CN104529866A - Indole derivatives and pharmaceutical application thereof - Google Patents

Abstract

The invention provides a novel indole derivative or a stereisomer, a stereomer, a tautomer, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof for treating Alzheimer's disease. The invention further provides a pharmaceutical composition comprising the compound and a method of using the compound or the pharmaceutical composition thereof for treating Alzheimer's disease.

Description

Indole derivatives and the application on medicine thereof

Technical field

The invention belongs to pharmaceutical field and relate to the compound being used for the treatment of Alzheimer's disease, comprising composition and use thereof and the using method of described compound.Especially, compound of the present invention is can as 5-HT ₆the indole derivatives of receptor antagonist.

Background technology

Multiple central nervous system disease such as anxiety, depression etc. are all relevant with the disorder of neurotransmitter serotonin (5-HT) or thrombotonin.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) is by being called as 5-HT ₁, 5-HT ₂, 5-HT ₃, 5-HT ₄, 5-HT ₅, 5-HT ₆and 5-HT ₇a large amount of receptor families mediations.Based on 5-HT high-caliber in brain ₆receptor mrna, proposes 5-HT ₆acceptor may play a role in the pathology of central nervous system disorders and treatment.Specifically, 5-HT is determined ₆selective ligands has potential therapeutic action to some CNS (central nervous system) illness, and such as Parkinson's disease, Huntington Chorea, anxiety disorder, dysthymia disorders, manic depressive illness, psychosis, epilepsy, obsession, migraine, Alzheimer's disease (cognition and memory enhancing), somnopathy, eating disorder are as anorexia and Bulimia nerovsa, panic attack, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, Drug abuse such as Cocaine, ethanol, Nicotine and benzodiazepine the de-recessive brain syndrome that class causes, schizophrenia and the illness relevant with spinal trauma or head injury are as hydrocephalus.Estimate that described compound also can be used for treating some stomach intestinal disease as functional bowel disorder.(see such as Roth, B.L. etc., J.Pharmacol.Exp.Ther., 268,1403-14120 page (1994), Sibley, D.R. etc., Mol, Pharmacol., 43,320-327 (1993), A.J.Sleight etc., Neurotransmission, 11,1-5 (1995) and Sleight, A.J. etc., Serotonin ID Research Alert, 1997,2 (3), 115-118).

Research finds, known 5-HT ₆selective antagonist improves the level of L-glutamic acid in cortex of frontal lobe and aspartic acid significantly, and does not improve hormone, Dopamine HCL or 5-HT on first kidney ₆level.The selectivity of this specific neurochemical noticed in memory and cognition process raises and indicates 5-HT consumingly ₆effect (Dawson, the L.A. of part in cognition; Nguyen, H.Q.; Li, P., British Journal ofPharmacology, 2000,130 (1), 23-26).With known selectivity 5-HT ₆effect (Rogers, D.C. that the research that the memory of antagonists in animals and study are carried out has some positive; Hatcher, P.D.; Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).5-HT ₆the relevant potential therepic use of part is the ADD for the treatment of children and grownup.Because 5-HT ₆antagonist seems the activity that improve nigrostriatal dopamine approach, and because ADHD (Ernst, M relevant to the exception in caudatum; Zametkin, A.J.; Matochik, J.H.; Jons, P.A.; Cohen, R.M., Journal of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT ₆antagonist can treat ADD.Also determine 5-HT ₆antagonist is the potentially useful compound for the treatment of of obesity.See such as Bentley etc., Br.J.Pharmac.1999, supplementary issue 126; Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255; Wooley etc., Neuropharmacology 2001,41:210-129 and WO02098878.

Summary of the invention

The present invention relates to the method for new indole derivatives and treatment Alzheimer's disease.The compounds of this invention or comprise described compound pharmaceutical composition to 5-HT ₆there is good affinity interaction, particularly have good result for the treatment of to Alzheimer's disease.

On the one hand, the present invention relates to a kind of compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug

Wherein:

R ¹for H, D, F, Cl, Br, I ,-CN, C _1-6alkyl, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6halogenated alkoxy;

R ²and R ³be D, C independently of one another _1-6alkyl, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6halogenated alkoxy, or R ²and R ³, and C is formed together with their jointly connected carbon atoms _3-8cycloalkyl; With

R ⁴for H, D, C _1-6alkyl or C _1-6haloalkyl.

In one embodiment, R ¹for H, D, F, Cl, Br, I ,-CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group or C _1-4halogenated alkoxy;

R ²and R ³be D, C independently of one another _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group or C _1-4halogenated alkoxy, or R ²and R ³, and C is formed together with their jointly connected carbon atoms _3-6cycloalkyl; With

R ⁴for H, D, C _1-4alkyl or C _1-4haloalkyl.

In another embodiment, R ¹for H, D, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy.

In another embodiment, R ²and R ³be D, methyl, ethyl, n-propyl or sec.-propyl independently of one another, or R ²and R ³, and cyclopropyl is formed together with their jointly connected carbon atoms.

In another embodiment, R ⁴for H, D, methyl, ethyl, n-propyl or sec.-propyl.

In another embodiment, compound of the present invention, it has one of them structure following:

, or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

In one embodiment, pharmaceutical composition of the present invention, it comprises additional treatment agent further, and described additional treatment agent is the medicine for the treatment of A Cihaimo disease, the medicine for the treatment of nervous disorders or their combination.The medicine of the medicine nervous disorders for the treatment of Alzheimer's disease or their combination.

In another embodiment, additional treatment agent of the present invention is E2020 (donepezil), Nalmefene (nalmefene), risperidone (risperidone), vitamin E (Vitamin E), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, tacrine (tacrine), rivastigmine (rivastigmine), lycoremine (galantamine), memantine (memantine), meter Ta Zhaping (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), nortriptyline (nortriptyline), zolpidem (zolpidem), Zopiclone (zopiclone), nicergoline (nicergoline), piracetam (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their combination.

On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition for the preparation of prevention, treat or alleviate and 5-HT ₆purposes in the medicine of relevant disease.

In one embodiment, to the present invention relates to and 5-HT ₆relevant disease is CNS illness, disorder of gastrointestinal tract or fat disease.

In another embodiment, to the present invention relates to and 5-HT ₆relevant CNS illness is ADHD, anxiety, the disease relevant to stress, schizophrenia, obsessional idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington Chorea.

The present invention relates to the preparation of compound shown in formula (I), the method for abstraction and purification on the other hand.

Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.

Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.These aspects and otherwise content will do more specifically complete description below.

Embodiment

definition and general terms

Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.

Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.

Unless otherwise indicated, this paper institute should be applied and use to obtain following definition.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.

Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.

Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.

Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.

Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.

Term " steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.

Term " chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.

Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.

Term " racemoid " or " racemic mixture " be optically active two the corresponding isomer species of hypodactylia etc. molar mixture.

Term " diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.

Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S, " Stereochemistry of OrganicCompounds ", John Wiley & Sons, Inc, New York, 1994.Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.

The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.

By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, can with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles ofAsymmetric Synthesis (2 ^nded.Robert E.Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agents andOptical Resolutions p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral SeparationTechniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.

Term " optionally " or " optionally " refer to the event that describes subsequently or situation can but not necessarily occur, and this description comprises situation that wherein said event or situation occur and wherein its absent variable situation.Such as, " optional key " refers to that this key can exist or can not exist, and this description comprises singly-bound, double bond or triple bond.

Term " unsaturated " or " undersaturated " represent that part is containing one or more degree of unsaturation.

As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or unsubstituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, azido-, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, haloalkyl, halogenated alkoxy, the alkyl that hydroxyl replaces, the haloalkyl that hydroxyl replaces, the alkoxyl group that hydroxyl replaces, alkyl-the C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) ₂-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) ₂-, Carboxyalkoxy etc.

