CN104292126A - Naphthalene derivatives and their application in medicine - Google Patents

Abstract

The present invention provides some naphthalene derivatives or their stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrugs for exciting melatonin receptors. The present invention also discloses pharmaceutical compositions containing such compounds and uses of the compounds of the present invention or their pharmaceutical compositions in treating central nervous system dysfunction in mammals, especially humans.

Description

Naphthalene derivatives and their application in medicine

technical field

The invention belongs to the field of medicines, and in particular relates to a class of novel compounds that can be used for treating central nervous system dysfunction, their preparation methods, pharmaceutical compositions containing the compounds, and the role of the compounds and their pharmaceutical compositions in treating central nervous system dysfunction. applications in obstacles. More specifically, the present invention describes naphthalene compounds that can be used as melatonin receptor agonists. the

Background technique

Melatonin is a neuroendocrine hormone secreted by the pineal gland. Its main physiological functions are: 1. Anti-tumor effect. Melatonin can inhibit breast cancer, melanoma, prostate cancer, liver cancer, etc. The growth of cancer cells is an important physiological tumor suppressor; 2. Antioxidation, the body can produce free radicals through enzymatic and non-enzymatic reactions, such as oxygen free radicals, hydroxyl free radicals, etc., melatonin mainly through Provide electrons to remove reactive oxygen species (ROS); 3. Immunomodulatory effect, melatonin is one of the important factors connecting the nervous system and immune system of the body, and plays an important role in maintaining the normal function of the body; 4. Anti-inflammatory and stress effects , melatonin can significantly promote the proliferation of peripheral blood lymphocytes in patients with rheumatoid arthritis, and has an antagonizing effect on low temperature, hypoxia, noise, and light disturbance stress; 5. Regulating glucose and lipid metabolism, melatonin can Reduce blood sugar and blood lipids, increase high-density lipoprotein; 6. Antidepressant and anti-anxiety effects 7. Effect on sleep latency, melatonin can also mediate through specific melatonin receptors, play a role in regulating the sleep-wake cycle Unique role (Malpaux B, Migaud M, et al. Biology of mam malian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms, 2001, 16(4): 336-347). Melatonin needs to play a biological role by activating receptors. Melatonin receptors are members of the G protein-coupled receptor superfamily and are widely found in the SCN, hippocampus, cerebellar cortex, prefrontal cortex, basal ganglia, and ventral substantia nigra of the nervous system. In the lateral tegmental area, nucleus accumbens, etc., and in the cell membranes and nuclei of other systems such as the retina, blood vessels, breast, liver, kidney, gastrointestinal tract, and gonads. There are three subtypes of human melatonin receptors, MT ₁ , MT ₂ and MT ₃ . MT ₁ , highly concentrated in the SCN, thalamic nucleus, etc., regulates sleep; MT ₂ , involves circadian rhythm; MT ₃ has unknown role. (Charlotte von Gal1, Jorg H, et al., Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue RPs, 2002, 309(1): 151-162).

Among the diseases associated with melatonin receptors, insomnia is a very important one. Insomnia refers to a sleep disorder syndrome in which sleep initiation and sleep maintenance are disturbed, resulting in sleep quality that cannot meet individual physiological needs and significantly affects patients' daytime activities. Insomnia is a common disease that makes people feel depressed and anxious. At the same time, it can weaken the immune mechanism and hinder physical recovery. With the acceleration of modern life rhythm, the occurrence of insomnia has an increasing trend. In real life, accidents caused by lack of sleep It also happens a lot. At present, nearly 1/4 of the people in the world suffer from insomnia, the prevalence rate of sleep disorders in my country is 42.7%, and about 300 million middle-aged people suffer from sleep disorders. The global hypnotics market was valued at USD 4 billion in 2009, growing at an annual rate of 11%. the

At present, drug therapy is one of the main methods for treating insomnia. The sedative and hypnotics used clinically include: barbiturates, benzodiazepines, non-benzodiazepines, antidepressants, melatonin and traditional Chinese medicine. Barbiturates are derivatives of barbituric acid (malonylurea), which selectively inhibit the ascending reticular activation system of the thalamus, thereby blocking the transmission of excitement to the cerebral cortex. Such drugs mainly include phenobarbital, amobarbital and secobarbital. Such drugs have relatively high toxicity and side effects, especially severe liver and kidney toxicity. Long-term use can lead to tolerance and dependence, and cumulative poisoning. Now they are rarely used for sedation and hypnosis in clinical practice. Benzodiazepines have sedative, muscle relaxant, anxiolytic and anticonvulsant effects, commonly used clinical drugs: mainly midazolam, triazolam, alprazolam, estazole Lun (estazolam), diazepam (diazepam), flurazepam (flurazepam), clonazepam (clonazepam) and so on. Although these drugs can prolong the total sleep time and shorten the sleep latency period, they can reduce slow-wave sleep and rapid eye movement (REM) sleep, and do not really improve sleep quality. Its adverse reactions and complications are obvious, and long-term application can cause drug tolerance, dependence and withdrawal symptoms. (Krystal AD. The changing perspective on chronic insomnia management. J Clin Psychiatry, 2004, 65 Suppl 8: 20-25). Non-benzodiazepines, approved drugs include zolpidem, zalepbn and zopiclone, these drugs do not affect the normal sleep structure, usually do not cause insomnia rebound and withdrawal reaction. Common adverse reactions include ataxia, headache, drowsiness, memory difficulties, mental disorders, etc. (Rotht, Soubranec, Titeuxl, et al., Efficacy and safety of zolpidem-MR: a double-blind. primary insomniam. Sleep Med, 2006, 7(5): 397-406). Antidepressants have no specific hypnotic effect, but they can improve insomnia symptoms by treating depression and anxiety. Commonly used clinically are paroxetine, sertraline, mirtazapine, trazodone ( trazodone) and amitriptyline, etc. When individual patients used SSRIs, their sleep did not improve, or even deteriorated (Uhlenhutheh, EH, Balter MB, et al., Trends in recommendations for the pharmacotherapy of anxiety disorders by an intemationa expert panel, 1992 -1997. Eur Neuropsyehopharmacol, 1999.9 Suppl 6: 393-398). Therefore, the development of sedative-hypnotic drugs with high efficiency, high selectivity and small side effects has become a research hotspot. the

Melatonin drugs have good curative effect and few side effects, so they have a good application prospect. The melatonin receptor agonist ramelteon (ramelteon), which was first listed in the United States in 2005, is used for the treatment of insomnia, which can shorten the sleep latency, improve sleep efficiency and sleep maintenance. Compared with traditional drugs, this drug does not damage the Cognitive activities on the next day, no withdrawal symptoms; but this drug has mild side effects, such as headache, fatigue, lethargy, etc. (Arendt J, Van Someren E J, Appleton R, et a1., Clinical update: melatonin and sleep disorders.Clin Med, 2008, 8(4):381-383). the

The invention provides some new compounds with melatonin receptor agonist activity, which have better clinical application prospects. Compared with existing similar compounds, the compound of the present invention has better drug efficacy, pharmacokinetic properties and/or toxicological properties. the

Contents of the invention

The invention provides a class of compounds with melatonin receptor agonist activity, which can be used to prepare and treat human central nervous system dysfunction, such as sleep disorders, stress response, seasonal affective disorder, insomnia and fatigue caused by jet lag and Medicines for insomnia. The present invention also provides methods for preparing these compounds, methods for using these compounds to treat mammals, especially humans, for the above-mentioned diseases, and pharmaceutical compositions containing these compounds. the

