CN105367474A

CN105367474A - Indoline derivative and application of indoline derivative in medicine

Info

Publication number: CN105367474A
Application number: CN201510493463.0A
Authority: CN
Inventors: 钟文和; 金传飞; 张英俊; 张
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-08-12
Filing date: 2015-08-12
Publication date: 2016-03-02

Abstract

The invention discloses an indoline derivative, or stereisomer, tautomer, nitric oxide, solvate, metabolite, pharmacy-acceptable salt or other prodrugs of the indoline derivative. The indoline derivative is used for resisting 5-HT6 receptors. The invention further relates to a method for preparing the compound and application of the compound in treating or preventing diseases related to 5-HT6 receptors.

Description

Indoline-like derivative 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, the composition and use thereof comprising described compound and using method.Especially, compound of the present invention is can as 5-HT ₆the indoline-like derivative 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 illness, 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, attention deficit disorder (Attention-deficithyperactivitydisorder, ADHD), 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., SerotoninIDResearchAlert, 1997,2 (3), 115-8).Research finds, known 5-HT ₆selective antagonist can improve 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., BritishJournalofPharmacology, 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., SocietyofNeuroscience, Abstracts, 2000,26,680).5-HT ₆the relevant potential therepic use of part is the ADD for the treatment of children and grownup.5-HT ₆antagonist improves the activity of nigrostriatal dopamine approach, and ADHD (Ernst, M relevant to the exception in caudatum; Zametkin, A.J.; Matochik, J.H.; Jons, P.A.; Cohen, R.M., JournalofNeuroscience, 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., Neuropharmacology2001,41:210-129 and WO02098878.

Summary of the invention

The present invention relates to the method for new indoline-like derivative 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, it is the steric isomer of structure shown in the structure shown in formula (I) or formula (I), tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug,

Wherein:

N is 1,2,3 or 4;

Q is CH or N;

M is NR ¹or O;

R ¹for H, D, C _1-4alkyl, C _2-4thiazolinyl, C _3-4alkynyl, 3-6 former molecular heterocyclic radical or C _3-6cycloalkyl;

Each R ²be H, D, F, Cl, Br, I, CN, NO independently ₂, OH, NH ₂, R ^ar ^bn-,-C (=O) C _1-6alkyl ,-C (=O) NR ^ar ^b,-OC (=O) NR ^ar ^b,-OC (=O) OR ^a,-N (R ^a) C (=O) NR ^ar ^b,-N (R ^a) C (=O) OR ^a,-N (R ^a) C (=O)-R ^b, R ^ar ^bn-S (=O) ₂-, R ^as (=O) ₂-, R ^as (=O) ₂n (R ^bthe C that)-, hydroxyl replaces _1-6alkyl, the C of carboxyl substituted _1-6alkyl, C _1-6alkyl-OC (=O) C _1-6alkyl-, R ^as (=O)-C _1-6alkyl-, R ^ar ^bn-C (=O)-C _1-6alkyl-, R ^ar ^bn-C _1-6alkoxyl group-, R ^as (=O)-C _1-6alkoxyl group-, R ^ar ^bn-C (=O)-C _1-6alkoxyl group, 5-12 former molecular heteroaryl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group, C _1-6alkyl, C _6-10aryl C _1-6alkyl, or adjacent two R ²and form substituted or unsubstituted 5-7 former molecular carbocylic radical, heterocyclic radical, aromatic base or aromatic heterocyclic group together with the ring carbon atom to be connected respectively with them;

R ³, R ⁴, R ⁵and R ⁶be H, D, Cl, Br, I, CN, OH, NH independently of one another ₂, C _2-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl ,-C (=O) R ^a, halo C _1-4alkyl, halo C _1-4alkoxyl group or-C (=O) NR ^ar ^b;

R ⁷, R ⁸, R ⁹and R ¹⁰be H, D, F, Cl, Br, CN, CHF independently of one another ₂, C _2-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _1-4alkoxyl group, C _2-4alkylthio, halo C _1-4alkoxyl group or C _6-10aryl; With

Each R ^aand R ^bbe separately H, D, C _1-6alkyl, halo C _1-6alkyl, C _1-6alkoxyl group, C _6-10aryl, 3-12 former molecular heterocyclic radical, C _3-8cycloalkyl, C _6-10aryl C _1-6alkyl, C _6-10aryloxy, 3-12 former molecular heterocyclyloxy base, C _3-8cycloalkyl oxy, C _6-10virtue is amino, 3-12 former molecular heterocyclylamino group, C _3-8cycloalkyl amino, 5-12 former molecular heteroaryl or C _3-8carbocylic radical, or R ^a, R ^bsubstituted or unsubstituted 3-8 former molecular heterocyclic radical or aromatic heterocyclic group is formed together with the nitrogen-atoms be attached thereto.

In some embodiments, R ¹for H, D, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl or cyclopentyl.

In some embodiments, each R ²be H, D, F, Cl, Br, I, CN, OH, NH independently ₂, R ^ar ^bn-,-C (=O) C _1-4alkyl ,-C (=O) NR ^ar ^b, 5-12 former molecular heteroaryl, C _1-4alkoxyl group, halo C _1-4alkyl, halo C _1-4alkoxyl group, C _1-4alkyl, C _6-10aryl C _1-4alkyl, or adjacent two R ²and form substituted or unsubstituted 5-7 former molecular carbocylic radical or fragrant cyclic group together with the ring carbon atom to be connected respectively with them;

Wherein each R ^aand R ^bthere is implication as described in the present invention.

In other embodiment, each R ²be H, D, F, Cl, Br independently, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base ,-CHF ₂,-CF ₃or-CH ₂cF ₃, or adjacent two R ²and form substituted or unsubstituted phenyl together with the ring carbon atom to be connected respectively with them.

In some embodiments, R ³, R ⁴, R ⁵and R ⁶be H, D, Cl, Br, I, CN, OH, NH independently of one another ₂, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl;

R ⁷, R ⁸, R ⁹and R ¹⁰be H, D, F, Cl, Br, CN, CHF independently of one another ₂, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base ,-OCHF ₂,-OCF ₃or-OCH ₂cF ₃.

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 some embodiments, pharmaceutical composition of the present invention, it further comprises the medicine for the treatment of Alzheimer's disease, for medicine or their combination of nervous disorders;

Wherein said additional treatment agent is: E2020, Nalmefene, risperidone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, tacrine, rivastigmine, lycoremine, memantine, meter Ta Zhaping, Venlafaxine, desipramine, nortriptyline, zolpidem, Zopiclone, nicergoline, piracetam, selegiline, pentoxifylline or their combination.

On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition is preparing the purposes in medicine, described medicine is used for the treatment of or prevents and 5-HT ₆relevant disease;

Wherein said and 5-HT ₆relevant disease is disorder of gastrointestinal tract, obesity or CNS illness.

In some embodiments, 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 and 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.

Biological results shows, compound provided by the invention can be used as good 5-HT ₆antagonist.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 " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork: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.

" 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.

" 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.

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

" diastereomer " refers to two or more chiral centre 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-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 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, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2 ^nded.RobertE.Gawley, JeffreyAub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) 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 (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valencetautomer) 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.

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 non-substituted " 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, amino, fluorine, chlorine, bromine, iodine, cyano group, azido-, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl that hydroxyl replaces, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) ₂-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces _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.With R ^afor example, structural formula "-N (R ^a) C (=O) NR ^ar ^b" and structural formula " R ^ar ^bn-C _1-6alkoxyl group-" R between the two ^aconcrete option mutually between unaffected, meanwhile, at same chemical formula "-N (R ^a) C (=O) NR ^ar ^b" in, multiple R ^aconcrete option mutually between unaffected.

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-C 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, wherein said substituting group is, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano group, azido-, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl 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-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces ₂-, Carboxyalkoxy etc.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 " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from saturated straight or branched alkyl.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene group contains 1-6 carbon atom; In another embodiment, alkylidene group contains 1-4 carbon atom; In yet another embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (-CH ₂-), ethylidene (-CH ₂cH ₂-), isopropylidene (-CH (CH ₃) CH ₂-) 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 can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " trans ", 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 can 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.

No matter term " carboxyl ", be used alone or be used in conjunction with other terms, as " carboxyalkyl ", and expression-CO ₂h; No matter term " carbonyl ", be used alone or be used in conjunction with other terms, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-.

Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as is connected with Sauerstoffatom, forms oh group.

Term " D " or " ²h " represent single D atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (-CDH ₂), two D atoms are connected with a methyl, form two-deuterated methyl (-CD ₂h), and three D atoms are connected with a methyl, form three-deuterated methyl (-CD ₃).

Term " undersaturated " used in the present invention represents in group containing one or more degree of unsaturation.

Term " heteroatoms " refers to O, S, N, P and Si, comprises the form of any oxidation state of N, S and P; 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 " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " alkyl that hydroxyl replaces " represents that alkyl group is optionally substituted with one or more hydroxyl group and replaces, and wherein alkyl group has implication of the present invention.Such example comprises, but is not limited to methylol, hydroxyethyl, 1,2-dihydroxy ethyl etc.

Term " alkyl of carboxyl substituted " represent alkyl group replace by one or more carboxylic group, wherein alkyl group has implication of the present invention.Such example comprises, but is not limited to carboxymethyl group, carboxy ethyl, 1,2-dicarboxyethyl etc.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxy base replace by one or more halogen atom, such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc.

