CN107021964A

CN107021964A - 7-naphthyridine derivatives and application thereof

Info

Publication number: CN107021964A
Application number: CN201710037259.7A
Authority: CN
Inventors: 金传飞; 高华伟; 张英俊
Original assignee: Dongguan Het Pharm Research And Development Co Ltd; Guangdong HEC Pharmaceutical
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2016-02-01
Filing date: 2017-01-18
Publication date: 2017-08-08

Abstract

The present invention relates to 7-naphthyridine derivatives and application thereof；Wherein, compound of the present invention and the pharmaceutical composition comprising the compound can be used for antagonism orexin receptor.The invention further relates to prepare the method for this kind of compound and pharmaceutical composition, and their purposes in treatment or prevention and orexin receptor relevant disease.

Description

7-naphthyridine derivatives and application thereof

Invention field

The invention belongs to technical field of pharmaceuticals, and in particular to a class 7-naphthyridine derivatives and its pharmaceutical composition, and described The purposes of compound or pharmaceutical composition.More specifically, compound or pharmaceutical composition of the present invention can be used as appetite Hormone receptor antagonists are used to treating, prevent or mitigating the disease related to orexin receptor.

Background of invention

Orexin (orexin) is also referred to as inferior colliculus krinin, appetite peptide, and it includes orexin-A and orexin B (or inferior colliculus Krinin -1 and inferior colliculus krinin -2), it is a kind of neuropeptide secreted by hypothalamus, its main physiological action has：1. regulation Ingest, orexin can be obviously promoted feed, and in dose-dependant reaction, and have activated the neuron of regulation feed；2. participate in The regulation of energetic supersession, orexin can dramatically increase metabolic rate；3. participating in the regulation of Sleep-Wake, orexin can suppress quick Eye Movement Sleep, extends the awakening time, blocks the effect of orexin and can promote sleep；4. participate in endocrine metabolic diseases, orexin Influence endocrine on pituitrin is apparent；5. it is related to remuneration sense, learning and memory；6. promote gastric acid secretion；7. promote Drinking-water increases；8. raise blood pressure；9. played an important role in reward system and drug habit mechanism, wait (Piper et al., The novel brain neuropeptide,orexin-A,modulates the sleep-wake cycle of rats.Eur.J.Neuroscience,2000,12(2),726-730；and Sakurai,T.,et al.,The neural circuit of orexin(hypocretin):Maintaining sleep and wakefulness.Nature Review Neuroscience,2007,8:171181)。

Orexin produces physiological effect by acting on orexin receptor (orexin receptor, OXR).Orexin Acceptor is a kind of G- G-protein linked receptors, has two types, is referred to as OX₁Acceptor and OX₂Acceptor, wherein OX₁Acceptor is to appetite Plain A has selectively, and OX₂Acceptor be for orexin-A and orexin B non-selective receptor (Sakurai T.et al., Orexins and orexin receptors:a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573- 585)。OX₁Acceptor and OX₂Acceptor is almost existed only in brain tissue, and is optionally expressed in brain, wherein OX₁Acceptor with High Cell Density And High Expression is in locus coeruleus (locus coeruleus), and it is the nuclei of origin of noradrenergic neuron, and OX₂Acceptor With High Cell Density And High Expression in nodular nipple nucleus, it is the nuclei of origin of histaminergic neuron.OX₁Acceptor and OX₂The expression of both acceptors can See in nuclei of median raphe, it is the nuclei of origin of serotoninergic nerve member, and is found in ventral tegmental area, and it is dopaminergic neuron Nuclei of origin.In addition, OX₂Expression of receptor is also seen in the brain stem cholinergic neuron of responsible regulation rapid-eye-movement sleep and to it Nuclear activity has influence (Marcus, J.N.et al., Differential expression of orexin receptors 1and 2in the rat brain.J.Comp.Neurol.,2001,435(1):6-25；and Trivedi,P.et al., Distribution of orexin receptor mRNAin the rat brain.FEBS Lett.,1998,438(1- 2):71-75)。

As can be seen here, orexin receptor has great importance on pathology, is related to related to a variety of diseases, for example, sleep Dormancy obstacle, depression, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious neuropathy, the heart Border obstacle, panic attack obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, spirit point Split disease, manic depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, op parkinson's Disease, dyskinesia, feeding desorder, headache, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, glycosuria Disease, metabolic disease, immune correlated disease, endocrine relevant disease and hypertension etc..

The invention provides the compound that a class has orexin receptor antagonistic activity.Such compound has good medicine Activity, physicochemical property, medicine are imitated for property and toxicological characteristics, therefore, possesses preferable potential applicability in clinical practice.

The content of the invention

Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by overall.Work as the disclosure of the specification With citation it is variant when, be defined by the disclosure of the specification.

The invention provides the compound that a class has orexin receptor antagonistic activity, and in particular to 7-naphthyridine derivatives, and Its pharmaceutical composition.The compounds of this invention shows good antagonistic activity to orexin receptor, with preferable drug effect, medicine generation Property and/or toxicological characteristics, the compound and pharmaceutical composition can be used for preventing or treat related to orexin receptor Disease.

On the one hand, the present invention relates to a kind of compound, its compound shown in the compound or formula (I) shown in formula (I) Stereoisomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein, L, R¹、R²、R³、R⁴, m, n, t and k there is implication described in the invention.

In some embodiments, L is-C (R⁹R¹⁰- C)-, (=O)-,-C (=S)-or-S (=O)_q-；Wherein, R⁹、R¹⁰ There is implication described in the invention with q.

In some embodiments, each R¹And R⁴It independently is H, D, F, Cl, Br, CN, C_1-6Alkyl, C_1-6Haloalkyl ,- OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C₃-12 Carbocylic radical, 3-12 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls；

Wherein, R¹And R⁴Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally By one or more R¹¹Replaced；

Wherein, R⁵、R⁶、R⁷、R⁸、R¹¹There is implication described in the invention with q.

In some embodiments, each R¹And R⁴It independently is H, D, F, Cl, Br, CN, methyl, ethyl, propyl group, butyl, three Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、- SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, Azelidinyl, aziridinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, benzene Base, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals；

Wherein, R¹And R⁴Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoros Ethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base, Tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrrole Oxazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R¹¹Replaced；

In some embodiments, each R²It independently is H, D, F, Cl, Br, NO₂、CN、C_1-4Alkyl, C_1-4Haloalkyl ,- OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C_3-8Carbon Ring group, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls；

Wherein, R²Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally by one Individual or multiple R¹¹Replaced；

In some embodiments, each R²It independently is H, D, F, Cl, Br, NO₂, CN, methyl, ethyl, propyl group, butyl, three Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、- SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azacyclo- Butyl, aziridinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrroles Base, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals；

Wherein, R²Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second Base, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base, thiophane Base, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazoles Base, triazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R¹¹Replaced；

In some embodiments, each R³It independently is H, D, F, Cl, Br, NO₂、CN、C_1-4Alkyl, C_1-4Haloalkyl ,- OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C_3-8Carbon Ring group, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls；

Wherein, R³Described in alkyl, haloalkyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl individually optionally by one Individual or multiple R¹¹Replaced；

In some embodiments, each R³It independently is H, D, F, Cl, Br, NO₂, CN, methyl, ethyl, propyl group, butyl, three Methyl fluoride, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、- SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, Azelidinyl, aziridinyl, tetrahydrofuran base, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furan Mutter base, thienyl, thiazolyl, pyrazolyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals or pyrimidine radicals；

Wherein, R³Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, aziridinyl, tetrahydrofuran base, pyrrole Cough up alkyl, piperidyl, morpholinyl, piperazinyl, phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, pyrazolyl, imidazole radicals, three Oxazolyl, tetrazole radical, pyridine radicals and pyrimidine radicals are individually optionally by one or more R¹¹Replaced；

In some embodiments, each R⁵It independently is H, C_1-4Alkyl, C_1-4Haloalkyl ,-(CR⁹R¹⁰)_pC (=O) NR⁶R⁷、-(CR⁹R¹⁰)_pC (=O) R⁸、-(CR⁹R¹⁰)_pC (=O) OR^5a、-(CR⁹R¹⁰)_pS (=O)_qR⁸、-(CR⁹R¹⁰)_pS (=O)_qOR^5a、-(CR⁹R¹⁰)_pS (=O)_qNR⁶R⁷、C_3-8Carbocylic radical, (C_3-6Carbocylic radical)-(C_1-4Alkylidene)-, 3-8 it is former molecular Heterocyclic radical, (3-6 former molecular heterocyclic radicals)-(C_1-4Alkylidene)-, C_6-10Aryl, (C_6-10Aryl)-(C_1-4Alkylidene)-, 5-6 former molecular heteroaryls or (5-6 former molecular heteroaryls)-(C_1-4Alkylidene)-；

Wherein, R⁵Described in alkyl, haloalkyl, carbocylic radical, carbocylic radical alkylidene, heterocyclic radical, heterocycloalkylene, Aryl, aryl alkylene, heteroaryl and heteroarylalkylenyl are individually optionally by one or more R¹¹Replaced；

Wherein, R⁶、R⁷、R⁸、R⁹、R¹⁰、R^5a, p and q there is implication described in the invention.