In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.

At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C _1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C ₃alkyl, C ₄alkyl, C ₅alkyl and C ₆alkyl.

At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.

The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH ₃), ethyl (Et ,-CH ₂cH ₃), n-propyl (n-Pr ,-CH ₂cH ₂cH ₃), sec.-propyl (i-Pr ,-CH (CH ₃) ₂), normal-butyl (n-Bu ,-CH ₂cH ₂cH ₂cH ₃), isobutyl-(i-Bu ,-CH ₂cH (CH ₃) ₂), sec-butyl (s-Bu ,-CH (CH ₃) CH ₂cH ₃), the tertiary butyl (t-Bu ,-C (CH ₃) ₃), n-pentyl (-CH ₂cH ₂cH ₂cH ₂cH ₃), 2-amyl group (-CH (CH ₃) CH ₂cH ₂cH ₃), 3-amyl group (-CH (CH ₂cH ₃) ₂), 2-methyl-2-butyl (-C (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butyl (-CH (CH ₃) CH (CH ₃) ₂), 3-methyl isophthalic acid-butyl (-CH ₂cH ₂cH (CH ₃) ₂), 2-methyl-1-butene base (-CH ₂cH (CH ₃) CH ₂cH ₃), n-hexyl (-CH ₂cH ₂cH ₂cH ₂cH ₂cH ₃), 2-hexyl (-CH (CH ₃) CH ₂cH ₂cH ₂cH ₃), 3-hexyl (-CH (CH ₂cH ₃) (CH ₂cH ₂cH ₃)), 2-methyl-2-amyl group (-C (CH ₃) ₂cH ₂cH ₂cH ₃), 3-methyl-2-amyl group (-CH (CH ₃) CH (CH ₃) CH ₂cH ₃), 4-methyl-2-amyl group (-CH (CH ₃) CH ₂cH (CH ₃) ₂), 3-methyl-3-amyl group (-C (CH ₃) (CH ₂cH ₃) ₂), 2-methyl-3-amyl group (-CH (CH ₂cH ₃) CH (CH ₃) ₂), 2,3-dimethyl-2-butyl (-C (CH ₃) ₂cH (CH ₃) ₂), 3,3-dimethyl-2-butyl (-CH (CH ₃) C (CH ₃) ₃), n-heptyl, n-octyl, etc.

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp ²double bond, wherein, described alkenyl group optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " tans ", or the location of " E " and " Z ".In one embodiment, alkenyl group comprises 2-8 carbon atom; In another embodiment, alkenyl group comprises 2-6 carbon atom; In yet another embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH ₂), allyl group (-CH ₂cH=CH ₂), etc.

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group optionally replace by one or more substituting group described in the invention.In one embodiment, alkynyl group comprises 2-8 carbon atom; In another embodiment, alkynyl group comprises 2-6 carbon atom; In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to, ethynyl (-C ≡ CH), propargyl (-CH ₂c ≡ CH), 1-proyl (-C ≡ C-CH ₃), etc.

Term " heteroatoms " represents one or more oxygen (O), sulphur (S), nitrogen (N), phosphorus (P) or silicon (Si), comprise 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 form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).

Term " halogen " and " halo " refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxy base replace by one or more halogen atom, wherein alkyl and alkoxy base have implication of the present invention, and such example comprises, but be not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2-difluoroethoxies, 2,2,2-trifluoro ethoxy, 2,2,3,3-tetrafluoro propoxy-, 2,2,3,3,3-five fluorine propoxy-, etc.Described haloalkyl or halo alkoxy group optionally replace by one or more substituting group described in the invention.

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base is optionally described by one or more the present invention replace.

The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH ₃), oxyethyl group (EtO ,-OCH ₂cH ₃), 1-propoxy-(n-PrO, n-propoxy-,-OCH ₂cH ₂cH ₃), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH ₃) ₂), 1-butoxy (n-BuO, n-butoxy ,-OCH ₂cH ₂cH ₂cH ₃), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH ₂cH (CH ₃) ₂), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH ₃) CH ₂cH ₃), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH ₃) ₃), 1-pentyloxy (n-pentyloxy ,-OCH ₂cH ₂cH ₂cH ₂cH ₃), 2-pentyloxy (-OCH (CH ₃) CH ₂cH ₂cH ₃), 3-pentyloxy (-OCH (CH ₂cH ₃) ₂), 2-methyl-2-butoxy (-OC (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butoxy (-OCH (CH ₃) CH (CH ₃) ₂), 3-methyl-l-butoxy (-OCH ₂cH ₂cH (CH ₃) ₂), 2-methyl-l-butoxy (-OCH ₂cH (CH ₃) CH ₂cH ₃), etc.

Term " cycloalkyl " expression contains 3-12 carbon atom, saturated monocycle, dicyclo or the three-ring system of unit price or multivalence.Dicyclo or three-ring system can comprise condensed ring, bridged ring and volution.In one embodiment, cycloalkyl comprises 3-10 carbon atom; In another embodiment, cycloalkyl comprises 3-8 carbon atom; In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.The example of group of naphthene base comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.Described group of naphthene base optionally replace by one or more substituting group described in the invention.

Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to the monocycle, dicyclo or the three-ring system that comprise 3-12 annular atoms, wherein on ring one or more atom independently replace by heteroatoms, described heteroatoms has implication as described in the present invention, ring can be completely saturated or comprise one or more degree of unsaturation, but an aromaticity ring all can not have.In one embodiment, heterocyclyl groups be 3-8 ring monocycle (2-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO ₂, PO, PO ₂group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-12 unit (4-9 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO ₂, PO, PO ₂group).Described heterocyclyl groups optionally replace by one or more substituting group described in the invention.

Heterocyclic radical can be carbon back or heteroatoms base.Wherein-the CH of ring ₂-group optionally by-C (O)-substitute, the sulphur atom of ring is optionally oxidized to S-oxide compound, and the nitrogen-atoms of ring is optionally oxidized to N-oxygen compound.The example of heterocyclic radical comprises, but be not limited to, Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl (morpholine-2-Ji, morpholine-3-base, morpholine-4-base), thio-morpholinyl, piperazinyl (piperazine-1-base, piperazine-2-base, piperazine-3-base), alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base, etc.-CH in heterocyclic radical ₂-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine bases, pyrimidine dione base by the example of-C (=O)-replacement, etc.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, thio-morpholinyl 1,1-dioxide, etc.Described heterocyclyl groups optionally replace by one or more substituting group described in the invention.

Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 former molecular ring.Aromatic yl group is usual, but is necessarily connected with parent molecule by the aromaticity ring of aromatic yl group.Term " aryl " can exchange with term " aromatic nucleus " or " aromatic ring " and use.The example of aromatic yl group can comprise phenyl, naphthyl and anthracene.Described aromatic yl group optionally replace by one or more substituting group described in the invention.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring.Heteroaryl groups is usual, but is necessarily connected with parent molecule by the aromaticity ring of heteroaryl groups.Term " heteroaryl " can with term " hetero-aromatic ring ", " fragrant heterocycle " or " heteroaromatics " exchange use.Described heteroaryl groups optionally replace by one or more substituting group described in the invention.In one embodiment, 5-10 former molecular heteroaryl comprises 1,2,3 or 4 and is independently selected from O, the heteroatoms of S and N.

The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..

As described in the invention, substituent R is connected to by a key member ring systems (shown in f) that the ring at center is formed and represents substituent R and only limit any desirable generation or any rational position on A ring to replace.Such as, formula f represents any position that may be substituted on A ring, such as formula f ¹-f ⁴shown in:

The structure that occurs in the present invention " " represent

Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug _1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: Higuchi et al., Pro-drugs as NovelDelivery Systems, Vol.14, A.C.S.Symposium Series; Roche et al., ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs:Designand Clinical Applications, Nature Reviews Drug Discovery, 2008,7,255-270, and Hecker et al, Prodrugsof Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every section of document is contained in this by reference.

