CN1701072A

CN1701072A - Heterocyclic substituted piperazines for the treatment of schizophrenia

Info

Publication number: CN1701072A
Application number: CN 03825236
Authority: CN
Inventors: 汤加·L·安德雷纳; 斯蒂芬·S·Y·乔; 詹姆斯·M·格雷厄姆; 特蕾西·F·格雷戈里; 小哈里·R·霍华德; 布赖恩·E·科恩伯格; 沙姆·S·尼卡姆; 德里克·A·弗卢姆
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2002-09-17
Filing date: 2003-09-05
Publication date: 2005-11-23
Also published as: ZA200502216B; TNSN05074A1; CR7735A

Abstract

This invention relates to compounds of the formula 1 wherein X, Y, Z, A, Rl, R2, R3, R4, R9, W1and W2are defined as in the specification, pharmaceutical compositions containing them and their use in the treatment of central nervous system and other disorders.

Description

The piperazine that is used for the treatment of schizoid heterocyclic substituted

Background of invention

The present invention relates to heterocyclic substituted piperazine, contain they pharmaceutical composition and they be used for the treatment of the purposes of schizophrenia and other central nervous system (CNS) disease.

The bridged piperazine derivatives of heterocyclic substituted of the present invention shows the activity as d2 dopamine receptor and thrombotonin 2A (5HT2A) receptor antagonist.

Be used for the treatment of schizoid other heterocycle bridged piperazine derivatives and in the US6127357 of the US5350747 of on September 27th, 1994 promulgation and promulgation on October 3rd, 2000, mention that these full patent texts are classified this paper reference as.

Illustrated that as other piperazine of Antipsychotic drug and piperidine derivative be those that mention among the disclosed EP4O2644A on March 18th, 1993 disclosed PCT patent disclosure WO 93/04684 and December 19 nineteen ninety, this paper reference is classified in these patent applications in full as.

Summary of the invention

The present invention relates to formula 1 compound:

Wherein X is S, O, SO, SO ₂, CH ₂Or NR ¹⁰

Y is N or CH;

Z is N or CH;

A is-(CH ₂) _mCH ₂-,-(CH ₂) _mO-,-(CH ₂) _mNR ¹¹-or-(CH ₂) _mC (R ¹²R ¹³)-, be R wherein ¹²And R ¹³Be selected from respectively by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkyl, by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkoxyl group, hydroxyl and aminoalkyl group;

Or R ¹²And R ¹³Form carbonyl with the carbon that links to each other with them;

M is the integer of 1-4;

R ⁴And R ⁹Be selected from respectively by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkyl, by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkoxyl group, halogen, nitro, cyano group, amino, (C ₁-C ₄) alkylamino and two (C ₁-C ₄) alkylamino;

Or when X be NR ¹⁰The time, R ⁴And R ⁹One of can be with carbon that links to each other with it and and R ¹⁰Form heterocycle with the N that links to each other with it, this heterocycle contains 4-7 ring element, and wherein 1-3 ring element is the heteroatoms that is selected from N, O and S, and all the other ring elements are carbon, and its prerequisite is to work as R ¹¹With R ⁴And R ⁹One of when forming ring, R ⁴And R ⁹In another does not exist;

R ¹⁰And R ¹¹Be selected from H respectively, chosen wantonly (the C that replaces by 1-3 fluorine atom ₁-C ₄) alkyl and by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkoxyl group;

R ¹Be H, by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkyl, aryl ,-C (O) R ¹⁴, R wherein ¹⁴Be aryl, (C ₁-C ₄) alkyl, aryl-(C ₁-C ₄) alkyl-or heteroaryl-(C ₁-C ₄) alkyl-, aryl-(C wherein ₁-C ₄) alkyl-or heteroaryl-(C ₁-C ₄) alkyl-moieties can be replaced by 1-3 fluorine atom is optional, wherein the aryl of these groups and heteroaryl moieties can be by one or more substituting groups, preferred 0-2 substituting group is optional to be replaced, and this substituting group is selected from halogen, nitro, amino, cyano group respectively, is chosen wantonly (the C of replacement by 1-3 fluorine atom ₁-C ₆) alkyl and by the optional (C that replaces of 1-3 fluorine atom ₁-C ₆) alkoxyl group;