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 can optionally be 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 " alkylthio " comprises C _1-6the alkyl of straight or branched is connected on the sulphur atom of divalence.Some of them embodiment is, alkylthio is more rudimentary C _1-4alkylthio, such example comprises, but is not limited to methylthio group (CH ₃s-).

Term " p former molecular ", wherein p is integer, typically describes the number of ring member nitrogen atoms in molecule, and in described molecule, the number of ring member nitrogen atoms is p.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is 10 former molecular groups of naphthene base.

Term " ring " comprises carbocyclic ring, heterocycle, aromatic nucleus, hetero-aromatic ring, volution, spiroheterocyclic, condensed ring, fused heterocycle etc., wherein said carbocyclic ring, heterocycle, aromatic nucleus, hetero-aromatic ring, volution, spiroheterocyclic, condensed ring, and fused heterocycle group has implication as described in the present invention.

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " commutative use herein, all refer to the undersaturated bridged-ring system of saturated or part of unit price or multivalence, described bridged-ring system refers to the bicyclic system of non-aromatic.Such system can comprise independently or the unsaturated system of conjugation, but its core texture does not comprise aromatic nucleus or hetero-aromatic ring (but aromatic group can as the substituting group on it).

Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell dicyclo " commutative use herein, refers to the unsaturated member ring systems of saturated or part of unit price or multivalence, and one of them ring originates from specific ring carbon atom on another ring.Such as, as described below, a saturated bridged-ring system (ring B and B ') is called as " condensed-bicyclic ", and ring A and ring B shares a carbon atom in two saturated member ring systems, is called as " volution " or " spiral shell dicyclo ".Each ring in condensed-bicyclic base and spiral shell bicyclic group can be carbocylic radical or heterocyclic radical, and each ring optionally replace by one or more substituting group described in the invention.

Term " carbocylic radical " or " carbocyclic ring " expression contain 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.Carbon bicyclic group comprises spiral shell carbon bicyclic group and condenses carbon bicyclic group, and suitable carbocylic radical group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group comprises further, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.

Term " cycloalkyl " expression contains 3-12 carbon atom, saturated monocycle, dicyclo or the three-ring system of unit price or multivalence.In one embodiment, cycloalkyl comprises 3-12 carbon atom; In another embodiment, cycloalkyl comprises 3-8 carbon atom; In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can not be substituted independently or replace by one or more substituting group described in the invention.

Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or the undersaturated monocycle of part, dicyclo or three rings, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be 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, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.-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 and pyrimidine dione base by the example of-C (O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, and refer to and comprise the saturated of 4-7 annular atoms or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 4-7 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 4-7 former molecular heterocyclic radical comprises, but be not limited to: 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, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base.-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 and pyrimidine dione base by the example of-C (=O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described 4-7 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

Also in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, and refer to and comprise the saturated of 7-12 annular atoms or the undersaturated spiral shell dicyclo of part or condensed-bicyclic, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: indoline base, and 1,2,3,4-tetrahydro isoquinolyl, 1,3-benzene is two Evil cyclopentadienyls, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base also.Described 7-12 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

Term " aromatic base " 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, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group can comprise phenyl, naphthyl and anthracene.Described aromatic yl group can independently optionally replace by one or more substituting group described in the invention or do not replace.Wherein said substituting group deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano group, azido-, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo, carboxyl, haloalkyl, the alkyl that hydroxyl replaces, the alkoxyl group that hydroxyl replaces, the alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) ₂-, the alkyl-S (=O) that hydroxyl replaces-, the alkyl-S (=O) that hydroxyl replaces ₂-, Carboxyalkoxy etc.

Term " aralkyl " comprises the alkyl group that aryl replaces.Some of them embodiment is, aromatic alkyl group refers to " more rudimentary aralkyl " group, and namely aromatic yl group is connected to C _1-6alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C _1-4" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl.Aryl on aralkyl can further by halogen, alkyl, alkoxyl group, and haloalkyl and halogenated alkoxy replaced.

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, and has one or more attachment point to be connected with molecule rest part.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, substituting group is drawn a key and is connected to the member ring systems (as follows) that the ring at center is formed and represents substituting group any commutable position on ring and can replace.Such as, formula e represents any position that may be substituted on A ring, such as formula f ¹-f ⁴shown in:

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: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal, Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal, ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.

" 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 is in affiliated field known by us, and as document: S.M.Bergeetal., J.PharmaceuticalSciences, 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.

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 ethanoyl and silyl." 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: TW.Greene, ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons, NewYork, 1991; AndP.J.Kocienski, ProtectingGroups, 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 " ADHD " is the abbreviation of Attention-deficithyperactivitydisorder, 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 " (HyperkineticDisorder), 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 DiagnosticandStatisticalManualofMentalDisorder, the 4th edition, AmericanPsychiatricAssociation, 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 ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (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 indoline-like derivative 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.

Wherein, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, Q, M and n have implication as described in the present invention.

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

In some embodiments, Q is CH or N.

In some embodiments, M is NR ¹or O;

R ¹there is implication as described in the present invention.

In some embodiments, R ¹for H, D, C _1-4alkyl, C _2-4thiazolinyl, C _3-4alkynyl, 3-6 former molecular heterocyclic radical or C _3-6cycloalkyl.

In some embodiments, each R ²be H, D, F, Cl, Br, I, CN, NO independently ₂, OH, NH ₂, R ^ar ^bn-,-C (=O) C _1-6alkyl ,-C (=O) NR ^ar ^b,-OC (=O) NR ^ar ^b,-OC (=O) OR ^a,-N (R ^a) C (=O) NR ^ar ^b,-N (R ^a) C (=O) OR ^a,-N (R ^a) C (=O)-R ^b, R ^ar ^bn-S (=O) ₂-, R ^as (=O) ₂-, R ^as (=O) ₂n (R ^bthe C that)-, hydroxyl replaces _1-6alkyl, the C of carboxyl substituted _1-6alkyl, C _1-6alkyl-OC (=O) C _1-6alkyl-, R ^as (=O)-C _1-6alkyl, R ^ar ^bn-C (=O)-C _1-6alkyl, R ^ar ^bn-C _1-6alkoxyl group-, R ^as (=O)-C _1-6alkoxyl group, R ^ar ^bn-C (=O)-C _1-6alkoxyl group, 5-12 former molecular heteroaryl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group, C _1-6alkyl, C _6-10aryl C _1-6alkyl, or adjacent two R ²and form substituted or unsubstituted 5-7 former molecular carbocylic radical, heterocyclic radical, aromatic base or heteroaryl groups together with the ring carbon atom to be connected respectively with them;

Each R ^aand R ^bthere is implication as described in the present invention.

In some embodiments, R ³, R ⁴, R ⁵and R ⁶be H, D, Cl, Br, I, CN, OH, NH independently of one another ₂, C _2-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl ,-C (=O) R ^a, halo C _1-4alkyl, halo C _1-4alkoxyl group or-C (=O) NR ^ar ^b;

Each R ^aand R ^bthere is implication as described in the present invention.

In some embodiments, R ⁷, R ⁸, R ⁹and R ¹⁰be H, D, F, Cl, Br, CN, CHF independently of one another ₂, C _2-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _1-4alkoxyl group, C _2-4alkylthio, halo C _1-4alkoxyl group or C _6-10aryl; With

Each R ^aand R ^bbe separately H, D, C _1-6alkyl, halo C _1-6alkyl, C _1-6alkoxyl group, C _6-10aryl, 3-12 former molecular heterocyclic radical, C _3-8cycloalkyl, C _6-10aryl C _1-6alkyl, C _6-10aryloxy, 3-12 former molecular heterocyclyloxy base, C _3-8cycloalkyl oxy, C _6-10virtue is amino, 3-12 former molecular heterocyclylamino group, C _3-8cycloalkyl amino, 5-12 former molecular heteroaryl or C _3-8carbocylic radical, or R ^a, R ^bsubstituted or unsubstituted 3-8 former molecular heterocyclic radical or heteroaryl groups is formed together with the nitrogen-atoms be attached thereto.

Each R ^aand R ^bthere is implication as described in the present invention.

In other embodiment, each R ²be H, D, F, Cl, Br independently, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base ,-CHF ₂,-CF ₃or-CH ₂cF ₃, or adjacent two R ²and form substituted or unsubstituted phenyl ring base together with the ring carbon atom to be connected respectively with them.

In some embodiments, the present invention comprises one of them structure following:

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

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 treat illness, particularly Alzheimer's disease that 5-HT mediates.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, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.

The salt of compound of the present invention also comprise for the preparation of or purifying formula I shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula I, but not necessarily pharmacy acceptable salt.

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, the 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, present disclosure also provides pharmaceutical composition, and this pharmaceutical composition comprises the formula I compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle for the treatment of significant quantity.

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, Lu-AE58054, 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 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, carrying agent 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 carrying agent can be solid or liquid.The preparation of solid form comprises: 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 carrying agent 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 carrying agent includes but not limited to carbonic acid money, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Terms " formulation " is intended to comprise house has coating material as carrying agent to provide the preparation of the active compound of capsule, in described capsule the activeconstituents of with or without carrier surround by this carrying agent 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 carrying agent, 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 without mattress packing 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 appropriate liquid carrying agent.

