CN108299437A - Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof - Google Patents

Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof Download PDF

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CN108299437A
CN108299437A CN201710025580.3A CN201710025580A CN108299437A CN 108299437 A CN108299437 A CN 108299437A CN 201710025580 A CN201710025580 A CN 201710025580A CN 108299437 A CN108299437 A CN 108299437A
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alkyl
alkoxy
compound
disease
halogenated
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CN108299437B (en
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金传飞
劳锦花
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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention relates to octahydro pyrrolo- [3,4 c] azole derivatives and application thereof.Compound of the present invention and pharmaceutical composition comprising the compound are used for antagonism orexin receptor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they treat or prevent with orexin receptor relevant disease in purposes.

Description

Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof
Invention field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of octahydro pyrrolo- [3,4-c] azole derivatives include this The pharmaceutical composition of class compound and their application method and purposes.More specifically, compound of the present invention and Pharmaceutical composition can be used as orexin receptor antagonists for treating, preventing or mitigating and the relevant disease of orexin receptor.
Background of invention
Orexin (orexin) is also referred to as inferior colliculus krinin, appetite peptide comprising orexin-A and orexin B (or inferior colliculus Krinin -1 and inferior colliculus krinin -2), it is a kind of neuropeptide secreted by hypothalamus, main physiological action has：1. adjusting It ingests, orexin can be obviously promoted feed, and be reacted in dose-dependant, and have activated the neuron for adjusting feed；2. participating in The adjusting of energetic supersession, orexin can dramatically increase metabolic rate；3. participating in the adjusting of Sleep-Wake, orexin can inhibit quickly Eye Movement Sleep extends the awakening time, blocks the effect of orexin that can promote to sleep；4. participating in endocrine metabolic diseases, orexin It is endocrine on pituitrin to influence clearly；5. related to remuneration sense, learning and memory；6. promoting gastric acid secretion；7. promoting Drinking-water increases；8. increasing blood pressure；9. it plays an important role in reward system and drug habit mechanism, wait (Piper et al., The novel brain neuropeptide,orexin-A,modulates the sleep-wake cycle of rats.Eur.J.Neuroscience,2000,12(2),726-730；and Sakurai,T.,et al.,The neural circuit of orexin(hypocretin):Maintaining sleep and wakefulness.Nature Review Neuroscience,2007,8:171181)。
Orexin generates physiological effect by acting on orexin receptor (orexin receptor, OXR).Orexin Receptor is a kind of G- G-protein linked receptors, and there are two types of types, are referred to as OX1Receptor and OX2Receptor, wherein OX1Receptor is to appetite Plain A has selectively, and OX2Receptor be for orexin-A and orexin B non-selective receptor (Sakurai T.et al., Orexins and orexin receptors:a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573- 585)。OX1Receptor and OX2Receptor almost exists only in brain tissue, and is selectively expressed in brain, wherein OX1Receptor with High Cell Density And High Expression is the nuclei of origin of noradrenergic neuron in locus coeruleus (locus coeruleus), and OX2Receptor It is the nuclei of origin of histaminergic neuron with High Cell Density And High Expression in nodular nipple nucleus.OX1Receptor and OX2The expression of both receptors can It sees in nuclei of median raphe, is the nuclei of origin of serotoninergic nerve member, and be found in ventral tegmental area, be dopaminergic neuron Nuclei of origin.In addition, OX2Expression of receptor is also seen in the responsible brain stem cholinergic neuron for adjusting rapid-eye-movement sleep and to it Nuclear activity has influence (Marcus, J.N.et al., Differential expression of orexin receptors 1 and 2 in the rat brain.J.Comp.Neurol.,2001,435(1):6-25；and Trivedi,P.et al.,Distribution of orexin receptor mRNA in the rat brain.FEBS Lett.,1998,438 (1-2):71-75)。
It can be seen that orexin receptor has great importance on pathology, it is related to a variety of diseases, such as sleep Obstacle, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mental state Obstacle, panic attack obstacle, behavioral disorder, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia Disease, manic depression, amentia, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, Dyskinesia, feeding desorder, headache, migraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, Metabolic disease, immune correlated disease, endocrine relevant disease and hypertension etc..But currently on the market with orexin receptor phase The drug of pass only has the anti-insomnia medicine Su Woleisheng (Suvorexant) of United States Merck company research and development, is orexin receptor antagonism Agent, the drug were also once once ratified because of safety issue by the refusal of U.S. FDA.
In consideration of it, the present invention provides a kind of compound with orexin receptor antagonistic activity, the compound of the present invention With preferable drug activity, and toxic side effect is smaller, and safety is higher, while also having excellent physicochemical property, medicine generation Therefore property and toxicological characteristics have preferable potential applicability in clinical practice.
Invention content
Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by whole.Work as the disclosure of the specification When variant with citation, it is subject to the disclosure of the specification.
The present invention provides a kind of compounds with orexin receptor antagonistic activity, and in particular to octahydro pyrrolo- [3, 4-c] azole derivatives and its pharmaceutical composition, the compound and pharmaceutical composition can be used for preventing or treat and appetite The plain relevant disease of receptor.
The compounds of this invention shows good antagonistic activity to orexin receptor, has good 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, less toxic side effect and high security etc..Meanwhile the good characteristic of the certain parameters of the compounds of this invention, such as partly decline The excellent spy of phase, clearance rate, selectivity, bioavilability, chemical stability, metabolic stability, permeability of the membrane, dissolubility etc. Property, the reduction of side effect, the expansion of therapeutic index or the improvement of tolerance can be promoted.
Specifically：
On the one hand, it is compound shown in formula (I) compound represented or formula (I) the present invention relates to a kind of compound Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein：
X is N or CH；With
Hy、R1、R2、R3、R4、R5And R6With meaning as described in the present invention.
In one embodiment, Hy is phenyl or 5-6 unit's heteroaryls, and the phenyl and 5-6 unit's heteroaryls are individually optionally D, F, Cl, Br, I, C are independently selected from by one or more1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy and The substituent group of benzyl is replaced.
In another embodiment, Hy is thienyl, furyl, pyrrole radicals, triazolyl, pyridyl group or includes two nitrogen originals The 5-6 unit's heteroaryls of son, the thienyl, furyl, pyrrole radicals, triazolyl, pyridyl group and the 5-6 members comprising two nitrogen-atoms Heteroaryl individually optionally by one or more selected from D, F, Cl, Br, I, methyl, ethyl, isopropyl, tertiary butyl, trifluoromethyl, Difluoromethyl, 1,2- bis-fluoro ethyls, methoxyl group, ethyoxyl, isopropoxy, trifluoromethoxy and benzyl substituent group replaced.
Also in one embodiment, Hy is triazolyl, is chosen in particular from subformula shown in i-1 to i-14：
Each subformula shown in wherein i-1 to i-14 is selected from by one or more individually optionally D, F, Cl, Br, I, methyl, ethyl, isopropyl, tertiary butyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy and benzyl Substituent group replaced.
In one embodiment, compound of the present invention is shown in formula (II) compound represented or formula (II) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt or preceding of compound Medicine,
Wherein, X, R1、R2、R3、R4、R5And R6With meaning as described in the present invention.
In one embodiment, the R in formula (I) or formula (II)1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C2-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C2-6Alkoxy, C1-6Haloalkoxy Base, C1-6Alkylamino, C1-6The alkyl, (C of hydroxyl substitution1-6Alkyl)-C (=O)-, (C1-6Alkoxy)-C (=O)-or (C1-6Alkane Amino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Haloalkoxy Base, C1-6Alkylamino, C1-6The alkyl, (C of hydroxyl substitution1-6Alkyl)-C (=O)-, (C1-6Alkoxy)-C (=O)-or (C1-6Alkane Amino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)1、R2The carbocyclic ring of 3-8 members is constituted with coupled carbon atom Or heterocycle, the carbocyclic ring and heterocycle of the 3-8 members are selected from D, F, Cl, Br, I, C by one or more individually optionally1-4Alkyl, C1-4 Halogenated alkyl, C1-4Alkoxy and C1-4The substituent group of halogenated alkoxy is replaced.
In one embodiment, the R in formula (I) or formula (II)3、R4、R5And R6Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkane Oxygroup, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6The alkyl, (C of hydroxyl substitution1-6Alkyl)-C (=O)-, (C1-6Alkoxy)- C (=O)-or (C1-6Alkylamino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C2-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C2-4Alkoxy, C1-4Haloalkoxy Base, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4Alkyl)-C (=O)-, (C1-4Alkoxy)-C (=O)-or (C1-4Alkane Amino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Haloalkoxy Base, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4Alkyl)-C (=O)-, (C1-4Alkoxy)-C (=O)-or (C1-4Alkane Amino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)1、R2The carbocyclic ring of 3-6 members is constituted with coupled carbon atom Or heterocycle, the carbocyclic ring and heterocycle of the 3-6 members individually optionally by one or more selected from D, F, Cl, Br, I, methyl, ethyl, N-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup and fluoroform The substituent group of oxygroup is replaced.
In one embodiment, the R in formula (I) or formula (II)3、R4、R5And R6Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkane Oxygroup, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4Alkyl)-C (=O)-, (C1-4Alkoxy)- C (=O)-or (C1-4Alkylamino)-C (=O)-.
In one embodiment, the R in formula (I) or formula (II)1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, ethyoxyl, n-propyl oxygroup, Isopropyl oxygroup ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethoxy Base, n-propyl oxygroup, isopropyl oxygroup ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3Or-C (=O) N (CH3)2。
In one embodiment, the R in formula (I) or formula (II)1、R2Constituted with coupled carbon atom have it is following it One structure：
Each subformula shown in wherein Formulas I-a to I-y individually optionally by one or more selected from D, F, Cl, Br, I, Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygen The substituent group of base and trifluoromethoxy is replaced.