Term used in the present invention " meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., J.Pharmaceutical Sciences, 66:1-19, described in 1977.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N ⁺(C _1-4alkyl) ₄salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

When described solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention molecule can combine with a water molecules, such as monohydrate; In another embodiment, a compounds of this invention molecule can combine with more than one water molecules, such as dihydrate, and in yet another embodiment, a compounds of this invention molecule can combine with the water molecules being less than, such as semihydrate.It should be noted that hydrate of the present invention remains with the biological effectiveness of the described compound of nonhydrated form.

Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises trialkylsilkl, ethanoyl, benzoyl and benzyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH ₂cH ₂sO ₂ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: Greene et al.; Protective Groupsin Organic Synthesis; John Wiley & Sons; New York; 1991and Kocienski et al., Protecting Groups, Thieme; Stuttgart, 2005.

Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.

Term " prevents " or " prevention " refers to that the minimizing of the risk obtaining disease or obstacle (that is: makes at least one clinical symptom of disease in main body, stop development, this main body may in the face of or in advance tendency in the face of this disease, but also do not experience or show the symptom of disease).

Term " ADHD " is the abbreviation of Attention-deficit hyperactivity disorder, means attention deficit hyperactivity disorder, be a kind of Childhood very common psychataxia.According to " Global Access classification of diseases handbook " the tenth edition (ICD-10 of the World Health Organization, WHO, 1992) claim this disease for " hyperactivity disorder " (Hyperkinetic Disorder), classifying and numbering is F90, is generally commonly called as again as " crossing dynamic youngster ".

Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and psychotic disorder, and wherein term " psychosis " refers to vain hope, significantly illusion, amorphous language or unorganized behavior or stiffization behavior.See Diagnosticand Statistical Manual of Mental Disorder, the 4th edition, American Psychiatric Association, Washington, D.C..

Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.

Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.

Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.

Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.

Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.

Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack PublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (Handbook of Pharmaceutical Salts:Properties; Selection; and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.

In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.

Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as ²h, ³h, ¹¹c, ¹³c, ¹⁴c, ¹⁵n, ¹⁷o, ¹⁸o, ¹⁸f, ³¹p, ³²p, ³⁵s, ³⁶cl and ¹²⁵i.

On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as ³h, ¹⁴c and ¹⁸those compounds of F, or wherein there is non radioactive isotope, as ²h and ¹³c.The compound of such isotopic enrichment can be used for metabolism research and (uses ¹⁴c), reaction kinetics research (uses such as ²h or ³h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. ¹⁸the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.

In addition, particularly deuterium is (that is, for higher isotope ²h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent ₂o, acetone-d ₆, DMSO-d ₆those solvates.

the description of the compounds of this invention

The indole derivatives that the present invention relates to, its pharmacy acceptable salt, and pharmaceutical preparation, have antagonism 5-HT ₆, especially have potential purposes to the treatment of Alzheimer's disease.

The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment Alzheimer's disease, comprises that those are described in the invention.Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treatment 5-HT ₆the illness mediated, particularly Alzheimer's disease.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula formula (I) and the pharmaceutically acceptable carrier of at least one, the effective treatment consumption needed for the combination of assistant agent or thinner.

Unless other aspects show, all suitable isotropic substance changes of compound of the present invention, steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.

Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.

The present invention's compound of coming into the open can contain asymmetric or chiral centre, therefore can exist with different stereoisomer forms.The present invention is intended to all stereoisomer forms making compound shown in formula (I), include but not limited to diastereomer, enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture is as racemic mixture, become integral part of the present invention.

In structure disclosed by the invention, when the stereochemistry of the chiral atom of any specific does not indicate, then all steric isomers of this structure are all considered within the present invention, and comprise in the present invention as the present invention's compound of coming into the open.When stereochemistry is expressed the real wedge shape line (solid wedge) of particular configuration or dotted line indicates, then the steric isomer of this structure clear and definite and definition at this point.

The oxynitride of the compounds of this invention is also contained within scope of the present invention.Can by using conventional oxygenant (such as hydrogen peroxide) at an elevated temperature, under having the acid of such as acetic acid to exist, be oxidized corresponding nitrogenous alkaline matter, or by be applicable to solvent in cross acid-respons, such as react with peracetic acid in methylene dichloride, ethyl acetate or methyl acetate, or react with 3-chloroperoxybenzoic acid in chloroform or methylene dichloride, prepare the oxynitride of the compounds of this invention.

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

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

Shown in formula (I), compound can exist in a salt form.In one embodiment, described salt refers to pharmacy acceptable salt.Term " pharmaceutically acceptable " refer to material or composition must with comprise preparation other composition and/or with its Mammals treated chemically and/or compatible in toxicology.In another embodiment, described salt not necessarily pharmacy acceptable salt, can be for the preparation of and/or purification formula (I) shown in the intermediate of compound and/or the enantiomorph for separating of compound this formula (I) Suo Shi.

If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.

If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.

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

When can be used for treatment, formula (I) compound for the treatment of significant quantity and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, the present invention also provides a kind of pharmaceutical composition, comprises compound or its independent steric isomer of formula (I), the racemize of isomer or non-racemic mixture or its pharmacy acceptable salt or solvate.In an embodiment of the invention, described pharmaceutical composition comprises the pharmaceutically acceptable carrier of at least one, assistant agent or vehicle further, and optionally, other treat and/or prevent composition.

Suitable carrier, assistant agent and vehicle agent be for those skilled in the art know and be described in detail in such as Ansel H.C.etal., 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) Pharmaceutical Press, in Chicago.

Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise administration patient being carried out to other anti-Alzheimer disease drugs (combination therapy) further, wherein the medicine of other anti-Alzheimer diseases is E2020, Nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, tacrine, rivastigmine, lycoremine, memantine, meter Ta Zhaping, Venlafaxine, desipramine, nortriptyline, zolpidem, Zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination.

Term as used herein " treatment significant quantity " refers to the total amount of each active ingredient being enough to demonstrate significant patient benefit.When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause the combined amount of the activeconstituents of result for the treatment of.Formula formula (I) compound and pharmacy acceptable salt described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the another aspect of present disclosure, be also provided for the method for useful in preparing drug formulations, the method comprises and formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle being mixed.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.

Usually, compound of the present invention is applied to treat significant quantity by any conventional method of application of the material for playing similar effectiveness.Suitable dosage range typically is 1-500mg every day, preferred every day 1-100mg, most preferably every day 1-30mg, this depends on many factors, such as the seriousness of institute's disease therapy, the age of subject and relative health, the effect of compound used therefor, the approach used and form, use for indication and the preference of relevant medical practitioner and experience.Treat the those of ordinary skill of described disease areas without the need to too much testing the treatment significant quantity relying on the disclosure of personal knowledge and the application can determine the compounds of this invention of given disease.

Usually, compound of the present invention is used with pharmaceutical dosage forms, described pharmaceutical preparation comprise those be suitable for oral (comprise oral cavity and sublingual), rectum, nose, locally, pharmaceutical preparation that lung, vagina or parenteral (comprise intramuscular, intra-arterial, sheath interior, subcutaneous and intravenously) are used or the pharmaceutical preparation that is suitable for sucking or being blown into administration form.Preferred method of application is generally oral, uses suitable per daily dose scheme, can adjust according to disease degree to it.