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 carrying agent 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 carrying agent will form gel in nasal cavity.Powder composition can such as exist with gelatine capsule agent or cartridge case or bubble Army packaged form in a unit ' by sucker by wherein using powder.

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 carrying agent.The compound paid close attention to also can with penetration enhancer, such as laurocapram " 1-12 pit foundation nitrogen heterocyclic-2-in heptan ketone) combinationally use.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 medicinal carrying agent and their preparation are edited at Remington:TheScienceandPracticeofPharmacy1995Martin, E.W, and MackPublishingCompany, has description in Easton, Pennsylvania by the 19th edition.

the purposes of the compounds of this invention and pharmaceutical composition

The feature of pharmaceutical composition of the present invention comprises the compound listed by the compound shown in formula I or 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.

the general synthetic method of the compounds of this 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 as shown in formula 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 Ling Kai medicine, AldrichChemicalCompany, Inc., ArcoChemicalCompany and AlfaChemicalCompany, 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, N,N-dimethylacetamide and sherwood oil 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 ₃or DMSO-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 (doubletofdoublets, double doublet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).

The condition determination of Algorithm (MS) data is: (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min to Agilent6120 level Four bar HPLC-M.Moving phase: 5%-95% is (containing the CH of 0.1% formic acid ₃cN) (containing the H of 0.1% formic acid ₂o) ratio in), adopt electron spray ionisation (ESI), under 210nm/254nm, detect with UV.

Use Agilent1260pre-HPLC or Caleseppump250pre-HPLC (pillar model: NOVASEP50/80mmDAC) of pure compound, detects at 210nm/254nm UV.

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

CDC1 ₃deuterochloroform

DMSO-d ₆deuterated dimethyl sulfoxide

MgCl ₂magnesium chloride

ML, ml milliliter

Min minute

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 ⁷, R ⁸, R ⁹and R ¹⁰there is definition as described in the present invention.

Synthetic method 1

Formula ( 5) shown in compound can be prepared by following process:

Formula ( 1) shown in compound be obtained by reacting under the effect of reductive agent formula ( 2) shown in compound.Formula ( 2) shown in compound and SULPHURYL CHLORIDE compounds be obtained by reacting formula ( 3) shown in compound; Formula ( 3) shown in compound deprotection under the effect of alkali obtain formula ( 4) shown in compound; Formula ( 4) shown in compound and formaldehyde reaction reduction amination obtain formula ( 5) shown in compound.Reaction process is as follows:

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

Embodiment

the synthesis of embodiment 15-methoxyl group-1-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

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

By 1-(2-p-methoxy-phenyl) piperazine hydrochloric acid (1.0g, 4.39mmol) with triethylamine (2.5mL, 17.70mmol) join in methylene dichloride (15mL), trichoroacetic chloride (1.0mL is slowly dripped under 0 DEG C of low temperature bath, 8.96mmol), after dripping, react 24 hours at being transferred to 25 DEG C, stopped reaction, add methylene dichloride (50mL), wash with saturated sodium bicarbonate solution (40mL), after separatory, organic phase is filtered through anhydrous sodium sulfate drying, filtrate reduced in volume, it is faint yellow solid (763mg that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound, 52%).

MS(ESI,pos.ion)m/z:337.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.09-7.06(m,1H),6.96-6.91(m,3H),4.03(br.s,4H),3.91(s,3H),3.18(t,J＝4.4Hz,4H)；

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

By 2,2, the chloro-1-of 2-tri-(4-(2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone (550mg, 1.63mmol) be dissolved in methylene dichloride (5mL), then be added drop-wise in chlorsulfonic acid (3mL) under 0 DEG C of low temperature bath, react after 1 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 obtaining title compound is faint yellow solid (548mg, 78.5%).

MS(ESI,pos.ion)m/z:435.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.75(dd,J＝8.8,2.4Hz,1H),7.47(d,J＝2.4Hz,1H),7.01(d,J＝8.8Hz,1H),4.00(brs,7H),3.21(t,J＝4.8Hz,4H)；

step 3) synthesis of 5-methoxy-Indole quinoline

At 25 DEG C, by 5-methoxy-Indole (1.5g, 10.2mmol) join in acetic acid (20mL), then add sodium cyanoborohydride (0.77g in batches, 12.2mmol), react after 1 hour, add sodium hydroxide solution (20%) and be neutralized to pH=9 ~ 10, then ethyl acetate (50mL) extraction is added, organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is brown solid (1.46g, 95.9%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=10/1) obtains title compound.

MS(ESI,pos.ion)m/z:150.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)6.76(s,1H),6.63-6.59(m,2H),3.77(s,3H),3.54(t,J＝8.2Hz,2H),3.01(t,J＝8.3Hz,2H)。

step 4) synthesis of 2,2,2-tri-chloro-1-(4-(2-methoxyl group-5-((5-methoxy-Indole quinoline-1-base) alkylsulfonyl) phenyl) piperazine-1-base) ethyl ketone

By 5-methoxyindole quinoline (257mg at 0 DEG C; 1.72mmol) with triethylamine (487ul; 3.44mmol) join in methylene dichloride (8.0mL); then 4-methoxyl group-3-(4-(2 is slowly added; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (500mg, 1.15mmol).React after 10 minutes, be warming up to 25 DEG C, reaction is spent the night.Add 50mL methylene dichloride, then wash (40mL) with saturated nacl aqueous solution, organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is white solid (554mg, 87.9%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=5/1) obtains title compound.

MS(ESI,pos.ion)m/z:548.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.56(d,J＝8.8Hz,1H),7.47(dd,J＝8.5,2.0Hz,1H),6.97(d,J＝2.0Hz,1H),6.87(d,J＝8.6Hz,1H),6.73(dd,J＝8.8,2.4Hz,1H),6.60(d,J＝1.8Hz,1H),3.90(br,7H),3.85(t,J＝8.2Hz,2H),3.73(s,3H),2.94-2.92(m,4H),2.62(t,J＝8.2Hz,2H)。

step 5) synthesis of 5-methoxyl group-1-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

At 25 DEG C; by 2; 2; the chloro-1-of 2-tri-(4-(2-methoxyl group-5-((5-methoxy-Indole quinoline-1-base) alkylsulfonyl) phenyl) piperazine-1-base) ethyl ketone (690mg; 1.26mmol) be dissolved in tetrahydrofuran (THF) (10mL); then potassium hydroxide (212mg, 3.78mmol 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 is washed (30mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression be spin-dried for, it is white solid (357.9mg, 70.4%) that column chromatography purification (methylene chloride/methanol (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:404.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.56(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.03(s,1H),6.82(d,J＝9.0Hz,1H),6.73(d,J＝1.8Hz,1H),6.59(s,1H),3.86-3.84(m,5H),3.72(s,3H),3.00-2.98(m,4H),2.84(brs,4H),2.63(t,J＝7.8Hz,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)157.1,156.0,141.6,135.8,134.6,128.4,122.9,117.5,117.2,112.7,110.8,110.6,55.8,55.6,51.4,50.5,45.9,28.4。

the synthesis of embodiment 25-methoxyl group-1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

5-methoxy-1-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (126mg, 0.31mmol) is dissolved in methyl alcohol (10mL), adds two acetic acid.At 0 DEG C, sodium cyanoborohydride (59mg, 0.94mmol) and formaldehyde (40%, 0.07mL, 0.94mmol) are slowly joined in reaction solution.React after 10 minutes, be warming up to 25 DEG C; Continue reaction after 5 hours, add water (10mL) and sodium carbonate (212mg, 2.0mmol) cancellation, then use dichloromethane extraction (30mLx2).Merge organic phase, anhydrous sodium sulfate drying; Filter, filtrate decompression is spin-dried for, and it is gray solid (100mg, 49%) that column chromatography purification (methylene chloride/methanol (v/v)=30/1) obtains title compound.

MS(ESI,pos.ion)m/z:418.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.56(d,J＝8.4Hz,1H),7.40(dd,J＝8.4,2.4Hz,1H),7.05(d,J＝2.4Hz,1H),6.81(d,J＝8.4Hz,1H),6.72(d,J＝6.0Hz,1H),6.59(s,1H),3.90-3.83(m,5H),3.72(s,3H),2.92(brs,4H),2.64(t,J＝8.4Hz,2H),2.54(brs,4H),2.32(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)157.1,155.9,141.2,135.7,134.5,128.5,122.8,117.4,117.1,112.7,110.8,110.5,55.8,55.6,54.9,50.5,50.0,45.9,28.4。

the synthesis of embodiment 35-methoxyl group-1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 2,2,2-tri-chloro-1-(4-(1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone

By 1-(1-methoxynaphthalene-2-base) piperazine (680mg, 2.81mmol) with triethylamine (1.12mL, 8.42mmol) join in methylene dichloride (15mL), trichoroacetic chloride (0.47mL is slowly dripped under 0 DEG C of low temperature bath, 4.21mmol), after dripping, react 24 hours at being transferred to 25 DEG C, stopped reaction, add methylene dichloride (50mL), wash with saturated sodium bicarbonate solution (40mL), organic phase anhydrous sodium sulfate drying after separatory.Filter, filtrate decompression is spin-dried for, and it is faint yellow solid (788mg, 72.3%) that column chromatography purification (petrol ether/ethyl acetate (v/v)=20/1) obtains title compound.