In one embodiment, the R in formula (I) or formula (II)3、R4、R5And R6Be each independently H, D, F, Cl, Br, I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、- CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3 Or-C (=O) N (CH3)2。
In one embodiment, compound of the present invention, for one of following structure compound or have The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,
On the other hand, the present invention relates to a kind of pharmaceutical compositions, and it includes compounds of the present invention.
In one embodiment, pharmaceutical composition of the present invention optionally includes pharmaceutically acceptable carrier, assigns Shape agent, adjuvant or their arbitrary combination.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine preparation, The drug is for preventing, treating or mitigating and the relevant disease of orexin receptor.
In one embodiment, the described and relevant disease of orexin receptor is sleep disturbance, depression, anxiety disorder, fears Flurried disease, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior Not normal, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, spirit are wrong Unrest, dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, feeding desorder, head Bitterly, migraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune related disease Disease, endocrine relevant disease or hypertension.
On the other hand, the purposes the present invention relates to compound of the present invention or pharmaceutical composition in medicine preparation, The drug is used for antagonism orexin receptor.
On the other hand, the side of preparation, separation and the purifying of the compound for being included the present invention relates to formula (I) or formula (II) Method.
Biological results show that compound provided by the invention can be used as preferable orexin receptor antagonists.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
There is apparent conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " embodiment " refers to one or more embodiments.
Term " optional " or " optionally " refer to the event then described or situation can with but not necessarily occur, and this is retouched State the case where occurring including the wherein described event or situation and the case where wherein it does not occur.
Term " optionally by ... replace " can exchange use, i.e., with term " unsubstituted or by ... replace " The structure or group are unsubstituted or are replaced by one or more substituent groups of the present invention, wherein the substitution is anticipated Taste the rational position for being happened at that any chemical valence allows on given structure or group.Substituent group of the present invention includes, But it is not limited to D, F, Cl, Br, I ,-N3、-CN、-NO2、-OH、-SH、-NH2, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, Alkylthio group, alkylamino, naphthenic base, heterocycle, aryl, heteroaryl, etc..
In general, " substituted " expression of term is specifically replaced to one or more of structure or group hydrogen atom Base is replaced.Unless otherwise indicated, a substituent group can be replaced in each commutable rational position of group. When in given structural formula more than one position can by selected from the specific substituent groups of one or more replace, then substituent group It can each rational position be replaced in structural formula identical or differently.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " indicates single D-atom.
Term " hetero atom " indicates one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), The form of sulphur (S) and phosphorus (P) any oxidation state；The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the hydrogen in heterocycle on nitrogen-atoms Substituted form, for example, N (as the N in 3,4- dihydro-2 h-pyrrole bases), NH (as the NH in pyrrolidinyl) or NR are (as N- NR in substituted pyrrolidinyl).
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Substitution.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one carbon- Carbon sp2Double bond, wherein the alkenyl group is optionally replaced by one or more substituent groups described in the invention, wraps Include the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one carbon- Tri- keys of carbon sp, wherein the alkynyl group is optionally replaced by one or more substituent groups described in the invention.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), etc..
Term " halogenated alkyl " indicates that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF3、-CF2CF3、-CH2CF2CHF2Deng.It is real one It applies in scheme, " halogenated alkyl " is the C of lower level1-4Halogenated alkyl the, wherein " C1-4Halogenated alkyl " includes fluorine-substituted C1-4 The C that alkyl, chlorine replace1-4The C that alkyl, bromine replace1-4The C that alkyl, iodine replace1-4Alkyl, etc..Specifically, halogen atom replaces C1-4Alkyl includes-CH2F、-CHF2、-CF3、-CH2Cl、-CHCl2、-CCl3、-CH2Br、-CHBr2、-CBr3、-CH2CH2F、- CH2CHF2、-CH2CF3、-CF2CH2F、-CF2CHF2、-CF2CF3、-CHFCF3、-CHFCHF2、-CHFCH2F、-CH2CH2CF3、- CH2CF2CHF2Etc..The halogenated alkyl is optionally replaced by one or more substituent groups described in the invention.
Term " halogenated alkoxy " indicates that alkoxy base is replaced by one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF3、-OCF2CF3、-OCH2CF2CHF2 Deng.The halogenated alkoxy is optionally replaced by one or more substituent groups described in the invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.
Term " alkyl of hydroxyl substitution " indicates that alkyl group is replaced by one or more hydroxyl groups, wherein alkyl base Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl, Etc..
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, indicate containing 3-12 ring carbon atom, it is monovalent or The monocycle of multivalence, bicyclic or three-ring system, middle ring can be fully saturated or comprising one or more degrees of unsaturation, but One armaticity ring cannot all have.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitable carbocylic radical group packet It includes, but is not limited to, naphthenic base, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3-8 ring carbon atom； In another embodiment, carbocylic radical includes 3-6 ring carbon atom.The example of carbocylic radical group includes, but are not limited to：Cyclopropyl, Cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- hexamethylenes Base -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, etc..The carbocylic radical group can be with It is independently unsubstituted or replaced by one or more substituent groups described in the invention.
Term " heterocycle " and " heterocycle " are used interchangeably here, indicate to include 3-12 annular atom, unit price or more The monocyclic, bicyclic or tricyclic system of valence, one or more atoms are independently replaced by hetero atom in middle ring, the hetero atom With meaning as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, but a fragrance Property ring cannot all have.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.The example of heterocycle includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, etc..It is miscellaneous - CH in ring group2Group includes, but are not limited to 2- oxo-pyrrolidines base, oxo -1,3-thiazoles by-C (=the O)-examples substituted Alkyl, 2- piperidone bases, 3,5- dioxy piperazines piperidinyl and hybar X base.The example that sulphur atom is aoxidized in heterocycle includes, But it is not limited to, sulfolane base, 1,1- dioxothiomorpholinyls.The heterocyclyl groups can be optionally one or more Substituent group described in the invention is replaced.
Term " naphthenic base " indicates containing 3-12 ring carbon atom, monovalent or multivalence saturation monocyclic, bicyclic or tricyclic System.
Term " aryl " is indicated containing 6-14 annular atom or 6-10 annular atom or 6 annular atoms, monovalent or more The carbocyclic ring system of the monocyclic, bicyclic or tricyclic of valence, wherein at least one ring are aromatic.Aryl group is in general, but necessarily Ground is connect by the armaticity ring of aryl group with parent molecule.Term " aryl " can be handed over term " aromatic rings " or " aromatic ring " Change use.The example of aryl group may include phenyl, naphthalene, anthracene, etc..The aryl group is optionally one or more Substituent group described in the invention is replaced.
Term " heteroaryl " indicates (the i.e. 5-6 containing 5-14 annular atom or 5-10 annular atom or 5-6 annular atom Member), the monocyclic, bicyclic or tricyclic system of unit price or multivalence, wherein at least one ring is aromatic, and at least one ring includes One or more hetero atoms.Heteroaryl groups are in general, but unnecessarily pass through the armaticity ring and parent molecule of heteroaryl groups Connection.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is replaced by one or more substituent groups described in the invention.
The example of heteroaryl groups includes, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazole Base (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl (such as 2- pyrazolyls), isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,3- triazolyls, 1,2,3- thio biphospholes base, 1,3,4- sulphur For di azoly, 1,2,5- thio biphospholes base, pyrazinyl, cyanuro 1,3,5；Also include below bicyclic, but be not limited to these It is bicyclic：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolines Quinoline base, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1, 2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine Base, etc..
As described in the present invention, attachment point can be connected any attachable position on ring with molecule rest part. For example, Hy in the present invention can be triazolyl, on the triazolyl any attachable position can be used as with molecule remaining The connected tie point in part, specifically comprising subformula shown in i-1 to i-14：
Term " stereoisomer " refers to having identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, rotamer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc,New York,1994.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed, prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is can refer to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to some such compounds, raw material, composition and/or dosage form, they are cured rationally Learn judge in the range of, be suitable for patient tissue contacts and without excessive toxicity, irritation, allergy or with rational profit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " prodrug " used in the present invention represents a compound and is converted into vivo shown in formula (I) or (II) Compound.Such conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for precursor structure It rings.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound include hydroxyl, you can be acylated to obtain the compound of prodrug form.Other pro-drug shapes Formula includes phosphate, if these phosphate compounds are being obtained through the di on parent.It is complete about pro-drug Whole discussion can refer to following documents：Higuchi et al.,Pro-drugs as Novel Delivery Systems, Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery, 2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every document are included herein by reference.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, niacin Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through alkali appropriate Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The compound of group is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic Ammonium, the amine cation that quaternary ammonium 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 that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to cause individual Object or medicinal response (such as enzyme or protein active are reduced or inhibit, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevent disease etc.) the compounds of this invention amount.
The present invention relates to substituted (octahydro pyrrolo- [3,4-c] pyrroles -2 (1H)-yl) phenyl ketone compound, its pharmacy Upper acceptable salt, its pharmaceutical composition and its pharmaceutical preparation, they have orexin receptor antagonism, can be used as orexin Receptor antagonist is for preventing or treating and the relevant disease of orexin receptor, such as sleep disturbance, psychiatry, neurology With neurodegeneration obstacle, pharmacological dependence, habituation, cognitive disorder, dyskinesia, feeding desorder, etc..
