CN106674207A - Substituted aryl heteroaryl compound and application thereof - Google Patents

Substituted aryl heteroaryl compound and application thereof Download PDF

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Publication number
CN106674207A
CN106674207A CN201611129959.0A CN201611129959A CN106674207A CN 106674207 A CN106674207 A CN 106674207A CN 201611129959 A CN201611129959 A CN 201611129959A CN 106674207 A CN106674207 A CN 106674207A
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compound
alkyl
base
medicine
group
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CN106674207B (en
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金传飞
韦德活
薛亚萍
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a substituted aryl heteroaryl compound and application thereof, and further relates to a pharmaceutical composition containing the substituted aryl heteroaryl compound and application thereof. The compound or the pharmaceutical composition can be used for an antagonistic orexin receptor. The invention further relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition to preparation of drugs for treating or preventing nervous and psychogenic disorders and diseases of central nervous systems of mammals, especially human beings.

Description

Substituted aryl heteroaryl compound and application thereof
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a class can be used to treating or preventing central nervous system nerve Compound, composition with psychiatric disorders and disease and its production and use.More specifically, it is of the present invention to be Can be used as the aryl heteroaryl class compound of orexin receptor antagonists.
Background technology
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 in a kind of nerve worked in central nervous system secreted by hypothalamus Secreting hormone, its main physiological action has：1st, adjust and ingest, orexin can be obviously promoted feed, and anti-in dose-dependant Should, and have activated the neuron for adjusting feed；2nd, the regulation of energetic supersession is participated in, orexin can dramatically increase metabolic rate；3rd, join With the regulation of Sleep-Wake, orexin can suppress rapid eye movement sleep, extend the awakening time, block the effect of orexin Sleep can be promoted；4th, endocrine metabolic diseases are participated in, orexin is endocrine on pituitrin to affect apparent；5 and remuneration sense, learn Practise related to memory；6th, gastric acid secretion is promoted；7th, drinking-water is promoted to increase；8th, raising blood pressure；9th, in alcohol addiction disease, drug habit Work in disease, the treatment of jimjams, 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)。
Orexin plays biological agent by combining with orexin receptor (orexin receptor, OXR), and orexin is received Body is a kind of G- G-protein linked receptors, there is two types, is referred to as OX1Acceptor and OX2Acceptor, they are only distributed in brain tissue In, there were significant differences for the distribution of the two, wherein, OX1Acceptor be distributed mainly on ventromedial nucleus of hypothalamus, nucleus paraventricularis, hippocampal formation, Nucleus raphes dorsalis and locus coeruleus area, OX2Acceptor is distributed mainly on cerebral cortex, bottom thalamus, thalamic paraventricular nucleus and NPO (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)。
Orexin has very important significance for mammal, the especially mankind, its wide participation central nervous system Every regulation activity of system, is significant in pathology.The nerve related to orexin and orexin receptor and essence Godhead obstacle and kinds of Diseases are very more, common central nervous system nerve and psychiatric disorders and disease have depression, Have a sleepless night and tired caused by anxiety disorder, SAD, mania, bipolar disorders, besetment and behavior disorder, the time difference Labor, schizophrenia, convulsions, panic attack, melancholia, alcohol addiction disease, drug habit disease, jimjams, substance abuse, Drug addiction withdrawal symptom, insomnia, psychotic disorder, epilepsy, sleep-disorder, sleep confusion, sleep apnea synthesis Levy, the mandatory disturbance of food intake, fibromyalgia, stress reaction, obesity, Parkinson's, senile dementia, cognitive disorder, memory disorders, Premenstrualtension syndrome, antimigraine, the loss of memory, Alzheimer disease or other are related to normal or pathological seaility each Obstacle is planted, these diseases have badly influenced the stable and patient of society and its quality of life of household, and some are resulted even in It is dead.But, the anti-insomnia medicine Soviet Union that medicine related to orexin receptor in the market only has United States Merck company research and development is fertile Lei Sheng (Suvorexant), it is orexin receptor antagonists, and the medicine was also once once suffering because of safety issue the U.S. The refusal approval of FDA.
In consideration of it, at present orexin receptor antagonists have become anti-central nervous system nerve and psychiatric disorders and The research and development focus of disease class medicine.
The invention provides a class has the compound of orexin receptor antagonism, it has preferable drug activity, It is safe and toxic and side effect is little, while also there is excellent physicochemical property, medicine for property and toxicological characteristics.Therefore, possess Preferable potential applicability in clinical practice.
The content of the invention
Hereinafter some aspects of the present invention are only summarized, 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 When variant with citation, it is defined by the disclosure of the specification.
The invention provides a class has the compound of orexin receptor antagonists activity, can be used for preparing prevention or control Treat mankind's central nervous system nerve and psychiatric disorders and disease, such as depression, anxiety disorder, mania, alcohol addiction Disease, drug habit disease, jimjams, bipolar disorders, besetment and behavior disorder, stress reaction, sleep-disorder, the time difference lead The insomnia of cause and the medicine of fatigue and insomnia.Present invention provides the preparation method of these compounds and comprising these chemical combination The pharmaceutical composition of thing and using these compounds or the side of the above-mentioned disease of composition treatment mammal, the especially mankind Method.
The compounds of this invention shows good antagonistic activity to orexin receptor, with preferable drug effect, medicine for property And/or toxicological characteristics, such as it is good brain/blood plasma ratio (brain plasma ratio), good bioavilability, good Metabolic stability, low toxicity side effect and high security etc..Meanwhile, good characteristic of the compounds of this invention in some parameters, such as Half-life, clearance rate, selectivity, bioavilability, chemical stability, metabolic stability, permeability of the membrane, dissolubility etc., energy Enough promote the reduction of side effect, the expansion of therapeutic index or the improvement of tolerance.
Specifically：
On the one hand, the present invention relates to the alloisomerism of compound or formula (I) shown in compound of the one kind as shown in formula (I) Body, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein：
Z is-NR5- ,-C (=O) NR5- or-S (=O)2NR5-；
U is N or CR3a；
V is N or CR3b；
X is N or CR3c；
Y is N or CR3d；With
R1、R2、R3、R3a、R3b、R3c、R3d、R4、R5、R6, m, n, p and k there is implication as described in the present invention.
In some embodiments, each R1It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino, C1-4Hydroxyl Base alkyl, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radical, C6-10Aryl or 5-6 former molecular heteroaryl, wherein, Each R1Individually optionally by 1,2,3,4 or 5 R6Group is replaced；Wherein, each R6With implication as described in the present invention.
In some embodiments, each R3a、R3b、R3cAnd R3dIt independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkane Base, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Alkyl halide Base amino, C1-4Hydroxy alkyl, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radical, C6-10Aryl or 5-6 original are molecular Heteroaryl；
In some embodiments, each R2And R3It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Alkene Base, C2-4Alkynyl, C1-4Alkoxyl, C1-4Alkyl amino, C1-4Hydroxy alkyl or C1-4Haloalkyl；
In some embodiments, each R4It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino, C1-4Hydroxyl Base alkyl, (C1-4Alkyl)-C (=O)-, (C1-4Alkoxyl)-C (=O)-, (C1-4Alkyl amino)-C (=O)-, C3-8Carbocylic radical, 3-8 former molecular heterocyclic radical, C6-10Aryl, 5-6 former molecular heteroaryl, wherein, each R4Individually optionally by 1,2, 3rd, 4 or 5 R6Group is replaced；Wherein, each R6With implication as described in the present invention.
In some embodiments, R5For H, D, C1-4Alkyl, C1-4Haloalkyl, C3-8Carbocylic radical, 3-6 original are molecular miscellaneous Ring group, C6-10Aryl or 5-6 former molecular heteroaryl.
In some embodiments, each R6It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino or C1-4 Hydroxy alkyl.
In some embodiments, m is 0,1,2,3,4 or 5.
In some embodiments, n is 0,1,2,3 or 4.
In some embodiments, p is 1,2,3 or 4.
In some embodiments, k is 0,1 or 2.
In some embodiments, each R1It independently is H, F, Cl, Br, OH, NH2、NO2, CN, methyl, ethyl, propyl group, isopropyl Base, normal-butyl, isobutyl group, vinyl, acetenyl, methoxyl group, ethyoxyl, methylamino, ethylamino, methylol, ethoxy, trifluoro Methyl, cyclopropane base, piperidyl, piperazinyl, morpholinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl or thienyl.
In some embodiments, each R3a、R3b、R3cAnd R3dIt independently is H, F, Cl, Br, OH, NH2、NO2, CN, methyl, second Base, propyl group, isopropyl, normal-butyl, isobutyl group, vinyl, acetenyl, methoxyl group, ethyoxyl, methylamino, ethylamino, hydroxyl first Base, ethoxy, trifluoromethyl, cyclopropane base, piperidyl, piperazinyl, morpholinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl or Thienyl.
In some embodiments, each R2And R3It independently is H, F, Cl, OH, NH2、NO2, CN, methyl, ethyl, propyl group, isopropyl Base, vinyl, pi-allyl, propargyl, methoxyl group, ethyoxyl, methylamino, ethylamino, methylol, ethoxy or trifluoromethyl.
In some embodiments, each R4It independently is H, F, Cl, OH, NH2、NO2, CN, methyl, ethyl, propyl group, isopropyl, just Butyl, isobutyl group, vinyl, acetenyl, methoxyl group, ethyoxyl, methylamino, ethylamino, methylol, ethoxy, trifluoromethyl, Cyclopropane base, piperidyl, piperazinyl, morpholinyl, phenyl, pyrrole radicals, imidazole radicals, thiazolyl or thienyl.
Also in certain embodiments, the present invention relates to the compound of one of or its stereoisomer, change Isomers, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but it is not limited to these changes Compound：
Unless otherwise mentioned, the stereoisomer of compound shown in formula (I), dynamic isomer, solvate, metabolism is produced Thing, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
The present invention discloses compound can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms Exist.It is contemplated that all stereoisomer forms of compound shown in formula (I), including but not limited to diastereo-isomerism Body, enantiomter, atropisomer and geometry (or conformation) isomers, and their mixture such as racemic mixture, Become the part of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, then the structure All stereoisomers all consider within the present invention, and disclose compound and be included in the invention as the present invention.When When spatial chemistry is expressed the real wedge shape line (solid wedge) or dotted line of particular configuration and indicates, then the alloisomerism of the structure Body is with regard to this clear and definite and definition.
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.
Compound shown in formula (I) can be present in a salt form.In one embodiment, the salt referred to and pharmaceutically can connect The salt received.Term " pharmaceutically acceptable " refer to material or composition must with other compositions comprising preparation and/or use it The mammal for the treatment of is compatible in chemistry and/or in toxicology.In another embodiment, the salt is not necessarily pharmaceutically Acceptable salt, could be for preparing and/or compound shown in purification formula (I) and/or for separating chemical combination shown in this formula (I) The intermediate of the enantiomer of thing.
Pharmaceutically useful acid-addition salts can be disclosed compound and acted on inorganic acid or organic acid and be formed by the present invention, such as acetic acid Salt, hydroxyl acetate, esilate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/ Carbonate, disulfate/sulfate, camsilate, chloride/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, Fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionic acid Salt, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonic acid Salt, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalates, palmitic acid Salt, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- galactolipin hydrochlorate, propionate, stearate, succinate, sulphur Base salicylate, tartrate, tosilate and trifluoroacetate.
Pharmaceutically acceptable base addition salts can be disclosed compound and acted on inorganic base or organic base and be formed by the present invention.Described is inorganic Alkali includes, the metal of the I races to XII races of such as ammonium salt and periodic table.In certain embodiments, the salt derived from sodium, potassium, Ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt includes ammonium, potassium, sodium, calcium and magnesium salts；Organic base include primary amine, secondary amine and Tertiary amine, substituted amine includes naturally occurring substituted amine, cyclic amine, deacidite etc..Some organic amines include, For example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, Meglumine (meglumine), piperazine and tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or by making the free alkali form and chemistry of these compounds The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of appropriate, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
In addition, compound disclosed by the invention, including their salt, it is also possible to their hydrate forms or comprising it The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) is inherently or by design forming solvate；Therefore, it is contemplated that including the present invention Open compound solvation and unsolvated form.