Specifically:

In one aspect, the present invention relates to a compound, which is the structure shown in formula (I) or stereoisomers, tautomers, nitrogen oxides, metabolites of the structure shown in formula (I), pharmaceutically available Accepted salts or prodrugs,

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed in the present invention. the

In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof. the

In another aspect, the present invention relates to the use of the compound or composition disclosed in the present invention in the preparation of medicaments for preventing, treating or alleviating central nervous system dysfunction in mammals, including humans: referring to sleep disorders, stress Reactions, depression, anxiety, seasonal affective disorder, jet lag, insomnia and fatigue, schizophrenia, convulsions, panic attacks, depression, insomnia, psychotic disorders, epilepsy, Parkinson's disease, dementia, and Various disorders associated with normal or pathological aging, migraine, memory loss or Alzheimer's disease. the

In another aspect, the present invention relates to the use of the compound or composition disclosed in the present invention in the preparation of a medicament for selectively stimulating melatonin receptors in biological samples. the

In another aspect, the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I). the

Biological test results show that the compound provided by the invention can be used as a better melatonin receptor agonist. the

Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them. the

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described more specifically and fully below. the

Detailed ways

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, etc.), this Application shall prevail. the

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

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety. the

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007 , the entire contents of which are incorporated herein by reference. the

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment. the

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content. the

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. . the

"Chiral" is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" is a molecule that is superimposable to its mirror image. the

"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other. the

"Diastereoisomer" refers to stereoisomers that have two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC. the

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. the

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. the

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. the

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

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization. the

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

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

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkyl Thio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy , hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) ₂ -, hydroxy-substituted alkyl-S( =O), hydroxy-substituted alkyl-S(=O) ₂ , carboxyalkoxy and the like.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other. Taking R ^a as an example, the ratio of R a between the structural formula "-N(R ^a )C(=O)NR ^a R ^b " and the structural formula "-(C ₁ -C ₆ alkyl)-NR ^a R ^{b "} The specific options are not affected by each other, and at the same time, in the same chemical formula "-N(R ^a )C(=O)NR ^a R ^b ", multiple specific options of R ^a are not affected by each other.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group. the

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described in the present invention, wherein the substituents are, hydroxyl, amino, fluorine, cyano, azido, heteroaryl, alkoxy, alkylamino, alkylthio , alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, hydroxy Substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) ₂ -, hydroxy substituted alkyl-S(=O ), hydroxy-substituted alkyl-S(=O) ₂ , carboxyalkoxy and the like. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), and the like.

The term "alkylene" means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Such examples _include methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), isopropylidene (-CH( _CH3 ) _CH2- ), and the like.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "tans" orientation, or the "E" and "Z" orientation. In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl ( _-CH2C≡CH ), 1-propynyl (-C≡C- _CH3 ), and the like .

The term "H" denotes a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups. the

As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation. the

The term "heteroatom" refers to O, S, N, P, and Si, including forms of any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR). the

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). the

The term "hydroxy-substituted alkyl" means that an alkyl group is substituted by one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like. the

The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc. the

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), and the like.

The term "p atoms", where p is an integer, typically describes the number of ring atoms in a molecule, the number of ring atoms in said molecule being p. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and tetrahydronaphthalene is a cycloalkyl group of 10 atoms. the

The term "carbocyclyl" or "carbocycle" denotes a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the carbocycle contains 3-8 carbon atoms; in another embodiment, the carbocycle contains 3 carbon atoms; in yet another embodiment, the carbocycle contains 5-8 carbon atoms. Carbocyclyls include spirocarbobicyclyls and fused carbocyclyls, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, etc. the

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, cycloalkyl contains 3-12 carbon atoms; In another embodiment, cycloalkyl contains 3-8 carbon atoms; In yet another embodiment, cycloalkyl contains 3-6 carbon atom. The cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein. the

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group can be carbonyl or nitrogenyl, and a _-CH2- group can optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidinyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-oxa-5-azabicyclo[2.2.1] Hept-5-yl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone , 3,5-dioxopiperidinyl and pyrimidinedione. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.

In one embodiment, the heterocyclic group is a heterocyclic group consisting of 4-7 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group of 4-7 atoms may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups consisting of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline Base, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone , 3,5-dioxopiperidinyl and pyrimidinedione. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclyl group consisting of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 4-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 4 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms replaced. Unless otherwise stated, a 4-atom heterocyclic group may be carbon or nitrogen, and a _-CH2- group may optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 4-atom heterocyclic groups include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, heterocyclyl is a 5-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 5 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms . Unless otherwise stated, a 5-atom heterocyclic group may be carbon or nitrogen, and a _-CH2- group may optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, Tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolyl, dithiocyclopentyl. Examples of -CH ₂ - groups in heterocyclic groups substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane groups. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.

In another embodiment, the heterocyclyl is a 6-atom heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring comprising 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms . Unless otherwise stated, a 6-atom heterocyclic group may be carbon or nitrogen, and a _-CH2- group may optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Piperazinyl, Dioxanyl, Dithianyl, Thioxanyl. Examples of heterocyclic groups in which the -CH ₂ - group is substituted by -C(O)- include, but are not limited to, 2-piperidinonyl, 3,5-dioxopiperidinyl and pyrimidinedionyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, 1,1-dioxothiomorpholinyl. The 6-atom heterocyclyl group can be optionally substituted with one or more substituents described in the present invention.

In another embodiment, the heterocyclic group is a heterocyclic group consisting of 7-12 atoms, which refers to a saturated or partially unsaturated spirobicyclic or fused bicyclic ring containing 7-12 ring atoms, wherein at least one ring atom Atoms selected from nitrogen, sulfur and oxygen. Unless otherwise stated, a heterocyclyl group of 7-12 atoms may be carbonyl or nitrogenyl, and a _-CH2- group may optionally be replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. Examples of heterocyclic groups consisting of 7-12 atoms include, but are not limited to: indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2- Oxa-5-azabicyclo[2.2.1]hept-5-yl. The heterocyclyl group consisting of 7-12 atoms can be optionally substituted with one or more substituents described in the present invention.

The term "aryl" means monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracene. The aryl groups may be independently optionally substituted with one or more substituents described herein. the

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl", "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. the

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, etc. the

As described in the present invention, substituents drawing a bond to the central ring to form a ring system (shown below) means that substituents can be substituted at any substitutable position on the ring. For example, formula e represents any possible substituted position of the substituent on ring A, as shown in formulas f ¹ -f ⁴ :

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, nontoxic ammonium, quaternary ammonium salts, and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The invention discloses a class of naphthalene derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used as melatonin receptor agonists to treat human central nervous system dysfunction, such as sleep disorders and stress reactions , seasonal affective disorder, insomnia and fatigue caused by jet lag, and the treatment of insomnia have potential uses. the

In one aspect, the present invention relates to a compound, which is the structure shown in formula (I) or stereoisomers, tautomers, nitrogen oxides, metabolites of the structure shown in formula (I), pharmaceutically available Accepted salts or prodrugs,

in:

Ring A is cyclopropyl, or a ring consisting of 5-6 carbon atoms or a heterocyclic ring consisting of 3-12 atoms;

R ¹ is H, OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl;