MS(ESI,pos.ion)m/z:387.9[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.14(d,J＝8.5Hz,1H),7.81(d,J＝8.2Hz,1H),7.63(d,J＝8.8Hz,1H),7.51(t,J＝7.5Hz,1H),7.42(t,J＝7.4Hz,1H),7.28(d,J＝8.5Hz,1H),4.13-3.89(m,7H),3.39-3.33(m,4H)。

step 2) synthesis of 4-methoxyl group-3-(4-(2,2,2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE

By 2,2, the chloro-1-of 2-tri-(4-(1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (782mg, 2.02mmol) be dissolved in (5mL) in methylene dichloride, then under 0 DEG C of low temperature bath, chlorsulfonic acid (352.9mg is slowly dripped, 3.03mmol), then reaction after 24 hours at 25 DEG C, add phosphorus pentachloride (624mg, 3.0mmol), continue stirring reaction 5 hours, 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 (595mg, 60.7%).

MS(ESI,pos.ion)m/z:484.9[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.69(d,J＝8.5Hz,1H),8.30(d,J＝8.2Hz,1H),8.13(s,1H),7.73-7.64(m,2H),4.10(br.s,7H),3.38-3.32(m,4H)。

step 3) synthesis of 2,2,2-tri-chloro-1-(4-(1-methoxyl group-4-((5-methoxy-Indole quinoline-1-base) alkylsulfonyl) naphthalene-2-base) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-methoxy-Indole quinoline (600mg; 4.02mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (630mg; 1.29mmol) with triethylamine (0.8ml; 5.8mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is brown solid (734mg, 95%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:598.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.70(d,J＝8.7Hz,1H),8.17(d,J＝8.4Hz,1H),7.83(s,1H),7.52(dd,J＝13.7,7.9Hz,2H),7.47-7.44(m,4.1Hz,1H),6.79-6.69(m,2H),4.03(s,3H),3.99(t,J＝8.2Hz,4H),3.76(s,3H),3.58(t,J＝8.2Hz,2H),3.21-3.14(m,4H),3.05(t,J＝8.2Hz,2H)。

step 4) synthesis of 5-methoxyl group-1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(1-methoxyl group-4-((5-methoxy-Indole quinoline-1-base) alkylsulfonyl) naphthalene-2-base) piperazine-1-base) ethyl ketone (720mg, 1.2mmol), potassium hydroxide (202mg, 3.6mmol, 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)=30/1), it is white solid (331mg that concentrate drying obtains title compound, 61%).

MS(ESI,pos.ion)m/z:454.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.64(d,J＝8.5Hz,1H),8.16(d,J＝8.5Hz,1H),7.93(s,1H),7.48(t,J＝8.6Hz,2H),7.44-7.37(m,1H),6.74-6.72(m,1H),6.59(s,1H),4.04-3.94(m,5H),3.74(d,J＝8.9Hz,3H),3.08(brs,8H),2.66(t,J＝8.2Hz,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.9,150.9,138.4,135.8,134.0,130.1,128.8,126.7,126.6,126.4,124.7,124.0,122.1,116.8,112.5,111.0,59.2,55.7,51.2,50.5,46.3,28.5。

the synthesis of embodiment 45-methoxyl group-1-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by 5-methoxyl group-1-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (296mg; 0.65mmol); sodium cyanoborohydride (123mg; 1.96mmol) with formaldehyde (40%; 0.147mL; 1.96mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (265mg, 86.8%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:468.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.64(d,J＝8.7Hz,1H),8.15(d,J＝8.5Hz,1H),7.93(s,1H),7.49-7.47(m,2H),7.40(t,J＝7.7Hz,1H),6.72(dd,J＝8.8,2.3Hz,1H),6.60(s,1H),4.02(t,J＝8.2Hz,2H),4.00(s,3H),3.74(s,3H),3.15(brs,4H),2.69(t,J＝8.2Hz,2H),2.61(brs,4H),2.37(s,3H)。

the synthesis of the fluoro-1-of embodiment 55-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 5-fluoro indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 5-fluoro indole (500mg, 3.70mmol) with sodium cyanoborohydride (349mg, 5.55mmol) reaction preparation in acetic acid (5mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (384mg, 75.7%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:138.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)6.86(dd,J＝8.4,1.2Hz,1H),6.77-6.68(m,1H),6.60-6.53(m,1H),3.58(td,J＝8.4,1.2Hz,2H),3.54(brs,1H),3.03(t,J＝8.4Hz,2H)。

step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-((5-fluoro indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-fluoro indole quinoline (350mg; 2.55mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (556mg; 1.29mmol) with triethylamine (0.53ml; 3.83mmol) reaction preparation in methylene dichloride (10mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (564mg, 82.3%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:536.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.56(dd,J＝9.0,4.8Hz,1H),7.45(dd,J＝8.4,2.4Hz,1H),7.07(d,J＝2.8Hz,1H),6.87(d,J＝8.4Hz,1H),6.87(td,J＝8.4,3.0Hz,1H),6.79-6.72(m,1H),3.99(brs,4H),3.89(s,3H),3.88(t,J＝8.4Hz,2H),2.98(t,J＝4.8Hz,4H),2.73(t,J＝8.4Hz,2H)。

step 3) synthesis of the fluoro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((5-fluoro indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone (200mg, 0.37mmol), potassium hydroxide (63mg, 1.12mmol, 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)=30/1), it is white solid (120mg that concentrate drying obtains title compound, 82.3%).

MS(ESI,pos.ion)m/z:392.1[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.63(d,J＝8.5Hz,1H),8.23-8.16(m,1H),7.94(s,1H),7.58-7.52(m,1H),7.30(dd,J＝8.6,2.0Hz,1H),7.08(dd,J＝8.2,2.0Hz,1H),4.18-3.91(m,9H),3.28-3.18(m,4H),2.79(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,DMSO-d ₆):δ(ppm)159.6(d,J＝241.2Hz),156.4,141.2,138.5(d,J＝1.8Hz),135.7(d,J＝8.8Hz),127.7,123.3,116.9,116.4(d,J＝8.7Hz),114.2(d,J＝23.4Hz),113.1(d,J＝24.0Hz),112.3,56.5,50.9,48.8,44.4,27.9(d,J＝1.6Hz)。

the synthesis of the fluoro-1-of embodiment 65-((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the fluoro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (179mg; 0.46mmol); sodium cyanoborohydride (85mg; 1.35mmol) with formaldehyde (40%; 0.1mL; 1.37mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (121mg, 64.7%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:406.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.58(dd,J＝9.0,4.8Hz,1H),7.40(dd,J＝8.4,1.8Hz,1H),7.10(d,J＝1.8Hz,1H),6.86(td,J＝8.4,2.4Hz,1H),6.82(d,J＝9.0Hz,1H),6.77-6.71(m,1H),3.89(t,J＝8.4Hz,2H),3.37(s,3H),2.94(brs,4H),2.73(t,J＝8.4Hz,2H),2.54(brs,4H),2.32(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)159.9(d,J＝241.2Hz),156.1,141.5,138.4(d,J＝1.9Hz),134.6(d,J＝8.5Hz),128.3,122.8,116.9,116.9(d,J＝8.2Hz),114.1(d,J＝23.4Hz),112.3(d,J＝23.8Hz),110.6,55.8,55.0,50.5,50.2,46.1,28.1(d,J＝1.5Hz)。

the synthesis of the fluoro-1-of embodiment 75-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 2,2,2-tri-chloro-1-(4-(4-((5-fluoro indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-fluoro indole quinoline (604mg; 4.40mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (1.07g; 2.20mmol) with triethylamine (0.92ml; 6.60mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is brown solid (1.08g, 83%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:586.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.61(d,J＝8.4Hz,1H),8.19(d,J＝8.4Hz,1H),7.94(s,1H),7.58-7.49(m,2H),7.49-7.40(m,1H),6.88(td,J＝8.8,2.8Hz,1H),6.75(dd,J＝8.0,2.4Hz,1H),4.02(brs,4H),4.02(s,3H),3.99(t,J＝8.4Hz,2H),3.22(t,J＝4.8Hz,4H),2.73(t,J＝8.4Hz,2H)。

step 2) synthesis of the fluoro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(1-methoxyl group-4-((5-fluoro indole quinoline-1-base) alkylsulfonyl) naphthalene-2-base) piperazine-1-base) ethyl ketone (1.07g, 1.82mmol), potassium hydroxide (307mg, 5.47mmol, 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)=30/1), it is white solid (637mg that concentrate drying obtains title compound, 79.1%).