Any structural formula that the present invention is given is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The compound of isotope enrichment has the structure that the formula that the present invention is provided 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 in the compounds of this invention Including 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 the defined compound of the present invention of isotope enrichment, for example, its In there is radio isotope, such as3H、14C and18Those compounds of F, or wherein there is non radioactive isotope, such as2H and13Those compounds of C.The compound of such isotope enrichment can be used for metabolism research and (use14C), Reaction kinetics research (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate group The SPECT (SPECT) of measure of spread is knitted, or be can be used in the radiotherapy of patient.18The change of F enrichments Compound is especially desirable for PET or SPECT researchs.Compound can pass through ability shown in the formula (I) of isotope enrichment Suitable isotope mark is used described by routine techniques familiar to field technique personnel or the embodiment in the present invention and preparation process Note reagent substitutes original used unmarked reagent to prepare.
Additionally, higher isotope is particularly deuterium (i.e.,2H or D) replacement some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements are reduced or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration that such higher isotope is particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to indication Fixed ratio between isotopic isotope abundance and natural abundance.If the substituent of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least for each D-atom specified 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium mix), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be that isotope replaces2O, acetone-d6、 DMSO-d6Those solvates.
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
On the other hand, the present invention relates to the preparation of compound shown in formula (I), the method for separating and purifying.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further including pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
In further embodiments, pharmaceutical composition of the present invention, further comprising other preventions or treatment Central nervous system is prevented or treated to the medicine of central nervous system nerve and psychiatric disorders and disease, described others The medicine of nerve and psychiatric disorders and disease be antidepressant, anxiolytic drugs, as the salts of mood stabilizers Medicine, antipsychotics, atypical antipsychotic drug, antiepileptic, anti-parkinson class medicine, hypnotic sedative agent Thing, antihistamine drug, GABA receptor stimulating agents and/or GABA reuptaking inhibitor class medicines, as MAOI Medicine, the medicine as melatonin receptors activator and the medicine as orexin receptor antagonists or their any group Close.
On the other hand, the present invention relates to the purposes of compound disclosed by the invention or composition in medicine is prepared, described Medicine is used to preventing, treat or mitigating mammal, including the central nervous system nerve and psychiatric disorders and disease of the mankind Disease.
In certain embodiments, described central nervous system nerve and psychiatric disorders and disease refer to depression, Have a sleepless night and tired caused by anxiety disorder, SAD, mania, bipolar disorders, besetment and behavior disorder, the time difference Labor, schizophrenia, convulsions, panic attack, melancholia, alcohol addiction disease, drug habit disease, jimjams, substance abuse, Drug addiction withdrawal symptom, insomnia, psychotic disorder, epilepsy, sleep-disorder, sleep confusion, sleep apnea synthesis Levy, the mandatory disturbance of food intake, fibromyalgia, stress reaction, obesity, Parkinson's, senile dementia, cognitive disorder, memory disorders, Premenstrualtension syndrome, antimigraine, the loss of memory, Alzheimer disease or other are related to normal or pathological seaility each Plant obstacle.
On the other hand, the present invention relates to the purposes of compound disclosed by the invention or composition in medicine is prepared, described Medicine is used for selective antagonism orexin receptor.
Biological results show that the compound that the present invention is provided is to OX1Acceptor and OX2Acceptor is respectively provided with preferable antagonism Effect, and there is preferable pharmacokinetic property in rat, dog and monkey body, can be used as preferable orexin receptor antagonism Agent.
Any embodiment of the either side of the present invention, can be combined, as long as they are not with other embodiments Contradiction occurs.Additionally, in any embodiment of either side of the present invention, arbitrary 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 below make more specific complete description.
Definition and general terms
Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula and chemical formula explanation enclosed.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and similar material for being combined Or many it is different from the application or conflicting in the case of it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carry 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 according to the present invention and public publication are integrally incorporated by reference this It is bright.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by.
There are significantly conflict, article " " used herein, " one (kind) " unless otherwise stated or in context " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment adopt or use.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some enforcements In scheme, " patient " refers to people.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " is referred to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image Molecule.
" enantiomter " refers to two isomers that can not be overlapped but be mutually mirror of a compound.
" diastereoisomer " refers to two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Compound can be by high resolution analysis operation such as electrophoresis and chromatogram, and such as HPLC is separating.
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.
With optical active forms presence, i.e., they have rotates the plane of linearly polarized light to many organic compounds Ability.When optically active compound is described, represent molecule with regard to one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during without stereoselectivity or during stereospecificity, May occur in which such case.
The present invention is disclosed any asymmetric atom (for example, carbon etc.) of compound and can be enriched with racemic or enantiomer In the form of, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Optically active (R)-or (S)-isomers can be prepared using chiral synthon or chiral reagent, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.
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, by 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 Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " dynamic isomer " or " tautomeric form " refer to that Tong Guo the low energy with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), 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 carries out by proton migration, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Tautomeric another example is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention optionally can be replaced by one or more substituents, such as General formula compound above, or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included.
In general, term it is " substituted " represent taken by concrete substituent to one or more hydrogen atoms in structure Generation.Unless other aspects show, a group for replacing can have a substituent, and in group, each commutable position is carried out Replace.When more than one position can be selected from one or more substituents of concrete group and be replaced in given structural formula, So substituent can be replaced with identical or different in each position.
Term " unsubstituted ", represents and specifies group without substituent.
Term " optionally by ... replace ", can exchange with term " unsubstituted or quilt ... replaces " and use, i.e., The structure is unsubstituted or is replaced by one or more substituents of the present invention.Substituent bag of the present invention Include, but be not limited to D, F, Cl, Br, I, CN, NO2、OH、NH2, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl, alkyl amino, Cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode for being adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between expressed concrete option between same-sign, it is also possible to represent in phase In same group, do not affect mutually between expressed concrete option between same-sign.
In each several part of this specification, the present invention discloses the substituent of compound and discloses according to radical species or scope.It is special Do not point out, the present invention includes these radical species and each independent sub-combinations thereof of each member of scope.For example, term “C1-4Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl and C4Alkyl.
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.For example, if the structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then represent respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", represent the straight or branched univalent hydrocarbyl group of saturation, Wherein, the alkyl group optionally can be replaced by the substituent of one or more present invention descriptions.Unless in addition in detail Illustrate, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；Another In embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom. The example of alkyl group is included, but is not limited to, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, uncle Butyl, n-pentyl, 2- amyl groups, 3- amyl groups, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acids-butyl, 2- methyl isophthalic acids - Butyl, n-hexyl, 2- hexyls, 3- hexyls, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 3- methyl -3- Amyl group, 2- methyl -3- amyl groups, 2,3- dimethyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl, etc..
Term " thiazolinyl " represents straight or branched monovalent hydrocarbon, wherein at least one carbon-to-carbon sp2Double bond, wherein, it is described Alkenyl group optionally can be replaced by one or more substituents described in the invention, and it includes " cis " and " trans " Positioning, or the positioning of " E " and " Z ".In one embodiment, alkenyl group includes 2-12 carbon atom；In another enforcement In scheme, alkenyl group includes 2-6 carbon atom；In yet another embodiment, alkenyl group includes 2-4 carbon atom.Thiazolinyl The example of group is included, but is not limited to, vinyl, pi-allyl etc..
Term " alkynyl " straight or branched monovalent hydrocarbon of the expression containing 2-12 carbon atom, wherein at least one carbon- The keys of carbon sp tri-, wherein, the alkynyl group optionally can be replaced by one or more substituents described in the invention. In one embodiment, alkynyl group includes 2-12 carbon atom；In another embodiment, alkynyl group is former comprising 2-6 carbon Son；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example of alkynyl group is included, but is not limited to, second Alkynyl, propargyl, 1- propinyls etc..
Term " alkoxyl " 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 an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can optionally by one or more The substituent of present invention description is replaced.The example of alkoxy base is included, but is not limited to, methoxyl group, ethyoxyl, the oxygen of 1- third Base, 2- propoxyl group, 1- butoxy, 2- methyl-l- propoxyl group, 2- butoxy, 2- methyl -2- propoxyl group, etc..
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is replaced by one or two alkyl group；The alkyl has implication described in the invention.Some of them embodiment is, Alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Other one A little embodiments are that alkyl amino is one or two C1-4Lower level alkyl be connected on nitrogen-atoms formed alkyl amino Group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but does not limit In, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " hydroxy alkyl " represents that alkyl group is replaced by one or more hydroxyls, and wherein alkyl group has such as this The described implication of invention；Such example is included, but is not limited to, methylol, 2- hydroxyethyls, 2- hydroxyl -1- propyl group, 3- hydroxyls Base -1- propyl group, 2,3- dihydroxypropyls etc..
Term " haloalkyl ", " halogenated alkoxy " or " haloalkylamino " represents alkyl, alkoxyl or alkyl amino Group is replaced by one or more halogen atoms, wherein alkyl, and alkoxyl or alkylamino group have as described herein Implication, such example is included, but is not limited to, trifluoromethyl, 2,2,3,3- tetra- fluoropropyls, trifluoromethoxy, fluoroform Base amino etc..
Term " carbocylic radical " or " carbocyclic ring " represent that containing 3-12 ring carbon atom unit price or the nonaromatic of multivalence are satisfied And/or unsaturated monocyclic, the bicyclic or three-ring system in part.Carbon bicyclic group is including spiral shell carbon bicyclic group and condenses carbon bicyclic group, properly Carbocylic radical group include, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3- 8 ring carbon atoms；In yet another embodiment, carbocylic radical includes 3-6 ring carbon atom.The example of carbocylic radical group includes, but It is not limited to：Cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyls, 1- cyclopenta -2- thiazolinyls, 1- cyclopenta -3- thiazolinyls, Etc..The carbocylic radical group can be independently unsubstituted or be taken by one or more substituents described in the invention Generation.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated nonaromatic unit price or multivalence are monocyclic, bicyclic or tricyclic, and wherein at least one annular atom is selected from nitrogen, sulphur and oxygen Atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can optionally by-C (=O)-replacement. The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds. The example of heterocyclic radical includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidines Base, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, morpholinyl, piperazinyl, etc..- CH in heterocyclic radical2- group quilt-C (= The example of O)-replacement includes, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidone bases, 3,5- bis- Oxo-piperidine base and hybar X base.In heterocyclic radical the oxidized example of sulphur atom include, but not limited to sulfolane base, 1,1- Dioxothiomorpholinyl.Described heterocyclyl groups can optionally by one or more substituent institutes described in the invention Replace.
" Z is former molecular " in term " Z former molecular heterocyclic radical ", " Z former molecular heteroaryl ", its Middle Z is integer, typically describes the number of ring member nitrogen atoms in molecule, and the number of ring member nitrogen atoms is Z in the molecule.For example, Piperidyl is the molecular Heterocyclylalkyl of 6 originals, and decahydro naphthyl is the molecular carbocylic radical group of 10 originals.
Term " undersaturated " expression for being used in the present invention contain in group one or more degrees of unsaturation.
Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (as the NR in the pyrrolidinyl that N- replaces).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The carbocyclic ring system of ring or three rings, wherein, each ring is 3-7 former molecular ring, and at least one ring is aromatic；Institute The aromatic yl group stated has one or more attachment points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " is exchanged and used.In one embodiment, aryl is the carbocyclic ring system being made up of 6-10 annular atom.The example of aromatic yl group Phenyl, naphthyl and anthryl can be included.The aromatic yl group can be with individually optional described in the invention by one or more Substituent is replaced.
Term " heteroaryl " represents and contains 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic or three rings, wherein at least one ring is aromatic, and at least one ring includes one or more hetero atoms；The heteroaryl Each member ring systems includes 5-7 former molecular ring in base, and has one or more attachment points to be connected with molecule remainder. Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups optionally by One or more substituents described in the invention are replaced.In one embodiment, heteroaryl is only comprising 1,2,3 or 4 The vertical heteroatomic 5-12 selected from O, S and N former molecular heteroaryl；In another embodiment, heteroaryl be comprising 1, 2nd, the 3 or 4 heteroatomic 5-6 for being independently selected from O, S and N former molecular heteroaryls.