R ³ is H, F, Cl, Br, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)-(C ₁ -C ₆ alkyl ), -C(=O)NR ^a R ^b , -O-(carbocycle consisting of 3-8 atoms), -(C ₁ -C ₆ alkyl)-(carbocycle consisting of 3-8 atoms) , -(C ₁ -C ₆ alkyl)-NR ^a R ^b , heteroaryl or C ₆ -C ₁₀ aryl consisting of 5-12 atoms;

Each R ² and R ⁴ are independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , -NR ^a R ^b , -C(=O)R ^c , C ₁ -C ₆ alkane radical, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, -C(=O)-(C ₁ -C ₆ alkyl ), -C(=O)NR ^a R ^b , -(C ₁ -C ₆ alkyl)-C(=O)OR ^c , -O-(carbocyclic ring composed of 3-8 atoms), -(C ₁ -C ₆ alkyl)-(carbocyclic ring consisting of 3-8 atoms), -(C ₁ -C ₆ alkyl)-NR ^a R ^b , heterocyclic group consisting of 3-12 atoms, hydroxy-substituted C ₁ -C ₆ alkyl, -NR ^a -(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -(C ₁ -C ₆ alkyl) -(C ₆ -C ₁₀ aryl radical), -(C ₁ -C ₆ alkyl)-(heteroaryl consisting of 5-12 atoms) or heteroaryl consisting of 5-12 atoms;

Each of R ^a and R ^b is independently H, C ₁ -C ₆ alkyl, -(C ₁ -C ₆ alkyl) -(C ₆ -C ₁₀ aryl), -C(=O)Rc or - S(=O) ₂ -(C ₁ -C ₆ alkyl); and

Each R ^c is independently H, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₃ -C ₈ cycloalkyl.

In some of these embodiments, ^R is H, OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In other embodiments, ^R3 is H, F, Cl, Br, OH, CN, _NO2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

In some other embodiments, each R ² and R ⁴ are independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, oxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

In other embodiments, the present invention comprises a structure of one of the following:

Or its stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrugs.

The compounds disclosed herein may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention intends to make all stereoisomer forms of compounds shown in formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers Identities, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. the

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are contemplated and included in the invention as disclosed compounds . When stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, then the stereoisomers of that structure are identified and defined. the

The compound represented by formula (I) can exist in different tautomer forms, and all these tautomers, as described in the claims, are included in the scope of the present invention. the

The compounds represented by formula (I) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but may be used for preparing and/or purifying the compound shown in formula (I) and/or for isolating the compound shown in formula (I) intermediates of enantiomers. the

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/ Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline Salt, Citrate, Ethionate, Fumarate, Glucoheptonate, Glucose Sugarate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lactobionate, Lauryl Sulfate, Malate, Malate Malonate, Mandelate, Methanesulfonate, Methylsulfate, Naphthoate, Naphthalenesulfonate, Nicotinate, Nitrate, Octadenate, Oleate, Oxalate Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate , tosylate and trifluoroacetate. the

Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like. the

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc. the

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

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. the

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine . the

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use)", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can find some other list of suitable salts. the

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed in this invention may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that this invention embrace both solvated and unsolvated forms. the

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

In another aspect, the present invention relates to intermediates for the preparation of compounds represented by formula (I). the

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

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

Compounds of the present invention and pharmaceutical compositions, formulations and administration

When therapeutically effective, a therapeutically effective amount of a compound of formula (I) and pharmaceutically acceptable salts thereof may be administered as a raw chemical or as an active ingredient in a pharmaceutical composition. Therefore, the present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. Forming agent. the

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit meaningful patient benefit. When a separate active ingredient is administered alone, the term refers to that ingredient alone. When used in combination, the term then refers to combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of formula (I) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure, there is also provided a method for preparing a pharmaceutical preparation, the method comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluting agents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which, within the scope of sound medical judgment, are suitable for contact with patient tissues without undue toxicity, irritation , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended use. the

It will also be recognized that some of the compounds of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or the ability to directly or indirectly provide the present invention when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues. the

The pharmaceutical composition disclosed in the present invention can be prepared and packaged in a bulk form, wherein a safe and effective amount of the compound represented by formula (I) can be extracted, and then administered to patients in the form of powder or syrup. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound represented by formula (I). When prepared in unit dosage form, the pharmaceutical compositions disclosed herein may generally contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of a compound disclosed herein. the

The "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the compounds disclosed in this invention when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable. Interaction. Furthermore, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity. the

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected according to their specific function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the carrying or transport of the disclosed compounds from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance. the

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

The skilled artisan possesses the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Furthermore, there are numerous resources available to the skilled artisan which describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). the

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Various carriers for formulating pharmaceutically acceptable compositions, and known techniques for their preparation are disclosed in , the contents of each of which are incorporated herein by reference. Concerned about the use of any of the compounds disclosed herein, except for any commonly used carriers that are incompatible with the compounds disclosed herein, such as by producing any undesired biological effects, or by interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition scope of the invention. the

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some of the methods commonly used in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company). the

Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition, said pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, the process comprising Mix the various ingredients. Pharmaceutical compositions comprising compounds disclosed herein can be prepared by mixing, for example, at ambient temperature and atmospheric pressure. the

The compounds disclosed herein are generally formulated in dosage forms suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppository; (5) inhalation, such as aerosol, solution and dry powder; and (6) topical administration, such as cream, ointment, lotion, solution, paste , sprays, foams and gels. the

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

The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, triturated tablets, chewable lozenges, quick-dissolving tablets, recompressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the acidic effects of the stomach but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Dragees are compressed tablets surrounded by a coating of sugar, which helps to mask an unpleasant taste or odor and to protect the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets prepared by more than one compression cycle, including multilayer tablets, and press-coated or dry-coated tablets. the

Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or granular form alone or in combination with one or more carriers or excipients as described herein, including binders, disintegrating Debonding agents, release-controlling polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. the

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

The pharmaceutical compositions provided herein can be presented in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of globules in another liquid, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifying agents and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. The aqueous alcoholic solution may include a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkylaldehyde, such as acetaldehyde diethyl acetal; and a water-soluble solvent having one or more hydroxyl groups, such as Propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. A syrup is a concentrated aqueous solution of a sugar such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration. the

Other useful liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and secondary mono- or poly-alkylene glycols including: 1,2-Dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-di Methyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin , cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates. the

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. They may also be formulated as prolonged or sustained release compositions, for example by coating or embedding the particulate material in polymers, waxes or the like. the

The oral pharmaceutical composition provided by the present invention can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458. the

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources. the

Coloring and flavoring agents may be used in all of the above dosage forms. the

The compounds disclosed in this invention can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in the controlled release of drugs, for example, polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoester , polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphilic block copolymers of hydrogels. the

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

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

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

The pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and formulations suitable for administration in liquids before injection. Solid forms made into solutions or suspensions. Such dosage forms may be prepared according to conventional methods known to those skilled in the pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra). the

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, anti- Antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, polyvalent Chelating or chelating agents, antifreezes, cryoprotectants, thickeners, pH regulators and inert gases. the

Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and Lactated Ringers Injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil. chain triglycerides, and palm seed oil. Water-miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (such as polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide and dimethylsulfoxide. the

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl and propyl parabens and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax-free sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin Butyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS).