In some embodiments, each R⁵Independently be H, methyl, ethyl, propyl group, butyl, trifluoromethyl, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis- ,-(CR⁹R¹⁰)_pC (=O) NR⁶R⁷、-(CR⁹R¹⁰)_pC (=O) R⁸、-(CR⁹R¹⁰)_pC (= O)OR^5a、-(CR⁹R¹⁰)_pS (=O)_qR⁸、-(CR⁹R¹⁰)_pS (=O)_qOR^5a、-(CR⁹R¹⁰)_pS (=O)_qNR⁶R⁷, cyclopropyl, ring penta Base, cyclobutyl, cyclohexyl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinylmethyl, piperidyl second Base, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl or pyridyl-ethyl group；

Wherein, R⁵Described in methyl, ethyl, propyl group, butyl, difluoromethyl, 1,2 ,-two fluoro ethyls, 2,2- difluoro second Base, cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinyl Methyl, piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl and pyridine radicals Ethyl is individually optionally by one or more R¹¹Replaced；

In some embodiments, each R^5aIt independently is H, C_1-4Alkyl, C_1-4Haloalkyl, C_3-8Carbocylic radical, 3-8 original Molecular heterocyclic radical, C_6-10Aryl or 5-10 former molecular heteroaryls；Wherein, R⁵Described in alkyl, haloalkyl, Carbocylic radical, heterocyclic radical, aryl and heteroaryl are individually optionally by one or more R¹¹Replaced；R¹¹With described in the invention Implication.

In some embodiments, each R^5aIndependently be H, methyl, ethyl, propyl group, butyl, trifluoromethyl, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azelidinyl, pyrrolidines Base, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals or pyrimidine radicals；Wherein, R^5aDescribed in methyl, ethyl, propyl group, fourth Base, difluoromethyl, 1,2 ,-two fluoro ethyls, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, azacyclo- Butyl, pyrrolidinyl, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals and pyrimidine radicals are individually optionally one or more R¹¹Replaced；R¹¹With implication described in the invention.

In some embodiments, each R⁶And R⁷It independently is H, C_1-4Alkyl, C_3-8Carbocylic radical, (C_3-6Carbocylic radical)-(C_1-4 Alkylidene)-, 3-8 former molecular heterocyclic radicals, (3-6 former molecular heterocyclic radicals)-(C_1-4Alkylidene)-, C_6-10Aryl, (C_6-10Aryl)-(C_1-4Alkylidene)-, 5-6 former molecular heteroaryls or (5-6 former molecular heteroaryls)-(C_1-4It is sub- Alkyl)-；

Wherein, R⁶And R⁷Described in alkyl, haloalkyl, carbocylic radical, carbocylic radical alkylidene, heterocyclic radical, heterocyclic radical alkylene Base, aryl, aryl alkylene, heteroaryl and heteroarylalkylenyl are individually optionally by one or more R¹¹Replaced；R¹¹Have Implication described in the invention.

In some embodiments, each R⁶And R⁷Independently be H, methyl, ethyl, propyl group, butyl, cyclopropyl, cyclopenta, Cyclobutyl, cyclohexyl, Cvclopropvlmethvl, cyclohexyl-ethyl, pyrrolidinyl, azelidinyl, piperidyl, pyrrolidinylmethyl, Piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, pyrrol ylmethyl or pyridyl-ethyl group.

In some embodiments, each R⁸It independently is H, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Halo Alkyl, C_1-4Halogenated alkoxy, C_1-4Haloalkylamino, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls；

Wherein, R⁸Described in alkyl, haloalkyl, alkoxy, alkyl amino, halogenated alkoxy, haloalkylamino, Carbocylic radical, heterocyclic radical, aryl and heteroaryl are individually optionally by one or more R¹¹Replaced；R¹¹With described in the invention Implication.

In some embodiments, each R⁸It independently is H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino or three Methyl fluoride.

In some embodiments, each R⁹And R¹⁰It independently is H, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4 Haloalkyl, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls；

Wherein, R⁹And R¹⁰Described in alkyl, haloalkyl, alkoxy, alkyl amino, carbocylic radical, heterocyclic radical, aryl and Heteroaryl is individually optionally by one or more R¹¹Replaced；R¹¹With implication described in the invention.

In some embodiments, each R⁹And R¹⁰Independently be H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino, Trifluoromethyl, cyclopropyl, cyclopenta, cyclohexyl, the ethyl group of ring third, pyrrolidinyl, piperidyl, phenyl, pyrrole radicals or pyridine radicals.

In some embodiments, k is 0,1,2,3,4,5,6,7,8,9 or 10.

In some embodiments, t is 0,1,2,3,4 or 5.

In some embodiments, n is 0,1,2,3 or 4.

In some embodiments, m is 0,1 or 2.

In some embodiments, each p independently is 1,2,3 or 4.

In some embodiments, each q independently is 1 or 2.

In some embodiments, each R¹¹It independently is H, D, F, Cl, Br, NO₂, CN, hydroxyl, amino, C_1-4Alkyl, C_1-4 Haloalkyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Halogenated alkoxy, C_1-4Haloalkylamino, the C of amino substitution_1-4Alkane Base, the C of hydroxyl substitution_1-4Alkyl, the C of cyano group substitution_1-4Alkyl, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Virtue Base or 5-10 former molecular heteroaryls.

In some embodiments, each R¹¹It independently is H, D, F, Cl, Br, NO₂, CN, hydroxyl, amino, methyl, ethyl, Propyl group, butyl, trifluoromethyl, methoxyl group, methylamino, dimethylamino, trifluoromethoxy, amino methyl, hydroxymethyl, ring Propyl group, cyclohexyl, piperidyl, morpholinyl, phenyl, pyrrole radicals or pyridine radicals.

On the other hand, the present invention relates to the structure of one of：

Or its solid is different Structure body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.

On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes compound of the present invention；Wherein, it is described Pharmaceutical composition further includes at least one of pharmaceutically acceptable excipient, carrier, adjuvant and solvent.

In some embodiments, pharmaceutical composition of the present invention is further comprising in other preventions or treatment The medicine of pivot nervous system nerve and psychiatric disorders and disease, described other preventions or treatment central nervous system god Medicine through property and psychiatric disorders and disease is antidepressant, anxiolytic drugs, the salts medicine as mood stabilizers Thing, antipsychotics, atypical antipsychotic drug, antiepileptic, anti-parkinson class medicine, hypnotic sedative agent Thing, antihistamine drug, GABA receptor stimulating agents and/or GABA reuptaking inhibitor classes medicine, it is used as MAOI Medicine, the medicine as melatonin receptors activator and the medicine as orexin receptor antagonists or their any group Close.

In other embodiments, other preventions of the present invention or treatment central nervous system nerve and essence Godhead obstacle and the medicine of disease are amitriptyline, desipramine, Mirtazapine, Bupropion, Reboxetine, Prozac, bent azoles Ketone, Sertraline, Duloxetine, Fluvoxamine, Milnacipran, left-handed Milnacipran, desmethylvenlafaxine, vilazodone, Wen La Method is pungent, Dapoxetine hydrochloride, Nefazodone, femoxetine, chlorimipramine, Citalopram, escitalopram, Paxil, carbonic acid Lithium, buspirone, Olanzapine, Quetiapine, Risperidone, Ziprasidone, Aripiprazole, Perospirone, Clozapine, modafinil, Mecamylamine, Cabergoline, adamantane, imipramine, Pramipexole, thyroxine, dextromethorphan, quinindium, naltrexone, Samidorphan, buprenorphine, melatonin, alprazolam, Pipamperone, dimension replace smooth, perphenazine, midazolam, a triazole Logical sequence, estazolam, diazepam, Flurazepam, nitrazepam, Clonazepam, Temazepam, Flunitrazepam, Oxazepam, zolpidem, Zaleplon, zopiclone, eszopiclone, English general grand, Tiagabine, Gaboxadol, clomipramine, doxepin, hydration chlorine Aldehyde, haloperole, chlorpromazine, carbamazepine, fenazil, Lorazepam, hydroxyzine, aspirin, diphenhydramine, chlorpheniramine, bromine For azoles logical sequence, Ramelteon, Te Simeiertong, agomelatine, mianserin, method Mack Xi Ting, nabilone, doxepin plus bar Spray fourth, librium, suvorexant, Xuezang Guben or their any combination.

On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine is prepared, The medicine is used to preventing, treat or mitigating the disease related to orexin receptor.

In one embodiment, the disease related to orexin receptor be sleep-disorder, depression, anxiety disorder, probably Flurried disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior Not normal, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, spirit are wrong Unrest, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, feeding desorder, head Bitterly, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease Disease, endocrine relevant disease or hypertension.

On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine is prepared, The medicine is used for antagonism orexin receptor.

On the other hand, the method for preparation, separation and the purifying of the compound included the present invention relates to formula (I).

Biological results show that the compound that the present invention is provided can be as preferable orexin receptor antagonists.

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

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

Definition and general terms

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

It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.

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

There is obvious conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are intended to include " at least one " or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " embodiment " refers to one or more embodiments.

Term " optional " or " optionally " refer to the event or situation that then describe can with but not necessarily occur, and this is retouched State situation about occurring including wherein described event or situation and the situation that wherein it is occurred without.