The example of heteroaryl groups is included, but is not limited to, furyl, imidazole radicals, oxazolyls, thiazolyl, isothiazolyl, Tetrazole radical (such as 2H-1,2,3,4- tetrazole radicals, 1H-1,2,3,4- tetrazole radicals), triazolyl (such as 2H-1,2,3- triazolyls, 1H-1, 2,4- triazolyls, 4H-1,2,4- triazolyls), thienyl, 1H- pyrazolyls, N- pyrrole radicals, pyrrole radicals, pyridine radicals, pyrimidine radicals； Including following bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indyl are (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), etc..
As described in the invention, substituent draws one and is bonded the member ring systems formed on the ring at the center of being connected to (such as formula b institute Show) represent substituent any commutable position on the ring and can replace.For example, formula b represent substituent R can be on C rings It is monosubstituted or polysubstituted on any position that may be substituted, as shown in formula c1~formula c17.
As described in the present invention, group "-C (=O) NR5- " on have two connection sites to be connected with molecule remainder, The connected mode of two connection sites can be exchanged.For example, group can be by E ends or E ' ends and molecule remainder in formula a (for example, the phenylene in structure shown in formula (I) of the present invention) is connected.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or protection compound in amino feature, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protect the feature of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refers to the substituent of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. It is such conversion by pro-drug hydrolyze in blood or in blood or tissue Jing enzymatic conversions are affected for precursor structure.This Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that have of pro-drug, aliphatic in existing invention (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include Phosphate, such as these phosphate compounds are that the di on Jing parents is obtained.Beg for regard to pro-drug is complete By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" 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 pass through the present invention such as and retouch by technology known to art Adopt as stating and experimentally characterized.Such product can be by the way that compound is administered through oxidation, reduction, water Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the metabolite being fully contacted compound and the mammal of the present invention produced by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in 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, inorganic acid salt There is hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, an and acylate such as acetate, oxalates, maleate, Tartrate, citrate, succinate, malonate, or handed over by additive method described on books document such as ion Change method to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, Digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, phosphoglycerol Salt, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactic acid Salt, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, Oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionic acid Salt, stearate, rhodanate, tosilate, undecylate, valerate, etc..The salt bag obtained by appropriate alkali Include alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate the chemical combination of any group comprising N The quaternary ammonium salt that thing is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or alkaline earth Slaine includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further included appropriate, nontoxic ammonium, quaternary ammonium The amine cation that salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid Compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that one or more solvent molecules are formed with the compound of the present invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
When the solvent is water, it is possible to use term " hydrate ".In certain embodiments, a compounds of this invention Molecule can be in combination with a hydrone, such as monohydrate；In other embodiment, a compounds of this invention point Son can be in combination with more than one hydrone, such as dihydrate, in further embodiments, a compounds of this invention Molecule can be in combination with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention is remained with The biological effectiveness of the compound of nonhydrated form.
The as used in the present invention any disease of term " treatment " or illness, refer to it is all can slow down, interrupt, preventing, Control stops the progress of disease or illness, but not necessarily represents that all diseases or the symptom of illness all disappear, and it also includes Prophylactic treatment to the symptom, especially in the patient for easily suffering from such disease or obstacle.Some enforcements wherein Scheme middle finger improves disease or illness (slowing down or prevent or mitigate the development of disease or its at least one clinical symptoms).Another In some embodiments, " treatment " refers to mitigation or improves at least one body parameter, including the body that may not be discovered by patient Body parameter.In other embodiments, " treatment " refer to and (for example stablize perceptible symptom) from body or physiologically (example Such as stablize the parameter of body) or above-mentioned two aspect regulation diseases or illness.In other embodiments, " treatment " refer to prevention or Postpone outbreak, generation or the deterioration of disease or illness.
As used in the present invention term " therapeutically effective amount " or " treatment effective dose " are to refer to cause individual life 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.In a non-limiting embodiment, " treatment has term Effect amount " is referred to when to individual administration the compounds of this invention, to the effective amount of situations below：(1) alleviate at least in part, press down Make, prevent and/or improve (i) to be mediated by orexin, or (ii) related to orexin receptor activity, or (iii) is by appetite Illness or disease that the abnormal activity of plain acceptor is characterized；Or the activity of (2) reduction or appetite-suppressing element acceptor；Or (3) drop The expression of the plain acceptor of low or appetite-suppressing.In another embodiment, term " therapeutically effective amount " is referred to when to cell or device When official or acellular organism material or medium apply, can reduce at least in part or appetite-suppressing element receptor active；Or extremely Partially reduce or appetite-suppressing peptide expression of receptor effective the compounds of this invention amount.
As used in the present invention term compound " giving " and " administration " compound should be understood to its individual of needs Body provides the compound of the present invention or the prodrug of the compounds of this invention.It will be appreciated that those skilled in the art are by using effective The compounds of this invention treatment of the amount patient with this obstacle or prophylactically patient of the treatment with this obstacle can be with present Impact is produced on nerve and psychiatric disorders.
As used in the present invention term " composition " refers to the product of the predetermined component comprising ormal weight, and ormal weight Predetermined component the spawn that directly or indirectly produces of combination.The implication of this term related to pharmaceutical composition Including the product comprising active component (single either multiple) and the inert fraction (single or multiple) of composition carrier, Yi Jiyou Any two or Multiple components mixing, compound or aggregation, or by one or more ingredient breakdown, or by one or more one-tenth The other kinds of reaction for dividing or the spawn for interacting and directly or indirectly producing.Therefore, pharmaceutical composition of the present invention Including any combinations thing prepared by the way that the compounds of this invention is mixed with pharmaceutical acceptable carrier.
The pharmaceutical composition of the compounds of this invention, preparation and administration
Such as the present invention provides a kind of pharmaceutical composition, and it includes the present invention and discloses compound, listed chemical combination in embodiment Thing；With pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combinations thereof.
The present invention provides treatment, the method for preventing or improve disease or illness, including give safe and effective amount comprising this The combination medicine of disclosure of the invention compound and one or more therapeutically active agent.Wherein, combination medicine comprising one or more its His treatment central nervous system nerve and the medicine of psychiatric disorders and disease.
The medicine of other treatment central nervous system nerves and psychiatric disorders and disease is included but is not limited to：Antidepression Medicine, anxiolytic drugs, the salts medicine as mood stabilizers, antipsychotics, atypical antipsychotic drug, Antiepileptic, anti-parkinson class medicine, sedative hypnotic drug, antihistamine drug, GABA receptor stimulating agents and/or GABA are again Uptake inhibitor class medicine, the medicine as MAOI, as the medicine and work of melatonin receptors activator Medicine or their any combination for orexin receptor antagonists.
Described other treatment central nervous system nerves and the medicine of psychiatric disorders and disease are amitriptyline (amitriptyline), desipramine (desipramine), Mirtazapine (mirtazapine), Bupropion (bupropion), Reboxetine (reboxetine), Prozac (fluoxetine), Trazodone (trazodone), Sertraline (sertraline), Duloxetine (duloxetine), Fluvoxamine (fluvoxamine), Milnacipran (milnacipran), left-handed Milnacipran (levomilnacipran), desmethylvenlafaxine (desvenlafaxine), Wella Oxazolone (vilazodone), Venlafaxine (venlafaxine), Dapoxetine hydrochloride (dapoxetine), Nefazodone (nefazodone), femoxetine (femoxetine), chlorimipramine (clomipramine), Citalopram (citalopram), escitalopram (escitalopram), Paxil (paroxetine), lithium carbonate (lithium Carbonate, Eskalith), buspirone (buspirone), Olanzapine (olanzapine), Quetiapine (quetiapine), Risperidone (risperidone), Ziprasidone (ziprasidone), Aripiprazole (aripiprazole), Perospirone (perospirone), Clozapine (clozapine), modafinil (modafinil), U.S. Prepared-Calamine (mecamylamine), Cabergoline (cabergoline), adamantane (adamantane), imipramine (imipramine), Pramipexole (pramipexole), thyroxine (thyroxine), dextromethorphan (dextromethorphan), quinindium (quinidine), naltrexone (naltrexone), samidorphan, buprenorphine (buprenorphine), melatonin (melatonin), alprazolam (alprazolam), Pipamperone (pipamperone), dimension for smooth (vestipitant), perphenazine (perphenazine), midazolam (midazolam), Triazolam (triazolam), estazolam (estazolam), diazepam (diazepam), Flurazepam (flurazepam), nitre Dissolve (nitrazepam), Clonazepam (clonazepam), Temazepam (temazepam), Flunitrazepam in west (flunitrazepam), Oxazepam (oxazepam), zolpidem (zolpidem), Zaleplon (zaleplon), assistant gram Grand (zopielone), eszopiclone (eszopiclone), general grand (indiplon) Tiagabine (tiagabine) in English ground, plus Bo Shaduo (gaboxadol), clomipramine (clomipramine), doxepin (doxepin), chloraldurate (chloral Hydrate), haloperole (haloperidol), chlorpromazine (chlorpromazine), carbamazepine (carbamazepine), fenazil (promethazine), Lorazepam (lorazepam), hydroxyzine (hydroxyzine), Ah A department woods (aspirin), diphenhydramine (diphenhydramine), chlorpheniramine (chlorphenamine), brotizolam (lendormin), Ramelteon (ramelteon), Te Simeiertong (tasimelteon), agomelatine (agomelatine), mianserin (mianserine), method Mack Xi Ting (femoxetine), nabilone (nabilone), many Consider flat (doxepin), Gabapentin (gabapentin), librium (chlordiazepoxide), suvorexant, Xuezang Guben or their any combination.
The amount of compound refers to energy effective detection to antibionts sample or patient in pharmaceutical composition disclosed by the invention The amount of internal orexin receptor.The dosage of active component can change in the present composition, but, the amount of active component is necessary It can be the amount for obtaining appropriate dosage forms.Active component can be with the dosed administration of offer optimal drug effect in this treatment of needs Patient (animal and people).Selected dosage depends on desired therapeutic effect, when continuing depending on method of administration and treatment Between.Dosage will be different with patient, this depend on disease attribute and the order of severity, the weight of patient, the concrete diet of patient, Medicine used at the same time and it will be recognized by those skilled in the art other factorses.It is every that dosage range is usually each patient Its about 0.5mg to 1.0g, can be administered in the form of single dose or multi-agent.In one embodiment, dosage range is each patient Daily about 0.5mg to 500mg；It is in another embodiment the daily about 0.5mg to 200mg of each patient；In also another enforcement It is the daily about 5mg to 50mg of each patient in scheme.
It will also be appreciated that some compounds of the present invention can be present in a free form and for treating, or it is if suitable When can be in the form of its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates include pharmaceutically acceptable Prodrug, salt, ester, the salt of these esters, or of the present inventionization can be directly or indirectly provided when being administered to patient in need Any other adduct or derivative of compound or its metabolite or residue.
Medicine disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) form in bulk, wherein extractable peace Compound shown in the formula (I) of full effective dose, then gives patient with powder or syrup form.Generally, arrive with daily 0.0001 Dosage level between 10mg/kg body weight is administered to obtain antagonism effective to orexin receptor to patient.Or, this The pharmaceutical composition of disclosure of the invention can prepare and be packaged as unit dosage forms, and wherein each physically discrete unit contains safety and has Compound shown in the formula (I) of effect amount.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention generally can contain, example Such as, the compound disclosed by the invention of 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg.
When the pharmaceutical composition of the present invention also contains one or more other activearm in addition to containing the compounds of this invention Timesharing, the compounds of this invention can change and depending on the effective of every kind of component with the compound weight ratio of the second active component Dosage.Generally, using every kind of effective dose.Thus, for example, when the compounds of this invention mixes with another kind of medicament, this Bright compound and the weight ratio of another kind of medicament generally range from about 1000: 1 to about 1: 1000, e.g., from about 200: 1 to about 1: 200.The mixture of the compounds of this invention and other active components generally also within the above range, but in each case, all The effective dose of every kind of active component should be used.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used by the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with other of pharmaceutical composition into Split-phase is held, and the interaction of effect for disclosing compound of the invention can be substantially reduced during avoiding that patient is administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example Such as, with sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete formulation.Additionally, can be according to them in group Specific function in compound is selecting pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Some the pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.May be selected to contribute to when patient be administered to carry or transport it is of the invention compound is disclosed from an organ of body or partly to Another organ of body or the pharmaceutically acceptable excipient of some partial.Some medicines for strengthening patient compliance may be selected Acceptable excipient on.
