim 1 for the compound with one of following structure or has one of following knot The stereoisomer of the compound of structure, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug:

12. a kind of pharmaceutical composition includes compound described in claim 1-11 any one；With

Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.

13. pharmaceutical composition described in compound described in claim 1-11 any one or claim 12 any one exists The purposes in drug is prepared, the drug is for preventing, treating or mitigating the disease that patient is adjusted by MAO-B inhibitor Disease；

Wherein, the disease being adjusted by MAO-B inhibitor is neurodegenerative disease, mental disease or cancer；

Wherein, the neurodegenerative disease is Parkinson's disease, cerebral ischemia, Alzheimer disease, amyotrophic lateral sclerosis Disease, bovine spongiform encephalopathy, Huntington chorea, gram refined Er Shi disease, ataxia telangiectasia, cerebral atrophy, ridge Marrow muscular atrophy, primary lateral sclerosis or multiple sclerosis.