Term " optionally by ... replace ", can exchange with term " unsubstituted or by ... replace " and use, i.e., The structure or group are unsubstituted or replaced by one or more substituents of the present invention, wherein the substitution meaning Taste the rational position for occurring that any chemical valence allows in given structure or group.Substituent of the present invention includes, But it is not limited to D, F, Cl, Br, I ,-N₃、-CN、-NO₂、-OH、-SH、-NH₂, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, Alkylthio group, alkylamino, carbocylic radical, heterocyclic radical, aryl, heteroaryl, carbocylic radical alkylidene, heterocycloalkylene, aryl alkylene, Heteroarylalkylenyl, etc..

In general, term is " substituted " to represent that institute is specifically replaced to one or more of structure or group hydrogen atom Base is replaced.Unless otherwise indicated, a substituent can be replaced each commutable rational position in group. When one or more specific substituents that more than one position can be selected from given structural formula are replaced, then substituent It can be replaced with identical or different each rational position in structural formula.

Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.

In each several part of this specification, the substituent that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term “C_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

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

Term " D " represents D-atom.

Term " hetero atom " represents oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulphur (S) and phosphorus (P) form of any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the shape that the hydrogen in heterocycle on nitrogen-atoms is substituted Formula, for example, N (as the N in 3,4- dihydro-2 h-pyrrole bases), NH (as the NH in pyrrolidinyl) or the NR (pyrroles replaced as N- NR in alkyl).

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

Terminology used in the present invention " alkyl " or " alkyl group ", are represented containing 1-20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the substituent institute that the alkyl group can be described optionally by one or more present invention Substitution.In some embodiments, alkyl group contains 1-6 carbon atom；In other embodiments, alkyl group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.The example of alkyl group is included, but It is not limited to, methyl, ethyl, propyl group (including n-propyl and isopropyl), butyl (including normal-butyl, isobutyl group, sec-butyl and uncle Butyl), etc..

Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In some implementations In scheme, alkoxy base contains 1-6 carbon atom；In other embodiments, alkoxy base contains 1-4 carbon original Son；In other embodiment, alkoxy base contains 1-3 carbon atom.The example of alkoxy base includes, but does not limit In methoxyl group, ethyoxyl, propoxyl group, butoxy, etc..The alkoxy base can be optionally by one or more hairs The substituent of bright description is replaced.

Term " haloalkyl " represents that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Implication as described in the present invention, such example is included, but is not limited to ,-CF₃、-CF₂CF₃、-CH₂CF₂CHF₂Deng.At some In embodiment, " haloalkyl " is the C of lower level_1-4Haloalkyl the, wherein " C_1-4Haloalkyl " replaces comprising fluorine C_1-4Alkyl, the C of chlorine substitution_1-4Alkyl, the C of bromine substitution_1-4Alkyl, the C of iodine substitution_1-4Alkyl, etc..The haloalkyl is optional Ground is replaced by one or more substituents described in the invention.

Term " halogenated alkoxy " represents that alkoxy base is replaced by one or more halogen atoms, wherein alkoxy base Group has implication as described in the present invention, and such example is included, but is not limited to ,-OCF₃、-OCF₂CF₃、-OCH₂CF₂CHF₂ Deng.The halogenated alkoxy is optionally replaced by one or more substituents described in the invention.

Term " alkyl of amino substitution ", " alkyl of hydroxyl substitution " and " alkyl of cyano group substitution " represents alkyl group quilt One or more amino, hydroxyl or cyano group are replaced, and wherein alkyl group has implication as described in the present invention.

Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.

Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, represent containing 3-12 ring carbon atom, it is monovalent or Monocyclic, the bicyclic or three-ring system of multivalence, its middle ring can be fully saturated or comprising one or more degrees of unsaturation, but One armaticity ring can not all have.In some embodiments, carbocylic radical group contains 3-8 ring carbon atom；In other realities Apply in scheme, carbocylic radical group contains 3-6 ring carbon atom.

Term " cycloalkyl " represents that, containing 3-12 ring carbon atom, the saturation of monovalent or multivalence is monocyclic, bicyclic or tricyclic System.

Term " heterocyclic radical " and " heterocycle " are used interchangeably here, represent comprising 3-12 annular atom, monovalent or many The monocyclic, bicyclic or tricyclic system of valency, wherein the member ring systems include at least one hetero atom, the hetero atom has such as this hair Bright described implication, heterocycle can be fully saturated or comprising one or more degrees of unsaturation, but an armaticity ring is not Can have.In some embodiments, heterocyclyl groups contain 3-8 annular atom；In other embodiments, heterocyclyl groups Contain 3-6 annular atom.

Term " aryl " is represented containing 6-14 annular atom or 6-10 annular atom or 6 annular atoms, monovalent or many The monocyclic, bicyclic or tricyclic carbocyclic ring system of valency, wherein at least one ring is aromatic.Aromatic yl group is usual, but necessarily Ground is connected by the armaticity ring of aromatic yl group with parent molecule.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring " Change and use.The example of aromatic yl group can include phenyl, naphthyl, anthryl, etc..The aromatic yl group is optionally by one or many Individual substituent described in the invention is replaced.

Term " heteroaryl " represents individual containing 5-14 annular atom or 5-10 annular atom or 5-9 annular atom or 5-6 Annular atom, the monocyclic, bicyclic or tricyclic system of unit price or multivalence, wherein at least one ring is aromatic, and at least one Ring includes one or more hetero atoms.Heteroaryl groups are usual, but the unnecessarily armaticity ring by heteroaryl groups and mother Body molecule is connected.Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl Group is optionally replaced by one or more substituents described in the invention.

The descriptions such as " 3-8 former molecular heterocyclic radicals ", " 5-10 former molecular heteroaryls " represent composition ring structure Annular atom number, wherein, described annular atom includes the hetero atoms such as carbon atom and N, O, S, P, and the species of atom is depended on The species of the specific group formed.For example, " 3-8 former molecular heterocycles " refers to by 3-7 former molecular heterocyclic radicals, Wherein, the heterocyclic radical includes at least one hetero atom.When the ring structure is by specific substituent group, the atom of substituent Number is not included in the number of described annular atom.

Term " carbocylic radical alkylidene ", " heterocycloalkylene ", " aryl alkylene ", " heteroarylalkylenyl " expression " carbon Ring group ", " heterocyclic radical ", " aryl ", " heteroaryl " are connected by " alkylidene " with the remainder of molecule, wherein, described " carbon Ring group ", " heterocyclic radical ", " aryl ", " heteroaryl " and " alkylidene " have implication described in the invention.

As described in the present invention, substituent R is connected to the member ring systems formed on the ring at center by a key and represents substitution Base R any on ring can may replace or any rational position is replaced.For example, formula a represent it is any on ring A or ring B can Position that can be substituted can be replaced by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the whole text in the present invention " each ... and ... independently be ", " ... and ... be each independently " and " ... with ... separately for " can exchange, and refer to institute It is separate and be independent of each other between each option of description；Also illustrate that the specifically chosen scope of each option (that is, after " being " in description The option content in face) it is independent of each other.For example, " each R¹、R²And R³It independently is " " R can be described as¹For ", " R²For ", " R³ For ", represent R¹、R²And R³It is separate, and R¹、R²And R³Each expressed specific item can be the same or different.

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

Stereochemical definitions used in the present invention and rule typically 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.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face is rotated.When describing optically active compound, represent molecule on one using prefix D and L or R and S Individual or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are to be used to linearly polarized light caused by appointed compound revolve The symbol turned, wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for (+) or d compound.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or three-dimensional special When different in nature, such case may occur in which.

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

The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

Term " dynamic isomer " or " tautomeric form " refer to that (low can be built by low energy with different-energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), it can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases that is carried out by proton migration, such as keto-enol isomerization and Imine-enamine isomerizations.

" pharmaceutically acceptable " refers to such some compounds, raw material, composition and/or formulation, and they are cured rationally Learn judge in the range of, it is adaptable to patient tissue contacts without excessive toxicity, excitant, allergy or with rational profit The symmetrical other problemses of benefit/Hazard ratio and complication, and effective for given application.

Term " prodrug " used in the present invention, the chemical combination shown in formula (I) can be converted into vivo by representing a compound Thing.Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug. Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class, fat as pro-drug in existing invention Fat race (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.For example, in the present invention One compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms It is being obtained through the di on parent including phosphate, such as these phosphate compounds.It is complete on pro-drug Discussion may be referred to documents below：Higuchi et al.,Pro-drugs as Novel Delivery Systems, Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., this is incorporated herein by reference in 2008,51,2328-2345, every document.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt and experimentally characterized as stating.Such product can be by passing through oxidation, reduction, water to drug compound Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention is fully contacted to the metabolite produced by a period of time with mammal.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through appropriate alkali Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any included N's The quaternary ammonium salt that the compound of group is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is appropriate, nontoxic that pharmaceutically acceptable salt further comprises Ammonium, quaternary ammonium salt and gegenions formation amine cation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, monoethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

When the solvent is water, term " hydrate " can be used.In some embodiments, a chemical combination of the present invention Thing molecule can be combined with a hydrone, such as monohydrate；In other embodiments, a compounds of this invention Molecule can be combined with more than one hydrone, such as dihydrate；In other embodiment, a present inventionization Adduct molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention is protected Leave the biological effectiveness of the compound of nonhydrated form.

Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to trigger individual Thing or medicinal response (for example reduce or inhibitory enzyme or protein active, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevention disease etc.) the compounds of this invention amount.