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 It is taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stable Agent, surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable excipient can provide more than one Function, and alternative function is provided, this depend on existing in preparation which be present in how many excipient and preparation other 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.Resource obtained by a large amount of technical staff is additionally, there are, 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 Disclose in Dekker, New York for configuring the various carriers of pharmaceutically acceptable composition, and prepare for it 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 so that any other composition in harmful way and pharmaceutically acceptable composition occurs to interact with the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to prepare the technique of pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, the technique includes that mixing is each Plant composition.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.
Compound disclosed by the invention is usually formulated as being adapted to pass through the formulation that required approach is administered patient.Example Such as, formulation is suitable for the formulation of following method of administration including those：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) local is administered, for example cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration formulation.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
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 providing.Enteric coatel tablets are to use the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving in intestines or be disintegrated 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 solubility The compressed tablets that the thin layer of material or film are covered.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethylcellulose calcium Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses and sweet tablet identical general characteristic.It is multiple Compressing tablet is the compressed tablets through preparing more than press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by the one kind in powder, crystallization or granular active component individually or with present invention description Or variety carrier or excipient composition, preparing, 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 chewable tablets and lozenge is formed.
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 Tie up element, starch or calcium alginate 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.SEC (SEC) is soft, spherical shell, such as gelatin shell, It passes through to add the plasticizing of glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can be comprising 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 Liquid, semisolid and the solid dosage forms that invention is provided 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 such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Described in 4,409,239 and 4,410,545 preparing.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 pellet form in another kind of liquid, 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 acceptance, 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 also preservative can be included.For liquid dosage form, for example, the solution in polyethylene glycol Can be with such as water dilution of enough pharmaceutically acceptable liquid-carriers, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to the active component provided comprising the present invention and two grades Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate mean molecule quantity of glycol -750- dimethyl ether, wherein 350,550,750 finger polyethylene glycol.These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, the dosage unit preparations microencapsulation that will can be administered orally.Can also be prepared into extending or tieing up The composition of release is held, such as by by microparticle material coating or being embedded in polymer, wax or the like.
The combination of oral medication that the present invention is provided can be being carried in the form of liposome, micella, microballoon or nanometer system For.Micella formulation can be prepared with the method that U.S.Pat.No.6,350,458 is described.
The pharmaceutical composition that the present invention is provided can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.Pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis can include dilution Agent, sweetener and wetting agent.Pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can be wrapped Include organic acid and carbon dioxide source.
Can be using colouring agent and flavor enhancement in all above-mentioned formulations.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl The oxide polylysine that amine phenol or palmitoyl residues replace.Additionally, compound disclosed in this invention can with reality A class Biodegradable polymeric used in the control release of existing medicine is combined, for example, PLA, poly-epsilon-caprolactone, poly- The crosslinking of hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are common Polymers.
The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including postpone-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention is provided can be common with other active components without compromising on expected therapeutic action Prepare, or the material co-formulation with supplementary expected effect.
The pharmaceutical composition that the present invention is provided can be by injecting, being transfused or being implanted into parenteral, for local or complete Body is administered.The parenteral that such as present invention is used is included in intravenous, intra-arterial, intraperitoneal, intrathecal, 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 be suitable to any formulation of parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and being suitable to makes in a liquid before the injection consolidating for solution or suspension 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 carrier and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersion that thing grows Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter：Water, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solutions, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solutions.Non- transporter includes, but not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and PEG400), propane diols, glycerine, METHYLPYRROLIDONE, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but not limited to phenol, cresols, mercurial, phenmethylol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitable antioxidant is including the sulfurous acid such as present invention description Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone such as present invention description. Suitable emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is moved back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to NaOH, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, HP-β-CD, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrins (CyDex,Lenexa,KS)。
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 being mounted in ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All of parenteral administration all must be aseptic, as known in the art with practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, medicine Composition is provided with aseptic dried soluble product, including freeze-dried powder and hypodermic tablet, and it is using front using carrier Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into before use and are dried insolubility product with the aseptic of carrier reconstruct.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, the administration of the reservoir as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, its be insoluble to body fluid but The outside polymeric membrane that the active component in pharmaceutical composition is diffused through is allowed to be surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the PET of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, hydrogel, collagen, the crosslinking of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable outside polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable to the formulation with dry powder doses to patient's inhalation.In yet another embodiment, it is disclosed in this invention Pharmaceutical composition can be configured to be suitable to the formulation by sprayer to patient's inhalation.By the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and one or more it is fine powdered pharmaceutically Acceptable excipient.The pharmaceutically acceptable excipient for being especially suitable for use as dry powder doses is known to those skilled in the art Dawn, it includes lactose, starch, mannitol and single-, two- and polysaccharide.Fine powder can be prepared for example, by micronizing and grinding Obtain.In general, reduced size of (as micronized) compound can pass through about 1 to 10 micron of D50Value (for example, is used and swashed The measurement of optical diffraction method) defining.
Aerosol can be by being suspended or dissolved in compound disclosed in this invention to prepare in liquefied propellant.It is adapted to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), HFC-134a (HFA-134a), 1,1- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention generally passes through Metered dose inhaler (MDI) is administered to patient, such device dawn known to those skilled in the art.
Aerosol can include pharmaceutically acceptable excipient that is extra, can using by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
Being suitable for the pharmaceutical composition of cutaneous penetration can be prepared into discontinuous paster agent, it is intended that keep with the epidermis of patient It is in close contact the time of an elongated segment.For example, can be by ion infiltration from delivering active ingredients in paster agent, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can be with water or oil Matrix, and suitable thickener and/or gel and/or solvent are configuring.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.
Lotion can be prepared with water or oil matrix, and generally also contain one or more emulsifying agent, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of arbitrarily suitable powder matrix such as talcum powder, lactose or starch.Drops Can be formulated with the water comprising one or more dispersant, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered daily in affected part using one or many, and the impermeable plastic wound dressing for covering skin is preferential Used.Adhesiveness store system is capable of achieving administration that is continuous or extending.
The purposes of the compounds of this invention and composition
Compound disclosed in this invention or pharmaceutical composition can be used for preparing for treating, prevent, improving, controlling or Mitigate mammal, including the central nervous system nerve and psychiatric disorders and the medicine of disease of the mankind, it is also possible to be used for Prepare other medicines for antagonism orexin receptor.
Specifically, in composition of the invention compound amount can effectively detectably antagonism orexin receptor, The compound of the present invention can be used as prevention or treatment mankind's central nervous system (CNS) nerve and psychiatric disorders and disease Such as depression, anxiety disorder, SAD, mania, bipolar disorders, besetment and behavior disorder, the time difference cause Insomnia and fatigue, schizophrenia, convulsions, panic attack, melancholia, alcohol addiction disease, drug habit disease, alcoholism Disease, substance abuse, drug addiction withdrawal symptom, insomnia, psychotic disorder, epilepsy, sleep-disorder, sleep be chaotic, Sleep apnea syndrome, the mandatory disturbance of food intake, fibromyalgia, stress reaction, obesity, Parkinson's, senile dementia, cognitive barrier Hinder, memory disorders, premenstrualtension syndrome, antimigraine, the loss of memory, Alzheimer disease or other and normal or pathologic The medicine of the related various obstacles of aging.
The compound or composition of the present invention can apply to, but be not limited to, the compound or combination using the present invention Mammal is prevented patient's administration, treats or mitigated to the effective dose of thing, including the central nervous system nerve of the mankind and Psychiatric disorders and disease.The central nervous system nerve and psychiatric disorders of the described mankind and disease, further include But be not limited to, depression, anxiety disorder, SAD, mania, bipolar disorders, besetment and behavior disorder, when Insomnia and fatigue, schizophrenia, convulsions, panic attack, melancholia, alcohol addiction disease, drug habit disease, alcohol caused by difference Nosotoxicosis, substance abuse, drug addiction withdrawal symptom, insomnia, psychotic disorder, epilepsy, sleep-disorder, sleep are mixed Unrest, sleep apnea syndrome, the mandatory disturbance of food intake, fibromyalgia, stress reaction, obesity, Parkinson's, senile dementia, recognize Know obstacle, memory disorders, premenstrualtension syndrome, antimigraine, the loss of memory, Alzheimer disease or other and normal or disease The related various obstacles of rationality aging.
The compound and pharmaceutical composition of the present invention applies also for veterinary treatment and dotes 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, the compound of the present invention includes its pharmaceutically acceptable derivates.
Treatment method
In one embodiment, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by having The patient of needs gives the present invention of safe and effective amount and discloses compound or disclose the pharmaceutical composition of compound comprising the present invention, Method to treat disease mentioned above.
In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound It is administered by any suitable method of administration, including Formulations for systemic administration and local are administered.Formulations for systemic administration includes oral administration, stomach and intestine External administration, cutaneous penetration and rectally.Typical parenteral referred to by injection or administered by infusion, including intravenous, Intramuscular and hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and intranasal Administration.In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound It is to be administered orally.In another embodiment, the present invention discloses compound or discloses the drug regimen of compound comprising the present invention Thing can be inhalation.In a further embodiment, the present invention discloses compound or discloses compound comprising the present invention can be Intranasal administration.
In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound Once daily, or according to dosage regimen, at the appointed time in section, be administered several times in different time intervals.For example, often It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.Can be administered until reaching the therapeutic effect wanted or indefinitely maintaining the therapeutic effect wanted.It is of the invention public Become civilized compound or comprising the present invention disclose compound pharmaceutical composition appropriate dosage regimen depending on the compound medicine generation Kinetic property, such as dilution, distribution and half-life, these can be by determination of technical staff.Additionally, the present invention discloses compound Or the appropriate dosage regimen comprising the pharmaceutical composition for disclosing compound of the invention, including the duration of the enforcement program, take Certainly in treated disease, the order of severity of disease being treated, the age of patient under consideration and health, patient under consideration Medical history, while the factor in the range of technical staff's knowledge and experience such as the property of therapy, therapeutic effect for wanting.It is such Technical staff should also be understood that the reaction for individual patient to dosage regimen, or over time passage individual patient needs to become During change, in order to be sufficiently accurate it may be desired to adjust suitable dosage regimen.
The present invention discloses compound and with one or more other therapeutic agent simultaneously, or can before it or afterwards be administered. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different method of administration, or therewith with same medicine group Solvate form is administered.
For the individuality of about 50-70kg, the present invention pharmaceutical composition disclosed and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active components Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individuality species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinician or animal doctor can easily determine to prevent, treat or suppress disease (disorder) or disease (disease) development During required each active component effective dose.
Dose Characteristics cited above using favourable mammal (such as mouse, rat, dog, monkey) or its from Confirm in the external and in vivo studies of body organ, tissue and sample.The present invention discloses compound with solution, such as aqueous solution form Use in vitro, it is also possible to such as suspension or aqueous solution form enteral in vivo, it is parenteral, it is especially intravenous to use.
In one embodiment, the treatment effective dose that the present invention discloses compound is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg compounds of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, about 10mg to about 1,000mg, and about 20mg is to about The combination of each main component in 500mg, or the main active or every dosage unit form of about 25mg to about 250mg.One In particular, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention discloses compound " prodrug " when be administered to patient, finally can in vivo discharge the functional derivatives that the present invention discloses compound.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement the one kind in following manner and more than：(a) The internal onset time of change compound；B () changes the internal acting duration of compound；C () changes the internal of compound Conveying is distributed；D () changes the internal solubility of compound；And (e) overcomes the side effect or other difficult points that compound faced. For preparing the typical functional derivatives of prodrug, comprising in vivo chemically or enzyme the mode compound that cracks Variant.Comprising preparing these variants of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.
General synthesis step
For the description present invention, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment is used to that this to be further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods for preparing the compound of the present invention are considered as the model in the present invention Within enclosing.For example, can 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 reagents 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 other aspects show that all of temperature is 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 through being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain through metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain through calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that in advance drying is used Jing anhydrous sodium sulfates.
Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects 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.