MS(ESI,pos.ion)m/z:442.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.65-8.55(m,1H),8.18(dd,J＝15.0,8.4Hz,1H),8.00(d,J＝12.92Hz,1H),7.57-7.47(m,2H),7.47-7.37(m,1H),6.95-6.85(m,1H),6.75(d,J＝6.6Hz,1H),4.05-3.96(m,5H),3.35(d,J＝7.2Hz,4H),3.18(brs,2H),2.75(q,J＝7.6Hz,4H)；

¹³CNMR(150MHz,DMSO-d ₆):δ(ppm)159.8(d,J＝241.5Hz),151.0,138.4(d,J＝2.1Hz),138.3,134.2(d,J＝8.7Hz),130.2,128.5,126.9(d,J＝6.5Hz),126.4(d,J＝1.6Hz),124.7,124.5,123.9,122.3,116.5(d,J＝8.6Hz),114.0(d,J＝17.1Hz),112.4(d,J＝12.2Hz),59.1,51.9,50.1,45.0,28.2(d,J＝1.6Hz)。

the synthesis of the fluoro-1-of embodiment 85-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the fluoro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (180mg; 0.48mmol); sodium cyanoborohydride (77mg; 1.22mmol) with formaldehyde (40%; 0.09mL; 1.22mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (130mg, 70.0%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:456.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.59(d,J＝8.4Hz,1H),8.16(d,J＝8.4Hz,1H),7.97(s,1H),7.54-7.43(m,2H),7.40(t,J＝7.8Hz,1H),6.86(td,J＝8.4,1.2Hz,1H),6.73(d,J＝7.8Hz,1H),4.01(t,J＝8.4Hz,2H),3.98(s,3H),3.16(brs,4H),2.76(t,J＝8.4Hz,2H),2.60(brs,4H),2.36(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)159.7(d,J＝240.9Hz),150.9,138.4(d,J＝2.1Hz),138.1,134.1(d,J＝8.4Hz),130.2,128.7,126.8,126.4(d,J＝5.6Hz),126.3,124.5,123.9,122.2,116.3(d,J＝8.6Hz),114.0(d,J＝23.4Hz),112.4(d,J＝23.8Hz),59.2,55.5,50.6,50.0,46.2,28.2(d,J＝1.5Hz)。

the synthesis of the chloro-1-of embodiment 95-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 5-chloro-indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 5-chloro-indole (2.0g, 13.2mmol) with sodium cyanoborohydride (1.66g, 26.4mmol) reaction preparation in acetic acid (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (1.65g, 81.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:154.2[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃)δ7.10-7.06(m,1H),6.98(dd,J＝8.4,2.4Hz,1H),6.55(d,J＝8.4Hz,1H),3.58(t,J＝8.4Hz,2H),3.03(t,J＝8.4Hz,2H)。

step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-((5-chloro-indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-chloro-indole quinoline (650mg; 4.23mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (1.23g; 2.82mmol) with triethylamine (1.18ml; 8.46mmol) reaction preparation in methylene dichloride (15mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (1.19g, 76.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:552.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.57(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,1.8Hz,1H),7.16(dd,J＝8.4,1.2Hz,1H),7.11(d,J＝1.2Hz,1H),7.03(d,J＝0.6Hz,1H),6.89(d,J＝8.4Hz,1H),3.95(brs,4H),3.91(s,3H),3.89(t,J＝8.4Hz,2H),3.01(t,J＝4.8Hz,4H),2.78(t,J＝8.4Hz,2H)。

step 3) synthesis of the chloro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((5-chloro-indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone (553mg, 1.0mmol), potassium hydroxide (176mg, 3.14mmol, 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)=30/1), it is white solid (376mg that concentrate drying obtains title compound, 88%).

MS(ESI,pos.ion)m/z:408.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.55(d,J＝7.2Hz,1H),7.41(d,J＝6.6Hz,1H),7.12(d,J＝6.6Hz,1H),7.08(s,1H),7.00(s,1H),6.83(d,J＝7.8Hz,1H),3.86(brs,5H),2.99(brs,4H),2.87(brs,4H),2.74(s,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.2,141.9,141.1,134.4,129.2,128.2,127.5,125.3,122.8,117.0,116.7,110.7,55.8,51.5,51.4,50.3,46.0。

the synthesis of the chloro-1-of embodiment 105 – ((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the chloro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (490mg; 1.2mmol); sodium cyanoborohydride (226mg; 3.6mmol) with formaldehyde (40%; 0.25mL; 3.6mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (220mg, 43.4%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:422.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.57(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.15-7.13(m,2H),7.01(s,1H),6.83(d,J＝8.4Hz,1H),3.88(s,3H),3.87(t,J＝8.4Hz,2H),2.96(brs,4H),2.77(t,J＝8.4Hz,2H),2.55(brs,4H),2.33(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.2,141.5,141.1,134.2,129.1,128.3,127.6,125.3,122.7,116.9,116.6,110.7,55.87,55.07,50.2,50.1,46.1,27.8。

the synthesis of the chloro-1-of embodiment 115-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 2,2,2-tri-chloro-1-(4-(4-((5-chloro-indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-chloro-indole quinoline (442mg; 2.88mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (700mg; 1.44mmol) with triethylamine (0.6ml; 4.32mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is brown solid (720mg, 82.9%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:602.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.62(d,J＝9.0Hz,1H),8.20(d,J＝8.4Hz,1H),7.95(s,1H),7.55(t,J＝7.2Hz,1H),7.51(d,J＝9.0Hz,1H),7.48(t,J＝7.2Hz,1H),6.94(dd,J＝7.2,1.2Hz,2H),4.03(s,3H),4.01(brs,4H),3.98(t,J＝8.4Hz,2H),3.23(t,J＝4.8Hz,4H),2.78(t,J＝8.4Hz,2H)。

step 2) synthesis of the chloro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(4-((5-chloro-indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (720mg, 1.2mmol), potassium hydroxide (202mg, 3.6mmol, 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)=30/1), it is white solid (349mg that concentrate drying obtains title compound, 63.5%).

MS(ESI,pos.ion)m/z:458.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.60(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,1H),7.99(s,1H),7.52-7.45(m,2H),7.46-7.41(m,1H),7.14(dd,J＝8.4,1.8Hz,1H),7.02(s,1H),4.02(s,3H),4.00(t,J＝8.4Hz,2H),3.10(brs,4H),3.09(brs,4H),2.81(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,CDCl ₃)δ151.2,141.1,138.5,133.7,130.2,128.8,128.6,127.5,126.8,126.6,126.4,125.3,124.4,124.2,122.4,116.0,59.2,51.4,50.3,46.4,27.9。

the synthesis of the chloro-1-of embodiment 125-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the chloro-1-of 5-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (300mg; 0.65mmol); sodium cyanoborohydride (124mg; 1.97mmol) with formaldehyde (40%; 0.13mL; 1.97mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (220mg, 71.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:472.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.60(d,J＝4.8Hz,1H),8.17(s,1H),7.99(s,1H),7.51-7.48(m,2H),7.42(s,1H),7.12(s,1H),7.00(s,1H),3.99(s,5H),3.18(brs,4H),2.81(brs,2H),2.62(brs,4H),2.37(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.0,141.1,138.1,133.6,130.3,128.7,128.6,127.5,126.8,126.6,126.4,125.3,124.4,124.0,122.3,115.8,59.2,55.5,50.4,49.9,46.2,27.9。

the synthesis of the bromo-1-of embodiment 135-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 5-bromo indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 5-bromo indole (2.0g, 10.2mmol) with sodium cyanoborohydride (1.28g, 20.4mmol) reaction preparation in acetic acid (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (1.6g, 79.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:198.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.22(s,1H),7.12(d,J＝8.4Hz,1H),6.52(d,J＝8.4Hz,1H),3.58(t,J＝8.4Hz,2H),3.50(brs,NH),3.04(t,J＝8.4Hz,2H)。

step 2) synthesis of 1-(4-(5-((5-bromo indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base)-2,2,2-trichlorine ethyl ketones

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-bromo indole quinoline (800mg; 4.04mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (1.17g; 2.69mmol) with triethylamine (1.13ml; 8.08mmol) reaction preparation in methylene dichloride (15mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (1.31g, 81.4%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:595.8[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.53(d,J＝8.4Hz,1H),7.50(dd,J＝8.4,2.4Hz,1H),7.31(d,J＝9.0Hz,1H),7.19(s,1H),7.08(d,J＝2.4Hz,1H),6.89(d,J＝8.4Hz,1H),4.00(brs,4H),3.91(s,3H),3.88(t,J＝8.4Hz,2H),3.00(t,J＝4.8Hz,4H),2.79(t,J＝8.4Hz,2H)。

step 3) synthesis of the bromo-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 1-(4-(5-((5-bromo indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base)-2, 2, 2-trichlorine ethyl ketone (1.3g, 2.18mmol), potassium hydroxide (366mg, 6.54mmol, 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)=30/1), it is white solid (722mg that concentrate drying obtains title compound, 73.3%).