The compound of the present invention

Unless otherwise mentioned, all suitable isotope changes of compound of the invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

Compound shown in formula (I) can exist with different tautomeric forms, and all these dynamic isomers It is included within the scope of the present invention.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.Can be by an elevated temperature using normal With oxidant (such as hydrogen peroxide), in the presence of having sour (such as acetic acid), corresponding nitrogen-containing basic material, Huo Zhetong are aoxidized Cross with crossing acid reaction in suitable solvent, such as reacted in dichloromethane, ethyl acetate or methyl acetate with peracetic acid, or Reacted in chloroform or dichloromethane with 3- chloroperoxybenzoic acids, prepare the nitrogen oxides of the compounds of this invention.

In addition, when the compound formation hydrate or solvate of the present invention, they are also included within the scope of the present invention It is interior.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within the model of the present invention In enclosing.

Compound shown in formula (I) can exist in a salt form.In some embodiments, the salt refers to pharmaceutically may be used The salt of receiving.The pharmaceutically acceptable salt of the present invention can be with conventional chemical processes by parent compound, alkalescence or acidity portion Divide to synthesize.In general, such salt can be by making the free acid form of these compounds and the suitable alkali of stoichiometry (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate) reacts, or by making the free alkali of these compounds It is prepared by the suitable acid reaction of form and stoichiometry.Such reaction is generally in water or organic solvent or the mixing of the two Carried out in thing.Usually, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol Or acetonitrile.In such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley- VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.

The compounds of this invention is alkaline, therefore is generally possible to form pharmaceutically acceptable by using suitable acid treatment Acid-addition salts.Suitable acid includes pharmaceutically acceptable inorganic acid and pharmaceutically acceptable organic acid.Representational medicine Acceptable acid-addition salts include hydrochloride, hydrobromate, nitrate, methyl nitrate, sulfate, disulfate, ammonia on Base sulfonate, phosphate, acetate, hydroxyl acetate, phenyl acetate salt, propionate, butyrate, isobutyrate, valerate, horse Carry out hydrochlorate, it is hydroxymaleic acid salt, acrylates, fumarate, malate, tartrate, citrate, salicylate, right Aminosalicylate, glycollate, lactate, enanthate, phthalate, oxalates, succinate, benzoate, neighbour Acetoxy-benzoic acid salt, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzene Formates, mandelate, tannate, formates, stearate, ascorbate, palmitate, oleate, acetonate, Pamoate, malonate, laruate, glutarate, glutamate, estolate, mesylate, sulfonate, 2- hydroxyls Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..

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

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there is radio isotope, such as³H、¹⁴C and¹⁸F those compounds, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research (to use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.¹⁸The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

On the other hand, the present invention relates to the intermediate for preparing compound shown in formula (I).

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

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

A kind of pharmaceutical composition of present invention offer, including compound shown in compound shown in formula (I) or formula (I) are three-dimensional different Structure body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.The medicine group Compound is further comprising at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, others treatment And/or prevention composition.

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

" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and the interaction of effect of the compounds of this invention can be substantially reduced during avoiding that patient is administered and can cause not being medicine The interaction of acceptable pharmaceutical composition on.In addition, every kind of excipient must be pharmaceutically acceptable, for example, tool There is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.The some pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.It may be selected to help to carry when patient is administered or transport the compounds of this invention from an organ of body or partly to body Another organ or partial some pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is some pharmaceutically Acceptable excipient.

Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably Agent, surfactant and buffer.One skilled in the art will recognize that, some pharmaceutically acceptable excipient can be provided not Only a kind of function, and provide alternative function, this depends in preparation having in how much excipient and preparation which be present Other a little excipient.

Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes 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)。

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 The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing is acted on, or with interaction occurs for any other composition in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pay close attention to its application and belong to the scope of the present invention.

The compounds of this invention is usually formulated as the formulation for being suitable for that patient is administered by required approach.For example, formulation It is suitable for the formulation of following method of administration including those：(1) it is administered orally, such as tablet, capsule, caplet agent, pill, lozenge Agent, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, such as it is sterile Solution, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as suppository；(5) inhale Enter, for example aerosol, solution and dry powder doses；(6) local administration, such as cream, ointment, lotion, solution, paste Agent, spray, foaming agent and gel.

It will also be appreciated that some compounds of the present invention can exist and for treating in a free form, or it is if suitable When can exist and for treating in the form of its pharmaceutically acceptable derivates.Some of pharmaceutically acceptable derivative are non- Restricted embodiment includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or patient in need is given Can directly or indirectly be provided during medicine compound of the present invention or its metabolite or residue any other adduct or Derivative.

In some embodiments, the compounds of this invention can be configured to peroral dosage form.In other embodiments, originally Invention compound can be configured to inhalant dosage form.In other embodiments, the compounds of this invention can be configured to intranasal to Pharmaceutically dosage form.In other embodiment, the compounds of this invention can be configured to transdermal administration.Also in some embodiments In, the compounds of this invention can be configured to Topical dosage forms.

The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are provided.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat is surrounded Piece, it can be beneficial to cover taste beastly or smell and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of material.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Tabletting is to pass through compressed tablets prepared by more than one press cycles, including multilayer tablet and pressed coated or dry coating tablet.

Tabules can be by one kind for individually or with the present invention being described in powder, crystallization or granular active component Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.

The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate is tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section Fill in another section, therefore enclose active component completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plastified by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This Inventing the liquid provided, semi-solid and solid dosage forms can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.

The pharmaceutical composition that the present invention is provided can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used Two (low alkyl group) acetals of the acetal of receiving, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and preservative can also be included.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.

The pharmaceutical composition that the present invention is provided can be configured to be suitable to any formulation to patient's inhalation, such as dry powder Agent, aerosol, supensoid agent or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared Into suitable for formulation of the dry powder doses to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable to the formulation by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes are obtained comprising fine powdered Shape agent.The pharmaceutically acceptable excipient dawn known to those skilled in the art of dry powder doses is especially suitable for use as, it includes breast Sugar, starch, mannitol and single-, two- and polysaccharide.Fine powder can be prepared for example, by micronizing and grinding.It is general next Say, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D₅₀Value with laser diffractometry (for example, surveyed Amount) define.

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

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

The compounds of this invention can also be combined with as the soluble polymer of target medicine carrier.Such polymer bag Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can be with realizing medicine The class Biodegradable polymeric that is used in control release is combined, for example, PLA, poly-epsilon-caprolactone, poly butyric, Poe, polyacetals, poly- dihydropyran, crosslinking or the amphiphilic block copolymer of polybutylcyanoacrylate and hydrogel.

The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the parenteral that uses of the present invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, in urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

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

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

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

The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be sterile, as known in the art with practice.

The pharmaceutical composition that the present invention is provided can with will not to damage other active components of expected therapeutic action common Prepare, or the material co-formulation with the expected effect of supplement.

In some embodiments, treatment method of the invention includes the sheet that safe and effective amount is given to patient in need Invention compound or the pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention is included by suffering in need Person gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.

In some embodiments, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by appointing What suitable method of administration is administered, including Formulations for systemic administration and local is administered.Formulations for systemic administration includes being administered orally, parenteral given Medicine, cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular With hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and intranasal administration. In some embodiments, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be administered orally. In other embodiments, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.Also Have in some embodiments, the compounds of this invention or can be intranasal administration comprising the compounds of this invention.

In some embodiments, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be disposable Administration, or according to dosage regimen, at the appointed time in section, in different time interval administrations several times.For example, daily administration Once, twice, three times or four times.In one embodiment, it is administered once a day.In other embodiment, daily administration Twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention Or the appropriate dosage regimen of the pharmaceutical composition comprising the compounds of this invention depends on the pharmacokinetic property of the compound, example As absorbed, being distributed and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including chemical combination of the present invention The appropriate dosage regimen of the pharmaceutical composition of thing, including implement the duration of the program, it depends on treated disease, quilt Treat the order of severity, the age of patient under consideration and the health of disease, the medical history of patient under consideration, while the property of therapy The factor in the range of technical staff's knowledge and experience such as matter, desired therapeutic effect.Such technical staff should also be understood that Reaction for individual patient to dosage regimen, or when passage individual patient needs change over time, in order to be sufficiently accurate it may be desired to adjust matters Dosage regimen.

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

The compounds of this invention can be with sedative, hypnotic, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole Ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the element that fades can medicament, benzene phenodiazines Leather, barbiturate, 5HT-2 antagonists etc. are used in combination, for example：Adinazolam, allobarbital, alonimid, Alprazolam, amitriptyline, amytal, amoxapine, bentazepam, benzoctamine, brotizolam, biphenylacetone, fourth Spirocyclic ketone, cloth tower barbital, cloth tower are than appropriate, capuride, Carbocloral, chloral betaine, chloraldurate, librium, chlorine rice handkerchief Bright, Clonazepam, Domperidone, Decacil, cloretate, Clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine Aldehyde willow amine, double valproic acids, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west Dissolve, Flurazepam, Fluvoxamine, fluoxetine, fosazepam, glutethimide, Halazepam, hydroxyzine, imipramine, lithium, chlorine hydroxyl go first Stable, Lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles Logical sequence, Buddhist nun's method oxazolone, Nisobamate, intrazepam, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, amobarbital, piperazine Even up, perphenazine, nardil, phenobarbital, prazepam, fenazil, propofol, protriptyline, quazepam, auspicious chlorine West is dissolved, rolipram, quinalbarbitone, Sertraline, Suproclone, Temazepam, thioridazine, Tracazolate, anti-phenyl ring third Amine, Trazodone, triazole benzene phenodiazine, Trepipam, trimeglamide, trichloroethyl phosphate, triperazine, trimethoxy benzoyl Quinoline, trimeprimine, uldazepam, venlafaxine new, Zaleplon, Zolazepam, zolpidem and their salt and composition Etc., or the compounds of this invention can administration while physical method such as light therapy or electro photoluminescence is used in combination.