R ²And R ³Be selected from H, halogen, (C respectively ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryl, aryl-(C ₁-C ₄) alkyl-, heteroaryl and heteroaryl-(C ₁-C ₄) alkyl-, (C wherein ₁-C ₄) alkyl and (C ₁-C ₄) moieties of alkoxyl group can replace by 1-3 fluorine atom is optional, also can be independently by amino or hydroxyl substituent is optional replaces, aryl-(C wherein ₁-C ₄) alkyl-and heteroaryl-(C ₁-C ₄) alkyl-moieties can be replaced by 1-3 fluorine atom is optional, wherein the aryl of these groups and heteroaryl moieties can be by one or more substituting groups, preferred 0-2 substituting group is optional to be replaced, and this substituting group is selected from halogen, nitro, amino, cyano group respectively, is chosen wantonly (the C of replacement by 1-3 fluorine atom ₁-C ₆) alkyl and by the optional (C that replaces of 1-3 fluorine atom ₁-C ₆) alkoxyl group;

Or R ²And R ³One of can be with carbon that links to each other with it and and W ¹Quinolinone ring carbon form saturated or unsaturated heterocycle together, this heterocycle contains 4-7 ring element, wherein 1-3 ring element is the heteroatoms that is selected from N, O and S, all the other ring elements are carbon, its prerequisite is to work as W ¹With R ²And R ³One of when forming ring, R ²And R ³In another does not exist;

W ¹Be CR ⁵R ⁶And W ²Be CR ⁷R ⁸, by W ¹-W ²Dotted line represent that two keys of choosing wantonly, its prerequisite are when at W ¹And W ²Between when having two key, R ⁵And R ⁷Do not exist;

R ⁵, R ⁶, R ⁷And R ⁸Be selected from H, halogen, nitro, cyano group, amino, (C respectively ₁-C ₄) alkylamino, two (C ₁-C ₄) alkylamino, by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkyl and by the optional (C that replaces of 1-3 fluorine atom ₁-C ₄) alkoxyl group;

Or be connected in the R of carbon atom ⁵, R ⁶, R ⁷And R ⁸Any two carbon that link to each other with their form (C ₃-C ₇) saturated or unsaturated carbocyclic or (C ₅-C ₇) saturated or unsaturated heterocycle, one of them or two ring elements are selected from N, O and S, and its prerequisite is W ¹Quinolinone carbon not with R ⁵, R ⁶, R ⁷And R ⁸In two form ring, and and R ²Or R ³Form ring;

With the pharmaceutically useful salt of this compound.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein A is-(CH ₂) _mO-.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein A is-(CH ₂) _mNR ¹¹-.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein A is-(CH ₂) _mC (R ¹²R ¹³)-.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein A is-(CH ₂) _mCH ₂-.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein X is S.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein X is SO or SO ₂

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein X is CH ₂Or NR ¹⁰

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein X is O.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein Z is N.

Another more particular embodiment of the present invention relates to compound and its pharmaceutically useful salt of formula 1, and wherein Y is N.

The example of preferential embodiment of the present invention is following compound and their pharmaceutically useful salt:

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4S-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4R-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,3,3,4,4-pentamethyl--3,4-dihydro-1H-quinoline-2-one-;

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-;

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-4-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,3,3,4,4-pentamethyl--3,4-dihydro-1H-quinoline-2-one-;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-, mesylate;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-chloro-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-mesylate;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-hydrochloride;

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-;

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

7-chloro-6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

7-chloro-6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-;

6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-; With

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-3-methyl-3,4-dihydro-1H-quinoline-2-one-.

The compound of listing above is referred to as " A organizes compound " hereinafter.

Be used for the term " alkyl " of this paper, except as otherwise noted, comprise saturated univalence hydrocarbyl, comprise straight chain, side chain and cyclic group or its combination.The example of " alkyl " comprises, but be not limited to, methyl, ethyl, propyl group, sec.-propyl, butyl, different-, secondary-and tertiary butyl, amyl group, hexyl, heptyl, 3-ethyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, norcamphyl etc.

The term " aryl " that is used for this paper, except as otherwise noted, expression does not have the aromatic ring (for example phenyl or naphthyl) of ring hetero atom.

The term " alkoxyl group " that is used for this paper, except as otherwise noted, expression " alkyl-O-", wherein " alkyl " is as defined above.The example of " alkoxyl group " includes, but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy and pentyloxy.

The term " thiazolinyl " that is used for this paper except as otherwise noted, comprises the unsaturated alkyl with one or more pairs of keys that connect two carbon atoms, and wherein said alkyl can be straight or branched or cyclic group or its combination.The example of " thiazolinyl " includes, but not limited to vinyl, propenyl, butenyl, pentenyl.

The term " heteroaryl " that is used for this paper, except as otherwise noted, comprise that containing 1-4 is selected from the heteroatomic of N, S and O respectively and contains the monocycle aromatic heterocycle of 5 or 6 ring elements and contain 1-4 the heteroatomic 8-12 of containing ring element Bicyclic heterocycle that is selected from N, S and O respectively.