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
Compound shown in formula (I) or formula (II) can exist with different tautomeric forms, and all these mutual Tautomeric is included within the scope of the present invention.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be normal by using at an elevated temperature Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts with peracid in suitable solvent, such as is reacted with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or It is reacted with 3- chloroperoxybenzoic acids in chloroform or dichloromethane, prepares the nitrogen oxides of the compounds of this invention.
In addition, when the compound of the present invention forms hydrate or solvate, they are also included within the scope of the present invention It is interior.Similarly, the hydrate of the compounds of this invention or the pharmaceutically acceptable salt of solvate are also included within the model of the present invention In enclosing.
Compound can exist in a salt form shown in formula (I) or formula (II).In one embodiment, the salt refers to medicine Acceptable salt on.The present invention pharmaceutically acceptable salt can use conventional chemical processes by parent compound, alkalinity or Acidic moiety synthesizes.In general, such salt can be by making the free acid form and stoichiometry of these compounds It is reacted suitable for alkali (hydroxide, carbonate, the bicarbonate of such as Na, Ca, Mg or K), or by making these compounds Free alkali form reacts to be prepared with the suitable acid of stoichiometry.Such reaction is usually in water or organic solvent or the two Mixture in carry out.Usually, in appropriate cases, need using non-aqueous medium for example ether, ethyl acetate, ethyl alcohol, Isopropanol or acetonitrile.At 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 List of the other suitable for salt can be found in (Wiley-VCH, Weinheim, Germany, 2002).
The compounds of this invention is alkaline, therefore is generally possible to pharmaceutically acceptable to be formed by being handled with suitable acid Acid-addition salts.Suitable acid includes pharmaceutically acceptable inorganic acid and pharmaceutically acceptable organic acid.Representative medicine Acceptable acid-addition salts include hydrochloride, hydrobromate, nitrate, methyl nitrate, sulfate, disulfate, ammonia on Base sulfonate, phosphate, acetate, hydroxyl acetate, phenyl acetate salt, propionate, butyrate, isobutyrate, valerate, horse Carry out hydrochlorate, hydroxymaleic acid salt, acrylates, fumarate, malate, tartrate, citrate, salicylate, right Aminosalicylate, glycollate, lactate, enanthate, phthalate, oxalates, succinate, benzoate, neighbour Acetoxy-benzoic acid salt, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzene Formates, mandelate, tannate, formates, stearate, ascorbate, palmitate, oleate, acetonate, Pamoate, malonate, laruate, glutarate, glutamate, estolate, mesylate, sulfonate, 2- hydroxyls Esilate, benzene sulfonate, sulfanilate, tosilate and naphthalene-2-sulfonic acid salt, etc..
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compounds, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound can pass through this field skill shown in the formula (I) or formula (II) of isotope enrichment It is tried using suitable isotope labelling described by routine techniques known to art personnel or the embodiment in the present invention and preparation process Agent substitutes original used unmarked reagent to prepare.
On the other hand, the present invention relates to the intermediates for preparing compound shown in formula (I) or formula (II).
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound or formula (I) or formula (II) institute shown in formula (I) or formula (II) Show the stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or Prodrug.Described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al., Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams& Wilkins,Philadelphia；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid that can substantially reduce the compounds of this invention when administering to a patient and can cause not being medicine The interaction of acceptable pharmaceutical composition on.In addition, each excipient must be pharmaceutically acceptable, for example, tool There is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Contribute to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partly to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.One skilled in the art will recognize that certain pharmaceutically acceptable excipient can provide not A kind of only function, and alternative function is provided, this is depended in preparation in the presence of there are which in how much excipient and preparation Other a little excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object acts on, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.
The compounds of this invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.For example, dosage form It is suitable for the dosage form of following administration route including those：(1) it is administered orally, such as tablet, capsule, caplet agent, pill, lozenge Agent, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, for example, it is sterile Solution, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as suppository；(5) it inhales Enter, such as aerosol, solution and dry powder doses；(6) local administration, such as cream, ointment, lotion, solution, paste Agent, spray, foaming agent and gelling agent.
It will also be appreciated that certain compounds of the present invention can exist for treating in a free form, or if it is appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
In one embodiment, the compounds of this invention can be configured to peroral dosage form.In another embodiment, of the invention Compound can be configured to inhalant dosage form.In another embodiment, the compounds of this invention can be configured to nose administration dosage form. In yet another embodiment, the compounds of this invention can be configured to transdermal administration.Also in one embodiment, of the present inventionization Topical dosage forms can be configured to by closing object.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by being prepared more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plasticized by the way that glycerine, sorbierite or similar polyalcohol is added.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative be 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 provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution in propene carbonate, vegetable oil or triglycerides and suspension.Including the capsule of such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, for example, low alkyl group aldehyde two (low alkyl group) acetals, such as acetaldehyde diethyl acetal；With tool there are one or it is more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared At suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Including fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising breast Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next It says, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed Amount) it defines.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, 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, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
The compounds of this invention can also be combined with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can with realizing drug A kind of Biodegradable polymeric for using combines in control release, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Crosslinking or the amphiphilic block copolymer of polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition for being intended for parenteral administration may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
In one embodiment, therapy of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.
In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral medication, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral medications.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administrations.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably be given Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, including implement the duration of the program, treated disease is depended on, disease is treated The severity of disease, the age of patient under consideration and physical condition, are thought the property of the medical history of patient under consideration while therapy The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs variation as time goes by it may require that adjust it is suitable to Prescription case.
The compounds of this invention can simultaneously, or before it or later be administered with one or more other therapeutic agents.This hair Bright compound can be respectively administered with other therapeutic agents by identical or different administration route, or therewith with same pharmaceutical composition Form is administered.
The compounds of this invention can be with sedative, hypnotic, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole Ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the element that fades can medicament, benzene phenodiazines Leather, barbiturate, 5HT-2 antagonists etc. are used in combination, such as：Adinazolam, allobarbital, alonimid, Alprazolam, amitriptyline, amytal, amoxapine, bentazepam, benzoctamine, brotizolam, biphenylacetone, fourth Spirocyclic ketone, cloth tower barbital, cloth tower are than appropriate, capuride, Carbocloral, chloral betaine, chloraldurate, librium, chlorine rice pa Bright, Clonazepam, Domperidone, Decacil, cloretate, Clozapine, cyprazepam, desipramine, dexclamol, stable, chlorine Aldehyde willow amine, double valproic acids, benadryl, doxepin, estazolam, ethchlorvynol, amidate, fenobam, fluorine nitre west It dissolves, Flurazepam, Fluvoxamine, fluoxetine, fosazepam, glutethimide, Halazepam, hydroxyzine, imipramine, lithium, chlorine hydroxyl go first Stable, Lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, peacefulness, methaqualone, midaflur, miaow reach azoles Logical sequence, Buddhist nun's method oxazolone, Nisobamate, intrazepam, nortriptyline, oxazepan, paraaldehyde, Paro former times spit of fland, amobarbital, piperazine Even up, perphenazine, nardil, phenobarbital, prazepam, fenazil, propofol, protriptyline, quazepam, auspicious chlorine West dissolves, rolipram, quinalbarbitone, Sertraline, Suproclone, Temazepam, thioridazine, Tracazolate, anti-phenyl ring third Amine, Trazodone, triazole benzene phenodiazine, Trepipam, trimeglamide, trichloroethyl phosphate, triperazine, trimethoxy benzoyl Quinoline, trimeprimine, uldazepam, venlafaxine new, Zaleplon, Zolazepam, zolpidem and their salt and composition Etc. or the compounds of this invention can administration while physical method such as light therapy or electro photoluminescence be used in combination.
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, those skilled in the art can implement one kind or more in following manner：(a) the internal action of compound is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of change compound；(d) modification Close the internal solubility of object；And the side effect for (e) overcoming compound to be faced or other difficult points.It is used to prepare the typical of prodrug Functional derivatives, including in vivo chemically or the variant of compound that cracks of the mode of enzyme.Including prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.
The purposes of the compounds of this invention and pharmaceutical composition
Compound and pharmaceutical composition of the present invention are as orexin receptor antagonists, to preventing or treating and appetite The plain relevant disease of receptor is effective, can be used for preparing the drug of antagonism orexin receptor.
All types of sleep disturbance, all types of psychiatry, god are can be selected from the relevant disease of orexin receptor It is learned and neurodegeneration obstacle, all types of pressure correlation syndromes, all types of habituation (especially psychotropic activity object through disease The use of matter is abused, seeks and is restored), it is all types of in healthy population and in psychiatric patient and nervous system disease Cognition dysfunction, all types of feeds in patient or drinking-water obstacle, etc..
In one embodiment, include sleep disturbance, depression, anxiety disorder, fear with the relevant disease of orexin receptor Disease, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavior are lost Often, emotionally disturbed, posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, amentia, Dementia, pharmacological dependence, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, feeding desorder, headache, It is migraine, pain, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune correlated disease, interior Secrete relevant disease or hypertension.
In one embodiment, sleep disturbance is can be selected from the relevant disease of orexin receptor, it includes all types of Insomnia, Narcolepsy and other hyper somnolence diseases, parasomnia, the relevant myodystony of sleep, uneasy leg Syndrome, sleep apnea, circadian disorders, jet lag, shift worker syndrome and sleep phases Syndrome or the relevant insomnia of mental disease is retarded or advanced, etc..
In one embodiment, psychiatry, neurology and nerve are can be selected from the relevant disease of orexin receptor to become Sexual dysfunction, it includes depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective disease, depressibility neuropathy, anxiety nerves Disease, mood disorder, panic attack obstacle, posttraumatic stress disorder, sex dysfunction, mental disease, Parkinson's disease, dementia or essence Refreshing hypoevolutism, etc..