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single-dose formulations are packaged in ampoules, vials or syringes. Such multiple dose parenteral formulations must contain the antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art. the

In one embodiment, the pharmaceutical compositions are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion. the

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

The pharmaceutical composition can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in bodily fluids but allows the active ingredients in the pharmaceutical composition to diffuse through. the

Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized Polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, dimethicone, silicone Carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and partially hydrolyzed polyvinyl acetate of coach. the

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinyl acetate copolymer, silicone rubber, dimethicone, neoprene Rubber, Chlorinated Polyethylene, Polyvinyl Chloride, Copolymers of Vinyl Chloride and Vinyl Acetate, Vinylidene Chloride, Ethylene and Propylene, Ionomer Polyethylene Terephthalate, Butyl Chlorohydrin Rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/ethyleneoxyethanol copolymer. the

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

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with an aqueous or oily base, with suitable thickening and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid liquid paraffin and vegetable oils such as arachis oil or castor oil, or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or mono Glyceryl stearate and/or nonionic emulsifiers. the

Lotions may be formulated with an aqueous or oily base, and generally also contain one or more emulsifying, stabilizing, dispersing, suspending or thickening agents. the

Powders for external use may be formulated in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilizers, suspending agents or preservatives. the

Topical formulations may be administered by application to the affected area one or more times daily; occlusive dressings covering the skin are preferably used. Adhesive depot systems allow for continuous or prolonged drug delivery. the

Uses of the compounds and compositions of the present invention

The present invention provides medicines for treating, preventing, or alleviating central nervous system dysfunction in mammals, including humans, using the compounds and pharmaceutical compositions disclosed in the present invention, and can also be used to prepare medicines for stimulating melatonin receptors. the

Specifically, the amount of the compound in the composition of the present invention can effectively and detectably selectively excite melatonin receptors, and the compound of the present invention can be used as a treatment for human central nervous system (CNS) dysfunction such as sleep disorders, should agitation, seasonal affective disorder, insomnia and fatigue due to jet lag, insomnia, depression, anxiety disorders, drugs for psychotic disorders, epilepsy, Parkinson's disease, dementia, various conditions associated with normal or pathological aging disorders, migraines, memory loss, or Alzheimer's disease. the

The compounds of the present invention can be used, but not limited to, to prevent, treat or alleviate central nervous system dysfunction diseases in mammals, including humans, by administering an effective amount of the compounds or compositions of the present invention to patients. The human central nervous system dysfunction diseases further include, but are not limited to, sleep disorders, stress response, depression, anxiety, seasonal affective disorder, insomnia and fatigue caused by jet lag, schizophrenia, convulsions , panic attacks, depression, insomnia, psychotic mental disorders, epilepsy, Parkinson's disease, dementia, various disorders associated with normal or pathological aging, migraine, memory loss or Alzheimer's disease, etc. the

In addition to being useful in human therapy, the compounds and pharmaceutical compositions of the present invention are also useful in the veterinary treatment of mammals in pets, imported breeds and farm animals. Additional examples of animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives. the

combination therapy

The compounds of the present invention may be administered as the sole active agent, or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combination administration. the

In one aspect, the present invention provides a method for treating, preventing or ameliorating a disease or condition, comprising administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents. In one embodiment, the combination comprises one or more other drugs that treat central nervous system dysfunction. the

In another embodiment, other drugs to treat central nervous system dysfunction include, but are not limited to: sedative-hypnotics, antipsychotics, antiepileptics, antidepressants, antihistamines, antiparkinsonian drugs, GABA Receptor agonists and/or GABA reuptake inhibitors, as iron channel blockers, as monoamine oxidase inhibitors, as adenosine _A1 / _A2 receptor agonists and as melatonin Drugs that are agonists of hormone receptors.

In another embodiment, the other drugs for treating central nervous system dysfunction are midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), estazolam (estazolam) ), diazepam, flurazepam, nitrazepam, clonazepam, temazepam, flunitrazepam, oxazepam ( oxazepam, zolpidem, zaleplon, zopielone, eszopiclone, indiplon, tiagabine, gaboxadol (gaboxadol), clomipramine, doxepin, paroxetine, sertraline, mirtazapine, chloral hydrate, haloperidol (haloperidol), chlorpromazine, carbamazepine, promethazine, lorazepam, hydroxyzine, aspirin, diphenhydramine ), chlorphenamine, lendormin, ramelteon, tasimelteon, agomelatine, mianserine , amitriptyline, desipramine, mirtazapine, fluoxetine, trazodone, duloxetine, fluvoxamine (fluvoxamine), vilazodone, dapoxetine, femoxetine, clomipramine, citalopram, escitalopram ( escitalopram), paroxetine, quetiapine, clozapine, imipramine, nabilone, doxepin, gabapentin (g abapentin), pramipexole, melatonin (circadin), chlordiazepoxide, perphenazine, suvorexant, Xuezang Guben, or any combination thereof. the

In another aspect, the invention provides a product comprising a compound of the invention and at least one other therapeutic agent, prepared as a combination for simultaneous, separate or sequential administration in therapy. In one embodiment, the treatment is for a disease or condition associated with the melatonin receptor. Products provided in combination include compositions comprising a compound disclosed herein and the other therapeutic agent in the same pharmaceutical composition, or in different forms, eg, a kit. the

In another aspect, the invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, carrier, adjuvant or vehicle as described above. the

In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound disclosed herein. In one embodiment, the kit includes means for individually retaining the compositions, such as containers, divided bottles or divided foil boxes. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like. the

The present invention also provides the use of a compound of the present invention in the treatment of central nervous system dysfunction, wherein the patient has been previously (eg, within 24 hours) treated with another therapeutic agent. The invention also provides the use of other therapeutic agents in the treatment of central nervous system dysfunction, wherein the patient has been previously (eg, within 24 hours) treated with a compound of the invention. the

The compounds disclosed herein may be administered as the sole active ingredient or co-administered with other drugs, eg, as adjuvants. The other drugs include, sedative and hypnotic drugs, antipsychotic drugs, antiepileptic drugs, antidepressants, antihistamines, anti-Parkinson's disease drugs, GABA receptor agonists and/or GABA reuptake inhibitors, Drugs that act as iron channel blockers, drugs that act as monoamine oxidase inhibitors, drugs that act as adenosine A ₁ /A ₂ receptor agonists, and drugs that act as melatonin receptor agonists.

The combinations described above can be conveniently prepared for use as pharmaceutical compositions, thus, pharmaceutical compositions comprising the combinations defined above together with pharmaceutically acceptable excipients or carriers represent another aspect of the present invention. the

The individual compounds of these combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical preparations. In one embodiment, the individual compound components are administered simultaneously in a combined pharmaceutical formulation. Suitable dosages of known therapeutic agents are readily understood by those skilled in the art. the

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein in combination with another therapeutically active agent. the

The above-mentioned compounds that can be used in combination with the compounds disclosed in the present invention can be prepared and administered by those skilled in the art according to the methods described in the above-mentioned documents. the

treatment method

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

In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as ocular, otic, intravaginal, inhalation and intranasal administration. In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered orally. In another embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered by inhalation. In yet another embodiment, a compound disclosed herein or comprising a compound disclosed herein may be administered intranasally. the

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

A compound disclosed herein may be administered simultaneously with, or preceded or followed by, one or more other therapeutic agents. The compound of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or may be administered together with them in the form of a pharmaceutical composition. the

For an individual of about 50-70 kg, the pharmaceutical compositions and combinations disclosed herein may contain about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or Unit dosage forms of about 1-50 mg active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian with ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit a disorder or the progression of a disease. the