The term " one or more substituting group " that is used for this paper is meant and equals 1 to based on the substituent quantity of the possible maximum quantity of possible bonding position quantity.

Be used for term " halo " and " halogen " of this paper, except as otherwise noted, comprise fluorine, chlorine, bromine and iodine.

The term " treatment (treating) " that is used for this paper is meant reverse, slow down, suppress the process of disease that this term is suitable for or illness or prevent described disease or illness, or prevents one or more syndromess of this described illness or disease.

The term " treatment (treatment) " that is used for this paper is meant as above the therapeutic action of " treatment " definition.

The pharmaceutically useful salt of formula 1 compound and A group compound and these compounds is generically and collectively referred to as " new compound of the present invention " and " active compound of the present invention ".

The invention still further relates to pharmaceutical composition, it contains formula 1 compound or A group compound or its pharmaceutically useful salt and the pharmaceutically useful carrier for the treatment of significant quantity.

Formula 1 compound and A group compound can contain chiral centre, thereby can have different enantiomorphs and diastereomer form.The present invention relates to formula 1 compound and A the group compound optically active isomer and all steric isomers, comprise racemic mixture and one enantiomorph and the diastereomer and their mixture of this compound and contain and use their all pharmaceutical compositions and methods of treatment defined above respectively.One isomer can obtain in the preparation of final product or its intermediate by currently known methods, and for example optical resolution, fractional crystallization, optically-active selective reaction or chromatography are separated.Formula 1 compound is compared in treatment various diseases or illness with the single enantiomorph of A group compound with these compound racemic mixtures be favourable.

When formula 1 compound and A group compound was basic cpd, they all can form various salt with various inorganic and organic acids.Although be to animals administer, these salt must be pharmaceutically useful, but in practice usually need be by separating basic cpd with pharmaceutically useful salt in the reaction mixture, be converted into free alkali compound simply by handling subsequently, subsequently free alkali be converted into pharmaceutically useful acid salt with alkaline reagents.Inorganic or the organic acid that the acid salt of basic cpd of the present invention can easily pass through to use normal selection is basically for example handled the basic cpd preparation at water-containing solvent or suitable organic solvent in methyl alcohol or the ethanol.After careful evaporating solvent, easily obtain required solid salt.The acid that is used to prepare the pharmaceutically useful acid salt of above-mentioned basic cpd of the present invention is the acid that forms the non-toxic acid additive salt, described salt promptly contains pharmaceutically useful anionic salt, hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion or acid Citrate trianion, tartrate or acid tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)).

The present invention also comprises isotope-labeled compound, and they are identical with A group compound with formula 1 compound, but in fact one or more atom is had atomic mass or the atomic mass of total mass number or the atom replacement of total mass number that is different from common natural discovery.The isotopic example that can add The compounds of this invention comprises and the isotropic substance of H, C, N, O, P, S, F and Cl for example is respectively ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.Contain other isotopic The compounds of this invention, its prodrug and the described compound of above-mentioned isotropic substance and/or other atom or described prodrug or pharmaceutically useful salt within the scope of the invention.Some isotope-labeled compound of the present invention for example adds radio isotope, for example ³H and ¹⁴The compound of C be used for medicine and/matrix organization's distribution test.Because prepare easily and detectability, tritiate, promptly ³H and carbon-14, promptly ¹⁴The C isotropic substance is especially preferred.In addition, use higher isotope, deuterium for example, promptly ²H substitutes, because bigger metabolic stability produces some treatment advantage, for example therefore the dosage demand of transformation period or reduction in the body of Zeng Jiaing is preferred in some cases.The isotope-labeled compound of formula 1 compound, A group compound and its prodrug can be usually by being implemented in disclosed method among following diagram and/or the embodiment, by substitute the preparation of heterotope labelled reagent with the isotope-labeled reagent that obtains easily.

Formula 1 compound and A group compound have useful pharmacy and medical property.

The invention still further relates to treatment Mammals, the method that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because multiple etiology, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, this method comprise to formula 1 compound of the described disease of Mammals drug treatment of this treatment of needs or illness significant quantity or A group compound or its pharmaceutically useful salt.

Formula 1 compound and A group compound and their pharmaceutically useful salt also are generically and collectively referred to as " new compound of the present invention " and " active compound of the present invention " at this paper.

The invention still further relates to the Mammals that is used for the treatment of in the needs treatment, the pharmaceutical composition that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, said composition contain formula 1 compound or A group compound or its pharmaceutically useful salt and the pharmaceutically useful carrier of this disease of treatment or illness significant quantity.