In one embodiment, cognition dysfunction is can be selected from the relevant disease of orexin receptor, it includes normal , it is healthy, young, adult's or old crowd in transient episodes or chronic seizures all types of attentions, It practises and memory function declines, or the transient episodes or chronic in mental disease, neuropathy, angiocarpy and disease of immune system patient All types of attentions of breaking-out, learning and memory function reduction, etc..
It should be understood that in certain environmental conditions such as such as pressure or fear, (wherein, pressure may have social source such as Social pressures or have physiological sources such as physical stress, include by fear generate pressure) promote or accelerate it is any as previously described Conditions or diseases in the case of, the compound of the present invention to treat these environment adjusting conditions or diseases be useful.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, the compound of the present invention includes its pharmaceutically acceptable derivates.
The general synthetic method of the compounds of this invention
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment is for further lifting Example illustrates present disclosure.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.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 spectrometers.1H H NMR spectroscopies are with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as with reference to mark It is accurate.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level four bars HPLC-MS (column models of Agilent： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (containing the H of 0.1% formic acid2O the ratio in), using electron spray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses 1260 pre-HPLC or Calesep pump of Agilent, 250 pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), at 210nm/254nm, detected with UV.
The use of brief word below is through the present invention：
Boc tertbutyloxycarbonyls
CH2Cl2, DCM dichloromethane
Cs2CO3Cesium carbonate
CDC13Deuterochloroform
DMSO-d6Deuterated dimethyl sulfoxide
CuI cuprous iodides
DMF N,N-dimethylformamides
SOCl2Thionyl chloride, thionyl chloride
POCl3Phosphorus oxychloride
Pyridine pyridines
Et3N, TEA triethylamines
Urea urea
THF tetrahydrofurans
EtOAc, EA ethyl acetate
MeOH methanol
EtOH ethyl alcohol
Acetone acetone
1,4-dioxane 1,4- dioxane
G grams
H hours
CH3COOH glacial acetic acid
HCl hydrochloric acid
HCl in EA hydrogen chloride-ethyl acetate
CH3ONa sodium methoxides
NaOH sodium hydroxides
Na2SO4Sodium sulphate
NaCl sodium chloride
NaHCO3Sodium bicarbonate
ML, ml milliliters
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Following synthetic schemes describes the step of preparing the compounds of this invention.Unless otherwise stated, X, R1、R2、R3、R4、R5 And R6With definition as described in the present invention.
Intermediate synthetic schemes 1
Midbody compound of the present invention (5) can be prepared by the method described in intermediate synthetic schemes 1：It is different Substituent group substitution o-iodobenzoic acid (1) exist in [Cu] catalysis, alkali appropriate with 1H-1,2,3- triazoles and under heating condition Be obtained by the reaction intermediate (2).Compound (2) with chlorinating agent be obtained by the reaction in a heated condition compound (3), compound (3) With 2-Boc- hexahydropyrrolos simultaneously [3,4-c] pyrroles be obtained by the reaction under alkaline condition compound (4), compound (4) in acid item Under part deprotection obtain compound (5)。
Synthetic schemes 1
The compounds of this invention (7) can be prepared by the method that synthetic schemes 1 describes：Midbody compound (5) with Different substituents substitution compound (6) directly react up to target compound (7)。
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1:6- (5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4- C] pyrroles -2 (1H)-yl) pyridine -2 (1H) -one synthesis
The synthesis of step 1) 5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid
By 1,2,3- triazole (3.45g, 50mmol), the iodo- 5- methyl benzoic acids (5.24g, 20mmol) of 2-, cesium carbonate (11.72g, 36mmol), trans--N, N'- dimethyl -1,2- cyclohexanediamine (0.51g, 3.6mmol), cuprous iodide (0.38g, 2mmol), n,N-Dimethylformamide (30mL) is added sequentially in 100mL single necked round bottom flask, is gradually heated up under nitrogen protection It is reacted 4 hours to 100 DEG C.Stop reaction, it is cooling, it is diluted with tap water and ethyl acetate (200mL × 2) is used to extract.Water layer is used Concentrated hydrochloric acid is acidified (pH=1~2) and uses ethyl acetate (200mL × 2) to extract afterwards, merges organic layer, anhydrous sodium sulfate drying, mistake Filter, filtrate decompression, which is evaporated and carries out column chromatographic isolation and purification (methylene chloride/methanol (v/v)=50/1), obtains title compound (yellow solid, 2.76g, 68%).
MS(ESI,neg.ion)m/z:202.1[M-H]-；
1H NMR(MeOD,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)
The synthesis of step 2) 5- methyl -2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoic acid (2.03g, 10mmol) is added to 100mL single port In round-bottomed flask, dissolved with 20mL anhydrous methylene chlorides, then be slowly added into thionyl chloride (15mL, 200mmol), pyridine (0.15mL, 2mmol) is gradually heating to back flow reaction 3 hours.Stop reaction, cooling, decompression slowly boils off solvent, gained production Object is directly entered in next step.
Step 3) 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up the synthesis of -2 (1H)-t-butyl formates
By 2-Boc- hexahydropyrrolos, simultaneously [3,4-c] pyrroles (0.990g, 4.66mmol) is added in 100mL single port bottles, uses After dry methylene chloride (20mL) dissolving, under the conditions of cold-trap (- 8 DEG C), it is slowly added into triethylamine (5mL), adds dichloromethane 5- methyl -2- (1,2,3- triazole -2- bases) chlorobenzoyl chloride (1.250g, 5.640mmol) of (15mL) dissolving after 10min, turns Move to room temperature reaction 14h.Stop reaction, dichloromethane dilution, saturated common salt water washing, collected organic layer, water is added in reaction solution Layer extracts (20mL × 3) using dichloromethane, merges organic layer, and anhydrous sodium sulfate is dried, and filtering, filtrate decompression is evaporated and carries out Column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v)=1/1.2) obtain title compound (yellow oil, 1.793g, 96.7%).
MS(ESI,pos.ion)m/z:398.1[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.84 (d, J=7.4Hz, 1H), 7.77 (s, 2H), 7.30 (d, J= 8.0Hz, 1H), 7.20 (s, 1H), 3.77 (d, J=7.4Hz, 1H), 3.65~3.51 (m, 2H), 3.42 (d, J=40.6Hz, 1H), 3.26 (d, J=5.8Hz, 2H), 3.17~3.06 (m, 1H), 2.90 (d, J=31.5Hz, 2H), 2.76 (s, 1H), 2.39 (s, 3H), 1.44 (d, J=19.2Hz, 9H)
Step 4) (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (5- methyl -2- (2H-1,2,3- triazoles -2- Base) phenyl) ketone synthesis
By 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate (1.79g, 4.50mmol) is added in 100mL single port bottles, keeps it completely molten with dichloromethane (15mL) Xie Hou is slowly added into hydrogen chloride-ethyl acetate (30mL), reacts at room temperature 0.5h.Stop reaction, using saturated sodium bicarbonate solution PH is adjusted to alkaline (pH=8~9), water layer extracts (20mL × 3) using dichloromethane, merges organic layer, and anhydrous sodium sulfate is dry It is dry, filtering, filtrate decompression be evaporated and carry out column chromatographic isolation and purification (methylene chloride/methanol (v/v)=10/1) obtain it is titled Close object (yellow oil, 1.28g, 95.6%).
MS(ESI,pos.ion)m/z:298.4[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):7.81~7.79 (m, 3H), 7.29 (dd, J=8.3Hz, 0.8Hz, 1H), 7.17 (s, 1H), 3.72~3.64 (m, 2H), 3.38~3.31 (m, 2H), 3.21~3.18 (m, 1H), 3.09~3.06 (m, 1H), 2.97~2.95 (m, 2H), 2.85~2.77 (m, 2H), 2.38 (s, 3H)
(hexahydropyrrolo is simultaneously [3,4-c] by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by step 5) 6- Pyrroles -2 (1H)-yl) pyridine -2 (1H) -one synthesis
It will (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzene Base) ketone (0.35g, 1.18mmol), 6- chlorine-2-hydroxyls pyridine (0.17g, 1.29mmol), triethylamine (0.47g, It 4.71mmol) is added sequentially in 100mL reaction bulbs with Isosorbide-5-Nitrae-dioxane (20mL), reaction is warming up to back flow reaction 12h.Stop Only react, vacuum distillation remove solvent, remaining solid using dichloromethane (30mL) dissolve, organic phase using wash (10mL × 3), anhydrous sodium sulfate dry, filtering, filtrate decompression be evaporated and carry out column chromatographic isolation and purification (methylene chloride/methanol (v/v)= 30/1) title compound (faint yellow solid, 0.31g, 68.5%) is obtained.
MS(ESI,pos.ion)m/z:391.20[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.15 (s, 1H), 8.02~7.96 (m, 1H), 7.94 (d, J= 8.1Hz, 1H), 7.76 (s, 2H), 7.53~7.47 (m, 1H), 7.46~7.42 (m, 1H), 7.39~7.35 (m, 1H), 7.26 ~7.23 (m, 1H), 3.84 (dd, J=11.2,7.8Hz, 2H), 3.73~3.68 (m, 2H), 3.47~3.41 (m, 2H), 2.98 ~2.95 (m, 2H), 2.68~2.61 (m, 2H), 2.32 (s, 3H)；
HPLC:98.65%.