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

The purposes of the compounds of this invention and pharmaceutical composition

Compound and pharmaceutical composition of the present invention are as orexin receptor antagonists, to preventing or treating and appetite The related disease of plain acceptor is effective, available for the medicine for preparing antagonism orexin receptor.

The disease related to orexin receptor may be selected from all types of sleep-disorder, all types of psychiatry, god Learned through disease and neurodegeneration obstacle, all types of pressure correlation syndromes, all types of habituation (especially psychotropic activity thing The use of matter, abuse, seek and recover), it is all types of in healthy population and in psychiatric patient and nervous system disease Cognition dysfunction, all types of feeds or drinking-water obstacle in patient, etc..

In some embodiments, the disease related to orexin receptor comprising sleep-disorder, depression, anxiety disorder, probably Flurried disease, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior Not normal, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, spirit are wrong Unrest, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, feeding desorder, head Bitterly, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease Disease, endocrine relevant disease or hypertension.

In some embodiments, the disease related to orexin receptor may be selected from sleep-disorder, and it includes all types Insomnia, Narcolepsy's myodystony related to other hyper somnolence diseases, parasomnia, sleep, not peaceful When leg syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome are with sleep Phase retardation or in advance syndrome or the related insomnia of mental illness, etc..

In some embodiments, the disease related to orexin receptor may be selected from psychiatry, neurology and nerve Degenerative disorder, it includes depression, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious god Through disease, mood disorder, panic attack obstacle, posttraumatic stress disorder, sex dysfunction, mental disease, Parkinson's disease, dementia or Mental retardation, etc..

In some embodiments, the disease related to orexin receptor may be selected from cognition dysfunction, and it is included in just It is normal, health, young, adult's or old crowd in transient episodes or chronic seizures all types of attentions, Learning and memory function reduction, or the transient episodes or slow in mental disease, neuropathy, angiocarpy and disease of immune system patient Property breaking-out all types of attentions, learning and memory function reduction, etc..

It should be appreciated that in some environmental conditions such as such as pressure or fear, (wherein, pressure may have society source such as Social pressures or with physiological sources such as physical stress, including the pressure produced by fear) promote or accelerate it is any as previously described Illness or disease in the case of, compound of the invention is particularly useful to the illness or disease for the treatment of the regulation of these environment 's.

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

The general synthetic method of the compounds of this invention

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, the wherein definition of substituent compound as shown in formula (I).Following reaction scheme and embodiment are used to further illustrate Illustrate present disclosure.

Those skilled in the art will realize that：Chemical reaction described in the invention can be for suitably preparing perhaps Other compounds of many present invention, and be considered as preparing other methods of compound of the invention in model of the invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.

The embodiments described below, unless otherwise indicated, all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance Determined by Bruker Avance400 nuclear magnetic resonance spectrometers or the nuclear magnetic resonance spectrometers of Bruker Avance III HD 600, With CDC1₃,d₆-DMSO,CD₃OD or d₆- acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) is used as reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplets), ddd (doublet Of doublet of doublets, in pairs doublet), ddt (doublet of doublet of triplets, in pairs three Weight peak), dddd (doublet of doublet of doublet of doublets, in pairs double doublet).Coupling constant, Represented with hertz (Hz).

The condition of Algorithm (MS) data determination is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid₃CN) (H of 0.1% formic acid is being contained₂O the ratio in))), detected in 210/254nm with UV, with electron spray electricity From pattern (ESI).

The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or The preparative high performance liquid chromatographies of Calesep Pump 250 (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.

Synthetic schemes

Following synthetic schemes describes the step of preparation present invention discloses compound：

The synthetic schemes of intermediate

Midbody compound (3) can be prepared by following process, wherein, R¹、R², n and m there is the present invention to be retouched The implication stated.

Substituted benzoic acid (1) and the triazole (1a) of substitution are in [Cu] catalyst (such as cuprous iodide), appropriate part Under (such as trans-N, N'- dimethyl -1,2- cyclohexanediamine) and appropriate alkali (such as cesium carbonate) effect, in reaction under heating condition Obtain compound (2).Compound (2) obtains compound (3) in a heated condition with chlorinating agent (such as thionyl chloride).

Synthetic schemes 1

Target compound (8) can be prepared by following process, wherein, R¹、R²、R³、R⁴, n, t, k and m have this The described implication of invention.

Substituted or non-substituted 1,6- naphthyridines -5 (6H) -one (4) obtains compound (5) through chlorination, and compound (5) is entered One step is reacted in a heated condition with compound (6) obtains compound (7).Compound (7) is with midbody compound (3) in alkali Target compound (8) is directly reacted in the presence of (such as triethylamine).

Synthetic schemes 2

Target compound (14), (15) and (16) can be prepared by following process, wherein, R¹、R²、R⁴, n, k and m With implication described in the invention.

The oxidized reaction of compound (5) obtains compound (9), and compound (9) obtains compound through lactamization reaction (10), compound (10) is reacted with bromoacetate (11) in the presence of alkali (such as potassium carbonate) obtains compound (12), chemical combination Thing (12) further reacts in a heated condition with compound (6) obtains compound (13).Compound (13) and intermediate compound Directly reaction obtains target compound (14) to thing (3) in the presence of alkali (such as triethylamine).Compound (14) is in alkali (such as carbonic acid Caesium) in the presence of hydrolysis obtain target compound (15).Compound (15) occurs ammonolysis reaction and obtains target compound (16).

Embodiment

Embodiment 1：(4- (1,6- naphthyridines -5- bases) -1,4- Diazesuberane -1- bases) (5- methyl -2- (2H-1,2,3- Triazole -2- bases) phenyl) ketone synthesis

Step 1) 5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid synthesis

By 1,2,3- triazoles (3.45g, 50mmol), the iodo- 5- methyl benzoic acids (5.24g, 20mmol) of 2-, cesium carbonate (11.72g, 36mmol), trans-N, N'- dimethyl -1,2- cyclohexanediamine (0.51g, 3.6mmol), cuprous iodide (0.38g, 2mmol), DMF (30mL) is added sequentially in 100mL single necked round bottom flask, is gradually heated up under nitrogen protection Reacted 4 hours to 100 DEG C.Stop reaction, cooling is diluted with running water and washed with ethyl acetate (200mL × 2).Water layer is used Concentrated hydrochloric acid acidifying (pH=1~2) is extracted with ethyl acetate (200mL × 2) afterwards, merges organic layer, with anhydrous sodium sulfate drying, mistake Filter, filtrate decompression, which is evaporated and carries out column chromatographic isolation and purification (methylene chloride/methanol (v/v)=50/1), obtains title compound (yellow solid, 2.76g, 68%).

MS(ESI,neg.ion)m/z:202.1[M-H]^-；

¹H NMR(CD₃OD,600MHz)δ(ppm):7.88 (s, 2H), 7.66 (d, 1H), 7.59 (d, J=8.2Hz, 1H), 7.50~7.48 (dd, J=8.1Hz, 1.1Hz, 1H), 2.45 (s, 3H)；

¹³C NMR(CD₃OD,151MHz)δ(ppm):169.8,140.7,137.5,136.7,133.5,131.5,129.3, 126.0,21.0.

Step 2) 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride synthesis

5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid (2.03g, 10mmol) is added to 100mL single port In round-bottomed flask, dissolved with anhydrous methylene chloride (20mL), then be slowly added into thionyl chloride (15mL, 200mmol) and pyridine (0.15mL, 2mmol), is gradually heating to back flow reaction 3 hours.Stop reaction, cooling, decompression slowly boils off solvent, gained production Thing is directly used in next step reaction.

Step 3) the chloro- 1,6- naphthyridines of 5- synthesis

1,6- naphthyridines -5 (6H) -one (2.00g, 13.68mmol), POCl3 (20mL, 218.5mmol) are sequentially added Into 100mL single necked round bottom flask, back flow reaction is gradually heating to 16 hours.Stop reaction, cooling removes solvent under reduced pressure, institute Obtain dope dichloromethane (200mL) to dissolve, be slowly poured into mixture of ice and water (100mL), saturated aqueous sodium carbonate is adjusted PH is extracted to neutrality, water layer with dichloromethane (50mL × 2), merges organic layer, evaporated under reduced pressure simultaneously carries out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=1.5/1) obtains title compound (faint yellow solid, 1.986g, 88.17%).