One or more compounds of the present invention can be placed in pharmaceutical composition and unit dosage form together with one or more conventional adjuvant, carrier or thinner.Pharmaceutical composition and unit dosage form can comprise the conventional ingredient of conventional ratio, contain or do not contain other active compound or composition, and unit dosage form can contain the activeconstituents of any suitable significant quantity matched with applied plan per daily dose scope.The filling capsule that the application form of pharmaceutical composition can be solid such as tablet or filling capsule, semisolid, powder, sustained release preparation or liquid such as solution, suspensoid, emulsion, elixir or orally use; Or for the suppository form of rectum or vaginal application; Or for parenteral use sterile injectable solutions form.Therefore, in every sheet containing having an appointment 1mg activeconstituents or more broadly, the preparation containing 0.01 to about 100mg activeconstituents of having an appointment is suitable representational unit dosage form.

Compound of the present invention can be mixed with various Orally administered dosage form.Pharmaceutical composition and dosage form can comprise one or more compound or pharmaceutically acceptable salt thereofs of the present invention as activeconstituents.Pharmaceutically useful carrier can be solid or liquid.The preparation of solid form comprises: powder agent, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it also can be used as thinner, correctives, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material.In powder, carrier is generally the solid of porphyrize, and the activeconstituents of itself and porphyrize forms mixture.In tablets, activeconstituents usually mixes with the carrier with required adhesive capacity mutually with suitable ratio and is pressed into required shape and size.Powder and tablet are preferably containing the active compound of 1% to about 70% of having an appointment.Suitable carrier includes but not limited to magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Terms " formulation " to be intended to comprise containing coating material as carrier to provide the preparation of the active compound of capsule, in described capsule the activeconstituents of with or without carrier surround by this carrier of combining with it.Similarly, cachet and lozenge is also comprised.Tablet, powder, capsule, pill, cachet and lozenge are all be suitable for Orally administered solid form.

Other is suitable for Orally administered form and comprises the preparation that the preparation (comprising emulsion, syrup, elixir, aqueous solution agent, aqueous suspension) of liquid form or purport change the solid form of liquid form preparation before use at once into.Emulsion can be prepared in solution such as aqueous solution of propylene glycol maybe can contain emulsifying agent such as Yelkin TTS, polyoxyethylene-sorbitan mono-oleate or gum arabic.Aqueous solution agent is by adding suitable tinting material, correctives, stablizer and thickening material to prepare in water by solubilize active ingredients.The activeconstituents of porphyrize to be dispersed in water by the glue with viscous substance such as natural or synthesis, resin, methylcellulose gum, Xylo-Mucine and other known suspension agent by aqueous suspension to be prepared.The preparation of liquid form comprises solution, suspensoid and emulsion, and except activeconstituents, it can also contain tinting material, correctives, stablizer, buffer reagent, artificial with natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.

Compound of the present invention can be formulated for parenteral use (such as, being used as bolus injection or continuous infusion by injection) and ampoule can be present in a unit, syringe filling in advance, low capacity infuse in or be present in and with the addition of in the multi-dose container of sanitas.The adoptable form of composition has suspensoid, solution or emulsion such as in oiliness or aqueous vehicle, such as, solution in Aqueous Solutions of Polyethylene Glycol.The example of oiliness or non-aqueous carrier, thinner, solvent or vehicle comprises propylene glycol, polyoxyethylene glycol, vegetables oil (such as sweet oil) and injection organic ester (such as ethyl oleate), and can containing formulating substances as sanitas, wetting agent, emulsifying agent or suspension agent, stablizer and/or dispersion agent.Or activeconstituents can be powder type, its preparation method be sterile solid is carried out aseptic subpackaged or by by solution freeze-drying to build with suitable excipients such as aseptic, pyrogen-free water before use.

Compound of the present invention can be formulated for and be locally applied to epidermis with ointment, ointment or lotion form or with transdermal patch form.Ointment and ointment can such as be prepared by the water-based or oleaginous base that with the addition of suitable thickening material and/or jelling agent.Lotion can use or oleaginous base preparation and usually also containing one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.Be suitable for the preparation of topical application in mouth and comprise the lozenge comprising and be in flavored base, be generally the activeconstituents in sucrose and gum arabic or tragakanta; Comprise and be in the lozenge of inert base as the activeconstituents in gelatin and glycerine or sucrose and gum arabic; And comprise the mouth wash shua of the activeconstituents be in suitable liquid carrier.

Compound of the present invention can be formulated for and use with suppository form.Can first by low melt wax as fatty glyceride mixt or theobroma oil fusing, and by activeconstituents such as by the dispersion that stirs.Then the uniform mixture of melting is poured in the mould of suitable size, make it cool and solidify.

Compound of the present invention can be formulated for vaginal application.Vaginal suppository in addition to the active ingredient (s also containing carrier known in this field, tampon, newborn blue or green agent, gelifying agent, paste, foaming agent or sprays are suitable.

Compound of the present invention can be formulated for nasal administration.Can by solution or suspensoid by ordinary method, such as directly apply to nasal cavity with dropper, suction pipe or atomizer.Preparation can be single dose or multiple doses form.For the multiple doses form of dropper or suction pipe, this can by being used solution that is suitable, pre-determined volume or suspensoid realizes by patient.For atomizer, this can such as be realized by metering atomising atomizing pump.

Compound of the present invention can be formulated for aerosol and use, and is particularly applied to respiratory tract and comprises intranasal administration.Compound has little granularity usually, the granularity of such as 5 microns or more decimal magnitude.Described granularity is by method well known in the art, such as obtain by micronization.Activeconstituents is to provide containing the suitable pressurized package of propellent as chlorofluorocarbon (CFC) such as Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane or carbonic acid gas or other suitable gas.Aerosol also can contain tensio-active agent as Yelkin TTS suitably.Drug dose controls by metering valve.Or, activeconstituents can with dry powdered form, such as at suitable powder base as lactose, starch, the powdered mixture form of starch derivative as the compound in Vltra tears and polyvinylpyrrolidone provide.Powder carrier will form gel in nasal cavity.Powder composition can such as exist by sucker by wherein using powder with gelatine capsule agent or cartridge case or Blister Package form in a unit.

When needing, preparation can be prepared with the enteric coating being suitable for slowly-releasing or controlled release and using activeconstituents.Such as, compound of the present invention can be formulated into transdermal or subcutaneous drug delivery device.When necessary slow release compounds and when the compliance of patient for treatment's scheme is most important, these delivery systems are favourable.Compound in transdermal delivery system is often attached on skin-adhesive solid support.The compound paid close attention to also can combinationally use with penetration enhancer, such as laurocapram (1-dodecyl-aza-cycloheptane-2-ketone).Subcutaneous layer is inserted into by subcutaneous for Sustained release delivery systems by operation or injection.Compound is encapsulated in lipid soluble membrane, such as silicon rubber or Biodegradable polymeric such as poly(lactic acid) by hypodermic implant.

Pharmaceutical preparation is preferably unit dosage form.In this form, preparation is subdivided into the unitary dose containing sufficient quantity activeconstituents.Unit dosage form can be the preparation of packaging kit, containing the preparation of discrete magnitude in packaging, and the tablet of such as packaging kit, capsule and powder in the vial or ampulla agent.In addition, unit dosage form can be capsule, tablet, cachet or lozenge itself, or it can be any one in these forms of suitable number in packaging kit form.

Other suitable pharmaceutical carrier and their preparation are at Remington:The Science and Practice of Pharmacy 1995 Martin, E.W edits, Mack Publishing Company, the 19th edition, description is had in Easton, Pennsylvania.

the purposes of the compounds of this invention and pharmaceutical composition

Compound provided by the invention and pharmaceutical composition can be used for for the preparation of prevention, treat or alleviate and 5-HT ₆the medicine of relevant disease.

The feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I) or the compound listed by the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention, the amount of compound can detectably antagonism 5-HT effectively ₆with treatment of obesity, gastrointestinal tract disease, CNS illness, wherein said CNS illness is ADHD, anxiety, the disease relevant to stress, schizophrenia, obsessional idea and behavior disorder, manic depressive illness, nervous disorders, dysmnesia, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington Chorea, etc.

" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.

Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to the Mammals in veterinary treatment pet, the animal of introduced variety and the animal on farm.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.

the general synthetic method of the compounds of this invention

For describing the present invention, below list embodiment.But need be appreciated that and the invention is not restricted to these embodiments, only be to provide and put into practice method of the present invention.

Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I).Reaction scheme below and embodiment are used for illustrating content of the present invention further.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.

The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.

Anhydrous tetrahydro furan is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.

Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 ₃, DMSO-d ₆, CD ₃oD or acetone-d ₆for solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).

Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.

Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:

Table 1

Time (min)	A(CH 3CN，0.1％HCOOH)	B(H 2O，0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.

The use of brief word below runs through the present invention:

HCOOH formic acid

CH ₃cOOH acetic acid, acetic acid

CH ₃cOONa sodium-acetate

NH ₄oAc ammonium acetate

HCHO formaldehyde

MeCN, CH ₃cN acetonitrile

CNCH ₂cOOH 2-cyanoacetic acid

CH ₃nO ₂nitromethane 99Min.

CH ₃i methyl iodide

CHCl ₃chloroform

CDC1 ₃deuterochloroform

DMSO dimethyl sulfoxide (DMSO)

DMSO-d ₆deuterated dimethyl sulfoxide

EtOAc, EA ethyl acetate

MgSO ₄magnesium sulfate

MeOH, CH ₃oH methyl alcohol

EtOH ethanol

CH ₂cl ₂, DCM methylene dichloride

ML, ml milliliter

PE sherwood oil (60-90 DEG C)

NaOH sodium hydroxide

NaHCO ₃sodium bicarbonate

KOH potassium hydroxide

Rt retention time

H, hr hour

NaBH ₄sodium borohydride

LiAlH ₄lithium aluminum hydride

NaCl sodium-chlor

MgCl ₂magnesium chloride

NaH sodium hydride

Na ₂sO ₄sodium sulfate

THF tetrahydrofuran (THF)

DMF DMF

DMAP dimethyl aminopyridine

Boc ₂o tert-Butyl dicarbonate

H ₂o water

D ₂o deuterium-oxide

EDTA ethylenediamine tetraacetic acid (EDTA)

PEI polymine

Pargyline Pargyline

Tris-HCl tri-(methylol) aminomethane-hydrochloric acid

Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.Unless otherwise indicated, each R ¹and R ⁴there is definition as described in the present invention.

Synthetic method 1

The general synthetic method that the compounds of this invention can be described by synthetic schemes 1 prepares, and concrete steps can reference example.Compound ( 1) react with tert-Butyl dicarbonate under the effect of alkali, obtain compound ( 2); Then compound ( 2) be obtained by reacting with halogenated alkane under the effect of alkali compound ( 3).Compound ( 3) deprotection base obtain compound ( 4); Compound ( 4) obtain under the effect of reductive agent compound ( 5); Compound ( 5) with 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE be obtained by reacting compound ( 6).Compound ( 6) deprotection base obtain compound ( 7); Compound ( 7) in the alkylation of piperazine group obtain compound ( 8).

Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.

Embodiment

the synthesis of embodiment 1 N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(piperazine-1-base) benzsulfamide

step 1) synthesis of 2,2,2-tri-fluoro-1-(4-(2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone

By 1-(2-p-methoxy-phenyl) piperazine hydrochloric acid (5.0g, 21.9mmol) with triethylamine (10.0mL, 70.8mmol) join in methylene dichloride (50mL), trifluoroacetic anhydride (4.6mL is slowly dripped under 0 DEG C of low temperature bath, 33.0mmol), after dripping, react 2 hours at being transferred to 25 DEG C, stopped reaction, add methylene dichloride (50mL), with saturated sodium bicarbonate solution (60mL) washing, organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is pale yellow oil (5.98g, 95%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.

MS(ESI,pos.ion)m/z:289.1[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.25-7.19(m,1H),7.15(dd,J＝7.9,1.3Hz,1H),7.03-6.98(m,2H),4.06-3.96(m,2H),3.93(brs,5H),3.37-3.35(m,4H)。

step 2) synthesis of 4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE

By 2,2, the fluoro-1-of 2-tri-(4-(2-p-methoxy-phenyl) piperazine-1-base) acetyl (5.0g, 17.4mmol) be dissolved in methylene dichloride (5mL), then be added drop-wise in chlorsulfonic acid (15mL) under 0 DEG C of low temperature bath, react after one hour, reaction solution is imported in the mixed solution of frozen water (30mL) and methylene dichloride (50mL), separatory after vigorous stirring, organic phase anhydrous magnesium sulfate drying.Filter, filtrate decompression is spin-dried for and namely obtains title compound is faint yellow solid (5.6g, 83%).

MS(ESI,pos.ion)m/z:387.0[M+H] ⁺；

¹H NMR(400MHz,CDCl ₃)δ(ppm):7.78(dd,J＝8.7,2.3Hz,1H),7.49(d,J＝2.3Hz,1H),7.04(d,J＝8.8Hz,1H),4.03(s,3H),3.94-3.87(m,2H),3.86-3.77(m,2H),3.25-3.16(m,4H)。

step 3) synthesis of 3-(cyano methyl)-1H-indoles-1-t-butyl formate

At 25 DEG C, 2-(1H-indol-3-yl) acetonitrile (10.0g, 64.1mmol) and DMAP (500mg, 4.1mmol) are joined in methylene dichloride (50mL), then slowly add Boc ₂o (21.0g, 96.2mmol).Continue reaction 8 hours, then with saturated nacl aqueous solution washing (40mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is faint yellow solid (7.2g, 44.0%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.

MS(ESI,pos.ion)m/z:257.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.16(d,J＝6.6Hz,1H),7.62(s,1H),7.50(d,J＝7.8Hz,1H),7.38-7.34(m,1H),7.30-7.26(m,1H),3.75(d,J＝1.2Hz,2H),1.66(s,9H)。

step 4) synthesis of 3-(2-dicyanopropane-2-base)-1H-indoles-1-t-butyl formate

By 3-(cyano methyl)-1H-indoles-1-t-butyl formate (7.2g at 0 DEG C, 28.0mmol) with sodium hydride (2.5g, 63.0mmol) join in dry DMF (30mL), then methyl iodide (8.8mL, 125.0mmol) is slowly added dropwise to.React after ten minutes, be warming up to 25 DEG C, reaction is spent the night.Add water (100mL) cancellation, add methylene dichloride (100mL) extraction, organic phase washs (50mLx 3) with saturated nacl aqueous solution again, organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is white solid (2.2g, 28%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=50/1) obtains title compound.

MS(ESI,pos.ion)m/z:285.3[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.16(d,J＝6.0Hz,1H),7.80(d,J＝7.8Hz,1H),7.51(s,1H),7.35(t,J＝8.4Hz,1H),7.29(t,J＝7.8Hz,1H),1.83(s,6H),1.67(s,9H)。

step 5) synthesis of 2-(1H-indol-3-yl)-2-methyl propionitrile

By 3-(2-dicyanopropane-2-base)-1H-indoles-1-t-butyl formate (5.43g, 19.1mmol) join in the mixed solvent of dioxane (20mL) and water (20mL), react 14 hours at oil bath 110 DEG C; Stopped reaction, adds 50mL methylene dichloride, with saturated nacl aqueous solution washing (50mL), and organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is pale yellow oil (3.35g, 95.2%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.