MS(ESI,pos.ion)m/z:452.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.53(d,J＝8.4Hz,1H),7.45(dd,J＝7.6,2.4Hz,1H),7.30(dd,J＝7.6,2.4Hz,1H),7.00(s,1H),7.17(s,1H),7.10(d,J＝2.4Hz,1H),3.88(s,3H),3.88(t,J＝8.4Hz,2H),3.02(t,J＝5.2Hz,4H),2.88(t,J＝5.2Hz,4H),2.74(t,J＝8.4Hz,2H)；

¹³CNMR(100MHz,CDCl ₃):δ(ppm)156.3,142.0,141.7,134.7,130.5,128.3,128.2,122.7,117.2,117.0,116.7,110.8,58.3,55.8,51.6,50.2,46.0。

the synthesis of the bromo-1-of embodiment 145 – ((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the bromo-1-of 5-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (350mg; 0.77mmol); sodium cyanoborohydride (146mg; 2.32mmol) with formaldehyde (40%; 0.18mL; 2.32mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (201mg, 56%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:466.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.50(dd,J＝8.4,1.8Hz,1H),7.41(d,J＝8.4Hz,1H),7.26(d,J＝8.4Hz,1H),7.14(s,1H),7.09(s,1H),6.83(dd,J＝8.4,1.8Hz,1H),3.86(s,3H),3.85(t,J＝8.4Hz,2H),2.94(brs,4H),2.76(t,J＝8.4Hz,2H),2.54(brs,4H),2.31(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.2,141.6,141.5,134.6,130.4,128.1,128.0,122.7,116.9,116.8,116.6,110.7,55.8,55.0,50.1,46.0,30.9,27.7。

the synthesis of the bromo-1-of embodiment 155-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 1-(4-(4-((5-bromo indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base)-2,2,2-trichlorine ethyl ketones

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 5-bromo indole quinoline (570mg; 2.88mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (700mg; 1.44mmol) with triethylamine (0.6ml; 4.32mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is brown solid (895mg, 96.0%) that concentrate drying obtains title compound.

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.63(d,J＝8.4Hz,1H),8.23-8.16(m,1H),7.94(s,1H),7.55(td,J＝7.6,1.2Hz,1H),7.50-7.45(m,2H),7.30(dd,J＝8.6,2.0Hz,1H),7.08(dd,J＝8.2,2.0Hz,1H),4.03(s,3H),4.02(brs,4H),3.98(t,J＝8.4Hz,2H),3.23(t,J＝4.8Hz,4H),2.79(t,J＝8.4Hz,2H)。

step 2) synthesis of the bromo-1-of 5-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 1-(4-(4-((5-bromo indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base)-2, 2, 2-trichlorine ethyl ketone (895mg, 1.38mmol), potassium hydroxide (232mg, 4.14mmol, 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)=30/1), it is white solid (664mg that concentrate drying obtains title compound, 95.7%).

MS(ESI,pos.ion)m/z:502.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.60(d,J＝9.0Hz,1H),8.18(d,J＝8.4Hz,1H),7.98(s,1H),7.51(t,J＝7.8Hz,1H),7.46-7.44(m,2H),7.29(dd,J＝8.4,1.2Hz,1H),7.16(s,1H),4.01(s,3H),3.99(t,J＝8.4Hz,2H),3.11(brs,4H),3.10(brs,4H),2.81(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.3,141.6,138.5,134.1,130.4,130.2,128.5,128.2,126.8,126.7,126.4,124.4,124.1,122.4,116.4,116.2,59.2,51.3,50.3,46.4,29.7。

the synthesis of the bromo-1-of embodiment 165-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the bromo-1-of 5-((4-methoxy-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (300mg; 0.60mmol); sodium cyanoborohydride (113mg; 1.79mmol) with formaldehyde (40%; 0.12mL; 1.79mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (237mg, 76.8%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:516.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.62(d,J＝7.8Hz,1H),8.20(d,J＝8.4Hz,1H),8.02(s,1H),7.52(t,J＝7.2Hz,1H),7.46-7.44(m,2H),7.29(d,J＝8.4Hz,1H),7.18(s,1H),4.03(t,J＝8.4Hz,2H),4.01(s,3H),3.21(br.s,4H),2.86(t,J＝8.4Hz,2H),2.64(br.s,4H),2.40(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.1,141.6,138.1,133.9,130.4,130.3,128.6,128.2,126.8,126.6,126.4,124.4,124.0,122.3,116.2,116.1,59.2,55.5,50.3,50.0,46.2,27.8。

the synthesis of the fluoro-1-of embodiment 176-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 6-fluoro indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 6-fluoro indole (3.0g, 22.2mmol) with sodium cyanoborohydride (1.67g, 26.6mmol) reaction preparation in acetic acid (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (2.66g, 88.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:138.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)6.99-6.97(m,1H),6.40-6.29(m,2H),3.60(t,J＝8.4Hz,2H),3.52(brs,1H),2.98(t,J＝8.4Hz,2H)。

step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-((6-fluoro indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-fluoro indole quinoline (411mg; 3.0mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (1.96g; 4.5mmol) with triethylamine (1.1ml; 8.0mmol) reaction preparation in methylene dichloride (15mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (1.3g, 81%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:535.8[M+H] ⁺；

¹HNMR(600MHz,DMSO-d ₆):δ(ppm)7.52(dd,J＝8.6,2.2Hz,1H),7.23(dd,J＝10.2,2.3Hz,1H),7.19-7.12(m,3H),6.81(td,J＝9.1,2.4Hz,1H),3.90(t,J＝8.4Hz,2H),3.86(brs,7H),3.04(brs,4H),2.85(t,J＝8.4Hz,2H)。

step 3) synthesis of the fluoro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((6-fluoro indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone (1.3g, 2.42mmol), potassium hydroxide (366mg, 6.54mmol, 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)=30/1), it is white solid (812mg that concentrate drying obtains title compound, 85.6%).

MS(ESI,pos.ion)m/z:391.9[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.49(dd,J＝8.6,2.2Hz,1H),7.40(dd,J＝10.0,2.3Hz,1H),7.23(d,J＝2.2Hz,1H),7.00-6.96(m,1H),6.88(d,J＝8.6Hz,1H),6.66(td,J＝8.6,2.4Hz,1H),3.94-3.88(m,5H),3.07-3.01(m,4H),2.96-2.95(m,4H),2.83(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)162.6(d,J＝241.8Hz),156.3,143.7(d,J＝11.7Hz),141.9,128.3,127.2(d,J＝2.6Hz),125.5(d,J＝9.6Hz),122.8,117.0,110.8,110.2(d,J＝22.7Hz),103.3(d,J＝28.2Hz),55.8,51.4,50.8,45.9,27.2。

the synthesis of the fluoro-1-of embodiment 186 – ((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the fluoro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (392mg; 1.0mmol); sodium cyanoborohydride (189mg; 3.0mmol) with formaldehyde (40%; 0.23mL; 3.0mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (374mg, 92%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:406.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.49(dd,J＝8.5,2.1Hz,1H),7.40(dd,J＝10.0,2.2Hz,1H),7.24(d,J＝2.1Hz,1H),6.99(dd,J＝8.0,5.7Hz,1H),6.88(d,J＝8.6Hz,1H),6.66(td,J＝8.6,2.3Hz,1H),3.94-3.89(m,5H),3.05(brs,4H),2.84(t,J＝8.4Hz,2H),2.63(brs,4H),2.39(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)162.6(d,J＝241.6Hz),156.2,143.6(d,J＝11.7Hz),141.4,128.3,127.1(d,J＝2.6Hz),125.6(d,J＝9.8Hz),122.8,116.9,110.7,110.2(d,J＝22.6Hz),103.3(d,J＝28.2Hz),55.8,54.9,50.7,49.9,45.9,27.2。

the synthesis of the fluoro-1-of embodiment 196-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 2,2,2-tri-chloro-1-(4-(4-((6-fluoro indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-fluoro indole quinoline (177mg; 1.29mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (627mg; 1.29mmol) with triethylamine (0.85ml; 6.45mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is brown solid (331mg, 43.7%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:586.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.65(d,J＝8.4Hz,1H),8.20(d,J＝8.8Hz,1H),8.02(s,1H),7.58-7.47(m,2H),7.30(dd,J＝10.0,2.4Hz,1H),7.00(dd,J＝8.2,5.6Hz,1H),6.67(td,J＝8.6,2.4Hz,1H),4.16-3.92(m,9H),3.31-3.22(m,4H),2.84(t,J＝8.4Hz,2H)。

step 2) synthesis of the fluoro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(4-((6-fluoro indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (326mg, 0.56mmol), potassium hydroxide (93mg, 1.67mmol, 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)=30/1), it is white solid (207mg that concentrate drying obtains title compound, 83.6%).

MS(ESI,pos.ion)m/z:442.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.63(dd,J＝18.4,8.6Hz,1H),8.20-8.15(m,1H),8.05-8.00(m,1H),7.54-7.51(m,2H),7.35-7.28(m,1H),7.00(dd,J＝13.7,7.9Hz,1H),6.70-6.63(m,1H),4.17-3.95(m,7H),3.60-3.44(m,4H),2.87(t,J＝8.3Hz,2H),2.11-2.02(m,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)162.5(d,J＝241.5Hz),151.4,143.6(d,J＝9.0Hz),138.0,129.5(d,J＝213.0Hz),127.0,126.9,126.7(d,J＝3.0Hz),126.7,125.6(d,J＝10.5Hz),124.2(d,J＝70.5Hz),122.4,109.9(d,J＝22.5Hz),103.1(d,J＝28.5Hz),59.5,52.0,50.2,45.6,27.3。

the synthesis of the fluoro-1-of embodiment 206-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the fluoro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (276mg; 0.63mmol); sodium cyanoborohydride (118mg; 1.88mmol) with formaldehyde (40%; 0.14mL; 1.88mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (268mg, 94.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:456.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.61(d,J＝8.6Hz,1H),8.18(d,J＝8.4Hz,1H),8.02(s,1H),7.53-7.42(m,2H),7.29(m,2.2Hz,1H),6.99-6.93(m,1H),6.63(td,J＝8.6,2.3Hz,1H),4.04(t,J＝8.5Hz,2H),3.98(s,3H),3.23(brs,4H),2.86(t,J＝8.4Hz,2H),2.66(brs,4H),2.38(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)162.5(d,J＝241.5Hz),151.02,143.6(d,J＝12.0Hz),138.0,129.5(d,J＝240.0Hz),126.9,126.7,126.6,126.6,126.4,125.6(d,J＝105.0Hz),124.4,123.9,122.3,109.8(d,J＝22.5Hz),103.0(d,J＝28.5Hz),59.2,55.4,510,49.7,46.0,27.3。