MS(ESI,pos.ion)m/z:165.2[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):9.11 (dd, J=6.4Hz, 2.4Hz, 1H), 8.63~8.60 (m, 1H), (q, J=6.4Hz, the 1H) of 8.49 (d, J=8.8Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 7.60

Step 4) 5- (1,4- Diazesuberane -1- bases) -1,6- naphthyridines synthesis

By the chloro- 1,6- naphthyridines (1.50g, 9.11mmol) of 5-, 1,4- Diazesuberanes (9.128g, 91.14mmol) and Toluene (10mL) is added sequentially in 100mL single necked round bottom flask, is heated to 130 DEG C and is reacted 6 hours.Stop reaction, cool down, plus Enter running water (200mL), extracted with dichloromethane (100mL × 3), merge organic layer, use anhydrous sodium sulfate drying.Filtering, filter Column chromatographic isolation and purification (methylene chloride/methanol (v/v)=30/1) is carried out after liquid evaporated under reduced pressure and obtains title compound (yellow liquid Body, 1.70g, 81.7%).

MS(ESI,pos.ion)m/z:229.3[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):8.58 (dd, J=4.0Hz, 1.0Hz, 1H), 8.04 (d, J=8.5Hz, 1H), 8.89 (d, J=5.8Hz, 1H), 7.01 (dd, J=8.9Hz, 3.7Hz, 2H), 3.52~3.47 (m, 2H), 3.47~ (m, the 2H) of 3.44 (m, 2H), 2.91~2.86 (m, 2H), 2.82~2.72 (m, 2H), 1.78~1.68

Step 5) (4- (1,6- naphthyridines -5- bases) -1,4- Diazesuberane -1- bases) (5- methyl -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) phenyl) ketone synthesis

Under the conditions of ice-water bath, by 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.61g, 2.74mmol) it is added in 100mL single port bottles, dissolves it with anhydrous methylene chloride (30mL), then be slowly added into triethylamine (0.665g, 6.57mmol) and 5- (Isosorbide-5-Nitrae-Diazesuberane -1- bases) -1,6- naphthyridines (0.50g, 2.19mmol), stirring 10 Minute, ice-water bath is removed, reaction at room temperature is stayed overnight.Column chromatographic isolation and purification (dichloromethane is carried out after the direct evaporated under reduced pressure of reaction solution Alkane/methanol (v/v)=50/1) obtain title compound (yellow solid, 640mg, 70.67%).

MS(ESI,pos.ion)m/z:414.45[M+H]⁺.

Embodiment 2：(4- (1,6- naphthyridines -5- bases) -1,4- Diazesuberane -1- bases) (2- (2H-1,2,3- triazoles - 2- yls) phenyl) ketone synthesis

Step 1) 2- (2H-1,2,3- triazole -2- bases) benzoic acid synthesis

Method of this step title compound with reference to described by the step 1 of embodiment 1 is prepared, i.e., by 1,2,3- triazoles (0.7g, 10.08mmol), 2- iodo-benzoic acids (1g, 4.03mmol), cesium carbonate (2.36g, 7.2mmol), trans-N, N'- diformazans Base -1,2- cyclohexanediamine (0.103g, 0.752mmol), cuprous iodide (0.077g, 0.403mmol) are in N, N- dimethyl formyls In amine (18mL) prepared by reaction, and crude product is marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) Inscribe compound (yellow solid, 0.511g, 67%).

MS(ESI,neg.ion)m/z:188.1[M-H]^-；

¹H NMR(DMSO-d₆,600MHz)δ(ppm):13.06 (br, 1H), 8.08 (s, 2H), 7.78~7.75 (m, 2H), 7.72~7.68 (m, 1H), 7.60~7.57 (m, 1H)；

¹³C NMR(DMSO-d₆,151MHz)δ(ppm):167.7,137.5,136.3,131.7,129.6,128.9, 128.5,124.4.

Step 2) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride synthesis

Method of this step title compound with reference to described by the step 2 of embodiment 1 is prepared, i.e., by 2- (2H-1,2,3- Triazole -2- bases) benzoic acid (0.37g, 1.96mmol), thionyl chloride (6mL, 82.7mmol) and pyridine (0.04mL, 0.5mmol) in anhydrous methylene chloride (20mL) prepared by reaction, and products therefrom is directly used in next step reaction.

Step 3) (4- (1,6- naphthyridines -5- bases) -1,4- Diazesuberane -1- bases) (2- (2H-1,2,3- triazoles -2- Base) phenyl) ketone synthesis

Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e., by 2- (2H-1,2,3- Triazole -2- bases) chlorobenzoyl chloride (0.51g, 2.46mmol), triethylamine (1mL, 5.98mmol) and 5- (1,4- diaza cycloheptyls Alkane -1- bases) the reaction preparation in anhydrous methylene chloride (30mL) of -1,6- naphthyridines (0.45g, 1.97mmol), crude product is through silica gel Column chromatographic isolation and purification (methylene chloride/methanol (v/v)=50/1) obtain title compound (yellow solid, 450mg, 57.16%).

MS(ESI,pos.ion)m/z:400.45[M+H]⁺.

Embodiment 3：2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diazas Cycloheptane -1- bases) -1,6- naphthyridines -2- bases) epoxide) and ethyl acetate synthesis

Step 1) the chloro- 1,6- naphthyridines -1- nitrogen oxides of 5- synthesis

Under the conditions of 0 DEG C, by chloro- 1, the 6- naphthyridines (5.00g, 30.38mmol) of 5-, the metachloroperbenzoic acid of content 80% (7.863g, 36.45mmol), dichloromethane (100mL) are added sequentially in 250mL three neck round bottom flask, anti-under nitrogen protection Answer 3 hours, be subsequently moved to react at room temperature 13 hours.Stop reaction, be slowly added into saturated sodium bicarbonate aqueous solution (50mL), water Layer is extracted with dichloromethane (100mL × 3), merges organic layer, and evaporated under reduced pressure simultaneously carries out silica gel column chromatography separating purification (dichloromethane Alkane/methanol (v/v)=50/1) obtain title compound (yellow solid, 5.10g, 93.0%).

MS(ESI,pos.ion)m/z:181.1[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):8.63 (d, J=6.1Hz, 1H), 8.50 (d, J=6.0Hz, 1H), (dd, J=8.7Hz, 6.2Hz, the 1H) of 8.42 (d, J=6.0Hz, 1H), 8.10 (d, J=8.7Hz, 1H), 7.47

Step 2) chloro- 1,6- naphthyridines -2 (1H) -one of 5- synthesis

The chloro- 1,6- naphthyridines -1- nitrogen oxides (1.5g, 8.31mmol) of 5-, acetic anhydride (35mL) are added sequentially to 100mL In round-bottomed flask, under nitrogen protection, it is gradually heating to react 18 hours at 130 DEG C.100 DEG C are cooled the temperature to, is slowly added into certainly Water (10mL), stirs 0.5 hour, moves to room temperature.It is neutrality that saturated sodium bicarbonate aqueous solution, which is slowly added into, to pH, uses dichloromethane Alkane (50mL × 4) is extracted, and merges organic layer, and evaporated under reduced pressure simultaneously carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/ V)=50/1) obtain title compound (yellow solid, 0.505g, 33.67%).

MS(ESI,pos.ion)m/z:181.1[M+H]⁺；

¹H NMR(d₆-DMSO,600MHz)δ(ppm):12.31 (s, 1H), 8.26 (d, J=5.7Hz, 1H), 8.04 (dd, J =9.8Hz, 0.2Hz, 1H), 7.23 (dd, J=5.6Hz, 0.2Hz, 1H), 6.68 (d, J=9.8Hz, 1H)

Step 3) 2- ((the chloro- 1,6- naphthyridines -2- bases of 5-) epoxide) ethyl acetate synthesis

By chloro- 1,6- naphthyridines -2 (1H) -one (0.50g, 2.77mmol) of 5-, bromoacetate (1.39g, 8.31mmol), Potassium carbonate (1.16g, 8.30mmol), DMF (15mL) are added sequentially in 100mL single port bottles, at room temperature instead Answer 18 hours.Stop reaction, running water (30mL) be slowly added into reaction solution, water layer is extracted with dichloromethane (30mL × 3), Merge organic layer and washed with running water (30mL × 2), organic layer evaporated under reduced pressure simultaneously carries out silica gel column chromatography separating purification (oil Ether/ethyl acetate (v/v)=1/1) obtain title compound (white solid, 0.485g, 65.69%).

MS(ESI,pos.ion)m/z:267.1[M+H]⁺；

¹H NMR(CDCl₃,600MHz)δ(ppm):8.33 (d, J=6.0Hz, 1H), 8.15 (dd, J=9.9Hz, 0.3Hz, 1H), 6.91 (d, J=6.0Hz, 1H), 6.82 (d, J=9.9Hz, 1H), 5.01 (s, 2H), 4.24 (q, J=7.1Hz, 2H), 1.27 (t, J=7.1Hz, 3H)

Step 4) 2- ((5- (1,4- Diazesuberane -1- bases) -1,6- naphthyridines -2- bases) epoxide) ethyl acetate synthesis

By 2- ((the chloro- 1,6- naphthyridines -2- bases of 5-) epoxide) ethyl acetate (2.00g, 7.5mmol), 1,4- diaza cycloheptyls Alkane (7.51g, 75.0mmol), toluene (10mL) are added sequentially in 100mL single port bottles, are gradually heating to react 16 at 130 DEG C Hour.Stop reaction, running water (100mL) is slowly added into reaction solution, water layer is extracted with dichloromethane (100mL × 3), is closed And organic layer, evaporated under reduced pressure simultaneously carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=10/1) and obtains titled Compound (yellow liquid, 0.530g, 21.4%).