Embodiment 2:6- (5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles - 2 (1H)-yls) pyridine -2 (1H) -one synthesis
The synthesis of step 1) 2- (2H-1,2,3- triazole -2- bases) benzoic acid
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 1,2,3- triazole (0.7g, 10.08mmol), 2- iodo-benzoic acids (1g, 4.03mmol), cesium carbonate (2.36g, 7.2mmol), trans--N, N'- diformazans Base -1,2- cyclohexanediamine (0.103g, 0.752mmol), cuprous iodide (0.077g, 0.403mmol) is in N, N- dimethyl formyls In amine (18mL) prepared by reaction, and crude product is marked through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) Inscribe compound (yellow solid, 0.511g, 67%).
MS(ESI,neg.ion)m/z:188.1[M-H]-；
1H NMR(DMSO-d6,600MHz)δ(ppm):13.06 (s, 1H), 8.08 (s, 2H), 7.78~7.75 (m, 2H), 7.72~7.68 (m, 1H), 7.60~7.57 (m, 1H)
The synthesis of step 2) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by 2- (2H-1,2,3- Triazole -2- bases) benzoic acid (0.37g, 1.96mmol) 20mL anhydrous methylene chlorides dissolve, then are slowly added into thionyl chloride (6mL, 82.7mmol), pyridine (0.04mL, 0.5mmol), is gradually heating to back flow reaction 3 hours.Stop reaction, it is cooling, subtract Pressure slowly boils off solvent, and products therefrom is directly entered in next step.
Step 3) tertiary butyl 5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrrole Cough up the synthesis of -2 (1H)-methyl esters
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by 2-Boc- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles (0.96g, 4.52mmol), triethylamine (2.55mL), 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride Prepared by (1.12g, 5.39mmol) reaction in dry anhydrous methylene chloride (30mL), crude product is through silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=2/1) obtains title compound (brown color viscous liquid, 1.33g, 76.5%).
MS(ESI,pos.ion)m/z:384.3[M+H]+；
1H NMR(CDCl3, 400MHz) and δ (ppm):8.00 (d, J=8.1Hz, 1H), 7.81 (s, 2H), 7.55~7.50 (m, 1H), 7.45~7.42 (m, 2H), 3.79 (d, J=7.4Hz, 1H), 3.63 (d, J=10.9Hz, 2H), 3.46 (d, J= 8.4Hz, 1H), 3.29 (dd, J=11.2,5.0Hz, 2H), 3.20~3.11 (m, 1H), 2.90 (s, 2H), 2.80 (dd, J= 11.0,5.6Hz, 1H), 1.46~1.44 (m, 9H)
Step 4) (2- (2H-1,2,3- triazole -2- bases) phenyl) (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) first The synthesis of ketone
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e. tertiary butyl 5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-methyl esters (1.31g, 3.42mmol) in the ethyl acetate solution of hydrogen chloride (15mL) and dry anhydrous methylene chloride (30mL) prepared by reaction, thick to produce Product obtain title compound (the thick liquid of brown color through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) Body, 0.94g, 97.10%).
MS(ESI,pos.ion)m/z:284.2[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.97 (d, J=8.1Hz, 1H), 7.83 (s, 2H), 7.54~7.50 (m, 1H), 7.41 (q, J=7.7Hz, 2H), 3.79~3.67 (m, 2H), 3.29 (dd, J=13.1,9.0Hz, 2H), 3.15 (dd, J=11.2,7.3Hz, 1H), 3.08 (dd, J=11.4,3.4Hz, 1H), 2.95 (d, J=8.4Hz, 2H), 2.83~ 2.75(m,2H).
Step 5) 6- (5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) pyridine -2 (1H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e., (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) (2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.38g, 1.34mmol), the chloro- 2- of 6- Pyridone (0.19g, 1.48mmol), triethylamine (0.54g, 5.36mmol) the reflux 12h in 1,4- dioxane (20mL) It prepares.Gained crude product obtains title compound by silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) (faint yellow solid, 0.286g, 56.8%).
MS(ESI,pos.ion)m/z:377.26[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.20 (s, 1H), 8.10~8.06 (m, 1H), 7.90 (d, J= 8.1Hz, 1H), 7.71 (s, 2H), 7.56~7.53 (m, 1H), 7.44~7.41 (m, 1H), 7.39~7.36 (m, 2H), 7.27 ~7.23 (m, 1H), 3.78 (dd, J=11.2,7.8Hz, 2H), 3.72~3.69 (m, 2H), 3.44~3.41 (m, 2H), 2.97 ~2.93 (m, 2H), 2.69~2.65 (m, 2H)；
HPLC:97.25%.
Embodiment 3:(hexahydropyrrolo is simultaneously [3,4-c] by 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) by 6- Pyrroles -2 (1H)-yl) pyridine -2 (1H) -one synthesis
The synthesis of the fluoro- 6- of step 1) 2- (2H-1,2,3- triazole -2- bases) benzoic acid
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 1,2,3- triazole (6.9g, 100mmol), 2-Fluoro-6-iodobenzoic acid (10.64g, 40mmol), cesium carbonate (23.4g, 71.7mmol), trans--N, N'- dimethyl -1,2- cyclohexanediamine (1.02g, 7.04mmol), cuprous iodide (0.76g, 4.0mmol) is in N, N- dimethyl methyls In amide (50mL) prepared by reaction, and crude product is obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=50/1) Title compound (yellow solid, 5.62g, 67.90%).
MS(ESI,pos.ion)m/z:208.10[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):13.66 (s, 1H), 8.16 (s, 2H), 7.79 (d, J=8.2Hz, 1H), 7.68 (td, J=8.2,6.2Hz, 1H), 7.44 (t, J=8.8Hz, 1H)
The synthesis of the fluoro- 6- of step 2) 2- (2H-1,2,3- triazole -2- bases) chlorobenzoyl chloride
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the fluoro- 6- (2H- of 2- 1,2,3- triazole -2- bases) benzoic acid (0.69g, 3.33mmol) 20mL anhydrous methylene chlorides dissolve, then are slowly added into chlorination Sulfoxide (8mL, 109.0mmol), DMF (0.04mL, 0.5mmol), is gradually heating to back flow reaction 3 hours.Stop reaction, it is cold But, decompression slowly boils off solvent, and products therefrom is directly entered in next step.
Step 3) 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles - The synthesis of 2 (1H)-t-butyl formates
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by 2-Boc- hexahydro pyrroles Cough up simultaneously [3,4-c] pyrroles (0.426g, 2.01mmol), triethylamine (0.8mL), the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) Prepared by chlorobenzoyl chloride (0.54g, 2.39mmol) reaction in dry anhydrous methylene chloride (30mL), crude product is through silica gel column chromatography Isolate and purify (petroleum ether/acetone (v/v)=4/1) obtain title compound (brown color viscous liquid, 0.705g, 87.5%).
MS(ESI,pos.ion)m/z:346.20[M-56]+；
1H NMR(CDCl3,400MHz)δ(ppm):7.89~7.76 (m, 3H), 7.48 (dd, J=14.3,8.4Hz, 1H), 7.15 (td, J=8.4,3.0Hz, 1H), 3.90~2.86 (m, 10H), 1.47 (s, 9H)
Step 4) (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) ketone synthesis
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e. 5- (fluoro- 6- (the 2H- of 2- 1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-t-butyl formate (0.913g, 2.27mmol) in the ethyl acetate solution of hydrogen chloride (4mL) and dry anhydrous methylene chloride (10mL) prepared by reaction, crude product Title compound (the thick liquid of brown color is obtained through silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=20/1) Body, 0.604g, 88%).
MS(ESI,pos.ion)m/z:302.1[M+1]+；
1H NMR(d6-DMSO,400MHz)δ(ppm):9.91(s,1H),9.50(s,1H),8.23(s,1H),8.14(s, 1H), 7.82 (t, J=8.2Hz, 1H), 7.68 (tdd, J=8.4,6.4,2.0Hz, 1H), 7.44 (t, J=9.2Hz, 1H), 3.62 (d, J=6.2Hz, 1H), 3.57~3.42 (m, 2H), 3.41~3.14 (m, 3H), 3.13~2.85 (m, 4H)
Step 5) 6- (5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles Cough up -2 (1H)-yls) synthesis of pyridine -2 (1H) -one
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e., (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.37g, 1.23mmol), 6- Chlorine-2-hydroxyl pyridine (0.17g, 1.35mmol), triethylamine (0.50g, 4.91mmol) return in 1,4- dioxane (20mL) 12h is flowed to prepare.Gained crude product obtains title by silica gel column chromatography separating purification (methylene chloride/methanol (v/v)=30/1) Compound (faint yellow solid, 0.31g, 62.8%).
MS(ESI,pos.ion)m/z:395.16[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.27 (s, 1H), 8.15~8.13 (m, 1H), 8.09~8.06 (m, 1H), 7.90 (d, J=8.3Hz, 1H), 7.85~7.82 (m, 1H), 7.79 (d, J=20.3Hz, 2H), 7.48 (dt, J= 14.2,4.1Hz, 1H), 7.16~7.11 (m, 1H), 3.91~3.86 (m, 1H), 3.83~3.77 (m, 1H), 3.75~3.71 (m, 1H), 3.68~3.65 (m, 1H), 3.59 (dt, J=10.7,6.3Hz, 2H), 3.28~3.24 (m, 2H), 3.13~3.01 (m,2H)；
HPLC:96.65%.
Embodiment 4:2- (5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4- C] pyrroles -2 (1H)-yl) -6,7- dihydro -3H- cyclopentas [d] pyrimidine -4 (5H) -one synthesis
The synthesis of step 1) methyl -2- urea groups cyclopentene -1- carboxylate methyl esters
It is anti-that 2- oxocyclopentanecarboxylic acids methyl esters (2.28g, 16.04mmol) and ethyl alcohol (20mL) are added sequentially to 100mL It answers in bottle, then sequentially adds hydrochloric acid (0.21mL, 2.40mmol) and urea (1.44g, 23.98mmol).Reaction is warming up to 80 DEG C reaction 4h.Stop reaction, filter, the mashing in water (50mL) of gained crude product filters, and vacuum drying obtains title compound (pale solid, 2.17g, 73.28%).