the synthesis of the chloro-1-of embodiment 216-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 6-chloro-indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 6-chloro-indole (3.34g, 22.0mmol) with sodium cyanoborohydride (1.66g, 26.4mmol) reaction preparation in acetic acid (20mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (2.53g, 74.9%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:154.2[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)6.99(d,J＝7.7Hz,1H),6.65(d,J＝7.8Hz,1H),6.59(s,1H),3.58(t,J＝8.5Hz,2H),3.49(brs,1H),2.98(t,J＝8.4Hz,2H)。

step 2) synthesis of 2,2,2-tri-chloro-1-(4-(5-((6-chloro-indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-chloro-indole quinoline (262mg; 1.7mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (0.5g; 1.15mmol) with triethylamine (0.48ml; 3.44mmol) reaction preparation in methylene dichloride (15mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (605mg, 95.2%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:552.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.65(s,1H),7.54-7.52(m,1H),7.21(d,J＝1.5Hz,1H),6.97-6.89(m,3H),3.96-3.81(m,9H),3.05-3.03(m,4H),2.81(t,J＝8.4Hz,2H)。

step 3) synthesis of the chloro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(5-((6-chloro-indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base) ethyl ketone (600mg, 1.09mmol), potassium hydroxide (168mg, 3.0mmol, 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)=30/1), it is white solid (311mg that concentrate drying obtains title compound, 70.1%).

MS(ESI,pos.ion)m/z:408.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.66(s,1H),7.45(dd,J＝8.5,2.2Hz,1H),7.21(d,J＝2.2Hz,1H),6.95-6.84(m,2H),6.85(d,J＝8.6Hz,1H),3.88-3.84(m,5H),3.04-3.01(m,4H),2.95-2.92(m,4H),2.80(t,J＝8.4Hz,2H)；

¹³CNMR(100MHz,CDCl ₃):δ(ppm)156.5,143.7,142.2,133.5,130.6,128.3,125.9,123.8,122.8,117.3,115.7,110.9,55.8,51.6,50.4,46.2,27.6。

the synthesis of the chloro-1-of embodiment 226 – ((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the chloro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (268mg; 0.66mmol); sodium cyanoborohydride (123mg; 1.97mmol) with formaldehyde (40%; 0.15mL; 1.97mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (242mg, 87.1%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:422.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.66(s,1H),7.45(d,J＝1.8Hz,1H),7.22(s,1H),6.94(d,J＝7.8Hz,1H),6.90(d,J＝7.8Hz,1H),6.85(d,J＝8.4Hz,1H),3.88-3.85(m,5H),3.00(brs,4H),2.81(t,J＝8.4Hz,2H),2.55(brs,4H),2.33(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.2,143.5,141.5,133.3,130.4,128.0,125.8,123.6,122.7,116.9,115.5,110.7,55.8,55.0,50.4,50.1,46.0,27.4。

the synthesis of the chloro-1-of embodiment 236-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 2,2,2-tri-chloro-1-(4-(4-((6-chloro-indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-chloro-indole quinoline (198mg; 1.29mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (627mg; 1.29mmol) with triethylamine (0.85ml; 6.45mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is yellow solid (622mg, 79.9%) that concentrate drying obtains title compound.

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.72(d,J＝8.5Hz,1H),8.20(d,J＝8.1Hz,1H),8.05(s,1H),7.58-7.51(m,3H),6.96(d,J＝8.0Hz,1H),6.92(dd,J＝7.9,1.6Hz,1H),4.14-3.96(m,9H),3.30-3.24(m,4H),2.84(t,J＝8.4Hz,2H)。

step 2) synthesis of the chloro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 2, 2, the chloro-1-of 2-tri-(4-(4-((6-chloro-indole quinoline-1-base) alkylsulfonyl)-1-methoxynaphthalene-2-base) piperazine-1-base) ethyl ketone (615mg, 1.02mmol), potassium hydroxide (172mg, 3.06mmol, 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)=30/1), it is white solid (334mg that concentrate drying obtains title compound, 71.6%).

MS(ESI,pos.ion)m/z:457.9[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.66(d,J＝8.6Hz,1H),8.18(d,J＝8.3Hz,1H),8.05(s,1H),7.51-7.45(m,3H),6.97-6.88(m,2H),4.08-3.95(m,5H),3.30-3.29(m,4H),3.25-3.24(m,4H),2.85(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,CDCl ₃)δ151.5,143.4,138.0,133.2,130.2,130.1,128.5,127.0,126.9,126.7,125.8,124.5,124.3,123.4,122.4,115.1,59.5,50.7,50.1,45.5,27.5。

the synthesis of the chloro-1-of embodiment 246-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the chloro-1-of 6-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (320mg; 0.7mmol); sodium cyanoborohydride (132mg; 2.1mmol) with formaldehyde (40%; 0.16mL; 2.1mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (305mg, 92.5%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:472.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.67(d,J＝8.6Hz,1H),8.20(d,J＝8.3Hz,1H),8.06(s,1H),7.58(d,J＝1.5Hz,1H),7.56-7.52(m,1H),7.50(dd,J＝11.3,4.0Hz,1H),6.99(d,J＝7.9Hz,1H),6.94(dd,J＝7.9,1.7Hz,1H),4.04(t,J＝8.5Hz,2H),3.98(s,3H),3.30(brs,4H),2.87(t,J＝8.4Hz,2H),2.73(brs,4H),2.46(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.1,143.4,137.8,133.3,130.3,130.0,128.5,126.9,126.7,126.5,125.8,124.5,124.2,123.4,122.3,115.1,59.3,55.3,50.7,49.5,29.7,27.5。

the synthesis of the bromo-1-of embodiment 256-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

step 1) synthesis of 6-bromo indole quinoline

This step title compound prepares with reference to the method described by embodiment 1 step 3, by 6-bromo indole (1.0g, 5.1mmol) with sodium cyanoborohydride (0.38g, 6.12mmol) reaction preparation in acetic acid (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), it is brown solid (914mg, 90.9%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:198.0[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)6.94(d,J＝7.7Hz,1H),6.79(dd,J＝7.7,1.7Hz,1H),6.74(d,J＝1.6Hz,1H),3.57(t,J＝8.4Hz,2H),2.96(t,J＝8.3Hz,2H)。

step 2) synthesis of 1-(4-(5-((6-bromo indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base)-2,2,2-trichlorine ethyl ketones

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-bromo indole quinoline (432mg; 2.18mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) benzene-1-SULPHURYL CHLORIDE (0.5g; 1.15mmol) with triethylamine (0.48ml; 3.44mmol) reaction preparation in methylene dichloride (15mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is white solid (514mg, 75%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:595.9[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.85(s,1H),7.55(dd,J＝8.5,1.8Hz,1H),7.22(d,J＝1.7Hz,1H),7.12-7.09(m,1H),6.93(d,J＝8.4Hz,2H),3.94(br,7H),3.87(t,J＝8.4Hz,2H),3.08-3.03(m,4H),2.83(t,J＝8.4Hz,2H)。

step 3) synthesis of the bromo-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 1-(4-(5-((6-bromo indole quinoline-1-base) alkylsulfonyl)-2-p-methoxy-phenyl) piperazine-1-base)-2, 2, 2-trichlorine ethyl ketone (500mg, 0.84mmol), potassium hydroxide (141mg, 2.52mmol, 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)=30/1), it is white solid (266mg that concentrate drying obtains title compound, 70.2%).