The dosage properties cited above have been demonstrated in in vitro and in vivo tests using advantageously mammals (eg mice, rats, dogs, monkeys) or their isolated organs, tissues and specimens. The compounds disclosed herein are used in vitro as solutions, eg, aqueous solutions, and in vivo, eg, as suspensions or aqueous solutions, enterally, parenterally, especially intravenously. the

In one embodiment, the therapeutically effective dose of a compound disclosed herein is from about 0.1 mg to about 2,000 mg per day. Pharmaceutical compositions thereof should provide a dosage of about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the principal active ingredient or per dosage unit form Combinations of the main ingredients. In a particular embodiment, pharmaceutical dosage unit forms are prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the principal active ingredient. the

In addition, the compounds disclosed herein may be administered as prodrugs. In the present invention, the "prodrug" of the compound disclosed in the present invention is a functional derivative that can finally release the compound disclosed in the present invention in vivo when administered to a patient. When administering the compounds disclosed in the present invention in the form of prodrugs, those skilled in the art can implement one or more of the following methods: (a) change the in vivo onset time of the compound; (b) change the in vivo action duration of the compound; (c) ) alter the in vivo delivery or distribution of the compound; (d) alter the in vivo solubility of the compound; and (e) overcome side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of the compound that are chemically or enzymatically cleaved in vivo. These variations, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art. the

General Synthetic Methods for Compounds of the Invention

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I). The following reaction schemes and examples serve to further illustrate the present invention. the

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

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Linkchem, Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory. the

Anhydrous tetrahydrofuran was obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate before use. the

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried. the

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The nuclear magnetic resonance spectrum uses CDC1 ₃ or DMSO-d ₆ as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

The measurement conditions of low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x 30mm, 3.5 microns, 6min, flow rate is 0.6mL/min. Mobile phase: 5 % - 95% (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.

Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC) for pure compounds, and use UV detection at 210nm/254nm. the

The following abbreviations are used throughout this disclosure:

HOAc Acetic acid

MeCN, CH ₃ CN Acetonitrile

Cl ₃ C ₂ OCl Trichloroacetyl Chloride

CHCl ₃ Chloroform

CDCl ₃ deuterated chloroform

DMSO Dimethyl Sulfoxide

DMSO-d ₆ deuterated dimethyl sulfoxide

DMF N,N-Dimethylformamide

POCl ₃ phosphorus oxychloride

C ₄ H ₁₀ F ₃ NS Diethylaminosulfur trifluoride

ClSO ₂ OH Chlorosulfonic acid

EtOAc/EA Ethyl acetate

Et- CH ₃ CH ₂ -/ ethyl

HCl hydrochloric acid

MgSO ₄ magnesium sulfate

MgCl ₂ magnesium chloride

MeOH, CH ₃ OH Methanol

HCHO Formaldehyde

CH ₂ Cl ₂ , DCM dichloromethane

mL,m Milliliters

PE Petroleum ether (60-90℃)

Na ₂ CO ₃ sodium carbonate

NaHCO ₃ sodium bicarbonate

KOH Potassium Hydroxide

RT room temperature

Rt retention time

NaBH ₃ CN Sodium cyanoborohydride

NaCl Sodium Chloride

NaH Sodium hydride

Sodium Na ₂ SO ₄ Sulfate

THF Tetrahydrofuran

DDQ Dichlorodicyanobenzoquinone

The following synthetic schemes describe the steps involved in preparing the compounds disclosed in this invention. the

Synthetic method 1

The compound shown in formula ( 6 ) can be prepared by the following process:

The compound represented by formula ( 1 ) is reacted with cyanoacetic acid to obtain the compound represented by formula ( 2 ). The compound shown in formula ( 2 ) is dehydroaromatized under the action of oxidizing agent (DDQ) to obtain the compound shown in formula ( 3 ), and the compound shown in formula ( 3 ) can be obtained under the action of base in formula ( 4 ) The compound shown in the formula ( 4 ) is reduced under the effect of a reducing agent (such as borane) to obtain the compound shown in the formula ( 5 ), and the compound shown in the formula ( 5 ) reacts with acetyl chloride to obtain the formula ( 6 ) the product. The reaction process is as follows:

Example

Embodiment 1N-((1-(naphthalene-1-yl) cyclopropyl) methyl) acetamide

Step 1) Synthesis of 1-(naphthalene-1-yl)cyclopropanecarbonitrile

At -30°C, 2-(naphthalene-1-yl)acetonitrile (500mg, 2.99mmol) and sodium hydride (60%, 598mg, 14.95mmol) were added to 10mL of anhydrous DMF, and after stirring for 1h, slowly drop Add 1,2-dibromoethane (0.52mL, 5.98mmol, dissolved in 10mL DMF), slowly raise the temperature to 25°C, and react for 1 hour. The reaction was stopped, quenched by adding 30 mL of saturated brine, extracted with ethyl acetate (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=50/1) to obtain the title compound as a white solid (325 mg, 56.2%). the

MS(ESI,pos.ion)m/z:194.2[M+1] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.41(d, J=8.4Hz, 1H), 7.91(d, J=8.4Hz, 1H), 7.86(d, J=8.0Hz, 1H), 7.69-7.65 (m,1H),7.60-7.54(m,1H),7.50(dd,J=7.2,1.2Hz,1H),7.46-7.39(m,1H),1.86(q,J=4.8Hz,2H), 1.45 (q, J=4.8Hz, 2H).

Step 2) Synthesis of (1-(naphthalene-1-yl)cyclopropyl)methanamine

1-(Naphthalen-1-yl)cyclopropanecarbonitrile (325mg, 1.68mol) was added to tetrahydrofuran (10.0mL) at 0°C, then borane-tetrahydrofuran (1.0M, 9.3mL, 9.3mmol) was added slowly . After reacting for ten minutes, the temperature was raised to 80° C., and the reaction was stirred for 24 hours. The reaction was quenched with methanol (5 mL), the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a white solid (165 mg, 49.7%). the

MS(ESI,pos.ion)m/z:198.2[M+1] ⁺ ;

1H NMR (600MHz, CDCl3) δ8.35(d, J＝7.8Hz, 1H), 7.87(d, J＝7.8Hz, 1H), 7.75(t, J＝7.8Hz, 1H), 7.54(t, J =7.8Hz,1H),7.49(t,J=7.8Hz,1H),7.46(d,J=6.6Hz,1H),7.40(t,J=7.8Hz,1H),2.88(brs,2H), 0.98-0.97(m,4H). the

Step 3) Synthesis of N-((1-(naphthalene-1-yl)cyclopropyl)methyl)acetamide

Add (1-(naphthalene-1-yl)cyclopropyl)methanamine (165mg, 836μmol) and triethylamine (230μL, 1.67mmol) into dichloromethane (15mL), slowly add dropwise in a low-temperature bath at 0°C Acetyl chloride (88 μL, 1.25 mmol), after the dropwise addition, was transferred to 25° C. for 3 hours to stop the reaction. Add 30 mL of dichloromethane, wash with saturated sodium chloride solution (60 mL), separate the organic phase and dry over anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (180 mg, 89.9%). the

MS(ESI,pos.ion)m/z:240.2[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ8.37(d, J=7.8Hz, 1H), 7.87(d, J=8.4Hz, 1H), 7.77(d, J=7.8Hz, 1H), 7.55(t ,J=7.2Hz,1H),7.50(t,J=7.2Hz,1H),7.46(d,J=6.6Hz,1H),7.41(t,J=7.8Hz,1H),3.51(brs,2H ),1.85(s,3H),1.13(s,2H),0.96(s,2H);

¹³ C NMR (150 MHz, CDCl ₃ ) δ 170.3, 138.6, 134.1, 132.5, 128.9, 128.2, 128.0, 126.2, 125.9, 125.4, 124.7, 48.1, 24.7, 23.4, 12.2 (br).