More particular embodiment of the present invention relates to aforesaid method, and wherein disease of being treated or illness are selected from dysthymia disorders, post-natal depression, depression, cyclothymia and the bipolar disease that major depression, single outbreak dysthymia disorders, recurrent major depression, child abuse cause.

Another more particular embodiment of the present invention relates to aforesaid method, wherein disease of being treated or illness be selected from mental disorder, of short duration mental disorder that schizophrenia, Schizoaffective disease, vain hope disease, material cause, share mental disorder, because mental disorder and the schizophreniform diseases that the general medical science symptom causes.

Another more particular embodiment of the present invention relates to aforesaid method, and wherein disease of being treated or illness are selected from lonely disease, spread sexual development disease and scatterbrained hyperactivity disorder.

Another more particular embodiment of the present invention relates to aforesaid method, wherein disease of being treated or illness are selected from nervous disease and phobia after general anxiety disease, alarmed disease, obsessive-compulsive disorder, the wound, comprise social phobia, agoraphobe and special phobia.

Another more particular embodiment of the present invention relates to aforesaid method, wherein disease of being treated or illness are selected from movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, with the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, for example Parkinson's disease that cause of tranquilizer, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled.

Another more particular embodiment of the present invention relates to aforesaid method, wherein disease of being treated or illness are selected from delirium, dementia and forget and other cognition or neurodegenerative disease, for example Parkinson's disease (PD), Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, memory disease, vascular is dull-witted and other is dull-witted, for example because HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes.

Another more particular embodiment of the present invention relates to aforesaid method, wherein formula 1 compound is administered for any two or more of treatment to human body and is selected from those diseases that relate to and the comorbid disease or the illness of symptom in any aforesaid method.

For treat depression, anxiety, schizophrenia or any other disease or illness of mentioning in aforesaid method of the present invention and pharmaceutical composition, new compound of the present invention can be used in combination with one or more other thymoleptic or anxiolytic.The kind example of the thymoleptic that can be used in combination with active compound of the present invention comprises NRI, selective serotonin reuptake inhibitor (SSRI), the nk 1 receptor antagonist, oxidase inhibitor (MAOI), the reversible inhibitor of monoamine oxidase (RIMS), thrombotonin and NRI (SNRI), corticotropin releasing factor(CRF) (CRF) antagonist, alpha-2-adrenoceptor antagonists and atypia thymoleptic.Suitable NRI comprises tertiary amine three ring and secondary amine three rings, and suitable tertiary amine three rings and secondary amine three rings comprise that amitriptyline, chlorimipramine, P-3693A, imipramine, trimeproprimine, dosulepin, BUT, iprindole, Lofepramine, nortriptyline, protriptyline, amoxapine, desmethylimipramine and Ma Pu are for mark.Suitable selective serotonin reuptake inhibitor comprises fluoxetine, fluvoxamine, Paroxetine and Sertraline.The example of oxidase inhibitor comprises U-10387, Phenelzine and Tranylcypromine.The reversible inhibitor of suitable monoamine oxidase comprises Moclobemide.Be used for suitable thrombotonin of the present invention and NRI and comprise venlafaxine.Appropriate C RF antagonist is included in those compounds of describing among WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and the WO 94/13677.Suitable atypia thymoleptic comprise Wellbutrin, lithium, Nefazadone, Trazodone and Viloxazine.Suitable nk 1 receptor antagonist is included in those that mention among the WO 01/77100.

The anxiolytic of the suitable species that can be used in combination with active compound of the present invention comprises benzodiazepines and thrombotonin 1A (5-HT _1A) agonist or antagonist, especially 5-HT _1APartial agonist and corticotropin releasing factor(CRF) (CRF) antagonist.Suitable benzodiazepines comprise alprazolam, chlorine diaza heptan because of, rancedon, chlorine azepine heptan because of acid, stable, halazepam, lorazepam, oxazepan and prazepam.Suitable 5-HT _1AReceptor stimulant or antagonist comprise buspirone, flesinoxan, gepirone hydrochloride and ipsapirone.

The invention still further relates to the Mammals of treatment in this treatment of needs, the method that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, described method comprises to described Mammals administration:

(a) formula 1 compound or A group compound or its pharmaceutically useful salt; With

(b) another kind is pharmaceutical active compounds or its pharmaceutically useful salt of thymoleptic or anxiolytic;

Wherein significant quantity exists in described disease of treatment or the illness so that this is combined in for active compound " a " and " b ".

Another more particular embodiment of the present invention relates to aforesaid method, wherein formula 1 compound and additional thymoleptic or anxiolytic is administered for any two or more of treatment to human body and is selected from those diseases that relate to and the comorbid disease or the illness of symptom in any aforesaid method.