MS(ESI,pos.ion)m/z:185.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.24(s,1H),7.84(d,J＝8.4Hz,1H),7.37(d,J＝7.8Hz,1H),7.25-7.21(m,1H),7.19-7.16(m,1H),7.08(d,J＝3.0Hz,1H),1.84(s,6H)。

step 6) synthesis of 2-(1H-indol-3-yl)-2-methylpropane-1-amine

By 2-(1H-indol-3-yl)-2-methyl propionitrile (1.8g at 25 DEG C, 9.8mmol) be dissolved in tetrahydrofuran (THF) (4mL), add methyl alcohol (10mL) and Raney's nickel (200mg), react 72 hours under 2.2MPa hydrogen.Stopped reaction, filter, filtrate decompression is spin-dried for, and it is pale yellow oil (1.58g, 86%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:189.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.45(s,1H),7.76(d,J＝8.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.18-7.14(m,1H),7.09-7.05(m,1H),6.93(d,J＝2.4Hz,1H),2.99(s,2H),1.40(s,6H)。

step 7) synthesis of N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzsulfamide

By 2-(1H-indol-3-yl)-2-methylpropane-1-amine (350mg at 0 DEG C; 1.86mmol) with triethylamine (566 μ l; 4.0mmol) join in methylene dichloride (10mL); then slowly add 4-methoxyl group-3-(4-(2 in batches; 2; 2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (935mg, 2.79mmol).React after ten minutes, be warming up to 25 DEG C, reaction is spent the night.Add 50mL methylene dichloride, then with saturated nacl aqueous solution washing (40mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is faint yellow solid (940mg, 93.9%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1) obtains title compound.

MS(ESI,pos.ion)m/z:539.3[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.18(s,1H),7.36(dd,J＝8.4,2.4Hz,1H),7.33(t,J＝8.4Hz,2H),7.13-7.09(m,1H),6.98(t,J＝2.4Hz,2H),6.89-6.85(m,1H),6.82(d,J＝8.4Hz,1H),3.99(t,J＝6.0Hz,1H),3.92(s,3H),3.80-3.76(m,2H),3.72-3.68(m,2H),3.15(d,J＝6.0Hz,2H),2.95-2.85(m,4H),1.41(s,6H)。

step 8) synthesis of N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(piperazine-1-base) benzsulfamide

At 25 DEG C; by N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(4-(2; 2; 2-trifluoroacetyl group) piperazine-1-base) benzsulfamide (900mg; 1.67mmol) be dissolved in tetrahydrofuran (THF) (15mL); then potassium hydroxide (269mg, 4.8mmol are made into the 1mmol/mL aqueous solution) is slowly added.Reaction solution stirring reaction, after 24 hours, adds methylene dichloride (60mL).Organic phase saturated nacl aqueous solution washing (30mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression be spin-dried for, it is white solid (688mg, 93.0%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:443.4[M+H] ⁺.

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.46(s,1H),7.42(d,J＝8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,2.4Hz,1H),7.15-7.13(m,2H),6.99(s,1H),6.97-6.94(m,1H),6.82(d,J＝8.4Hz,1H),3.94(s,3H),3.49(s,1H),3.21(s,2H),3.07-3.03(m,4H),2.94-2.91(m,4H),1.43(s,6H)。

¹³C NMR(150MHz,CDCl ₃)δ(ppm):155.6,142.3,137.4,131.4,125.1,122.8,122.4,122.0,120.37,120.3,119.5,116.8,111.8,110.8,56.0,52.9,51.8,46.2,35.7,26.8。

the synthesis of embodiment 2 N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(4-methylpiperazine-1-yl) benzsulfamide

N-(2-(1H-indol-3-yl)-2-methyl-propyl)-4-methoxyl group-3-(piperazine-1-base) benzsulfamide (330mg, 0.75mmol) is dissolved in methyl alcohol (5mL), adds two acetic acid.At 0 DEG C, sodium cyanoborohydride (139mg, 2.2mmol) and formaldehyde (40%, 0.17mL, 2.2mmol) are slowly joined in reaction solution.React after ten minutes, be warming up to 25 DEG C, continue reaction after 5 hours, add water (10mL) and sodium carbonate (350mg, 3.3mmol) cancellation, then use dichloromethane extraction (20mL x 3).Merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, and it is white solid (310mg, 91.1%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:457.4[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.47(s,1H),7.36(d,J＝7.8Hz,1H),7.32-7.26(m,2H),7.13-7.07(m,2H),6.93(s,1H),6.90(t,J＝7.8Hz,1H),6.76(dd,J＝8.4,1.2Hz,1H),3.89(s,3H),3.17(s,2H),2.98(brs,4H),2.58(brs,4H),2.33(s,3H),1.37(s,6H)。

¹³C NMR(150MHz,CDCl ₃)δ(ppm):155.5,141.8,137.4,131.4,125.1,122.7,122.4,121.9,120.3,120.2,119.4,116.8,111.8,110.7,55.9,55.2,52.9,50.3,46.2,35.7,26.8。

the synthesis of embodiment 3 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(piperazine-1-base) benzsulfamide

step 1) synthesis of 2-(5-methoxyl group-1H-indol-3-yl)-2-methylpropane-1-amine

This step title compound prepares with reference to the method described by embodiment 1 step 6, by 2-(5-methoxyl group-1H-indol-3-yl)-2-methyl propionitrile (750mg, 3.5mmol), Raney's nickel (100mg) reaction preparation in tetrahydrofuran (THF) (5mL) and methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is pale yellow oil (391mg, 51%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:219.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.36(s,1H),7.21(d,J＝9.0Hz,1H),7.20(d,J＝1.8Hz,1H),6.91(d,J＝2.4Hz,1H),6.84(dd,J＝9.0,2.4Hz,1H),3.84(s,3H),2.98(s,2H),1.38(s,6H)。

step 2) 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzsulfamide synthesis

The method that this step title compound describes with reference to embodiment 1 step 7 prepares, by 2-(5-methoxyl group-1H-indol-3-yl)-2-methylpropane-1-amine (370mg, 1.7mmol), 4-methoxyl group-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (787mg, 2.04mmol) with triethylamine (0.5mL, 3.0mmol) reaction preparation in methylene dichloride (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is faint yellow solid (856mg that concentrate drying obtains title compound, 88.8%).

MS(ESI,pos.ion)m/z:569.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.08(s,1H),7.32(dd,J＝8.4,2.4Hz,1H),7.22(s,1H),6.97(dd,J＝12.0,1.8Hz,2H),6.83-6.77(m,2H),6.75(s,1H),3.91(s,3H),3.79-3.69(m,4H),3.65(s,3H),3.12(d,J＝6.6Hz,2H),2.96-2.85(m,4H),1.40(s,6H)。

step 3) synthesis of 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(piperazine-1-base) benzsulfamide

This step title compound prepares with reference to the method described by embodiment 1 step 8, by 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzsulfamide (830mg, 1.46mmol), potassium hydroxide (168mg, 3.0mmol, be made into the 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (THF) (15mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (609mg that concentrate drying obtains title compound, 88.3%).