Embodiment 2N-((1-(7-methoxynaphthalene-1-yl)cyclopropyl)methyl)acetamide

Step 1) Synthesis of 1-(7-methoxynaphthalene-1-yl)cyclopropanecarbonitrile

The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 2-(7-methoxynaphthalene-1-yl)acetonitrile (1.0g, 5.07mmol), sodium hydride (60%, 1.01g, 25.35 mmol) and 1,2-dibromoethane (0.88mL, 10.14mmol, dissolved in 10mL DMF) were prepared by reacting in anhydrous DMF (10mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v /v)=50/1), concentrated and dried to obtain the title compound as a white solid (615 mg, 54.4%). the

MS(ESI,pos.ion)m/z:224.1[M+1] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ7.79(t, J=9.2Hz, 2H), 7.64(d, J=2.0Hz, 1H), 7.46(dd, J=6.8, 0.8Hz, 1H), 7.28 (dd, J=7.2,8.0Hz,1H),7.24(dd,J=8.8,2.4Hz,1H),4.02(s,3H),1.84(q,J=4.8Hz,2H),1.43(q, J=4.4Hz, 2H).

Step 2) Synthesis of (1-(7-methoxynaphthalene-1-yl)cyclopropyl)methanamine

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, 1-(7-methoxynaphthalen-1-yl)cyclopropanecarbonitrile (300mg, 1.34mol) and borane-tetrahydrofuran (1.0M , 7.4mL, 7.4mmol) prepared by reaction, the crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v/v)=20/1), concentrated and dried to obtain the title compound as a colorless oily liquid solid (150mg, 49.2% ). MS(ESI,pos.ion)m/z:228.1[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.76(d, J=9.0Hz, 1H), 7.67(d, J=7.8Hz, 1H), 7.62(d, J=2.4Hz, 1H), 7.43(d ,J=7.2Hz,1H),7.26(t,J=8.4Hz,1H),7.17(dd,J=9.0,2.4Hz,1H),3.95(s,3H),2.87(brs,2H),0.95 (s,4H).

Step 3) Synthesis of N-((1-(7-methoxynaphthalene-1-yl)cyclopropyl)methyl)acetamide

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, (1-(7-methoxynaphthalen-1-yl)cyclopropyl)methanamine (150 mg, 660 μmol), triethylamine (180 μL , 1.32mmol) and acetyl chloride (70μL, 990μmol) were prepared by reacting in dichloromethane (15mL), the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated to dryness The title compound was obtained as a white solid (160 mg, 90.0%). the

MS(ESI,pos.ion)m/z:270.1[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.77(d, J=8.4Hz, 1H), 7.70(d, J=8.4Hz, 1H), 7.68(d, J=2.4Hz, 1H), 7.43(d ,J=6.6Hz,1H),7.28(t,J=7.8Hz,1H),7.17(dd,J=9.0,2.4Hz,1H),3.96(s,3H),3.53(brs,2H),1.87 (s,3H),1.26(s,2H),0.95(s,2H);

¹³ C NMR (150MHz, CDCl ₃ ) δ 170.1, 157.7, 137.1, 133.7, 130.4, 129.5, 128.5, 127.6, 123.1, 118.3, 103.2, 55.4, 47.4, 24.5, 23.3, 12.0.

Embodiment 3N-((1-(7-fluoronaphthalene-1-yl)cyclopropyl)methyl)acetamide

Step 1) Synthesis of 1-(7-fluoronaphthalen-1-yl)cyclopropanecarbonitrile

The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 2-(7-fluoronaphthalen-1-yl)acetonitrile (700mg, 3.78mmol), sodium hydride (60%, 756mg, 18.90mmol) and 1,2-Dibromoethane (0.65mL, 7.56mmol, dissolved in 10mL DMF) was prepared by reaction in anhydrous DMF (10mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =50/1), concentrated and dried to give the title compound as a white solid (520 mg, 65.1%). the

MS(ESI,pos.ion)m/z:212.1[M+1] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(dd, J=10.4,1.2Hz,1H),7.90(dd,J=8.8,5.6Hz,1H),7.85(d,J=8.4Hz,1H) ,7.53(d,J=7.2Hz,1H),7.40(t,J=7.6Hz,1H),7.34(td,J=8.8,2.0Hz,1H),1.87(q,J=4.8Hz,2H) , 1.43 (q, J=4.8Hz, 2H).

Step 2) Synthesis of (1-(7-fluoronaphthalen-1-yl)cyclopropyl)methanamine

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, 1-(7-fluoronaphthalen-1-yl)cyclopropanecarbonitrile (537mg, 2.54mol) and borane-tetrahydrofuran (1.0M, 14mL , 14mmol), the crude product was subjected to silica gel column chromatography (dichloromethane/methanol (v/v)=20/1), concentrated and dried to obtain the title compound as a colorless oily liquid (416mg, 76.0%). MS (ESI, pos.ion) m/z: 216.2[M+1] ⁺ ; ¹ H NMR (600MHz, CDCl ₃ ) δ7.96 (dd, J=11.4, 2.4Hz, 1H), 7.87 (dd, J =9.0,6.0Hz,1H),7.76(d,J=8.4Hz,1H),7.50(d,J=7.2Hz,1H),7.38(t,J=7.8Hz,1H),7.28(td,J =9.0, 2.4Hz, 1H), 2.88(brs, 2H), 0.99-0.94(m, 4H).

Step 3) Synthesis of N-((1-(7-fluoronaphthalen-1-yl)cyclopropyl)methyl)acetamide

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, (1-(7-fluoronaphthalen-1-yl)cyclopropyl)methanamine (200mg, 929μmol), triethylamine (260μL, 1.86 mmol) and acetyl chloride (99 μL, 1.39 mmol) were prepared by reacting in dichloromethane (15 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain The title compound was a white solid (140 mg, 58.6%). the

MS(ESI,pos.ion)m/z:258.2[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.96(dd, J=11.4,1.8Hz,1H),7.85(dd,J=9.0,6.0Hz,1H),7.76(d,J=7.8Hz,1H) ,7.48(d,J=7.2Hz,1H),7.37(t,J=7.8Hz,1H),7.28(dd,J=8.4,24Hz,1H),3.49(brs,2H),1.86(s,3H ),1.13(s,2H),0.93(s,2H);

¹³ C NMR (150MHz, CDCl ₃ ) δ170.2, 160.7(d, J=244.5Hz), 138.1(d, J=5.6Hz), 133.5(d, J=8.7Hz), 131.3(d, J=9.0Hz) , 131.0, 129.1, 127.8, 124.6 (d, J=2.4Hz), 116.2 (d, J=25.2Hz), 108.2 (d, J=21.2Hz), 47.6, 24.7, 23.2, 12.1.