1H H NMR spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), marked as reference with TMS (0ppm) or chloroform (7.26ppm) It is accurate.When there is multiplet, by using following abbreviation：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).Coupling constant, is represented with hertz (Hz).
The condition determination of Algorithm (MS) data is：Level Four bar HPLC-M (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Use Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (the pillar types of pure compound Number：NOVASEP 50/80mm DAC), detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
CH2Cl2, DCM dichloromethane；Cs2CO3Cesium carbonate；NiCl2Nickel Chloride；NaBH4Sodium borohydride；CDC13 Deuterochloroform；DMSO-d6Deuterated dimethyl sulfoxide；CD3OD deuterated methanols；CuI cuprous iodides；DMF N, N- dimethyl formyl Amine；CH3CH2Br bromoethanes；Pyridine pyridines；Et3N, TEA triethylamine；EtOAc, EA ethyl acetate；(Boc)2O、Boc Acid anhydrides di-tert-butyl dicarbonate；Acetone acetone；G gram；H hours；Min minutes；N2Nitrogen；HCl hydrochloric acid；CH3COOH Acetic acid；K2CO3Potassium carbonate；NaH sodium hydrides；Na2SO 4Sodium sulphate；MeOH methyl alcohol；ML, ml milliliter；Pd(PPh3)4Four (three Phenylphosphine) palladium；PE petroleum ethers (60-90 DEG C)；RT, rt, r.t. room temperature；Rt retention times；SOCl2Thionyl chloride, chlorination Sulfoxide；Toluene toluene；NMP 1-METHYLPYRROLIDONEs
The preparation present invention discloses the typical synthesis step of compound as shown in following synthetic schemes 1.Unless otherwise indicated, Each R1、R4, m and n there is as described in the present invention definition.
Synthetic schemes 1
The compounds of this invention (10) can be prepared by the general synthetic method described in synthetic schemes 1, and in tool Describe in detail in body embodiment：The bromo- 2- chlorine pyrimidines of 5- (1) obtain intermediate with t-butylcyanoacetate reaction in the basic conditions (2), intermediate (2) in acid condition heating response obtain intermediate (3), intermediate (3) with different substituents replace benzene Ylboronic acid is catalyzed in tetrakis triphenylphosphine palladium, under appropriate alkali existence condition heating response obtain intermediate (4), intermediate (4) The lower room temperature reaction of nickel catalysis obtain intermediate (5), intermediate (5) slough Boc protection groups in acid condition and obtain compound (6)。
Different substituents replace o-iodobenzoic acid (7) and 1H-1, the reaction of 2,3- triazoles, exist and add in appropriate alkali Under heat condition by catalyst (such as CuI) catalytic reaction obtain intermediate (8).Compound (2) with chlorinating agent in heating condition It is lower reaction obtain compound (9).Compound (9) with above-mentioned gained compound (6) direct reaction obtain final product target compound (10)。
Compound, pharmaceutical composition and its application for providing the present invention with reference to embodiments is further described.
Embodiment
Embodiment 1:N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzene The synthesis of formamide
Step 1) 2- (5- Bromopyrimidine -2- bases) -2- t-butylcyanoacetates synthesis
By the bromo- 2- chlorine pyrimidines (5.80g, 30.00mmol) of 5-, potassium carbonate (12.60g, 90.25mmol) and N- methylpyrroles Alkanone (25mL) is added sequentially in 100mL reaction bulbs, be then slowly added to t-butylcyanoacetate (6.50mL, 45.00mmol), add after finishing, reaction is warming up to 80 DEG C and reacts 3 hours.Stop reaction, reactant liquor is poured in water (400mL), Watery hydrochloric acid is adjusted to pH value of solution=5, and suction filtration collects solid, and crude product directly carries out silica gel column chromatography separating purification (petroleum ether/bis- Chloromethanes (v/v)=1/5) obtain title compound (yellow solid, 3.19g, 35.72%).MS(ESI,pos.ion)m/z: 298.14[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.60 (d, J=2.7Hz, 1H), 7.84 (s, 1H), 4.12 (q, J= 7.1Hz,1H),1.53(s,9H).
Step 2) 2- (5- Bromopyrimidine -2- bases) acetonitrile synthesis
By 2- (5- Bromopyrimidine -2- bases) -2- t-butylcyanoacetates (3.06g, 10.30mmol), the hydrochloric acid of 4mol/L (20mL) in being added sequentially to the reaction bulb of 100mL with acetic acid (20mL), reaction is warming up to 70 DEG C.Stop within 2 hours reaction, reaction Liquid is directly poured in frozen water (150mL), ethyl acetate (50mL × 3) extraction, merge organic phase, sequentially pass through water (50mL × 3), Saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying, and vacuum distillation removes solvent, and gained crude product directly carries out silicagel column Chromatography purifying (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (yellow solid, 1.37g, 67.40%).
MS(ESI,pos.ion)m/z:198.20[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.80(s,2H),4.07(s,2H).
Step 3) 2- (5- (4- fluorophenyls) pyrimidine) -2- bases) acetonitrile synthesis
By 2- (5- Bromopyrimidine -2- bases) acetonitrile (0.10g, 0.50mmol), 4- flurophenyl boronic acids (0.08g, 0.60mmol), Potassium carbonate (0.21g, 1.50mmol), tetrakis triphenylphosphine palladium (0.03g, 0.03mmol) and toluene (10mL) are added sequentially to In 50mL reaction bulbs, react and protected using nitrogen, 100 DEG C are reacted 8 hours.Stop reaction, vacuum distillation removes solvent, remaining solid Body is extracted using dichloromethane (10mL × 3), merges organic phase, and saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying subtracts Pressure is distilled off solvent, and gained crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=20/1) and obtains To title compound (white solid, 0.08g, 80.1%).
MS(ESI,pos.ion)m/z:214.24[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.91 (s, 2H), 7.59~7.50 (m, 2H), 7.23 (t, J= 8.6Hz,2H),4.16(s,2H).
Step 4) tert-butyl group (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) formamide synthesis
By 2- (5- (4- fluorophenyls) pyrimidine) -2- bases) acetonitrile (0.05g, 0.20mmol), Nickel Chloride (0.03g, 0.20mmol) it is added sequentially in 50mL reaction bulbs with absolute methanol (5mL), Boc is added dropwise in reaction system at 0 DEG C sour Acid anhydride (0.11g, 0.50mmol), after completion of dropping, stirs 1 hour at 0 DEG C, adds sodium borohydride (0.06g, 2.00mmol).Plus Enter after finishing, reaction switchs to room temperature reaction overnight.Stop reaction, suction filtration collects filtrate, and vacuum distillation removes solvent, and gained is thick Product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=20/3) and obtains title compound (white is solid Body, 0.02g, 30.2%).
MS(ESI,pos.ion)m/z:318.05[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.83 (s, 2H), 7.57~7.49 (m, 2H), 7.20 (t, J= 8.6Hz, 2H), 3.72~3.60 (m, 2H), 3.20 (t, J=6.0Hz, 2H), 1.42 (s, 9H).
Step 5) 2- (5- (4- fluorophenyls) pyrimidine -2-base) ethylamine hydrochloride synthesis
By the tert-butyl group (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) formamide (1.77g, 5.58mmol) and anhydrous two Chloromethanes (20mL) is added in 50mL reaction bulbs, is subsequently added the ethyl acetate solution (15mL) of hydrogen chloride, and room temperature reaction 2 is little When.Stop reaction, vacuum distillation remove solvent obtain title compound (faint yellow solid, 1.72g, 99.0%).
MS(ESI,pos.ion)m/z:218.12[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.76 (s, 2H), 7.52~7.46 (m, 2H), 7.18 (t, J= 8.7Hz, 2H), 3.78~3.65 (m, 2H), 3.22 (t, J=6.0Hz, 2H).
Step 6) 2- (2H-1,2,3- triazole -2- bases) benzoic synthesis
By 1,2,3- triazoles (0.70g, 10.08mmol), the iodo- benzoic acid of 2- (1.00g, 4.03mmol), cesium carbonate (2.36g, 7.20mmol), trans-N, N'- dimethyl -1,2- cyclohexanediamine (0.10g, 0.75mmol), cuprous iodide (0.08g, 0.40mmol), DMF (18mL) is added sequentially in 100mL single necked round bottom flask, nitrogen protection Under be gradually heating to 100 DEG C react 4 hours.Stop reaction, cooling is diluted with running water and extracted with ethyl acetate (200mL × 2) Take.Water layer concentrated hydrochloric acid acidifying (pH=1~2) is extracted afterwards with ethyl acetate (200mL × 2), and the organic layer for merging below is used in combination Anhydrous sodium sulfate drying, filters, and filtrate decompression is evaporated and carries out column chromatographic isolation and purification (methylene chloride/methanol (v/v)=30/ 1) obtain title 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 (w, 1H), 8.08 (s, 2H), 7.78~7.75 (m, 2H), 7.72~7.68 (m, 1H), 7.60~7.57 (m, 1H).
Step 7) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride synthesis
2- (2H-1,2,3- triazole -2- bases) benzoic acid (0.37g, 1.96mmol) is added to into 100mL single neck round bottom to burn In bottle, dissolved with 20mL anhydrous methylene chlorides, then be slowly added into thionyl chloride (6mL, 82.7mmol), pyridine (0.04mL, 0.50mmol), it is gradually heating to back flow reaction 3 hours.Stop reaction, cooling, decompression slowly boils off solvent, and products therefrom is direct Into next step.
Step 8) N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzene first The synthesis of acid amides
By 2- (5- (4- fluorophenyls) pyrimidine -2-base) ethylamine hydrochloride (0.30g, 1.40mmol), triethylamine (0.57mL, 4.00mmol) and anhydrous methylene chloride (10mL) are added sequentially in 50mL single port bottles, and at 0 DEG C 2- is added dropwise over Dichloromethane (10mL) solution of (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.35g, 1.68mmol).Completion of dropping Afterwards, room temperature reaction 2 hours.Stop reaction, reactant liquor sequentially passes through watery hydrochloric acid (5mL), water (20mL × 3), saturated aqueous common salt (20mL) wash, anhydrous sodium sulfate drying, organic phase directly carry out column chromatographic isolation and purification (methylene chloride/methanol (v/v)= 200/1) obtain title compound (white solid, 0.25g, 47.2%).
MS(ESI,pos.ion)m/z:388.90[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.76 (s, 2H), 7.75 (d, J=7.8Hz, 1H), 7.65~7.63 (m, 3H), 7.54~7.50 (m, 3H), 7.45 (t, J=7.8Hz, 1H), 7.20 (t, J=8.6Hz, 2H), 6.80 (s, 1H), 3.89 (dd, J=11.4,5.9Hz, 2H), 3.24 (t, J=5.9Hz, 2H).
13C NMR(CDCl3,151MHz)δ(ppm):167.90,167.56,154.87,135.77,130.62,130.44 (d, J=0.45Hz), 129.33,128.70 (d, J=8.5Hz), 124.08,116.76,116.62,37.46,37.44.
HPLC:96.15%.
Embodiment 2:N- ethyl-N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazoles - 2- yls) benzamide synthesis
By N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzamide During (0.20g, 0.51mmol) and dry DMF (5mL) are added sequentially to the reaction bulb of 50mL, be subsequently added sodium hydride (0.02g, 0.82mmol), stir 5 minutes at 0 DEG C, add bromoethane (0.07g, 0.62mmol), room temperature reaction 2 hours.Stop reaction, instead Liquid is answered to be diluted with water, organic phase is collected in ethyl acetate extraction, and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum distillation is removed Solvent, gained crude product is gone directly to carry out column chromatographic isolation and purification (petroleum ether/acetone (v/v)=5/1) and obtain title compound (pale yellow oil, 0.10g, 47%).
MS(ESI,pos.ion)m/z:417.20[M+H]+；
HPLC:95.05%.
Embodiment 3:N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazoles - 2- yls) benzamide synthesis
Step 1) 5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic synthesis
Method of this step title compound with reference to described by the step 6 of embodiment 1 is prepared, i.e., and 1,2,3- triazoles The iodo- 5- methyl benzoic acids (5.24g, 20mmol) of (3.45g, 50mmol), 2-, cesium carbonate (11.72g, 36mmol), trans-N, N'- dimethyl -1,2- cyclohexanediamine (0.51g, 3.6mmol) and cuprous iodide (0.38g, 2mmol) are in N, N- dimethyl formyls Nitrogen protects 100 DEG C of reactions to prepare for 4 hours in amine (30mL), crude product Jing silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1) obtain 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).