MS(ESI,pos.ion)m/z:185.20[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):9.41(s,1H),6.73(s,2H),3.64(s,3H),3.02(t,J =7.7Hz, 2H), 2.38 (t, J=7.4Hz, 2H), 1.79~1.71 (m, 2H)
The synthesis of step 2) 6,7- dihydro -1H- cyclopentas [d] pyrimidine -2,4 (3H, 5H)-diketone
By methyl -2- urea groups cyclopentene -1- carboxylate methyl esters (2.17g, 11.75mmol) and sodium hydroxide solution (30mL, It 1mol/L) is added sequentially in the reaction bulb of 100mL, 110 DEG C of reaction 1.5h.Stop reaction, is cooled to room temperature, using hydrochloric acid (3mol/L) adjusts pH value of solution=2, filters, and filter cake collects solid, vacuum drying obtains titled using washing (20mL × 2) Close object (white solid, 1.74g, 97.24%).
MS(ESI,pos.ion)m/z:153.2[M+H]+；
1H NMR(DMSO-d6,400MHz)δ(ppm):11.04 (s, 1H), 10.72 (s, 1H), 2.63 (t, J=7.6Hz, 2H), 2.44 (t, J=7.3Hz, 2H), 1.98~1.91 (m, 2H)
The synthesis of bis- chloro- 6,7- dihydros -5H- cyclopentas [d] pyrimidines of step 3) 2,4-
By 6,7- dihydro -1H- cyclopentas [d] pyrimidine -2,4 (3H, 5H)-diketone (1.74g, 11.40mmol) and three Chlorethoxyfos (26.09mL, 285mmol) are added sequentially in the reaction bulb of 100mL, 120 DEG C of reaction 2h.After reaction, it depressurizes Extra phosphorus oxychloride is distilled off, then to ice water is added in reaction bulb, ethyl acetate extracts (30mL × 3), collects organic Phase, anhydrous sodium sulfate drying, filtering, filtrate decompression are evaporated and carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/v) =20/1) title compound (white solid, 1.86g, 86.10%) is obtained.
MS(ESI,pos.ion)m/z:189.00[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):3.07 (t, J=7.9Hz, 2H), 2.97 (t, J=7.6Hz, 2H), 2.24~2.17 (m, 2H)
The synthesis of chloro- 6,7- dihydros -3H- cyclopentas [d] pyrimidine -4 (5H) -one of step 4) 2-
By bis- chloro- 6,7- dihydros -5H- cyclopentas [d] pyrimidines (1.86g, 9.81mmol) of 2,4- and tetrahydrofuran (15mL) is added sequentially in the reaction bulb of 100mL, and the sodium hydroxide solution (29.5mL) of 1.0mol/L is then added, and nitrogen is protected Shield is lower to react at room temperature 26h.Stop reaction, reaction solution glacial acetic acid adjusts pH=5, and ethyl acetate extracts (50mL × 3), and collection has Machine phase, anhydrous sodium sulfate drying, filtering, filtrate decompression are evaporated and carry out column chromatographic isolation and purification (petrol ether/ethyl acetate (v/ V) title compound (light green solid, 0.40g, 23.93%)=5/1) is obtained.
MS(ESI,pos.ion)m/z:171.10[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):12.86 (s, 1H), 2.89 (t, J=7.8Hz, 2H), 2.83 (t, J= 7.6Hz, 2H), 2.15~2.08 (m, 2H)
(hexahydropyrrolo is simultaneously [3,4-c] by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by step 5) 2- Pyrroles -2 (1H)-yl) -6,7- dihydro -3H- cyclopentas [d] pyrimidine -4 (5H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e. chloro- 6, the 7- dihydros-of 2- 3H- cyclopentas [d] pyrimidine -4 (5H) -one (0.32g, 1.85mmol), (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) (5- methyl -2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.50g, 1.68mmol) and triethylamine (0.68g, 6.73mmol) back flow reaction is prepared for 12 hours in 1,4- dioxane (20mL).Gained crude product is detached through silica gel column chromatography Purifying (methylene chloride/methanol (v/v)=30/1) obtains title compound (faint yellow solid, 0.53g, 72.48%).
MS(ESI,pos.ion)m/z:432.25[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):11.18 (s, 1H), 7.95 (d, J=8.2Hz, 1H), 7.79 (s, 2H), 7.55~7.47 (m, 1H), 7.44~7.42 (m, 1H), 3.82 (dd, J=11.2,7.8Hz, 2H), 3.73 (dd, J=10.6, 7.0Hz, 2H), 3.58 (dd, J=11.0,5.4Hz, 1H), 3.47~3.41 (m, 2H), 3.08 (td, J=11.9,6.2Hz, 2H), 2.98~2.95 (m, 1H), 2.68 (t, J=7.7Hz, 2H), 2.61 (t, J=7.3Hz, 2H), 2.32 (s, 3H), 1.96 (dt, J=15.0,7.7Hz, 2H)；
HPLC:97.12%.
Embodiment 5:2- (5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles - 2 (1H)-yls) -6,7- dihydro -3H- cyclopentas [d] pyrimidine -4 (5H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e. chloro- 6, the 7- dihydros-of 2- 3H- cyclopentas [d] pyrimidine -4 (5H) -one (0.19g, 1.10mmol), (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) (2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.28g, 1.01mmol) and triethylamine (0.60mL, 4.30mmol) back flow reaction is prepared for 12 hours in 1,4- dioxane (20mL).Gained crude product is detached through silica gel column chromatography Purifying (methylene chloride/methanol (v/v)=30/1) obtains title compound (faint yellow solid, 0.29g, 70.02%).
MS(ESI,pos.ion)m/z:418.25[M+H]+；
1H NMR(CDCl3,400MHz)δ(ppm):11.15 (s, 1H), 7.98 (d, J=8.2Hz, 1H), 7.77 (s, 2H), 7.55~7.49 (m, 1H), 7.44~7.41 (m, 2H), 3.87 (dd, J=11.1,7.8Hz, 2H), 3.70 (dd, J=10.8, 6.9Hz, 2H), 3.59 (dd, J=11.2,5.4Hz, 1H), 3.49~3.41 (m, 2H), 3.05 (td, J=12.1,6.2Hz, 2H), 2.98~2.96 (m, 1H), 2.71 (t, J=7.7Hz, 2H), 2.62 (t, J=7.3Hz, 2H), 1.98 (dt, J=15.0, 7.7Hz,2H)；
HPLC:96.70%.
Embodiment 6:(hexahydropyrrolo is simultaneously [3,4-c] by 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) by 2- Pyrroles -2 (1H)-yl) -6,7- dihydro -3H- cyclopentas [d] pyrimidine -4 (5H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e. chloro- 6, the 7- dihydros-of 2- 3H- cyclopentas [d] pyrimidine -4 (5H) -one (0.19g, 1.10mmol), (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H) - Base) (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.302g, 1.01mmol) and triethylamine (0.60mL, 4.30mmol) back flow reaction is prepared for 12 hours in 1,4- dioxane (20mL).Gained crude product is detached through silica gel column chromatography Purifying (methylene chloride/methanol (v/v)=30/1) obtains title compound (faint yellow solid, 0.296g, 67.89%).
MS(ESI,pos.ion)m/z:436.25[M+H]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.27 (s, 1H), 7.85~7.82 (m, 1H), 7.79 (d, J= 20.3Hz, 2H), 7.48 (dt, J=14.2,4.1Hz, 1H), 7.16~7.11 (m, 1H), 3.96 (ddd, J=14.6,12.0, 7.8Hz, 1H), 3.91~3.86 (m, 1H), 3.83~3.77 (m, 1H), 3.75~3.71 (m, 1H), 3.68~3.65 (m, 1H), 3.59 (dt, J=10.7,6.3Hz, 2H), 3.28~3.24 (m, 1H), 3.13~3.01 (m, 2H), 2.70 (d, J= 7.5Hz, 2H), 2.61 (t, J=7.1Hz, 2H), 1.98 (dt, J=14.7,7.3Hz, 2H)；
HPLC:95.94%.
Embodiment 7:2- (5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4- C] pyrroles -2 (1H)-yl) -5,6,7,8- tetrahydro quinazolines -4 (3H) -one synthesis
The synthesis of -2,4 (1H, 3H)-diketone of step 1) 5,6,7,8- tetrahydro quinazolines
By 2- cyclohexanone Ethyl formate (0.17g, 1.00mmol), urea (0.31g, 5.16mmol), sodium methoxide (0.165g, 2.96mmol), absolute methanol (3mL) and absolute ethyl alcohol (10mL) are added sequentially in the reaction bulb of 50mL, reflux React 12h.Stop reaction, be spin-dried for solvent, water (10mL) is added, dilute hydrochloric acid adjusts pH value of solution=5, and dichloromethane extracts (10mL × 3), collect organic phase, anhydrous sodium sulfate drying, vacuum distillation remove solvent obtain title compound (colourless oil liquid, 0.139g, 84%).