MS(ESI,pos.ion)m/z:452.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.83(s,1H),7.46(d,J＝8.5Hz,1H),7.23(s,1H),7.06(d,J＝7.9Hz,1H),6.89(d,J＝7.9Hz,1H),6.86(d,J＝8.5Hz,1H),3.88(s,3H),3.85(t,J＝8.4Hz,2H),3.02-3.00(m,4H),2.92(brs,4H),2.79(t,J＝8.4Hz,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.5,143.9,142.1,131.1,128.1,126.8,126.4,122.8,121.1,118.5,117.3,110.8,55.8,51.7,50.5,46.0,27.6。

the synthesis of the bromo-1-of embodiment 266 – ((4-methoxyl group-3-(4-methylpiperazine-1-yl) phenyl) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the bromo-1-of 6-((4-methoxyl group-3-(piperazine-1-base) phenyl) alkylsulfonyl) indoline (200mg; 0.44mmol); sodium cyanoborohydride (83mg; 1.33mmol) with formaldehyde (40%; 0.10mL; 1.33mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (180mg, 87.7%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:466.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.85(s,1H),7.48(dd,J＝8.5,1.9Hz,1H),7.25(d,J＝2.0Hz,1H),7.08(dd,J＝7.9,1.0Hz,1H),6.92(d,J＝7.9Hz,1H),6.88(d,J＝8.6Hz,1H),3.91(s,3H),3.88(t,J＝8.5Hz,2H),3.03(brs,4H),2.82(t,J＝8.4Hz,2H),2.59(brs,4H),2.36(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)156.2,143.7,141.5,130.9,127.9,126.6,126.2,122.6,121.0,118.3,117.0,110.7,55.8,55.0,50.3,50.1,46.1,27.5。

the synthesis of the bromo-1-of embodiment 276-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

step 1) synthesis of 1-(4-(1-methoxyl group-4-((6-bromo indole quinoline-1-base) alkylsulfonyl) naphthalene-2-base) piperazine-1-base)-2,2,2-trichlorine ethyl ketones

This step title compound prepares with reference to the method described by embodiment 1 step 4; by 6-bromo indole quinoline (255mg; 1.29mmol), 4-methoxyl group-3-(4-(2; 2; 2-tribromo-acetyl base) piperazine-1-base) naphthalene-1-SULPHURYL CHLORIDE (627mg; 1.29mmol) with triethylamine (0.85ml; 6.45mmol) reaction preparation in methylene dichloride (20mL); crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1); it is yellow solid (506mg, 60.6%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:645.6[M+H] ⁺；

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.77-8.72(m,1H),8.22-8.18(m,1H),8.08(s,1H),7.69(d,J＝1.6Hz,1H),7.59-7.50(m,2H),7.07(dd,J＝7.9,1.7Hz,1H),6.91(d,J＝7.9Hz,1H),4.15-3.96(m,9H),3.34-3.25(m,4H),2.83(t,J＝8.3Hz,2H)。

step 2) synthesis of the bromo-1-of 6-((4-methoxyl group-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 1 step 5, by 1-(4-(1-methoxyl group-4-((6-bromo indole quinoline-1-base) alkylsulfonyl) naphthalene-2-base) piperazine-1-base)-2, 2, 2-trichlorine ethyl ketone (504mg, 0.78mmol), potassium hydroxide (131mg, 2.33mmol, 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)=30/1), it is faint yellow solid (309mg that concentrate drying obtains title compound, 79.1%).

MS(ESI,pos.ion)m/z:502.1[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.68(d,J＝8.5Hz,1H),8.18(d,J＝8.4Hz,1H),8.06(s,1H),7.71(s,1H),7.57-7.50(m,2H),7.06(dd,J＝7.9,1.4Hz,1H),6.90(d,J＝7.9Hz,1H),4.07-3.95(m,5H),3.30-3.19(m,8H),2.85-2.81(m,2H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.5,143.5,138.0,130.6,130.2,128.4,126.9,126.9,126.7,126.3,126.2,124.5,124.4,122.4,120.9,117.8,59.5,50.6,50.2,45.5,27.6。

the synthesis of the bromo-1-of embodiment 286-((4-methoxyl group-3-(4-methylpiperazine-1-yl) naphthalene-1-base) alkylsulfonyl) indoline

This step title compound prepares with reference to the method described by embodiment 2; by the bromo-1-of 6-((4-methoxy-3-(piperazine-1-base) naphthalene-1-base) alkylsulfonyl) indoline (200mg; 0.4mmol); sodium cyanoborohydride (76mg; 1.2mmol) with formaldehyde (40%; 0.09mL; 1.2mmol) reaction preparation in methyl alcohol (10mL); crude on silica gel column chromatography (methylene chloride/methanol (v/v)=50/1); it is white solid (175mg, 84.6%) that concentrate drying obtains title compound.

MS(ESI,pos.ion)m/z:516.0[M+H] ⁺；

¹HNMR(600MHz,CDCl ₃):δ(ppm)8.65(d,J＝8.6Hz,1H),8.18(d,J＝8.2Hz,1H),8.04(s,1H),7.70(d,J＝1.4Hz,1H),7.54-7.44(m,2H),7.06(dd,J＝7.9,1.6Hz,1H),6.91(d,J＝7.9Hz,1H),4.04(t,J＝8.5Hz,2H),3.98(s,3H),3.29(br.s,4H),2.84(t,J＝8.4Hz,2H),2.72(br.s,4H),2.45(s,3H)；

¹³CNMR(150MHz,CDCl ₃):δ(ppm)151.1,143.6,137.9,130.6,130.3,128.4,126.9,126.7,126.5,126.3,126.2,124.5,124.3,122.3,121.0,117.8,59.3,55.3,50.6,49.5,45.9,27.6。

Biological test

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

1. by the avidity of radio ligand binding assay assessing compound to the people source 5-HT6 acceptor of expressing on Chinese hamster ovary celI

The expression that 32 μ g prepare there is people source 5-HT ₆the Chinese hamster ovary celI membranin of acceptor, compound and the assay buffer of 2nM radioactively labelled substance [3H] LSD, different test concentrations mix, and hatch 120min for 37 DEG C; Assay buffer composition is: 50mMTris-HCl (pH7.4), 10mMMgCl ₂, 0.5mMEDTA, 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 50mMTris-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 1, the avidity measurement result that table 1 provides for the embodiment of the present invention.

The avidity measurement result of the compound that table 1 embodiment of the present invention provides

Embodiment number	Ki(nM)	Embodiment number	Ki(nM)	Embodiment number	Ki(nM)
						Embodiment 5	57	Embodiment 9	11	Embodiment 13	17
Embodiment 21	5.2	Embodiment 25	3.3

As shown in Table 1, 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

1. a compound, it is the steric isomer of structure shown in the structure shown in formula I or formula I, tautomer, oxynitride, solvate, meta-bolites, pharmacy acceptable salt or prodrug,

Wherein:

N is 1,2,3 or 4;

Q is CH or N;

M is NR ¹or O;

Each R ²be H, D, F, Cl, Br, I, CN, NO independently ₂, OH, NH ₂, R ^ar ^bn-,-C (=O) C _1-6alkyl ,-C (=O) NR ^ar ^b,-OC (=O) NR ^ar ^b,-OC (=O) OR ^a,-N (R ^a) C (=O) NR ^ar ^b,-N (R ^a) C (=O) OR ^a,-N (R ^a) C (=O)-R ^b, R ^ar ^bn-S (=O) ₂-, R ^as (=O) ₂-, R ^as (=O) ₂n (R ^bthe C that)-, hydroxyl replaces _1-6alkyl, the C of carboxyl substituted _1-6alkyl, C _1-6alkyl-OC (=O) C _1-6alkyl-, R ^as (=O)-C _1-6alkyl-, R ^ar ^bn-C (=O)-C _1-6alkyl-, R ^ar ^bn-C _1-6alkoxyl group-, R ^as (=O)-C _1-6alkoxyl group-, R ^ar ^bn-C (=O)-C _1-6alkoxyl group, 5-12 former molecular heteroaryl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group, C _1-6alkyl, C _6-10aryl C _1-6alkyl, or adjacent two R ²and form substituted or unsubstituted 5-7 former molecular carbocylic radical, heterocyclic radical, aromatic base or heteroaryl groups together with the ring carbon atom to be connected respectively with them;

Each R ^aand R ^bbe separately H, D, C _1-6alkyl, halo C _1-6alkyl, C _1-6alkoxyl group, C _6-10aryl, 3-12 former molecular heterocyclic radical, C _3-8cycloalkyl, C _6-10aryl C _1-6alkyl, 5-12 former molecular heteroaryl or C _3-8carbocylic radical, or R ^a, R ^bsubstituted or unsubstituted 3-8 former molecular heterocyclic radical or heteroaryl groups is formed together with the nitrogen-atoms be attached thereto.

2. compound according to claim 1, wherein, R ¹for H, D, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl or cyclopentyl.

3. compound according to claim 1, wherein, each R ²be H, D, F, Cl, Br, I, CN, OH, NH independently ₂, R ^ar ^bn-,-C (=O) C _1-4alkyl ,-C (=O) NR ^ar ^b, 5-12 former molecular heteroaryl, C _1-4alkoxyl group, halo C _1-4alkyl, halo C _1-4alkoxyl group, C _1-4alkyl, C _6-10aryl C _1-4alkyl, or adjacent two R ²and form substituted or unsubstituted 5-7 former molecular carbocylic radical or fragrant cyclic groups together with the ring carbon atom to be connected respectively with them.

4. compound according to claim 3, wherein, each R ²be H, D, F, Cl, Br independently, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base ,-CHF ₂,-CF ₃or-CH ₂cF ₃, or adjacent two R ²and form substituted or unsubstituted phenyl together with the ring carbon atom to be connected respectively with them.

5. compound according to claim 1, wherein, R ³, R ⁴, R ⁵and R ⁶be H, D, Cl, Br, I, CN, OH, NH independently of one another ₂, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl;

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

7. pharmaceutical composition comprises the 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, wherein further comprises additional treatment agent, and described additional treatment agent is the medicine being used for the treatment of A Cihaimo disease, for medicine or their combination of nervous disorders;

Wherein said additional treatment agent is: E2020 (donepezil), Nalmefene (nalmefene), risperidone (risperidone), vitamin E (VitaminE), SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, Lu-AE58054, 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.

9. compound described in claim 1-6 any one or the pharmaceutical composition described in claim 7-8 any one are preparing the purposes in medicine, and described medicine is used for the treatment of or prevents and 5-HT ₆relevant disease;

10. purposes according to claim 9, 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 or Huntington Chorea.