MS(ESI,pos.ion)m/z:331.3[M+H]⁺；

¹H NMR(d₆-DMSO,600MHz)δ(ppm):8.09 (d, J=5.9Hz, 1H), 8.01 (d, J=9.8Hz, 1H), 6.79 (d, J=6.0Hz, 1H), 6.52 (d, J=9.8Hz, 1H), 5.00 (s, 2H), 4.16 (q, J=7.1Hz, 2H), 3.51~ 3.48 (m, 2H), 3.44~3.41 (m, 2H), 3.02~2.96 (m, 2H), 2.89~2.82 (m, 2H), 2.53~2.49 (m, 1H), 1.88 (dt, J=11.3Hz, 5.8Hz, 2H), 1.22 (t, J=7.1Hz, 3H)

Step 5) 2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diazacyclos Heptane -1- bases) -1,6- naphthyridines -2- bases) epoxide) and ethyl acetate synthesis

Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e., by 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.493g, 2.23mmol), triethylamine (0.450g, 4.45mmol), 2- ((5- (1,4- Diazesuberane -1- bases) -1,6- naphthyridines -2- bases) epoxide) ethyl acetate (0.490g, 1.48mmol) is in nothing Prepared by reaction in water dichloromethane (30mL), crude product through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)= 1/1) title compound (faint yellow dope, 470mg, 61.47%) is obtained.

MS(ESI,pos.ion)m/z:516.3[M+H]⁺.

Embodiment 4：2- ((5- (4- (2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- Diazesuberanes - 1- yls) -1,6- naphthyridines -2- bases) epoxide) and ethyl acetate synthesis

Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e., by 2- (2H-1,2,3- Triazole -2- bases) chlorobenzoyl chloride (0.377g, 1.82mmol), triethylamine (0.367g, 3.63mmol), 2- ((5- (1,4- phenodiazines Trioxepane -1- bases) -1,6- naphthyridines -2- bases) epoxide) ethyl acetate (0.40g, 1.21mmol) is in anhydrous methylene chloride In (30mL) prepared by reaction, and crude product is marked through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=1/1) Inscribe compound (faint yellow dope, 400mg, 65.88%).

MS(ESI,pos.ion)m/z:502.3[M+H]⁺.

Embodiment 5：2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diazas Cycloheptane -1- bases) -1,6- naphthyridines -2- bases) epoxide) and acetic acid synthesis

By 2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diaza cycloheptyls Alkane -1- bases) -1,6- naphthyridines -2- bases) epoxide) ethyl acetate (0.60g, 1.16mmol), cesium carbonate (1.137g, 3.49mmol) It is added sequentially in 100mL round-bottomed flasks, is made with methanol (30mL) after its dissolving, it is small that reaction solution is gradually heating to 60 DEG C of reactions 12 When.Under cooling, ice bath, pH to 2 is adjusted with 1mol/L aqueous hydrochloric acid solution, is stirred 0.5 hour, direct evaporated under reduced pressure simultaneously carries out silica gel Column chromatographic isolation and purification (methylene chloride/methanol (v/v)=10/1) obtain title compound (faint yellow solid, 0.40g, 70.5%).

MS(ESI,pos.ion)m/z:488.51[M+H]⁺.

Embodiment 6：2- ((5- (4- (2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- Diazesuberanes - 1- yls) -1,6- naphthyridines -2- bases) epoxide) and acetic acid synthesis

Method of this step title compound with reference to described by embodiment 5 is prepared, i.e., by 2- ((5- (4- (2- (2H- 1,2,3- triazole -2- bases) benzoyl) -1,4- Diazesuberane -1- bases) -1,6- naphthyridines -2- bases) epoxide) acetic acid second Prepared by the reaction in methanol (30mL) of ester (0.60g, 1.2mmol) and cesium carbonate (1.169g, 3.59mmol), crude product is through silica gel Column chromatographic isolation and purification (methylene chloride/methanol (v/v)=10/1) obtain title compound (faint yellow solid, 450mg, 79.44%).

MS(ESI,pos.ion)m/z:474.5[M+H]⁺.

Embodiment 7：2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diazas Cycloheptane -1- bases) -1,6- naphthyridines -2- bases) epoxide) and acetamide synthesis

By 2- ((5- (4- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- diaza cycloheptyls Alkane -1- bases) -1,6- naphthyridines -2- bases) epoxide) ethyl acetate (0.40g, 0.78mmol), ammonia methanol solution (7mol/L, 30mL) it is added sequentially in 100mL round-bottomed flasks, reacts 36 hours at room temperature.Stop reaction, direct evaporated under reduced pressure simultaneously carries out silicon Plastic column chromatography isolate and purify (methylene chloride/methanol (v/v)=20/1) obtain title compound (faint yellow solid, 0.34g, 90.08%).

MS(ESI,pos.ion)m/z:487.1[M+H]⁺.

Embodiment 8：2- ((5- (4- (2- (2H-1,2,3- triazole -2- bases) benzoyl) -1,4- Diazesuberanes - 1- yls) -1,6- naphthyridines -2- bases) epoxide) and acetamide synthesis

Method of this step title compound with reference to described by embodiment 7 is prepared, i.e., by 2- ((5- (4- (2- (2H- 1,2,3- triazole -2- bases) benzoyl) -1,4- Diazesuberane -1- bases) -1,6- naphthyridines -2- bases) epoxide) acetic acid second Prepared by ester (0.40g, 0.80mmol) reaction in the methanol solution (7mol/L, 30mL) of ammonia, crude product is through silica gel column chromatography point Title compound (faint yellow solid, 310mg, 82.26%) is obtained from purifying (methylene chloride/methanol (v/v)=20/1).

MS(ESI,pos.ion)m/z:473.5[M+H]⁺.

Biologic test

Embodiment A the compounds of this invention is to humanization OX₁The antagonism experiment of acceptor

Test method

Detect influence of the compounds of this invention to the cell calcium current of agonist induction to evaluate this hair with fluorescence detection Bright compound is to expressing the humanization OX on Chinese hamster ovary cell (CHO)₁The antagonistic ability of acceptor.Cell is suspended in In DMEM culture mediums (invitrogen), then with 2 × 10⁴The Density Distribution of cells/well is in micro reaction plate.It will contain glimmering The Hank of light probe (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids (invitrogen) is put down Weighing apparatus salting liquid (HBSS, invitrogen) (pH=7.4) is added in above-mentioned micro reaction plate, then arises from 37 DEG C with cell one 60min is incubated, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and add test compound or with reference to antagonist or Hank balanced salt solutions, 3nM appetite is added after 5min Plain A or Hank balanced salt solutions (blank control), then measure the change of fluorescence intensity, it is dense with free intracellular calcium That spends is changing into positive correlation.Experimental result is represented with the suppression percentage relative to control group 3nM orexin-As.

Standard is SB334867 with reference to antagonist, amount effect curve is obtained by the experiment test of series concentration, so as to calculate Go out IC₅₀Value.Experimental result is as shown in table 1.

The compounds of this invention of table 1 is to OX₁The antagonism of acceptor

Embodiment is numbered	OX₁IC₅₀(μM)
		Embodiment 1	0.411
Embodiment 2	0.408
		Embodiment 3	0.566
Embodiment 4	0.504
		Embodiment 5	0.618
Embodiment 6	0.625

Test result indicates that, the compounds of this invention is to OX₁Acceptor shows preferable antagonism.

Embodiment B the compounds of this invention is to humanization OX₂The antagonism experiment of acceptor

Test method

Detect influence of the compounds of this invention to the cell calcium current of agonist induction to evaluate this hair with fluorescence detection Bright compound is to expressing the humanization OX on HEK-293 cells₂The antagonistic ability of acceptor.Cell is suspended in DMEM culture mediums (invitrogen) in, then with 3 × 10⁴The Density Distribution of cells/well is in micro reaction plate.Fluorescence probe will be contained (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids Hank balanced salt solutions (HBSS, Invitrogen) (PH=7.4) is added in above-mentioned micro reaction plate, and 37 DEG C of incubation 60min are then arised from cell one, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and adds testization Compound or with reference to antagonist or Hank balanced salt solutions, adds 10nM orexin B or Hank balanced salt solution (empty after 5min White control), the change of fluorescence intensity is then measured, it is changing into positive correlation with free intracellular calcium concentration.Experiment knot Fruit is represented with the suppression percentage relative to control group 10nM orexins B.

Standard is JNJ10397049 with reference to antagonist, amount effect curve is obtained by the experiment test of series concentration, so as to count Calculate IC₅₀Value.Experimental result is as shown in table 2.

The compounds of this invention of table 2 is to OX₂The antagonism of acceptor

Embodiment is numbered	OX₂IC₅₀(μM)
		Embodiment 1	0.305
Embodiment 2	0.310
		Embodiment 3	0.423
Embodiment 4	0.298

Test result indicates that, the compounds of this invention is to OX₂Acceptor shows preferable antagonism.

Pharmacokinetic Evaluation after embodiment C rats, dog and monkey intravenous or the quantitative the compounds of this invention of gavage

The present invention is assessed pharmacokinetic of the compounds of this invention in rat, dog and monkey body, is moved Thing information refers to Table A.