MS(ESI,neg.ion)m/z:165.10[M-1]-；
1H NMR(DMSO-d6,400MHz)δ(ppm):10.82 (s, 1H), 10.54 (s, 1H), 2.28 (t, J=5.8Hz, 2H), 2.12 (t, J=5.8Hz, 2H), 1.68~1.52 (m, 4H)
The synthesis of bis- chloro- 5,6,7,8- tetrahydro quinazolines of step 2) 2,4-
This step title compound method with reference to described in 4 step 3 of embodiment is prepared, i.e., 5,6,7,8- tetrahydrochysene quinolines It is prepared by oxazoline -2,4 (1H, 3H)-diketone (2.90g, 17.45mmol) reflux 15h in phosphorus oxychloride (30mL).Gained crude product By silica gel column chromatography separating purification (petroleum ether/acetone (v/v)=20/1) obtain title compound (white solid, 3.21g, 91%).
MS(ESI,pos.ion)m/z:203.10[M+1]+；
1H NMR(CDCl3,400MHz)δ(ppm):2.88 (br.s, 2H), 2.72 (br.s, 2H), 1.95~1.80 (m, 4H).
The synthesis of chloro- -4 (3H) -one of 5,6,7,8- tetrahydro quinazolines of step 3) 2-
This step title compound method with reference to described in 4 step 4 of embodiment is prepared, i.e. 2,4- bis- chloro- 5,6, In 7,8- tetrahydro quinazolines (3.21g, 15.81mmol) and sodium hydroxide solution (100mL, 1mol/L) and tetrahydrofuran (12mL) 60 DEG C of reaction 12h.Gained crude product is marked by silica gel column chromatography separating purification (petrol ether/ethyl acetate (v/v)=4/1) Inscribe compound (white solid, 2.61g, 91%).
MS(ESI,pos.ion)m/z:185.15[M+1]+；
1H NMR(CDCl3,400MHz)δ(ppm):12.71 (s, 1H), 2.64 (t, J=6.1Hz, 2H), 2.51 (t, J= 6.0Hz, 2H), 1.85~1.70 (m, 4H)
(hexahydropyrrolo is simultaneously [3,4-c] by 5- (5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl) by step 4) 2- Pyrroles -2 (1H)-yl) -5,6,7,8- tetrahydro quinazolines -4 (3H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e., (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) (5- methyl -2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.50g, 1.68mmol), Chloro- -4 (3H) -one (0.34g, 1.85mmol) of 5,6,7,8- tetrahydro quinazolines of 2-, triethylamine (0.68g, 6.73mmol) are in 1,4- In dioxane (20mL) prepared by reflux 12h.Gained crude product passes through silica gel column chromatography separating purification (methylene chloride/methanol (v/ V) title compound (pale solid, 0.34g, 45.68%)=50/1) is obtained.
MS(ESI,pos.ion)m/z:446.25[M+1]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.77 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.73 (s, 2H), 7.29 (d, J=7.6Hz, 1H), 7.20 (s, 1H), 3.84 (s, 2H), 3.67 (s, 2H), 3.56 (d, J=5.0Hz, 1H), 3.44 (d, J=9.6Hz, 2H), 3.02 (s, 1H), 2.92~2.89 (m, 2H), 2.45~2.40 (m, 2H), 2.39 (s, 3H), 2.29 (t, J=5.9Hz, 2H), 1.72~1.69 (m, 2H), 1.64~1.61 (m, 2H)；
HPLC:97.70%.
Embodiment 8:2- (5- (2- (2H-1,2,3- triazole -2- bases) benzoyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles - 2 (1H)-yls) -5,6,7,8- tetrahydro quinazolines -4 (3H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e., (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) (2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.45g, 1.59mmol), 2- chloro- 5, 6,7,8- tetrahydro quinazolines -4 (3H) -one (0.32g, 1.75mmol), triethylamine (0.64g, 6.35mmol) are in 1,4- dioxies six In ring (20mL) prepared by reflux 12h.Gained crude product by silica gel column chromatography separating purification (methylene chloride/methanol (v/v)= 30/1) title compound (faint yellow solid, 0.40g, 58.6%) is obtained.
MS(ESI,pos.ion)m/z:432.10[M+1]+；
1H NMR(CDCl3,600MHz)δ(ppm):11.81 (s, 1H), 7.98 (d, J=8.2Hz, 1H), 7.76 (s, 2H), 7.56~7.47 (m, 1H), 7.45~7.35 (m, 2H), 3.85 (dd, J=11.0,7.8Hz, 2H), 3.77~3.63 (m, 2H), 3.59 (dd, J=11.2,5.4Hz, 1H), 3.46 (dd, J=11.2,3.6Hz, 1H), 3.40 (s, 1H), 3.11~2.98 (m, 2H), 2.94 (s, 1H), 2.46 (t, J=6.0Hz, 2H), 2.29 (t, J=6.0Hz, 2H), 1.78~1.69 (m, 2H), 1.68 ~1.60 (m, 2H)；
HPLC:98.91%.
Embodiment 9:(hexahydropyrrolo is simultaneously [3,4-c] by 5- (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) benzoyl) by 2- Pyrroles -2 (1H)-yl) -5,6,7,8- tetrahydro quinazolines -4 (3H) -one synthesis
This step title compound method with reference to described in 1 step 5 of embodiment is prepared, i.e., (hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) (the fluoro- 6- of 2- (2H-1,2,3- triazole -2- bases) phenyl) ketone (0.50g, 1.57mmol), 2- Chloro- 5,6,7,8- tetrahydro quinazolines -4 (3H) -one (0.35g, 1.87mmol), triethylamine (0.60g, 6.28mmol) are in 1,4- bis- In six ring of oxygen (20mL) prepared by reflux 12h.Gained crude product passes through silica gel column chromatography separating purification (methylene chloride/methanol (v/v) =30/1) title compound (white solid, 0.58g, 79.1%) is obtained.
MS(ESI,pos.ion)m/z:450.25[M+1]+；
1H NMR(CDCl3,400MHz)δ(ppm):12.01 (s, 1H), 7.80 (dd, J=10.9,7.1Hz, 2H), 7.73 (s, 1H), 7.44 (td, J=8.1,4.1Hz, 1H), 7.10 (q, J=8.2Hz, 1H), 3.96~3.49 (m, 7H), 3.22 (dd, J=10.4,5.0Hz, 1H), 3.06 (d, J=3.7Hz, 2H), 2.43 (s, 2H), 2.25 (s, 2H), 1.69 (d, J=5.2Hz, 2H),1.62(s,2H)；
HPLC:97.37%.
Biologic test
Embodiment A the compounds of this invention is to humanization OX1The antagonism of receptor is tested
Test method
This hair is evaluated with influence of the fluorescence detection detection the compounds of this invention to the cell calcium current of agonist induction Bright compound is to expressing the humanization OX on Chinese hamster ovary cell (CHO)1The antagonistic ability of receptor.Cell is suspended in In DMEM culture mediums (invitrogen), then with 2 × 104The Density Distribution of cells/well is in micro reaction plate.It will contain glimmering The Hank of light probe (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids (invitrogen) is flat Weighing apparatus salting liquid (HBSS, invitrogen) (pH=7.4) is added in above-mentioned micro reaction plate, then arises from 37 DEG C with cell one It is incubated 60min, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and test compound is added or with reference to antagonist or Hank balanced salt solutions, 3nM appetite is added after 5min Plain A or Hank balanced salt solutions (blank control) then measure the variation of fluorescence intensity, dense with free intracellular calcium The variation of degree is positively correlated.Experimental result is indicated with the suppression percentage relative to control group 3nM orexin-As.
Amount effect curve is obtained by the experiment test of series concentration, to calculate IC50Value.
The experimental results showed that the compounds of this invention is to OX1Receptor shows preferable antagonism.
Embodiment B the compounds of this invention is to humanization OX2The antagonism of receptor is tested
Test method
This hair is evaluated with influence of the fluorescence detection detection the compounds of this invention to the cell calcium current of agonist induction Bright compound is to expressing the humanization OX on HEK-293 cells2The antagonistic ability of receptor.Cell is suspended in DMEM culture mediums (invitrogen) in, then with 3 × 104The Density Distribution of cells/well is in micro reaction plate.Fluorescence probe will be contained (Fluo4NW, Invitrogen), probenecid and 20mM hydroxyethyl piperazine second thiosulfonic acids Hank balanced salt solutions (HBSS, Invitrogen) (PH=7.4) is added in above-mentioned micro reaction plate, and 37 DEG C of incubation 60min are then arised from cell one, then at 22 DEG C of incubation 15min.Reaction plate is placed in cell fluorescence work station (CellLux, PerkinElmer), and testization is added It closes object or with reference to antagonist or Hank balanced salt solutions, it is (empty that 10nM orexin B or Hank balanced salt solution is added after 5min White control), the variation of fluorescence intensity is then measured, the variation with free intracellular calcium concentration is positively correlated.Experiment knot Fruit is indicated with the suppression percentage relative to control group 10nM orexins B.
Amount effect curve is obtained by the experiment test of series concentration, to calculate IC50Value.Experimental result is as shown in table 1.
1 compound provided in an embodiment of the present invention of table is to OX2The antagonism experimental result of receptor
The experimental results showed that the compounds of this invention is to OX2Receptor shows preferable antagonism.
Embodiment C rats, dog and monkey intravenous or gavage quantify the Pharmacokinetic Evaluation after the compounds of this invention
The present invention assesses pharmacokinetic of the compounds of this invention in rat, dog and monkey body, moves Object information refers to Table A.
Table A animal subject information table of the present invention
Test method
By the compounds of this invention with the salt of 5%DMSO+5%Kolliphor HS 15+2% (2%HCl)+88%Saline The form of aqueous solution or 10%DMSO+10%Kolliphor HS 15+80% normal saline solutions, to animal subject carry out to Medicine.For be injected intravenously administration group, dosage be 1mg/kg or 2mg/kg, then time point upon administration be 0.083, 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour when venous blood sampling (0.3mL), and at 3,000 or 4,000rpm from The heart 10 minutes is collected plasma solutions, and is preserved at -20 DEG C or -70 DEG C.For gastric infusion group, dosage 2.5mg/ Kg or 5mg/kg, vein takes when then time point upon administration is 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hour Blood (0.3mL), and centrifuged 10 minutes at 3,000 or 4,000rpm, plasma solutions are collected, and protected at -20 DEG C or -70 DEG C It deposits.Positive control is suvorexant.