The invention still further relates to the Mammals that is used for the treatment of in the needs treatment, the pharmaceutical composition that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, described composition contains:

(d) formula 1 compound or A group compound or its pharmaceutically useful salt;

(e) another kind is pharmaceutical active compounds or its pharmaceutically useful salt of thymoleptic or anxiolytic; With

(f) pharmaceutically useful carrier;

The detailed description of invention

Active compound of the present invention can prepare described in following reaction scheme.Except as otherwise noted, at following reaction scheme and in question A, W ¹, W ², X, R and R ¹-R ¹¹Be as defined above.

Diagram A

Diagram A explanation is by making formula ii compound and formula XCO (CH ₂) _mThe method of compound prepared in reaction formula 2 compounds of Q, wherein m is the integer of 1-4, X is that halogen or OH and Q are halogen, methanesulfonate or tosylate.When X represents halogen, react usually at Lewis acid, for example aluminum bromide (AlBr ₃), aluminum chloride (AlCl ₃), gallium trichloride (GaCl ₃), iron(ic) chloride (FeCl ₃), zinc chloride (ZnCl ₂), antimony pentachloride (SbCl ₅), zirconium tetrachloride (ZrCl ₄), tin tetrachloride (SnCl ₄), boron trichloride (BCl ₃), boron trifluoride (BF ₃) or butter of antimony (SbCl ₃) carry out under existing.Reaction can be at non-polar solvent, and for example chloroform, methylene dichloride or dithiocarbonic anhydride or polar solvent for example carry out in the oil of mirbane, or can carry out in the presence of excessive Lewis acid purely.Reaction was usually carried out about 1 hour-6 hours under 25 ℃-Yue 120 ℃ temperature.When X represented OH, reaction was usually at protonic acid, and for example Tripyrophosphoric acid or sulfuric acid carry out under existing.

Diagram B

Diagram B explanation is by the method for corresponding formula 2 compound formulas 3 compounds of reduction.In formula 2 and 3 compounds, Q and m define described in describing in scheme 1.The reaction that illustrates in option b can use triethyl silicane to proceed to many about 24 hours in about room temperature to the reflux temperature of solvent in trifluoroacetic acid.Perhaps, reaction can use borine-tert-butylamine at Lewis acid, carries out under for example aluminum chloride exists or uses borine-dimethylamine at Lewis acid, and for example titanium tetrachloride for example carries out under described temperature in methylene dichloride, chloroform or the oil of mirbane at inert solvent.

Diagram C

Diagram C explanation comprises that by making formula 3 compounds and formula 4 compound prepared in reaction described in diagram B A organizes the method for formula 5 compounds of compound.Reaction is usually at alkali, and for example salt of wormwood, yellow soda ash, triethylamine or diisopropylethylamine carry out under existing.Employed solvent can be two kinds combination of water, acetonitrile, diox, benzene, toluene, tetrahydrofuran (THF), methyl iso-butyl ketone (MIBK) or above-mentioned solvent.Inorganic salt, for example sodium halide or potassium (for example sodium iodide or potassiumiodide) can be used as catalyzer in reaction.Temperature of reaction can change between the reflux temperature of employed solvent in room temperature, preferred about 80 ℃-120 ℃, carries out preferred about 12 hours-48 hours about 1 hour-Yue 96 hours.

Diagram D

Diagram D explanation is by making formula 5A compound, and wherein E is bromine, chlorine, methanesulfonate, tosylate or trifluoromethanesulfonic acid root, with the method for excessive piperazine (being the 5-6 molar equivalent with respect to 5 preferably) prepared in reaction formula 4 compounds (from diagram C).Reaction usually in sealed vessel at 100 ℃-250 ℃, preferred about 200 ℃ were carried out preferably about 12-24 hour purely about 1 hour-30 hours.Can adopt catalyzer, for example copper (bronze), tin or iron filings.Perhaps reaction can be at alkali, and for example yellow soda ash, salt of wormwood or saleratus are used catalyzer under existing, and for example sodium iodide or potassiumiodide for example carry out in acetonitrile, diox, toluene or the dimethylbenzene at solvent.Under this condition, temperature of reaction can change according to the reflux temperature of employed solvent, is preferably about 80 ℃-140 ℃.Reaction was carried out about 1 hour-Yue 96 hours usually, preferred about 12 hours-Yue 48 hours.