Embodiment 4N-((1-(naphthalene-1-yl) cyclopropyl) methyl) propanamide

Step 1) Synthesis of N-((1-(naphthalene-1-yl) cyclopropyl) methyl) propionamide

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, (1-(naphthalen-1-yl)cyclopropyl)methanamine (165 mg, 836 μmol), triethylamine (230 μL, 1.67 mmol) and Propionyl chloride (88 μL, 1.25 mmol) was prepared by reaction in dichloromethane (15 mL). The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain the title compound as White solid (148mg, 69.8%). MS(ESI,pos.ion)m/z:254.2[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ8.37(d, J=7.8Hz, 1H), 7.87(d, J=8.4Hz, 1H), 7.77(d, J=7.8Hz, 1H), 7.55(t ,J=7.2Hz,1H),7.50(t,J=7.2Hz,1H),7.46(d,J=6.6Hz,1H),7.41(t,J=7.8Hz,1H),3.51(brs,2H ), 2.28(q, J=5.4Hz, 2H), 1.13(s, 2H), 1.02(t, J=5.4Hz, 3H), 0.96(s, 2H).

Embodiment 5N-((1-(naphthalene-1-yl)cyclopropyl)methyl)butanamide

Step 1) Synthesis of N-((1-(naphthalene-1-yl)cyclopropyl)methyl)butanamide

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, (1-(naphthalene-1-yl)cyclopropyl)methanamine (165 mg, 836 μmol), triethylamine (230 μL, 1.67 mmol) and n- Butyryl chloride (88 μL, 1.25 mmol) was prepared by reaction in dichloromethane (15 mL). The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain the title compound as White solid (146 mg, 65.2%). MS(ESI,pos.ion)m/z:268.4[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ8.39(d, J=7.8Hz, 1H), 7.87(d, J=8.4Hz, 1H), 7.76(d, J=7.8Hz, 1H), 7.53(t ,J=7.2Hz,1H),7.50(t,J=7.2Hz,1H),7.47(d,J=6.6Hz,1H),7.41(t,J=7.8Hz,1H),3.53(brs,2H ), 2.37(t, J=5.4Hz, 2H), 1.17(m, 2H), 1.13(s, 2H), 0.96(s, 2H), 0.89(t, J=5.4Hz, 3H).

Embodiment 6N-((1-(7-methoxynaphthalene-1-yl) cyclopropyl) methyl) propanamide

Step 1) Synthesis of N-((1-(7-methoxynaphthalene-1-yl) cyclopropyl) methyl) propionamide

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, (1-(7-methoxynaphthalen-1-yl)cyclopropyl)methanamine (150 mg, 660 μmol), triethylamine (180 μL , 1.32mmol) and propionyl chloride (70μL, 990μmol) were prepared by reacting in dichloromethane (15mL), the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated to dryness The title compound was obtained as a white solid (149 mg, 80.0%). the

MS(ESI,pos.ion)m/z:285.3[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.79(d, J=8.4Hz, 1H), 7.68(d, J=8.4Hz, 1H), 7.64(d, J=2.4Hz, 1H), 7.43(d ,J=6.6Hz,1H),7.30(t,J=7.8Hz,1H),7.17(dd,J=9.0,2.4Hz,1H),3.98(s,3H),3.53(brs,2H),2.27 (q, J=5.4Hz, 2H), 1.15(s, 2H), 1.02(t, J=5.4Hz, 3H), 0.98(s, 2H).

Embodiment 7N-((1-(7-methoxynaphthalene-1-yl) cyclopropyl) methyl) butyramide

Step 1) Synthesis of N-((1-(7-methoxynaphthalene-1-yl) cyclopropyl) methyl) butanamide

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, (1-(7-methoxynaphthalen-1-yl)cyclopropyl)methanamine (150 mg, 660 μmol), triethylamine (180 μL , 1.32mmol) and n-butyryl chloride (70μL, 990μmol) were prepared by reacting in dichloromethane (15mL), the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated to dryness The title compound was obtained as a white solid (167 mg, 85.2%). the

MS(ESI,pos.ion)m/z:298.3[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.77(d, J=8.4Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.62(d, J=2.4Hz, 1H), 7.43(d ,J=6.6Hz,1H),7.29(t,J=7.8Hz,1H),7.17(dd,J=9.0,2.4Hz,1H),3.98(s,3H),3.53(brs,2H),2.39 (t, J = 5.4Hz, 2H), 1.15 (m, 2H), 1.09 (s, 2H), 0.96 (s, 2H), 0.89 (t, J = 5.4Hz, 3H).

Embodiment 8N-((1-(7-fluoronaphthalene-1-yl)cyclopropyl)methyl)propionamide

Step 1) Synthesis of N-((1-(7-fluoronaphthalen-1-yl) cyclopropyl) methyl) propionamide

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, (1-(7-fluoronaphthalen-1-yl)cyclopropyl)methanamine (200mg, 929μmol), triethylamine (260μL, 1.86 mmol) and propionyl chloride (99μL, 1.39mmol) were prepared by reacting in dichloromethane (15mL), the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain The title compound was a white solid (186 mg, 73.8%). the

MS(ESI,pos.ion)m/z:272.1[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.95(dd, J=11.4,1.8Hz,1H),7.81(dd,J=9.0,6.0Hz,1H),7.77(d,J=7.8Hz,1H) ,7.48(d,J=7.2Hz,1H),7.37(t,J=7.8Hz,1H),7.30(dd,J=8.4,24Hz,1H),3.49(brs,2H),2.25(q,J =5.4Hz, 2H), 1.14(s, 2H), 1.02(t, J=5.4Hz, 3H), 0.98(s, 2H).

Embodiment 9N-((1-(7-fluoronaphthalene-1-yl) cyclopropyl) methyl) butyramide

Step 1) Synthesis of N-((1-(7-fluoronaphthalen-1-yl) cyclopropyl) methyl) butanamide

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, (1-(7-fluoronaphthalen-1-yl)cyclopropyl)methanamine (200mg, 929μmol), triethylamine (260μL, 1.86 mmol) and n-butyryl chloride (99 μL, 1.39 mmol) were prepared by reacting in dichloromethane (15 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), concentrated and dried to obtain The title compound was a white solid (155 mg, 57.8%). the

MS(ESI,pos.ion)m/z:286.4[M+1] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ7.96(dd, J=11.4,1.8Hz,1H),7.81(dd,J=9.0,6.0Hz,1H),7.73(d,J=7.8Hz,1H) ,7.45(d,J=7.2Hz,1H),7.37(t,J=7.8Hz,1H),7.31(dd,J=8.4,24Hz,1H),3.53(brs,2H),2.36(t,J =5.4Hz, 2H), 1.15(m, 2H), 1.09(s, 2H), 0.96(s, 2H), 0.90(t, J=5.4Hz, 3H).