The plasma solutions obtained are collected to above-mentioned each group carries out LC/MS/MS analyses.
Test result shows that the compounds of this invention has preferable pharmacokinetic property in rat, dog or monkey body.
Embodiment D the compounds of this invention potentially causes the assessment that QT interval prolongations act on
Test method
Whether block the channels hERG by detecting the compounds of this invention and potentially causes the phase between QT to assess the compounds of this invention Extension acts on, and specific experimental method is as follows：
The compounds of this invention accurately weighed is dissolved in dimethyl sulfoxide (DMSO) (DMSO), the most highly concentrated of 10.0mM is configured to Then the solution of degree is diluted to the solution that initial concentration is 120.0 μM with hERG FP Assay Buffer (Invitrogen)； HERG Tracer Red stostes (Invitrogen) and positive reference substance E-4031 stostes (Invitrogen) are used into hERG respectively FP Assay Buffer (Invitrogen) are diluted to the solution that initial concentration is 4.0nM and 120.0 μM.Into 384 orifice plates, The compounds of this invention of 2.5 μ L initial concentrations or the positive reference substance E-4031 (positive controls) of 2.5 μ L initial concentrations is added Or 2.5 μ L hERG FP Assay Buffer (negative control group), 5 μ L hERG Membrane and 2.5 μ L hERG Tracer 5 μ L hERG FP Assay Buffer and 5 μ L hERG Membrane are added in Red solution, blank control group so that the present invention Compound, E-4031 and hERG Tracer Red test final concentration be respectively 30.0 μM, 30.0 μM and 1.0nM, each group of survey Have a fling at 4 multiple holes.Then 384 orifice plates are put into 25 DEG C, it is small to be incubated 4 in the concussion instrument (PHMP-4, Grant-sio) of 250rpm When, the fluorescence polarization value in each hole is measured with multi-function microplate reader (PHERAStarFS, BMG LABTECH), calculates compound pair The relative inhibition in the channels hERG and 50% inhibition concentration (IC50)。
In the case where E-4031 is as positive control, if opposite suppression of 30.0 μM of the compounds of this invention to the channels hERG Rate processed is less than 50%, then IC of the compounds of this invention to the channels hERG50More than 30.0 μM.If 30.0 μM of the compounds of this invention pair The relative inhibition in the channels hERG is more than 50%, then needs to do dose curve titration to the compounds of this invention, the specific method is as follows：
The compounds of this invention solution and E-4031 solution by above-mentioned initial concentration for 120 μM, use hERG FP respectively Assay Buffer carry out 5 times of gradient dilutions, be diluted to 120.0 μM, 24.0 μM, 4.8 μM, 960.0nM, 192.0nM, Totally 8 concentration to be measured, each concentration to be measured do 2 multiple holes by 38.4nM, 7.7nM and 1.5nM.2.5 μ L are added into 384 orifice plates to wait for Survey the compounds of this invention of concentration or the positive reference substance E-4031 (positive controls) or 2.5 μ L hERG of 2.5 μ L concentration to be measured FP Assay Buffer (negative control group), 5 μ L hERG FP Membrane and 2.5 μ L hERG Tracer Red solution, 5 μ L hERG FP Assay Buffer and 5 μ L hERG Membrane are added in blank control group.Then 384 orifice plates are put into 25 DEG C, it is incubated 4 hours in the concussion instrument (PHMP-4, Grant-sio) of 250rpm, with multi-function microplate reader (PHERAStarFS, BMG LABTECH the fluorescence polarization value for) measuring each hole, is corrected with the maximum value and minimum value of E-4031 fluorescence polarization values, GraphPad softwares calculate the IC of the compounds of this invention50。
The experimental results showed that the compounds of this invention to the channels hERG substantially without inhibitory activity, prompt the compound to cause The risk of QT interval prolongations is small.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in a or multiple embodiments or example.In addition, without conflicting with each other, the technology of this field The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (10)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein：
X is N or CH；
Hy is phenyl or 5-6 unit's heteroaryls, the phenyl and 5-6 unit's heteroaryls individually optionally by one or more selected from D, F, Cl、Br、I、C1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4The substituent group of halogenated alkoxy and benzyl is replaced；
R1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C2-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C2-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6The alkyl, (C of hydroxyl substitution1-6 Alkyl)-C (=O)-, (C1-6Alkoxy)-C (=O)-or (C1-6Alkylamino)-C (=O)-；
R2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6The alkyl, (C of hydroxyl substitution1-6 Alkyl)-C (=O)-, (C1-6Alkoxy)-C (=O)-or (C1-6Alkylamino)-C (=O)-；Or
R1、R2The carbocyclic ring or heterocycle of 3-8 members are constituted with coupled carbon atom, the carbocyclic ring and heterocycle of the 3-8 members are individually optional Ground is selected from D, F, Cl, Br, I, C by one or more1-4Alkyl, C1-4Halogenated alkyl, C1-4Alkoxy and C1-4Halogenated alkoxy Substituent group is replaced；With
R3、R4、R5And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Hydroxyl takes The alkyl, (C in generation1-6Alkyl)-C (=O)-, (C1-6Alkoxy)-C (=O)-or (C1-6Alkylamino)-C (=O)-.
2. compound according to claim 1, wherein Hy be thienyl, furyl, pyrrole radicals, triazolyl, pyridyl group or Include the 5-6 unit's heteroaryls of two nitrogen-atoms, the thienyl, furyl, pyrrole radicals, triazolyl, pyridyl group and includes two The 5-6 unit's heteroaryls of nitrogen-atoms are individually optionally by one or more selected from D, F, Cl, Br, I, methyl, ethyl, isopropyl, uncle Butyl, trifluoromethyl, methoxyl group, isopropoxy, trifluoromethoxy and benzyl substituent group replaced.
3. compound according to claim 1 is the vertical of compound shown in formula (II) compound represented or formula (II) Body isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
4. compound according to claim 1 or 3, wherein R1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2、C2-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C2-4Alkoxy, C1-4Haloalkoxy Base, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4Alkyl)-C (=O)-, (C1-4Alkoxy)-C (=O)-or (C1-4Alkane Amino)-C (=O)-；
R2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alkoxy, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4 Alkyl)-C (=O)-, (C1-4Alkoxy)-C (=O)-or (C1-4Alkylamino)-C (=O)-；Or
R1、R2The carbocyclic ring or heterocycle of 3-6 members are constituted with coupled carbon atom, the carbocyclic ring and heterocycle of the 3-6 members are individually optional Ground is by one or more selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxy Base, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup and trifluoromethoxy substituent group replaced.
5. compound according to claim 1 or 3, wherein R3、R4、R5And R6Be each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2、C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C1-4Halogenated alkyl, C1-4Alcoxyl Base, C1-4Halogenated alkoxy, C1-4Alkylamino, C1-4The alkyl, (C of hydroxyl substitution1-4Alkyl)-C (=O)-, (C1-4Alkoxy)-C (=O)-or (C1-4Alkylamino)-C (=O)-.
6. compound according to claim 1 or 3, wherein R1For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、- NO2,-COOH ,-C (=O) NH2, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, ethyoxyl, n-propyl oxygroup, Isopropyl oxygroup ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3Or-C (=O) N (CH3)2；
R2For H, D ,-CD3、F、Cl、Br、I、-CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, Isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-NHCH3、-N (CH3)2、-CH2OH ,-C (=O) NHCH3Or-C (=O) N (CH3)2；Or
R1、R2Being constituted with coupled carbon atom has one of following structure：
Each subformula shown in wherein Formulas I-a to I-y individually optionally by one or more selected from D, F, Cl, Br, I, methyl, Ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup and three The substituent group of fluorine methoxyl group is replaced.
7. compound according to claim 1 or 3, wherein R3、R4、R5And R6Be each independently H, D, F, Cl, Br, I ,- CN、-NH2、-OH、-NO2,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3、 Methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-NHCH3、-N(CH3)2、-CH2OH ,-C (=O) NHCH3Or-C (= O)N(CH3)2。
8. compound according to claim 1 or 3, for one of following structure compound or with one of following It is the stereoisomer of the compound of structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable Salt or prodrug,
9. a kind of pharmaceutical composition, it includes the compounds described in claim 1-8 any one；
Described pharmaceutical composition optionally includes pharmaceutically acceptable carrier, excipient, adjuvant or their arbitrary combination.
10. the pharmaceutical composition described in compound or claim 9 described in claim 1-8 any one is in medicine preparation Purposes, the drug is for preventing, treating or mitigate and the relevant disease of orexin receptor；
Wherein, the described and relevant disease of orexin receptor is sleep disturbance, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, feelings Perceptual neuropathy, depressibility neuropathy, anxious neuropathy, mood disorder, panic attack obstacle, behavioral disorder, emotionally disturbed, Posttraumatic stress disorder, sex dysfunction, mental disease, schizophrenia, manic depression, amentia, dementia, drug according to Bad, habituation, cognitive disorder, Alzheimer's disease, Parkinson's disease, dyskinesia, feeding desorder, headache, migraine, pain Bitterly, disease of digestive system, epilepsy, inflammation, angiocardiopathy, diabetes, metabolic disease, immune correlated disease, endocrine are related Disease or hypertension.
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