Diagram E

Diagram E explanation is by the benzisothiazole of formula 6, and wherein G is chlorine, bromine or piperazine-1-base, the method for the ring sulfinyl amine of preparation formula 7 and the cyclic sulfonamides of formula 8.Be reflected at oxygenant, for example H ₂O ₂, CrO ₃, NaIO ₄, t-BuOCl, Sodium peroxoborate, peracid (for example metachloroperbenzoic acid, peracetic acid), potassium hydrogen persulfate, formic acid, KNO ₃Or HNO ₃Exist down in sulfuric acid and acyl nitrite (acyl nitrite) at-10 ℃-100 ℃, but carry out in preferred-10 ℃-40 ℃ the temperature range approximately.Reaction was carried out 1 hour-48 hours usually, but preferred 4-12 hour.If use enough oxygenants, formula 8 compounds can obtain by a compound by formula 6 or 7.

Diagram F

Diagram F explanation is by making formula 9 compounds and formula X (CH ₂) _mThe method of prepared in reaction formula 10 compounds of the compound of X, wherein X is bromine or chlorine, and m is the integer of 1-4, and Y is OH or NHR ¹¹With YY be O or NR ¹¹Wherein Y is that formula 9 compounds of OH can be as DE415096, US3819637, J.Chin.Chem.Soc. (Taipei), 2000,47,155 and Chem.Heterocyclic Compd., 1970,6, and preparation described in 1283.Wherein Y is NHR ¹¹Formula 9 compounds can be as J.Chem.Soc., C, 1969,183, J.Med.Chem., 1989,32,1173, Chem.Ber., 1903,36,1175 and J.Chem.Res.Miniprint, 1997,9, preparation described in 2068.Above-mentioned reaction is usually at alkali, for example NaOH, KOH, K ₂CO ₃, NaH, NaOMe or NaOEt exist and use solvent down, for example tetrahydrofuran (THF), ethanol, methyl alcohol, fourth-2-ketone, methyl iso-butyl ketone (MIBK), acetone or N, dinethylformamide carries out.Reaction can be carried out about 12 hours of preferably about 4-about 1 hour-Yue 24 hours usually being carried out to the reflux temperature of employed approximately solvent by about room temperature.According in the method described in the diagram C, the reaction of formula 10 compounds and formula 4 compounds (diagram D) obtains corresponding formula 5 compounds.

Diagram G

For diagram G, formula 11 compounds can pass through at suitable alkali, for example pyridine or triethylamine, preferred triethylamine exists down, at suitable solvent, as pyridine, benzene, toluene, ethylene dichloride or methylene dichloride, in the preferred methylene dichloride, at about 0 ℃-Yue 60 ℃, under the preferred room temperature, handled about 30 minutes-Yue 24 hours with acyl chlorides, preferably be converted into formula 12 compounds in about 2 hours.Formula 13 compounds can by in the mixture of methyl alcohol and triethylamine 2, the 6-di-tertiary butyl methyl phenol is handled formula 12 compounds with the methyl aminoacetic acid ethyl ester and was prepared in about 24 hours under the reflux temperature of about reaction mixture.Formula 13 compounds can pass through at suitable polarity or etherificate solvent, for example dimethyl formamide (DMF), diglyme, diox or tetrahydrofuran (THF) (THF), preferably in (THF), under about 5-10 ℃ temperature with suitable alkali, for example sodium methylate or potassium tert.-butoxide, preferred potassium tert.-butoxide is handled and was converted into formula 14 compounds in about 4 hours.Formula 15 compounds can be by formula 14 compounds by use strong inorganic acid, for example hydrochloric acid, sulfuric acid or Tripyrophosphoric acid, and preferred Tripyrophosphoric acid was handled about 1 hour-Yue 10 hours under preferred about 130 ℃ temperature at about 100 ℃-Yue 150 ℃, prepared in preferred about 3 hours.

Formula 18 compounds can be by illustrated preparation among formula 16 compounds such as the following scheme H.

Diagram H

For diagram H, formula 17 compounds can pass through in methylene dichloride at suitable alkali, for example pyridine, salt of wormwood, yellow soda ash, diisopropylethylamine or triethylamine, preferred triethylamine exists down with 1,4,7-trioxa-spiral shell [4,4] nonane-9-carboxylic acid (its preparation method is described in embodiment 168), preferred acyl chlorides (its available oxalyl chloride is handled corresponding acid preparation) processing formula 16 compound.Formula 18 compounds can be by using strong inorganic acid, for example hydrochloric acid, sulfuric acid or Tripyrophosphoric acid processing formula 17 compound under about 0 ℃-Yue 100 ℃ temperature.The preferred sulfuric acid that uses of reaction carried out about 10 minutes-Yue 5 hours preferred about 45 minutes at about 60 ℃.

Preparation at not specifically described formula 1 other compound of above-mentioned experimental section and A group compound can use the combination of above-mentioned reaction to prepare, and this it will be apparent to those skilled in the art that.