Step 2) 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride synthesis
Method of this step title compound with reference to described by the step 7 of embodiment 1 is prepared, i.e. 5- methyl -2- (2H- 1,2,3- triazole -2- bases) benzoic acid (2.03g, 10mmol) and thionyl chloride (15mL, 200mmol), pyridine (0.15mL, 2mmol) backflow is prepared for 3 hours in anhydrous methylene chloride (20mL), and decompression slowly boils off solvent, and products therefrom is directly entered down One step.
Step 3) N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- Base) benzamide synthesis
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (4- fluorobenzene Base) pyrimidine -2-base) ethylcarbodiimide hydrochloride (0.30g.1.40mmol), triethylamine (0.57mL, 4.00mmol) and 5- methyl -2- It is prepared by the reaction in anhydrous methylene chloride (10mL) of (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.37g, 1.68mmol), Crude product Jing silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=200/1) obtain title compound (white solid, 0.22g, 40%).
MS(ESI,pos.ion)m/z:403.30[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.75 (s, 2H), 7.64~7.57 (m, 3H), 7.51 (dd, J=8.4, 5.4Hz, 2H), 7.45 (s, 1H), 7.31 (d, J=7.8Hz, 1H), 7.20 (t, J=8.4Hz, 2H), 6.74 (s, 1H), 3.86 (dd, J=11.6,6.0Hz, 2H), 3.22 (t, J=6.0Hz, 2H), 2.41 (s, 3H).
13C NMR(CDCl3,151MHz)δ(ppm):167.88,167.57,154.84,139.08,135.51,134.76, (131.59,131.17,130.87,130.44 d, J=3.5Hz), 129.83,128.69 (d, J=8.5Hz), 124.09, 116.75,116.60,37.46,37.39,21.13.
HPLC:96.01%.
Embodiment 4:N- ethyl-N- (2- (5- (4- fluorophenyls) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- Triazole -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (4- fluorophenyls) Pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.20g, 0.50mmol), hydrogenation The reaction in dry DMF (5mL) of sodium (0.03g, 0.80mmol) and bromoethane (0.07g, 0.60mmol) is prepared for 2 hours, gained Crude product crude product Jing silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) obtains title compound (yellow oil Shape liquid, 0.13g, 62%).
MS(ESI,pos.ion)m/z:430.20[M+H]+；
HPLC:96.91%.
Embodiment 5:N- (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzene The synthesis of formamide
Step 1) 2- (5- (4- chlorphenyls) pyrimidine) -2- bases) acetonitrile synthesis
Method of this step title compound with reference to described by the step 3 of embodiment 1 is prepared, i.e. 2- (5- Bromopyrimidine -2- Base) acetonitrile (0.98g, 4.95mmol), 4- chlorophenylboronic acids (1.16g, 7.42mmol), potassium carbonate (2.10g, 15.00mmol), Tetrakis triphenylphosphine palladium (0.35g, 0.30mmol) nitrogen in toluene (20mL) protects 100 DEG C of reactions to prepare for 8 hours.Crude product Directly carry out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/1) obtain title compound (yellow solid, 0.99g, 87.07%).
MS(ESI,pos.ion)m/z:230.00[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.92(s,2H),7.51(s,4H),4.16(s,2H).
Step 2) tert-butyl group (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) formamide synthesis
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e. 2- (5- (4- chlorobenzenes Base) pyrimidine) -2- bases) acetonitrile (0.87g, 3.78mmol), Boc acid anhydrides (1.75mL, 7.53mmol), Dehydrated nickel chloride (0.49g, 3.78mmol) prepare within 12 hours with sodium borohydride (1.02g, 26.40mmol) room temperature reaction in absolute methanol (20mL).It is thick to produce Product directly carry out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3/1), and (yellow is solid to obtain title compound Body, 0.684g, 54.20%).
MS(ESI,pos.ion)m/z:334.25[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.84 (s, 2H), 7.48 (s, 4H), 3.66 (d, J=5.3Hz, 2H), 3.20 (t, J=6.0Hz, 2H), 1.42 (s, 9H).
Step 3) 2- (5- (4- chlorphenyls) pyrimidine -2-base) ethylamine hydrochloride synthesis
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e. the tert-butyl group (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) ethyl acetate solution (6mL) of formamide (0.55g, 1.68mmol) and hydrogen chloride exists Prepare in anhydrous methylene chloride (15mL), after reaction terminates, vacuum distillation removes solvent and obtains title compound (pale yellow colored solid Body, 0.44g, 97.00%).
MS(ESI,pos.ion)m/z:234.00[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):9.16 (s, 2H), 8.29 (s, 3H), 7.88 (d, J=8.6Hz, 2H), 7.64 (d, J=8.5Hz, 2H), 3.35 (d, J=2.3Hz, 2H), 1.94 (s, 2H).
Step 4) N- (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzene first The synthesis of acid amides
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (4- chlorobenzenes Base) pyrimidine -2-base) ethylamine hydrochloride (0.55g, 2.04mmol), 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.50g, 2.40mmol) and triethylamine (1.75mL, the 12.40mmol) room temperature reaction 12 in anhydrous methylene chloride (20mL) is little When prepare.Crude product directly carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) and obtains titled Compound (light yellow solid, 0.40g, 48.20%).
MS(ESI,pos.ion)m/z:405.20[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.78 (s, 2H), 7.76 (d, J=8.0Hz, 1H), 7.64 (d, J= 7.5Hz, 3H), 7.55~7.52 (m, 1H), 7.48 (s, 3H), 7.47~7.45 (m, 2H), 6.78 (s, 1H), 3.89 (dd, J= 11.9,5.9Hz, 2H), 3.25 (t, J=5.9Hz, 2H).
13C NMR(CDCl3,101MHz)δ(ppm):168.1,167.5,154.8,136.9,135.7,135.2,132.7, 131.6,130.6,130.5,129.7,129.2,128.6,128.0,124.0,37.4,37.3.
HPLC:97.39%.
Embodiment 6:N- ethyl-N- (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazoles - 2- yls) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (4- chlorphenyls) Pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzamide (0.305g, 0.75mmol), sodium hydride (0.06g, 1.50mmol) and bromoethane (0.07mL, 0.90mmol) are stirred at room temperature 1.5 hours systems in dry DMF (10mL) Standby, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1), and to obtain title compound (pale yellow Color solid, 0.126g, 38.60%).
MS(ESI,pos.ion)m/z:433.15[M+H]+；
HPLC:95.16%.
Embodiment 7:N- (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazoles - 2- yls) benzamide synthesis
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (4- chlorobenzenes Base) pyrimidine -2-base) ethylamine hydrochloride (0.30g, 1.11mmol), triethylamine (0.95mL, 6.70mmol), 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.29g, 1.32mmol) is stirred at room temperature in anhydrous methylene chloride (20mL) Prepare within 17 hours, crude product directly carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) and marked Topic compound (light yellow solid, 0.36g, 77.20%).
MS(ESI,pos.ion)m/z:419.20[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.77 (s, 2H), 7.64~7.58 (m, 3H), 7.48~7.46 (m, 5H), 7.33 (d, J=7.0Hz, 1H), 6.72 (s, 1H), 3.87 (dd, J=11.9,6.0Hz, 2H), 3.23 (t, J=6.0Hz, 2H),2.42(s,3H).
13C NMR(CDCl3,151MHz)δ(ppm):168.1,167.5,154.8,139.0,135.4,135.3,134.7, 132.7,131.5,131.1,130.6,129.7,128.0,124.0,37.4,37.3,21.0.
HPLC:95.18%.
Embodiment 8:N- ethyl-N- (2- (5- (4- chlorphenyls) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- Triazole -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (4- chlorphenyls) Pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.288g, 0.69mmol), hydrogenation Sodium (0.055g, 1.40mmol) and bromoethane (0.065mL, 0.87mmol) are stirred at room temperature 1.5 hours in dry DMF (10mL) Prepare, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) and obtains title compound (tangerine Yellow solid, 0.134g, 43.60%).
MS(ESI,pos.ion)m/z:447.30[M+H]+；
HPLC:98.90%.
Embodiment 9:N- (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Step 1) 2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine) -2- bases) acetonitrile synthesis
Method of this step title compound with reference to described by the step 3 of embodiment 1 is prepared, i.e. 2- (5- Bromopyrimidine -2- Base) acetonitrile (2.00g, 10.10mmol), the chloro- 4- flurophenyl boronic acids (2.81g, 16.1mmol) of 2-, potassium carbonate (4.18g, 29.9mmol), tetrakis triphenylphosphine palladium (0.82g, 0.71mmol) nitrogen in toluene (20mL) protects 100 DEG C to react 8 hours Prepare.Crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=20/1) and obtains title compound (white solid, 1.98g, 79%).
MS(ESI,pos.ion)m/z:248.10[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.82 (s, 2H), 7.35~7.30 (m, 2H), 7.18~7.12 (m, 1H),4.18(s,2H).
Step 2) tert-butyl group (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) formamide synthesis
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 4- of 2- Fluorophenyl) pyrimidine) -2- bases) acetonitrile (3.20g, 12.9mmol), Boc acid anhydrides (5.65g, 25.9mmol), Dehydrated nickel chloride (1.67g, 12.9mmol) and sodium borohydride (3.35g, the 86.8mmol) room temperature reaction in absolute methanol (150mL) is made for 12 hours It is standby.Crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=20/3), and to obtain title compound (light Yellow solid, 1.49g, 33%).
MS(ESI,pos.ion)m/z:352.20[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.74 (s, 2H), 7.34~7.27 (m, 2H), 7.13 (td, J=8.2, 2.4Hz, 1H), 5.35 (s, 1H), 3.69 (dd, J=12.0Hz, 4.0Hz, 2H), 3.23 (t, J=6.0Hz, 2H), 1.44 (s, 9H).
Step 3) 2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethylamine hydrochloride synthesis
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e. the tert-butyl group (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) formamide (1.48g, 4.21mmol) and hydrogen chloride ethyl acetate solution (10mL) prepare in anhydrous methylene chloride (15mL), after reaction terminates, vacuum distillation removes solvent and obtains title compound (in vain Color solid, 0.997g, 97.00%).
MS(ESI,pos.ion)m/z:252.05[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.96 (s, 2H), 8.28 (s, 3H), 7.78 (t, J=8.2Hz, 1H), 7.61 (dd, J=10.6,1.7Hz, 1H), 7.43 (dd, J=8.1,1.8Hz, 1H), 3.37~3.29 (m, 4H).
Step 4) N- (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) The synthesis of benzamide
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 4- of 2- Fluorophenyl) pyrimidine -2-base) ethylamine hydrochloride (0.50g, 1.99mmol), triethylamine (0.60g, 5.96mmol) and 2- (2H- 1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.49g, 2.38mmol) is stirred overnight at room temperature in anhydrous methylene chloride (20mL) Prepare, silica gel column chromatography column separating purification (methylene chloride/methanol (v/v)=100/1) is carried out between gained crude product and obtains title Compound (white solid, 0.44g, 51%).
MS(ESI,pos.ion)m/z:423.70[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.67 (s, 2H), 7.75 (d, J=8.4Hz, 1H), 7.68~7.62 (m, 3H), 7.53 (td, J=8.4,1.2Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.31~7.27 (m, 2H), 7.12 (td, J=8.2,2.6Hz, 1H), 6.79 (s, 1H), 3.90 (dd, J=12.0,6.0Hz, 2H), 3.27 (t, J=5.8Hz, 2H).
13C NMR(CDCl3,151MHz)δ(ppm):168.31,167.55,156.96,135.80,133.85 (d, J= 10.57Hz), 132.22 (d, J=8.9Hz), 130.62,129.84~129.62 (m), 129.37,128.73,124.08, 118.08,117.91,115.19,115.05,37.56,37.27.
HPLC:98.43%.