MS(ESI,pos.ion)m/z:473.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.28(s,1H),7.25(d,J＝1.8Hz,1H),7.21(d,J＝8.4Hz,1H),7.10(d,J＝2.4Hz,1H),6.93(s,1H),6.82(d,J＝1.8Hz,1H),6.79(dd,J＝9.0,2.4Hz,1H),6.76(d,J＝8.4Hz,1H),3.89(s,3H),3.69(s,3H),3.14(s,2H),3.02-2.97(m,4H),2.88(brs,4H),1.38(s,6H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):155.6,153.6,142.3,132.6,131.4,125.5,123.2,122.6,119.9,116.8,112.4,111.9,110.7,102.8,55.9,52.7,51.8,46.2,35.6,29.9,26.7。

the synthesis of embodiment 4 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(4-methylpiperazine-1-yl) benzsulfamide

This step title compound prepares with reference to the method described by embodiment 2, by 4-methoxyl group-N-(2-(5-methoxyl group-1H-indol-3-yl)-2-methyl-propyl)-3-(piperazine-1-base) benzsulfamide (300mg, 0.63mmol), sodium cyanoborohydride (113mg, 1.8mmol) with formaldehyde (40%, 0.053mL, 1.8mmol) reaction preparation in methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1), it is white solid (263mg that concentrate drying obtains title compound, 85.1%).

MS(ESI,pos.ion)m/z:487.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.30(s,1H),7.23(d,J＝2.4Hz,1H),7.20(d,J＝9.0Hz,1H),7.12(d,J＝1.8Hz,1H),6.91(d,J＝2.4Hz,1H),6.81(d,J＝1.8Hz,1H),6.78(dd,J＝9.0,2.4Hz,1H),6.76(d,J＝8.4Hz,1H),4.03(t,J＝6.6Hz,1H),3.88(s,3H),3.68(s,3H),3.15(d,J＝6.0Hz,2H),2.98(brs,4H),2.57(brs,4H),2.33(s,3H),1.37(s,6H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):155.5,153.6,141.8,132.6,131.3,125.4,123.2,122.6,119.8,116.8,112.4,111.9,110.7,102.7,55.9,55.3,52.7,50.3,46.2,35.6,29.8,26.7。

the synthesis of embodiment 5 N-((1-(1H-indol-3-yl) cyclopropyl) methyl)-4-methoxyl group-3-(piperazine-1-base) benzsulfamide

step 1) synthesis of 3-(1-anocy clopropyl)-1H-indoles-1-t-butyl formate

This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(cyano methyl)-1H-indoles-1-t-butyl formate (5.0g, 19.5mmol), sodium hydride (1.72g, 42.9mmol) He 1,2-ethylene dibromide (2.0mL, 23.4mmol) reaction preparation in DMSO (45mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=100/1), it is weak yellow liquid (1.43g, 26.0%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:283.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.12(d,J＝6.0Hz,1H),7.79(d,J＝7.8Hz,1H),7.47(s,1H),7.38-7.34(m,1H),7.32-7.29(m,1H),1.67-1.64(m,2H),1.66(s,9H),1.36(q,J＝4.8Hz,2H)。

step 2) synthesis of 1-(1H-indol-3-yl) cyclopropylniitrile

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-anocy clopropyl)-1H-indoles-1-t-butyl formate (1.4g, 4.9mmol) reaction preparation in water (15mL) and dioxane (3mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), it is weak yellow liquid (735mg, 82%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:183.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.12(d,J＝6.0Hz,1H),7.78(d,J＝7.8Hz,1H),7.48(s,1H),7.38-7.34(m,1H),7.32-7.30(m,1H),1.67-1.63(m,2H),1.38-1.35(m,2H)。

step 3) synthesis of (1-(1H-indol-3-yl) cyclopropyl) methylamine

This step title compound prepares with reference to the method described by embodiment 1 step 6, by 1-(1H-indol-3-yl) cyclopropylniitrile (700mg, 3.8mmol), Raney's nickel (100mg) reaction preparation in tetrahydrofuran (THF) (5mL) and methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is pale yellow oil (483mg, 68%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:187.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.11(s,1H),7.67(d,J＝7.8Hz,1H),7.42(s,1H),7.32-7.28(m,1H),7.24-7.20(m,1H),2.80(s,2H),0.81-0.74(m,4H)。

step 4) synthesis of N-((1-(1H-indol-3-yl) cyclopropyl) methyl)-4-methoxyl group-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzsulfamide

The method that this step title compound describes with reference to embodiment 1 step 7 prepares, be about to (1-(1H-indol-3-yl) cyclopropyl) methylamine (249mg, 1.33mmol), 4-methoxyl group-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (770mg, 1.99mmol) with triethylamine (0.5mL, 3.0mmol) reaction preparation in methylene dichloride (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is faint yellow solid (360mg that concentrate drying obtains title compound, 50.5%).

MS(ESI,pos.ion)m/z:537.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.15(s,1H),7.49(d,J＝8.4Hz,1H),7.33-7.28(m,2H),7.13(t,J＝7.2Hz,1H),7.04(d,J＝2.4Hz,1H),7.02-6.98(m,2H),6.71(d,J＝8.4Hz,1H),3.87(s,3H),3.79-3.75(m,2H),3.72-3.66(m,2H),3.07(s,2H),2.92-2.89(m,2H),2.88-2.85(m,2H),0.84-0.77(m,4H)。

step 5) synthesis of N-((1-(1H-indol-3-yl) cyclopropyl) methyl)-4-methoxyl group-3-(piperazine-1-base) benzsulfamide

This step title compound prepares with reference to the method described by embodiment 1 step 8, by N-((1-(1H-indol-3-yl) cyclopropyl) methyl)-4-methoxyl group-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzsulfamide (200mg, 0.37mmol), potassium hydroxide (56mg, 1.0mmol, be made into the 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (THF) (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (138mg that concentrate drying obtains title compound, 84.0%).

MS(ESI,pos.ion)m/z:441.3[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.50(s,1H),7.52(d,J＝8.4Hz,1H),7.31-7.27(m,2H),7.13(t,J＝7.8Hz,1H),7.10(d,J＝2.4Hz,1H),7.02(t,J＝7.2Hz,1H),6.95(s,1H),6.69(d,J＝9.0Hz,1H),3.85(s,3H),3.09(s,2H),3.01-2.96(m,4H),2.87(brs,4H),0.81-0.75(m,4H)；

¹³C NMR(150MHz,CDCl ₃)δ(ppm):155.5,142.1,136.7,131.8,127.1,124.2,122.7,122.3,119.8,119.2,116.8,116.7,111.7,110.6,55.9,51.7,51.6,46.2,17.67,11.5。

the synthesis of embodiment 6 4-methoxyl group-N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl)-3-(piperazine-1-base) benzsulfamide

step 1) synthesis of 3-(1-anocy clopropyl)-5-methoxyl group-1H-indoles-1-t-butyl formate

This step title compound prepares with reference to the method described by embodiment 1 step 4, by 3-(cyano methyl)-5-methoxyl group-1H-indoles-1-t-butyl formate (5.0g, 17.5mmol), sodium hydride (1.75g, 43.8mmol) He 1,2-ethylene dibromide (2.28mL, 26.2mmol) reaction preparation in DMSO (45mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=100/1), it is weak yellow liquid (1.66g, 30.4%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:313.3[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.98(s,1H),7.43(s,1H),7.20(d,J＝2.4Hz,1H),6.96(dd,J＝9.0,2.4Hz,1H),3.89(s,3H),1.67-1.65(m,2H),1.64(s,9H),1.33(q,J＝4.8Hz,2H)。

step 2) synthesis of 1-(5-methoxyl group-1H-indol-3-yl) cyclopropylniitrile

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 3-(1-anocy clopropyl)-5-methoxyl group-1H-indoles-1-t-butyl formate (1.5g, 4.8mmol) reaction preparation in water (15mL) and dioxane (3mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=50/1), it is weak yellow liquid (685mg, 67%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:213.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.98(s,1H),7.44(s,1H),7.20(d,J＝2.4Hz,1H),6.95(dd,J＝8.8,2.4Hz,1H),3.89(s,3H),1.67-1.64(m,2H),1.32(q,J＝4.8Hz,2H)。

step 3) synthesis of (1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methylamine