In each reaction of as above discussing or illustrating, pressure is not crucial, except as otherwise noted.The atmospheric pressure of about 0.5 normal atmosphere-Yue 5 is normally acceptable, for simplicity, normal pressure, promptly 1 normal atmosphere is preferred.

Formula 1 compound and A organize compound and can use ordinary method at the intermediate shown in the above-mentioned reaction scheme, and for example recrystallization or chromatography separate and purifying.

But formula 1 compound and A group compound and its pharmaceutically useful salt oral administration, parenteral (in for example subcutaneous, intravenously, intramuscular, the thoracic cavity and inculcate technology), rectum, cheek or the interior approach of nose are to the Mammals administration.Usually, these compounds most suitably with the dosage range of the about 600mg of about 3mg-every day with single dose or dosage (being 1-4 dosage every day) administration that separates, although according to the patient's who is treated species, body weight and symptom and individual patients to the type of the reaction of described medicine and selected pharmaceutical preparation with carry out the time of administration cycle and will change necessarily at interval.Yet the dosage level of the about 100mg scope of about 25mg-every day is optimum use.In some cases, the dosage level that is lower than above-mentioned scope lower limit can be to be more suitable for, and can adopt bigger dosage, its prerequisite in other cases when not producing any harmful side effect is the low dose that this higher dose levels at first is divided into some administrations in whole day.

New compound of the present invention can combine administration individually or with pharmaceutically useful carrier or thinner by above-mentioned any approach, this administration can be single or multidose carry out.More particularly, new medicine of the present invention can various various dose form administrations, and promptly they can combine administration with forms such as tablet, capsule, lozenge, lozenge, hard candy, suppository, gelifying agent, gel, paste, ointment, aq suspension, injection solution, elixir, syrup with various pharmaceutically useful inert supports.This carrier comprises solid diluent or filler, sterile aqueous media and various nonpoisonous organic solvents etc.Yet combination of oral medication can increase sweet and/or seasoning suitably.Usually, the weight ratio of new compound of the present invention and pharmaceutically useful carrier will be about 1: about 2: 1 of 6-, preferred about 1: in about 1: 1 scope of 4-.

For oral administration, contain various vehicle, for example the tablet of Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and Padil can with various disintegrating agents, for example starch (with preferred corn, potato or tapioca (flour)), alginic acid and some composition silicate, with Granulating Bonding Agent, be used in combination as Polyvinylpyrolidone (PVP), sucrose, gelatin and Sudan Gum-arabic.In addition, lubricant, for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum are very useful to the compressing tablet purposes usually.The solids composition of similar type also can be used as the filler in gelatine capsule; Preferred substance in this filler comprises that also lactose or toffee and polymer are polyoxyethylene glycol.When aq suspension and/or elixir are applicable to oral administration, activeconstituents can combine with various sweeteners or seasonings, coloring material or dyestuff, and if desired, emulsifying agent and/or suspension agent also with thinner, for example water, ethanol, ethylene glycol, glycerine etc. are used in combination.

For administered parenterally, can adopt solution at sesame oil or peanut oil or the The compounds of this invention in aqueous propylene glycol.If desired, aqueous solution should be by buffering (preferred pH greater than 8) suitably, and liquid diluent at first becomes etc. and to ooze.The suitable intravenous injection purposes that is used for of these aqueous solutions.Oily soln is used for intraarticular, intramuscular and subcutaneous injection purposes suitably.The preparation of all these solution is easily finished with standard pharmaceutical technology well known by persons skilled in the art under aseptic condition.

The present invention relates to treat anxiety, depression, schizophrenia and the method for described other illness in the method for the invention, new compound wherein of the present invention and one or more above-mentioned other active medicines (for example NK1 receptor antagonist, tricyclics, 5HT1D receptor antagonist or serotonin reuptake inhibitors) are as the part administration together of same medicine composition, also relate to method, wherein said active medicine is used for obtaining the combined treatment effect as the part administration individually of suitable dose scheme.The patient who is treated, concrete active medicine and the disease specific of treatment or the character and the severity of illness of administration will be depended in the quantity of the each dosage of active medicine of proper dosage scheme, administration and the concrete interval between each active medicine dosage.Usually, when being used in combination as the single-activity medicine or with other active medicine, new compound of the present invention will be with the quantity of the about 300mg of about 3mg-every day, and preferred every day, about 25-100mg delivered medicine to the grownup with single or separate doses.This compound can every day 6 times at the most, preferred every day 1-4 time, especially every day 2 times, the most especially 1 time scheme administration every day.Yet, according to the kind of the animal of being treated, to the type of the individual reaction of described medicine and selected pharmaceutical preparation with carry out the time of administration cycle and still can change at interval.In some cases, the dosage level that is lower than above-mentioned scope lower limit can be to be more suitable for, and can adopt bigger dosage, its prerequisite in other cases when not producing any harmful side effect is the low dose that this higher dose levels at first is divided into some administrations in whole day.