Table A animal subject information table of the present invention

Test method

By the compounds of this invention with 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline salt The form of the aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, gives to animal subject Medicine.For intravenous injection administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25th, 0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours when venous blood sampling (0.3mL), and under 3,000 or 4,000rpm from The heart 10 minutes, collects plasma solutions, and in preservation at -20 DEG C or -70 DEG C.For gastric infusion group, dosage is 2.5mg/ Kg or 5mg/kg, then time point upon administration be 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours when vein take Blood (0.3mL), and centrifuged 10 minutes under 3,000 or 4,000rpm, plasma solutions are collected, and in guarantor at -20 DEG C or -70 DEG C Deposit.

The plasma solutions obtained are collected to above-mentioned each group and carry out LC/MS/MS analyses.Result of the test shows, chemical combination of the present invention Thing has preferable pharmacokinetic property in rat, dog and monkey body.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or the spy that the embodiment or example are described Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area Art personnel can be tied the not be the same as Example or the feature of example and non-be the same as Example or example described in this specification Close and combine.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims

1. a kind of compound, stereoisomer, the tautomerism of its compound shown in the compound or formula (I) shown in formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, L be-C (=O)-,-C (=S)-or-S (=O)_q-；

Each R¹And R⁴It independently is H, D, F, Cl, Br, CN, C_1-6Alkyl, C_1-6Haloalkyl ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C_3-12Carbocylic radical, 3-12 atom group Into heterocyclic radical, C_6-10Aryl or 5-10 former molecular heteroaryls；

Each R²It independently is H, D, F, Cl, Br, NO₂、CN、C_1-4Alkyl, C_1-4Haloalkyl ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C_3-8Carbocylic radical, 3-8 atom composition Heterocyclic radical, C_6-10Aryl or 5-10 former molecular heteroaryls；

Each R³It independently is H, D, F, Cl, Br, NO₂、CN、C_1-4Alkyl, C_1-4Haloalkyl ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷、C_3-8Carbocylic radical, 3-8 atom composition Heterocyclic radical, C_6-10Aryl or 5-10 former molecular heteroaryls；

Each R⁵It independently is H, C_1-4Alkyl, C_1-4Haloalkyl ,-(CR⁹R¹⁰)_pC (=O) NR⁶R⁷、-(CR⁹R¹⁰)_pC (=O) R⁸、- (CR⁹R¹⁰)_pC (=O) OR^5a、-(CR⁹R¹⁰)_pS (=O)_qR⁸、-(CR⁹R¹⁰)_pS (=O)_qOR^5a、-(CR⁹R¹⁰)_pS (=O)_qNR⁶R⁷、 C_3-8Carbocylic radical, (C_3-6Carbocylic radical)-(C_1-4Alkylidene)-, 3-8 former molecular heterocyclic radicals, (3-6 former molecular heterocycles Base)-(C_1-4Alkylidene)-, C_6-10Aryl, (C_6-10Aryl)-(C_1-4Alkylidene)-, 5-6 former molecular heteroaryls or (5-6 Individual former molecular heteroaryl)-(C_1-4Alkylidene)-；

Each R^5aIt independently is H, C_1-4Alkyl, C_1-4Haloalkyl, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Virtue Base or 5-10 former molecular heteroaryls；

Each R⁶And R⁷It independently is H, C_1-4Alkyl, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-6 are individual Former molecular heteroaryl；

Each R⁸It independently is H, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Haloalkyl, C_1-4Halogenated alkoxy, C_1-4 Haloalkylamino, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 former molecular heteroaryls Base；

Each R⁹And R¹⁰It independently is H, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Haloalkyl, C_3-8Carbocylic radical, 3-8 Individual former molecular heterocyclic radical, C_6-10Aryl or 5-10 former molecular heteroaryls；

K is 0,1,2,3,4,5,6,7,8,9 or 10；

T is 0,1,2,3,4 or 5；

N is 0,1,2,3 or 4；

M is 0,1 or 2；

Each p independently is 1,2,3 or 4；

Each q independently is 1 or 2；

Wherein, described alkyl, haloalkyl, alkoxy, alkyl amino, halogenated alkoxy, haloalkylamino, carbocylic radical, Carbocylic radical alkylidene, heterocyclic radical, heterocycloalkylene, aryl, aryl alkylene, heteroaryl and heteroarylalkylenyl are individually optional Ground is by one or more R¹¹Replaced；

Wherein, each R¹¹It independently is H, D, F, Cl, Br, NO₂, CN, hydroxyl, amino, C_1-4Alkyl, C_1-4Haloalkyl, C_1-4Alcoxyl Base, C_1-4Alkyl amino, C_1-4Halogenated alkoxy, C_1-4Haloalkylamino, the C of amino substitution_1-4Alkyl, the C of hydroxyl substitution_1-4 Alkyl, the C of cyano group substitution_1-4Alkyl, C_3-8Carbocylic radical, 3-8 former molecular heterocyclic radicals, C_6-10Aryl or 5-10 atom group Into heteroaryl.

2. compound according to claim 1, wherein, each R²It independently is H, D, F, Cl, Br, NO₂, CN, methyl, ethyl, Propyl group, butyl, trifluoromethyl, the fluoro ethyls of 2,2- bis- ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷, cyclopropyl, cyclopenta, Oxyranyle, piperidyl, pyrrolidinyl, phenyl or pyrrole Piperidinyl.

3. compound according to claim 1, wherein, each R³It independently is H, D, F, Cl, Br, NO₂, CN, methyl, ethyl, Propyl group, butyl, trifluoromethyl, the fluoro ethyls of 2,2- bis- ,-OR⁵、-NR⁶R⁷,-C (=O) NR⁶R⁷,-C (=O) R⁸、-SR⁵,-S (=O)_qR⁸,-S (=O)_qOR⁵,-S (=O)_qNR⁶R⁷, cyclopropyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrolidinyl, piperidyl, Morpholinyl, phenyl, naphthyl, pyrrole radicals, pyridine radicals, pyrimidine radicals or quinolyl；

Wherein, R³Described in methyl, ethyl, propyl group, butyl, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, epoxy Ethyl group, pyrrolidinyl, piperidyl, morpholinyl, phenyl, naphthyl, pyrrole radicals, pyridine radicals, pyrimidine radicals and quinolyl are individually optional Ground is by one or more R¹¹Replaced.

4. compound according to claim 1, wherein, each R⁵It independently is H, methyl, ethyl, propyl group, butyl, fluoroform Base, the fluoro ethyls of 2,2- bis- ,-(CR⁹R¹⁰)_pC (=O) NR⁶R⁷、-(CR⁹R¹⁰)_pC (=O) R⁸、-(CR⁹R¹⁰)_pC (=O) OR^5a、- (CR⁹R¹⁰)_pS (=O)_qR⁸、-(CR⁹R¹⁰)_pS (=O)_qOR^5a、-(CR⁹R¹⁰)_pS (=O)_qNR⁶R⁷, cyclohexyl, cyclohexyl-ethyl, pyrrole Cough up alkyl, piperidyl, pyrrolidinylmethyl, piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridine radicals first Base, pyrrol ylmethyl or pyridyl-ethyl group；

Wherein, R⁵Described in methyl, ethyl, propyl group, butyl, the fluoro ethyls of 2,2- bis-, cyclohexyl, cyclohexyl-ethyl, pyrrolidines Base, piperidyl, pyrrolidinylmethyl, piperidinoethyl, phenyl, benzyl, phenethyl, pyridine radicals, pyrrole radicals, pyridylmethyl, Pyrrol ylmethyl and pyridyl-ethyl group are individually optionally by one or more R¹¹Replaced.

5. compound according to claim 1, wherein,

Each R^5aIt independently is H, methyl, ethyl, propyl group, butyl, trifluoromethyl, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, ring Hexyl, Oxyranyle, azelidinyl, pyrrolidinyl, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals or pyrimidine radicals； Wherein, R^5aDescribed in methyl, ethyl, propyl group, butyl, the fluoro ethyls of 2,2- bis-, cyclopropyl, cyclopenta, cyclohexyl, oxirane Base, azelidinyl, pyrrolidinyl, piperidyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals and pyrimidine radicals are individually optionally by one Individual or multiple R¹¹Replaced；

Each R⁶And R⁷It independently is H, methyl, ethyl, propyl group or butyl；

Each R⁸It independently is H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino or trifluoromethyl；

Each R⁹And R¹⁰It independently is H, methyl, ethyl, propyl group, butyl, methoxyl group, methylamino or trifluoromethyl.

6. compound according to claim 1, it is the structure of one of：

Or it is three-dimensional Isomers, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug.

7. a kind of pharmaceutical composition, it includes the compound described in claim 1-6 any one；Wherein, the drug regimen Thing further includes at least one of pharmaceutically acceptable excipient, carrier, adjuvant and solvent.

8. the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7 are in medicine is prepared Purposes, wherein, the medicine be used for prevent, treat or mitigate the disease related to orexin receptor.

9. purposes according to claim 8, wherein, the disease related to orexin receptor is sleep-disorder, depression It is disease, anxiety disorder, panic disorder, obsession, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, terrified Break out obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic Depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's, Parkinson's disease, dyskinesia, Feeding desorder, headache, antimigraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, Immune correlated disease, endocrine relevant disease or hypertension.