Embodiment 10:N- ethyl-N- (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (the chloro- 4- fluorine of 2- Phenyl) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.30g, 0.71mmol), It is little that sodium hydride (0.034g, 1.42mmol) and bromoethane (0.93g, 0.85mmol) are stirred at room temperature 1.5 in dry DMF (10mL) When prepare, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) and obtains title compound (yellow oil, 0.21g, 66%).
MS(ESI,pos.ion)m/z:451.05[M+H]+；
HPLC:98.01%.
Embodiment 11:N- (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 4- of 2- Fluorophenyl) pyrimidine -2-base) ethylamine hydrochloride (0.49g, 1.70mmol), triethylamine (0.68mL, 4.80mmol) and 5- first Base -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.52g, 2.38mmol) room temperature in anhydrous methylene chloride (20mL) Preparation is stirred overnight, silica gel column chromatography column separating purification (methylene chloride/methanol (v/v)=100/1) is carried out between gained crude product Obtain title compound (white solid, 0.601g, 81%).
MS(ESI,pos.ion)m/z:437.10[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.66 (s, 2H), 7.62 (s, 2H), 7.59 (d, J=8.2Hz, 1H), 7.46 (s, 1H), 7.32~7.27 (m, 3H), 7.12 (td, J=8.4,2.4Hz, 1H), 6.74 (s, 1H), 3.88 (dd, J= 11.4,6.0Hz, 2H), 3.24 (t, J=2.9Hz, 2H), 2.41 (s, 3H).
13C NMR(CDCl3,151MHz)δ(ppm):168.18,163.54,161.98,156.83,138.98,135.44, 132.11 (d, J=9.0Hz), 131.47,131.08,129.84~129.52 (m), 124.02,117.96,117.80, 115.08,114.94,37.48,37.12,21.03.
HPLC:97.95%.
Embodiment 12:N- ethyl-N- (2- (5- (the chloro- 4- fluorophenyls of 2-) pyrimidine -2-base) ethyl) -5- methyl -2- (2H- 1,2,3- triazole -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (the chloro- 4- fluorine of 2- Phenyl) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.34g, 0.80mmol), It is little that sodium hydride (0.06g, 1.60mmol) and bromoethane (0.11g, 1.00mmol) are stirred at room temperature 1.5 in dry DMF (10mL) When prepare, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) and obtains title compound (yellow oil, 0.24g, 44%).
MS(ESI,pos.ion)m/z:465.10[M+H]+；
HPLC:96.47%.
Embodiment 13:N- (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- Base) benzamide synthesis
Step 1) 2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) acetonitrile synthesis
Method of this step title compound with reference to described by the step 3 of embodiment 1 is prepared, i.e. 2- (5- Bromopyrimidine -2- Base) acetonitrile (0.724g, 3.66mmol), the chloro- 2- flurophenyl boronic acids (0.829g, 4.75mmol) of 4-, potassium carbonate (1.517g, 10.98mmol), tetrakis triphenylphosphine palladium (0.338g, 0.292mmol) nitrogen in toluene (15mL) protects 100 DEG C of reactions 15 It is prepared by hour.Crude product directly carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains title Compound (crocus solid, 0.563g, 62.2%).
MS(ESI,pos.ion)m/z:248.20[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.90 (d, J=1.1Hz, 2H), 7.39 (t, J=8.1Hz, 1H), 7.34~7.27 (m, 2H), 4.17 (s, 2H).
Step 2) tert-butyl group (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) formamide synthesis
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 2- of 4- Fluorophenyl) pyrimidine) -2- bases) acetonitrile (0.248g, 1.00mmol), Boc acid anhydrides (0.58mL, 2.50mmol), Dehydrated nickel chloride (0.065g, 0.50mmol) and sodium borohydride (0.303g, 8.01mmol) room temperature reaction 15 hours in absolute methanol (15mL) Prepare.Crude product directly carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3/1) and obtains title compound Thing (orange/yellow solid, 0.110g, 31.2%).
MS(ESI,pos.ion)m/z:351.90[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.82 (s, 2H), 7.37 (t, J=8.1Hz, 1H), 7.31~7.25 (m, 2H), 5.32 (s, 1H), 3.68 (d, J=5.6Hz, 2H), 3.21 (t, J=6.1Hz, 2H), 1.43 (s, 9H).
Step 3) 2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethylamine hydrochloride synthesis
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e. the tert-butyl group (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) formamide (0.704g, 2.00mmol) and hydrogen chloride ethyl acetate solution (12mL) in anhydrous methylene chloride (15mL) prepared by room temperature reaction, and after reaction terminates, vacuum distillation removes solvent and obtains title Compound (crocus solid, 0.571g, 99.0%).
MS(ESI,pos.ion)m/z:252.00[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.98 (s, 2H), 8.30 (s, 3H), 7.73 (t, J=8.4Hz, 1H), 7.65 (dd, J=10.6,1.9Hz, 1H), 7.48 (dd, J=8.3,1.8Hz, 1H), 3.37~3.27 (m, 4H).
Step 4) N- (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) The synthesis of benzamide
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 2- of 4- Fluorophenyl) pyrimidine -2-base) ethylamine hydrochloride (0.65g, 2.58mmol), 2- (2H-1,2,3- triazole -2- bases) benzoyl Chlorine (0.60g, 2.84mmol) and triethylamine (1.57g, the 15.50mmol) room temperature reaction 18 in anhydrous methylene chloride (20mL) is little When prepare.Crude product directly carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) and obtains titled Compound (light yellow solid, 0.826g, 75.60%).
MS(ESI,pos.ion)m/z:423.25[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.74 (s, 2H), 7.74 (d, J=8.0Hz, 1H), 7.65~7.63 (m, 3H), 7.52 (td, J=7.9,1.3Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.29 ~7.25 (m, 2H), 6.72 (t, J=6.0Hz, 1H), 3.89 (q, J=5.9Hz, 2H), 3.25 (t, J=5.9Hz, 2H).
13C NMR(CDCl3,151MHz)δ(ppm):168.5,167.5,160.5,158.8,156.3,156.3,137.0, 136.1,136.1,135.8,131.7,130.7,130.6,129.4,128.7,126.3,126.3,125.7,125.7, 124.1,121.0,120.9,117.6,117.4,37.5,37.3.
HPLC:98.36%.
Embodiment 14:N- ethyl-N- (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (the chloro- 2- fluorine of 4- Phenyl) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzamide (0.50g, 1.18mmol), sodium hydride (0.071g, 2.96mmol) and bromoethane (0.15g, 1.42mmol) are stirred at room temperature preparation in 40 minutes in dry DMF (10mL), Crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1), and to obtain title compound (light yellow Grease, 0.20g, 38.1%).
MS(ESI,pos.ion)m/z:451.25[M+H]+；
HPLC:95.30%.
Embodiment 15:N- (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (the chloro- 2- of 4- Fluorophenyl) pyrimidine -2-base) ethylamine hydrochloride (0.565g, 1.96mmol), triethylamine (5.0mL, 36.0mmol) and 5- first Base -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.52g, 2.35mmol) room temperature in anhydrous methylene chloride (20mL) Stirring is prepared for 12 hours, and silica gel column chromatography column separating purification (petrol ether/ethyl acetate (v/v)=3/ is carried out between gained crude product 1) obtain title compound (faint yellow solid, 0.647g, 75.5%).
MS(ESI,pos.ion)m/z:436.85[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.73 (s, 2H), 7.60 (s, 2H), 7.58 (d, J=8.2Hz, 1H), 7.45 (s, 1H), 7.35 (t, J=8.1Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 7.29~7.24 (m, 1H), 6.72 (t, J =6.0Hz, 1H), 3.86 (q, J=5.9Hz, 2H), 3.23 (t, J=6.0Hz, 2H), 2.41 (s, 3H).
13C NMR(CDCl3,151MHz)δ(ppm):168.5,167.6,160.5,158.8,156.3,139.1,136.0, 135.5,134.7,131.5,131.2,130.7,129.8,126.2,125.7,124.1,120.9,117.5,37.6,37.2, 21.1
HPLC:95.35%.
Embodiment 16:N- ethyl-N- (2- (5- (the chloro- 2- fluorophenyls of 4-) pyrimidine -2-base) ethyl) -5- methyl -2- (2H- 1,2,3- triazole -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (the chloro- 2- fluorine of 4- Phenyl) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.333g, 0.76mmol), sodium hydride (0.055g, 1.40mmol) and bromoethane (0.085mL, 1.14mmol) are in dry DMF (10mL) Preparation in 1 hour is stirred at room temperature, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) and obtains Title compound (light yellow oil, 0.161g, 45.4%).
MS(ESI,pos.ion)m/z:465.35[M+H]+；
HPLC:94.92%.
Embodiment 17:N- (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- Base) benzamide synthesis
Step 1) 2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) acetonitrile synthesis
Method of this step title compound with reference to described by the step 3 of embodiment 1 is prepared, i.e. 2- (5- Bromopyrimidine -2- Base) acetonitrile (1.37g, 6.92mmol), (2,4 difluorobenzene base) boric acid (1.64g, 10.4mmol), potassium carbonate (2.90g, 20.80mmol), tetrakis triphenylphosphine palladium (0.48g, 0.415mmol) nitrogen in toluene (20mL) protects 100 DEG C of reactions 15 little When prepare.Crude product directly carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=5/1) and obtains titled Compound (crocus solid, 1.32g, 82.60%).
MS(ESI,pos.ion)m/z:232.00[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.89 (d, J=1.0Hz, 2H), 7.43 (td, J=8.6,6.2Hz, 1H), 7.09~6.99 (m, 2H), 4.17 (s, 2H).
Step 2) tert-butyl group (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) formamide synthesis
Method of this step title compound with reference to described by the step 4 of embodiment 1 is prepared, i.e. 2- (5- (2,4- difluoros Phenyl) pyrimidine) -2- bases) acetonitrile (0.24g, 1.04mmol), Boc acid anhydrides (0.48mL, 2.10mmol), Dehydrated nickel chloride (0.135g, 1.04mmol) and sodium borohydride (0.12g, the 3.11mmol) room temperature reaction in absolute methanol (15mL) is made for 15 hours It is standby.Crude product directly carries out silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=3/1) and obtains title compound (faint yellow solid, 0.185g, 53.10%).
MS(ESI,pos.ion)m/z:336.30[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.81 (s, 2H), 7.41 (td, J=8.6,6.3Hz, 1H), 7.06~ 6.96 (m, 2H), 3.68 (d, J=6.1Hz, 2H), 1.43 (s, 9H).
Step 3) 2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethylamine hydrochloride synthesis
Method of this step title compound with reference to described by the step 5 of embodiment 1 is prepared, i.e. the tert-butyl group (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) formamide (1.15g, 3.43mmol) and hydrogen chloride ethyl acetate solution (12mL) in anhydrous methylene chloride (15mL) prepared by room temperature reaction, and after reaction terminates, vacuum distillation removes solvent and obtains title Compound (crocus solid, 0.90g, 97.00%).
MS(ESI,pos.ion)m/z:236.05[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):9.00 (s, 2H), 8.28 (s, 2H), 7.79 (td, J=8.8,6.8Hz, 1H), 7.54~7.49 (m, 1H), 7.33 (td, J=8.5,2.1Hz, 1H), 3.36 (d, J=2.3Hz, 2H), 1.94 (s, 2H).
Step 4) N- (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) The synthesis of benzamide
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (2,4- difluoros Phenyl) pyrimidine -2-base) ethylamine hydrochloride (0.65g, 2.39mmol), 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.60g, 2.89mmol) and triethylamine (2.05mL, the 14.60mmol) room temperature reaction 18 in anhydrous methylene chloride (20mL) is little When prepare.Crude product directly carries out silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=100/1) and obtains titled Compound (light yellow solid, 0.55g, 56.60%).
MS(ESI,pos.ion)m/z:406.90[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):8.74 (s, 2H), 7.75 (d, J=8.0Hz, 1H), 7.65 (d, J= 6.9Hz, 3H), 7.53 (t, J=7.7Hz, 1H), 7.46 (t, J=7.5Hz, 1H), 7.39 (td, J=8.6,6.3Hz, 1H), 7.05~6.98 (m, 2H), 6.77 (s, 1H), 3.90 (dd, J=11.8,5.9Hz, 2H), 3.26 (t, J=5.9Hz, 2H).
HPLC:96.43%.