Compound 4-8, 10-14 is obtained according to the synthetic method of embodiment 1-9:

biological test

The LC/MS/MS system used for analysis includes Agilent 1200 series vacuum degassing oven, binary syringe pump, orifice autosampler, column oven, and Agilent G6430 triple quadrupole mass spectrometer with electrospray ionization (ESI) source . Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:

Table A

multiple reaction detection scan 490.2 → 383.1 Fragmentation voltage 230V capillary voltage 55V Dryer temperature 350°C atomizer 40psi Dryer flow rate 10L/min

The analysis used an Agilent XDB-C18, 2.1x 30mm, 3.5 μM column, injecting 5 μL of the sample. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL/min. The mobile phase gradient is shown in Table B:

Form B

time Gradient of mobile phase B 0.5min 5% 1.0min 95% 2.2min 95%

[0305] 2.3min 5% 5.0min stop

In addition, Agilent 6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source. Optimum analysis is achieved using standards with appropriate cation model processing and MRM conversion for each analyte. A Capcell MP-C18 column, 100x4.6 mm I.D., 5 μM (Phenomenex, Torrance, California, USA) was used during the analysis. Mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); flow rate is 0.6mL/min; column temperature is kept at room temperature; Inject 20 μL of sample. the

Example A Melatonin MT ₁ Receptor binding affinity assay

experiment method

The affinity of the compounds to the humanized MT1 receptor transfected in CHO cells was evaluated by radioligand binding method. At 22°C, to the mixed system formed by cell membrane homogenate protein (64 μg), 0.01 nM [ ¹²⁵ I]iodomelatonin and buffer (50 mM Tris-HCl (pH 7.4), 5 mM MgCl ₂ and 1% BSA), add Or without adding the test compound, incubate for 60 minutes. The standard reference compound is melatonin, and 1 μM melatonin is added to the mixed system of the above conditions to measure the non-specific binding value.

After incubation, the sample was passed through a glass fiber filter (GF/B, Packard) presoaked with 0.3% PEI under vacuum with a 96-sample cell harvester (Unifilter, Packard), and washed several times with ice-cold 50mM Tris-HCl. Second-rate. Filters were dried and residual radioactivity was counted with scintillation fluid (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). The experimental results are expressed as the percentage of inhibition of specific binding of radioligand relative to the control group. the

The standard reference compound is melatonin, and a competition curve is obtained through the experimental data of a series of concentrations of melatonin. the

data analysis

The affinity of the compounds to the humanized MT ₁ receptor transfected in CHO cells was evaluated by radioligand binding method. The test compounds were tested at least three times, and the data were determined by the Hill equation curve fitting method and the non-linear regression analysis of the competition curve to determine the IC ₅₀ value and the Hill coefficient, and then calculated by the ChengPrusoff equation to calculate the Ki value.

Experimental results show that the compound of the present invention shows strong binding affinity to _MT1 receptor.

Table 1 The results of the binding affinity experiments of the compounds provided in the examples of the present invention to the humanized _MT1 receptor transfected by CHO cells

Example number Ki(nM) Example number Ki(nM) Example 1 C Example 2 A Example 3 A Example 4 C Example 5 C Example 6 A Example 7 A Example 8 B Example 9 B the the

A:0.1～1nM, B:1～10nM, C:>10nM

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples" or "some examples" mean specific features described in connection with the embodiment or example, A structure, material or feature is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other. the

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations. the

Claims (10)

1. A compound, which is a structure shown in formula (I) or a stereoisomer of the structure shown in formula (I), tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrug, in: Ring A is cyclopropyl, or a ring consisting of 5-6 carbon atoms or a heterocyclic ring consisting of 3-12 atoms; R ¹ is H, OH, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ³ is H, F, Cl, Br, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)-(C ₁ -C ₆ alkyl ), -C(=O)NR ^a R ^b , -O-(carbocycle consisting of 3-8 atoms), -(C ₁ -C ₆ alkyl)-(carbocycle consisting of 3-8 atoms) , -(C ₁ -C ₆ alkyl)-NR ^a R ^b , heteroaryl or C ₆ -C ₁₀ aryl consisting of 5-12 atoms; Each R ² and R ⁴ are independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , -NR ^a R ^b , -C(=O)R ^c , C ₁ -C ₆ alkane radical, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, -C(=O)-(C ₁ -C ₆ alkyl ), -C(=O)NR ^a R ^b , -(C ₁ -C ₆ alkyl)-C(=O)OR ^c , -O-(carbocyclic ring composed of 3-8 atoms), -(C ₁ -C ₆ alkyl)-(carbocyclic ring consisting of 3-8 atoms), -(C ₁ -C ₆ alkyl)-NR ^a R ^b , heterocyclic group consisting of 3-12 atoms, hydroxy-substituted C ₁ -C ₆ alkyl, -NR ^a -(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -(C ₁ -C ₆ alkyl) -(C ₆ -C ₁₀ aryl radical), -(C ₁ -C ₆ alkyl)-(heteroaryl consisting of 5-12 atoms) or heteroaryl consisting of 5-12 atoms; Each of R ^a and R ^b is independently H, C ₁ -C ₆ alkyl, -(C ₁ -C ₆ alkyl)-(C ₆ -C ₁₀ aryl), -COR ^c or -SO ₂ -( C ₁ -C ₆ alkyl); and Each R ^c is independently H, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₃ -C ₈ cycloalkyl. 2. The compound according to claim ¹ , wherein R is H, OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 3. The compound according to claim 1, wherein R ³ is H, F, Cl, Br, OH, CN, NO ₂ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy. 4. The compound according to claim 1, wherein each R ² and R ⁴ are independently H, D, F, Cl, Br, I, CN, OH, NO ₂ , methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy. 5. The compound according to claim 1, which has the structure of one of the following: Or its stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrugs. 6. A pharmaceutical composition, which comprises the compound according to any one of claims 1-5, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or their combination. 7. The pharmaceutical composition according to claim 6, further comprising other medicines for treating central nervous system dysfunction, said other medicines for treating central nervous system dysfunction are sedative hypnotics, antipsychotics, Antiepileptic drugs, antidepressants, antihistamines, antiparkinsonian drugs, GABA receptor agonists and/or GABA reuptake inhibitors, drugs that act as iron channel blockers, drugs that act as monoamine oxidase inhibitors Drugs that act as adenosine A ₁ /A ₂ receptor agonists and drugs that act as melatonin receptor agonists or any combination thereof. 8. pharmaceutical composition according to claim 7, the medicine of other described treatment central nervous system dysfunction is midazolam (midazolam), triazolam (triazolam), alprazolam (alprazolam), Estazolam, diazepam, flurazepam, nitrazepam, clonazepam, temazepam, flunitrazepam , oxazepam, zolpidem, zaleplon, zopielone, eszopiclone, indiplon tiagabine ( tiagabine, gaboxadol, clomipramine, doxepin, paroxetine, sertraline, mirtazapine, chloral hydrate ), haloperidol, chlorpromazine, carbamazepine, promethazine, lorazepam, hydroxyzine, aspirin, Diphenhydramine, chlorphenamine, lendormin, ramelteon, tasimelteon, agomelatine, rice Anserine, amitriptyline, desipramine, mirtazapine, fluoxetine, trazodone, duloxetine ), fluvoxamine, vilazodone, dapoxetine, femoxetine, clomipramine, citalopram, Escitalopram, paroxetine, quetiapine, clozapine, imipramine, nabilone, doxepin ), gabapentin, pramipexole, melatonin (circadin), chlordiazepoxide, perphenazine, suvorexant, Xuezang Guben, or any combination thereof. 9. Use of the compound of any one of claims 1-5 or the pharmaceutical composition of any one of claims 6-8 in the preparation of medicines, which are used to prevent, treat or relieve mammals, including human Central Nervous System Disorders: Sleep Disorders, Stress Response, Depression, Anxiety, Seasonal Affective Disorder, Jet Lag Insomnia and Fatigue, Schizophrenia, Convulsions, Panic Attacks, Depression, Insomnia, Psychotic Psychosis disorders, epilepsy, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss or Alzheimer's disease. 10. Use of the compound of any one of claims 1-5 or the pharmaceutical composition of any one of claims 6-8 in the preparation of medicines for selective stimulation of melatonin in biological specimens hormone receptors.