This step title compound prepares with reference to the method described by embodiment 1 step 6, by 1-(5-methoxyl group-1H-indol-3-yl) cyclopropylniitrile (670mg, 3.1mmol), Raney's nickel (100mg) reaction preparation in tetrahydrofuran (THF) (5mL) and methyl alcohol (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), it is pale yellow oil (424mg, 63%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:217.1[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):7.98(s,1H),7.39(s,1H),7.10(d,J＝2.4Hz,1H),6.90(dd,J＝9.0,2.4Hz,1H),3.85(s,3H),2.14(s,2H),0.80-0.73(m,4H)。

step 4) 4-methoxyl group-N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl)-3-(4-(2,2,2-trifluoroacetyl group) piperazine-1-base) benzene sulfonyl the synthesis of amine

The method that this step title compound describes with reference to embodiment 1 step 7 prepares, be about to (1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methylamine (400mg, 1.84mmol), 4-methoxyl group-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (774mg, 2.0mmol) with triethylamine (0.5mL, 3.0mmol) reaction preparation in methylene dichloride (15mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), it is faint yellow solid (886mg that concentrate drying obtains title compound, 84.9%).

MS(ESI,pos.ion)m/z:567.2[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.07(s,1H),7.29(dd,J＝8.4,1.8Hz,1H),7.19(d,J＝8.4Hz,1H),7.02(d,J＝1.8Hz,1H),6.98(d,J＝1.8Hz,1H),6.91(s,1H),6.80(dd,J＝9.0,2.4Hz,1H),6.72(d,J＝8.4Hz,1H),3.87(s,3H),3.76(brs,5H),3.69(s,2H),3.04(d,J＝4.8Hz,2H),2.92-2.83(m,4H),0.82-0.79(m,4H)。

step 5) synthesis of 4-methoxyl group-N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl)-3-(piperazine-1-base) benzsulfamide

This step title compound prepares with reference to the method described by embodiment 1 step 8, by 4-methoxyl group-N-((1-(5-methoxyl group-1H-indol-3-yl) cyclopropyl) methyl)-3-(4-(2, 2, 2-trifluoroacetyl group) piperazine-1-base) benzsulfamide (280mg, 0.49mmol), potassium hydroxide (56mg, 1.0mmol, be made into the 1mmol/mL aqueous solution) reaction preparation in tetrahydrofuran (THF) (10mL), crude on silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), it is white solid (230mg that concentrate drying obtains title compound, 48.9%).

MS(ESI,pos.ion)m/z:471.3[M+H] ⁺；

¹H NMR(600MHz,CDCl ₃)δ(ppm):8.47(s,1H),7.27(dd,J＝8.4,2.4Hz,1H),7.17(d,J＝9.0Hz,1H),7.09(d,J＝2.4Hz,1H),6.96(d,J＝2.4Hz,1H),6.93(s,1H),6.79(dd,J＝8.4,2.4Hz,1H),6.69(d,J＝8.4Hz,1H),3.85(s,3H),3.78(s,3H),3.45(s,1H),3.06(s,2H),2.99-2.95(m,4H),2.86(brs,4H),0.79-0.75(m,4H)；

¹³C NMR(100MHz,CDCl ₃)δ(ppm):155.5,154.2,142.2,131.9,131.8,127.6,125.0,122.7,116.8,116.4,112.5,112.3,110.7,101.2,56.1,55.9,51.7,51.5,46.2,17.6,11.4。

Biological test

The present invention adopts following methods to carry out biological test to the compound shown in formula (I):

A. use radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI ₆the avidity of acceptor

The expression that 32 μ g prepare there is people source 5-HT ₆compound and the assay buffer of the Chinese hamster ovary celI membranin of acceptor, 2nM radioactively labelled substance [3H] LSD, different test concentrations mix, and hatch 120min for 37 DEG C; Assay buffer composition is: 50mMTris-HCl (pH 7.4), 10mM MgCl ₂, 0.5mM EDTA, 10 μMs of Pargylines and 20mg/L proteinase inhibitor.

Add 100 μMs of 5-HT and remove nonspecific binding site.After hatching, above-mentioned mixed solution is used glass filter under vacuum, filter first uses 0.3%PEI preimpregnation before filtration.Rinse several times with 50mM Tris-HCl again after filtration.After filter drying, with scintillation mixed solution counting radioactivity on scintiloscope.Standard reference compounds is 5-HT, all tests several concentration and obtains its Competitive assays curve, carry out nonlinear regression analysis, obtain IC through Hill equation curve in each experiment ₅₀value, then calculate through ChengPrusoff equation, obtain Ki value.

The compound provided the embodiment of the present invention according to the method described above carries out radio ligand binding assay assessing compound to expressing the people source 5-HT on Chinese hamster ovary celI ₆the avidity of acceptor measures, result see table 2, the avidity measurement result that table 2 provides for the embodiment of the present invention.

The avidity measurement result of the compound that table 2 embodiment of the present invention provides

Embodiment	Ki(nM)	Embodiment	Ki(nM)
				Embodiment 1	A	Embodiment 4	A

Embodiment	Ki(nM)	Embodiment	Ki(nM)
				Embodiment 2	A	Embodiment 5	B
Embodiment 3	B	Embodiment 6	C

Note: A<20nM, 20≤B≤50nM, 50<C<10nM, D >=100nM.

As shown in Table 2, compound of the present invention at radio ligand binding assay assessing compound to expressing people source 5-HT on Chinese hamster ovary celI ₆higher activity is generally demonstrated in the avidity test of acceptor.

In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.

Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (10)

1. a compound, its steric isomer for compound shown in the compound shown in formula (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug

Wherein:

R ¹for H, D, F, Cl, Br, I ,-CN, C _1-6alkyl, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6halogenated alkoxy;

R ²and R ³be D, C independently of one another _1-6alkyl, C _1-6haloalkyl, C _1-6alkoxyl group or C _1-6halogenated alkoxy, or R ²and R ³, and C is formed together with their jointly connected carbon atoms _3-8cycloalkyl; With

R ⁴for H, D, C _1-6alkyl or C _1-6haloalkyl.

2. compound according to claim 1, wherein R ¹for H, D, F, Cl, Br, I ,-CN, C _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group or C _1-4halogenated alkoxy;

R ²and R ³be D, C independently of one another _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group or C _1-4halogenated alkoxy, or R ²and R ³, and C is formed together with their jointly connected carbon atoms _3-6cycloalkyl; With

R ⁴for H, D, C _1-4alkyl or C _1-4haloalkyl.

3. compound according to claim 1 and 2, wherein R ¹for H, D, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy.

4. compound according to claim 1 and 2, wherein R ²and R ³be D, methyl, ethyl, n-propyl or sec.-propyl independently of one another, or R ²and R ³, and cyclopropyl is formed together with their jointly connected carbon atoms.

5. compound according to claim 1 and 2, wherein R ⁴for H, D, methyl, ethyl, n-propyl or sec.-propyl.

6. compound according to claim 1, it has one of them structure following:

, or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.

7. a pharmaceutical composition comprises compound described in claim 1-6 any one and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.

8. pharmaceutical composition according to claim 7, it comprises additional treatment agent further, and described additional treatment agent is be used for the treatment of the medicine of A Cihaimo disease, the medicine for the treatment of nervous disorders or their combination.

9. one kind use the compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one for the preparation of prevention, treat or alleviate and 5-HT ₆purposes in the medicine of relevant disease.

10. purposes according to claim 9, wherein said and 5-HT ₆relevant disease is CNS illness, disorder of gastrointestinal tract or obesity.