Embodiment 18:N- ethyl-N- (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (2,4- difluorobenzenes Base) pyrimidine -2-base) ethyl) -2- (2H-1,2,3- triazole -2- bases) benzamide (0.305g, 0.75mmol), sodium hydride (0.06g, 1.60mmol) and bromoethane (0.10g, 0.92mmol) are stirred at room temperature preparation in 40 minutes in dry DMF (10mL), Crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1), and to obtain title compound (light yellow Grease, 0.16g, 49.08%).
MS(ESI,pos.ion)m/z:435.25[M+H]+；
HPLC:97.17%.
Embodiment 19:N- (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- tri- Nitrogen azoles -2- bases) benzamide synthesis
Method of this step title compound with reference to described by the step 8 of embodiment 1 is prepared, i.e. 2- (5- (2,4- difluoros Phenyl) pyrimidine -2-base) ethylamine hydrochloride (0.90g, 3.31mmol), triethylamine (2.80mL, 19.80mmol) and 5- methyl- 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride (0.88g, 3.97mmol) room temperature in anhydrous methylene chloride (20mL) is stirred Preparation in 12 hours is mixed, silica gel column chromatography column separating purification (petrol ether/ethyl acetate (v/v)=3/1) is carried out between gained crude product Obtain title compound (faint yellow solid, 0.866g, 62.20%).
MS(ESI,pos.ion)m/z:421.30[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):8.72 (s, 2H), 7.60 (s, 2H), 7.59 (d, J=8.2Hz, 1H), 7.45 (s, 1H), 7.38 (td, J=8.6,6.4Hz, 1H), 7.31 (d, J=8.1Hz, 1H), 7.03 (td, J=8.1,1.8Hz, 1H), 7.00~6.94 (m, 1H), 6.73 (s, 1H), 3.86 (dd, J=11.9,5.9Hz, 2H), 3.22 (t, J=5.9Hz, 2H),2.41(s,3H).
HPLC:96.32%.
Embodiment 20:N- ethyl-N- (2- (5- (2,4 difluorobenzene base) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1, 2,3- triazole -2- bases) benzamide synthesis
Method of this step title compound with reference to described by embodiment 2 is prepared, i.e. N- (2- (5- (2,4- difluorobenzenes Base) pyrimidine -2-base) ethyl) -5- methyl -2- (2H-1,2,3- triazole -2- bases) benzamide (0.435g, 1.035mmol), Sodium hydride (0.083g, 2.10mmol) and bromoethane (0.14g, 1.28mmol) are stirred at room temperature 35 points in dry DMF (10mL) Prepared by clock, crude product directly carries out silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=5/1) and obtains title compound (light yellow oil, 0.264g, 56.87%).
MS(ESI,pos.ion)m/z:449.25[M+H]+；
HPLC:98.27%.
Biologic test
Embodiment A humanization OX 1 The antagonism experiment of acceptor
Test method
Compound is evaluated with the method for free calcium ion concentration in fluoroscopic examination kytoplasm to Chinese hamster ovary (CHO) The humanization OX transfected in cell1The antagonistic ability of acceptor.In cell culture medium (invitrogen), then cell is suspended in With 2 × 104The density of cells/well is averagely added in micro reaction plate.By fluorescence probe (Fluo4NW, Invitrogen) and third After easypro Hank balanced salt solutions (invitrogen) mixing of sulphur, 20mM hydroxyethyl piperazine second thiosulfonic acids are subsequently added (invitrogen) (pH 7.4), in ultimately joining the micropore containing cell.Cell is placed in into 37 DEG C of incubation 60min, then is put 15min is balanced in 22 DEG C.Microwell plate is placed in ELIASA (CellLux, PerkinElmer), the test of variable concentrations is added Compound solution or Hank balanced salt solutions, add 3nM orexin-As or balanced salt solution (control), measurement after incubation 5min The fluorescence intensity change being directly proportional to calcium ion concentration in kytoplasm.
Data analysis
Experimental result, with 3nM orexin-As 100%, records the inhibiting rate of each compound with substrate control as 0.Each reality Test it is middle measure several variable concentrations respectively, make amount effect curve, be calculated the IC of each compound50Value.
Result of the test shows, the compounds of this invention in above-mentioned test, to OX1Acceptor has preferable antagonism.
Embodiment B humanization OX 2 The antagonism experiment of acceptor
Test method
Compound is evaluated with the method for free calcium ion concentration in fluoroscopic examination kytoplasm to transfecting in HEK-293 cells Humanization OX2The antagonistic ability of acceptor.Cell is suspended in cell culture medium (invitrogen), then with 3 × 104Carefully The density in born of the same parents/hole is averagely added in micro reaction plate.By fluorescence probe (Fluo4NW, Invitrogen) and the Hank of probenecid After balanced salt solution (invitrogen) mixing, 20mM hydroxyethyl piperazine second thiosulfonic acid (invitrogen) (pH are subsequently added 7.4), ultimately join in the micropore containing cell.Cell is placed in into 37 DEG C of incubation 60min, then is placed in 22 DEG C of balance 15min. Microwell plate is placed in ELIASA (CellLux, PerkinElmer), add variable concentrations test compound solution or Hank balanced salt solutions, add 10nM orexins B or the slow solution (control) of balance salt after incubation 5min, in measurement and kytoplasm calcium from The fluorescence intensity change that sub- concentration is directly proportional.
Data analysis
Experimental result, with 10nM orexins B as 100%, records the inhibiting rate of each compound to compare as 0.Each experiment It is middle to measure several variable concentrations respectively, amount effect curve is made, it is calculated the IC of each compound50Value.As a result referring to table 1.
The compound provided in an embodiment of the present invention of table 1 is to OX2The antagonism experimental result of acceptor
Result of the test shows, the compounds of this invention in above-mentioned test, to OX2Acceptor has preferable antagonism.
Pharmacokinetic Evaluation after embodiment C rat, dog and monkey intravenous or oral quantitative the compounds of this invention
Pharmacokinetic of the present invention to the compounds of this invention in rat, dog or monkey body is assessed.This Invention compound is with the saline solution or 10% of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline DMSO+10%Kolliphor HS 15+80% normal saline solutions are administered.For intravenous injection administration, animal gives The dosage of 1mg/kg, blood (0.3mL) was taken in time point for 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours, And be centrifuged 10 minutes under 3,000 or 4,000rpm.For oral (p.o.) administration, animal gives the dosage of 5mg/kg, when Between point to take within 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours blood (0.3mL), and under 3,000 or 4,000rpm from The heart 10 minutes.Plasma solutions are collected, and is preserved at -20 DEG C or -70 DEG C until carrying out LC/MS/MS analyses.
Result of the test shows that the compounds of this invention has preferable pharmacokinetic property in rat, dog or monkey body.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention Modification or the equivalents added in the claims.All publications or patent cited in the present invention all will be used as this Bright bibliography.

Claims (10)

1. a kind of compound, it is stereoisomer, the tautomerism of the compound shown in formula (I) or compound shown in formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein：
Z is-NR5- ,-C (=O) NR5- or-S (=O)2NR5-；
U is N or CR3a；
V is N or CR3b；
X is N or CR3c；
Y is N or CR3d；
Each R1It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Alkyl halide Base, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino or C1-4Hydroxy alkyl, wherein, each R1 Individually optionally by 1,2,3,4 or 5 R6Group is replaced；
Each R3a、R3b、R3cAnd R3dIt independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl or C1-4Haloalkyl；
Each R2And R3It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Alcoxyl Base, C1-4Alkyl amino, C1-4Hydroxy alkyl or C1-4Haloalkyl；
Each R4It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Alkyl halide Base, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino, C1-4Hydroxy alkyl, (C1-4Alkyl)- C (=O)-, (C1-4Alkoxyl)-C (=O)-or (C1-4Alkyl amino)-C (=O)-, wherein, each R4Individually optionally by 1,2, 3rd, 4 or 5 R6Group is replaced；
R5For H, D, C1-4Alkyl or C1-4Haloalkyl；
Each R6It independently is H, D, F, Cl, Br, I, OH, NH2、NO2、CN、C1-4Alkyl, C2-4Thiazolinyl, C2-4Alkynyl, C1-4Alkyl halide Base, C1-4Alkoxyl, C1-4Halogenated alkoxy, C1-4Alkyl amino, C1-4Haloalkylamino or C1-4Hydroxy alkyl；
M is 0,1,2,3,4 or 5；
N is 0,1,2,3 or 4；
P is 1,2,3 or 4；With
K is 0,1 or 2.
2. compound according to claim 1, wherein, each R1It independently is H, F, Cl, Br, OH, NH2、NO2, CN, methyl, Ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, vinyl, acetenyl, methoxyl group, ethyoxyl, methylamino, ethylamino, hydroxyl first Base, ethoxy or trifluoromethyl.
3. compound according to claim 1, wherein, each R2And R3It independently is H, F, Cl, OH, NH2、NO2, CN, methyl, Ethyl, propyl group, isopropyl, vinyl, pi-allyl, propargyl, methoxyl group, ethyoxyl, methylamino, ethylamino, methylol, hydroxyl second Base or trifluoromethyl.
4. compound according to claim 1, wherein, each R4It independently is H, F, Cl, OH, NH2、NO2, CN, methyl, second Base, propyl group, isopropyl, normal-butyl, isobutyl group, vinyl, acetenyl, methoxyl group, ethyoxyl, methylamino, ethylamino, hydroxyl first Base, ethoxy or trifluoromethyl.
5. compound according to claim 1, the structure with one of：
Or its stereoisomer, Dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug.
6. a kind of pharmaceutical composition, comprising the compound described in claim 1-5 any one, and pharmaceutically acceptable figuration Agent, carrier, adjuvant, solvent or combinations thereof.
7. pharmaceutical composition according to claim 6, further prevents or treats central nervous system comprising other Central nervous system nerve and spirit are prevented or treated to the medicine of nerve and psychiatric disorders and disease, described others The medicine of sexual dysfunction and disease be antidepressant, anxiolytic drugs, as salts medicine, the antipsychotic of mood stabilizers Medicine, atypical antipsychotic drug, antiepileptic, anti-parkinson class medicine, sedative hypnotic drug, antihistamine Thing, GABA receptor stimulating agents and/or GABA reuptaking inhibitor class medicines, the medicine as MAOI, conduct The medicine of melatonin receptors activator and the medicine as orexin receptor antagonists or their any combination.
8. the pharmaceutical composition described in compound described in claim 1-5 any one or claim 6-7 any one exists The purposes in medicine is prepared, the medicine is used to preventing, treat or mitigating mammal, including the central nervous system god of the mankind Jing and psychiatric disorders and disease.
9. purposes according to claim 8, described central nervous system nerve and psychiatric disorders and disease are referred to Lose caused by depression, anxiety disorder, SAD, mania, bipolar disorders, besetment and behavior disorder, the time difference Sleep and fatigue, schizophrenia, convulsions, panic attack, melancholia, alcohol addiction disease, drug habit disease, jimjams, thing Matter abuse, drug addiction withdrawal symptom, insomnia, psychotic disorder, epilepsy, sleep-disorder, sleep confusion, sleep are stopped up Breath syndrome, the mandatory disturbance of food intake, fibromyalgia, stress reaction, obesity, Parkinson's, senile dementia, cognitive disorder, note Recall obstacle, premenstrualtension syndrome, antimigraine, the loss of memory, Alzheimer disease or other and normal or pathological seaility Related various obstacles.
10. the pharmaceutical composition described in compound described in claim 1-5 any one or claim 6-7 any one exists The purposes in medicine is prepared, the medicine is used for selective antagonism orexin receptor.
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Citations (5)

* Cited by examiner, † Cited by third party
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WO2016100161A1 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Ethyldiamine orexin receptor antagonists
WO2016095205A1 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Heteroaryl orexin receptor antagonists
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102066325A (en) * 2008-06-16 2011-05-18 弗·哈夫曼-拉罗切有限公司 Heteroaromatic monoamides as orexinin receptor antagonists
CN104364238A (en) * 2012-06-15 2015-02-18 大正制药株式会社 Branched chain alkyl heteroaromatic ring derivative
WO2016100161A1 (en) * 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Ethyldiamine orexin receptor antagonists
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