Be used for to average grow up that human body is oral, parenteral or suck integrated processes of the present invention and the composition that is administered for the above-mentioned illness of treatment, the 5HT reuptake inhibitor, the suggestion per daily dose of preferred Sertraline is the about 2000mg of the about 0.1mg-of per unit dosage, the 5HT reuptake inhibitor of the preferred about 200mg of about 1mg-, its for example administration every day 1-4 time.At, parenteral oral, rectum to average grownup or suck be administered for the treatment above-mentioned illness integrated processes of the present invention and composition in, the suggestion per daily dose of 5HT1D receptor antagonist is the about 2000mg of the about 0.01mg-of per unit dosage, the 5HT1D receptor antagonist of the preferred about 200mg of about 0.1mg-, its for example administration every day 1-4 time.

For intranasal administration or pass through inhalation, new compound of the present invention can be carried by the pump automiser spray by extrusion or pumping by the patient with solution or form of suspension easily, or with the aerosol spray form by using suitable propelling agent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas are carried by pressurizing vessel or atomizer.Under the situation of pressurized aerosol, dose unit can be determined by the valve that is provided for conveying and metering quantity.Pressurizing vessel or atomizer can contain the solution or the suspension of active compound.The capsule and the cartridge case (for example by the gelatin preparation) that are used for sucker or insufflator can be mixed with and contain compound of the present invention and suitable powder matrix, for example powdered mixture of lactose or starch.The preparation preferred arrangement that is used for the treatment of the active compound of the present invention of above-mentioned illness in the average human body of growing up makes the dosage of aerocolloidal each metering or " whenever pressing " contain 10 μ g-1000 μ g active compounds.Aerocolloidal total per daily dose will be in 100 μ g-10mg scopes, and administration can be several times every day, and for example 2,3,4 or 8 times, for example administration 1,2 or 3 dosage at every turn.

All title compounds of test implementation example, at least one steric isomer of each compound shows the binding affinity to the D2 acceptor, the inhibition percentage ratio of measuring under 0.1 μ m concentration is no less than 14% and at the most 100%.At least one steric isomer of each compound shows the binding affinity to the 5HT2 acceptor, and the inhibition percentage ratio of measuring under 0.1 μ m concentration is no less than 80% and at the most 100%.

New compound of the present invention can be measured with conventional planning ligand receptor binding assays in conjunction with the ability of dopamine D 2 and thrombotonin 2A (5HT2A) acceptor.All acceptors can be in clone heterogenous expression, experiment is carried out in the film preparation of the clone of using method as described below.IC ₅₀Concentration can be by in specific combination, depending on concentration the non-linear decline of decline measure.The Cheng-Prussoff formula can be used for IC ₅₀Change Ki concentration into.

The d2 dopamine receptor combination:

[ ³H] Spiropitan with contain 100mMNaCl, 1mMmgCl from being combined in of film preparation of CHO-hD2L cell ₂With the pH of 1%DMSO is to carry out in 7.4 the 250 μ l 50mMTris-HCl damping fluids.Contain (by the interpolation order) test compound, 0.4nM[ ³H] Spiropitan and the proteinic double sample of about 12 μ g at room temperature cultivated 120 minutes.Under reduced pressure radiate ligand by the quick filtering separation bonded of handling with 0.3% polymine in advance of WhatmangF/B fiber glass packing.Be retained in radioactivity on the filler with the liquid scintillation spectrophotometry.

With the title compound of above-mentioned experimental test embodiment 1-36, wherein the specific combination of measuring in the presence of the 1mM haloperidol is 95%.All title compounds of embodiment 1-36 all show the Ki value of being less than or equal to 1uM.The title compound of embodiment 8 shows the Ki of 7nM.The title compound of embodiment 31 shows the Ki of 1nM.The title compound of embodiment 23 shows the Ki of 0.9nM.

Thrombotonin 2A combination:

[ ³H] combining of Sufrexal and Swiss-h5HT2A cytolemma can carry out in pH is 7.4 250 μ l50mMTris-HCl damping fluids.Contain (by the interpolation order) test compound, 1.0nM[ ³H] Sufrexal and the proteinic double sample of about 75 μ g at room temperature cultivated 120 minutes.Under reduced pressure radiate ligand by the quick filtering separation bonded of handling with 0.3% polymine in advance of WhatmangF/B fiber glass packing.Be retained in radioactivity on the filler with the liquid scintillation spectrophotometry.

With the title compound of above-mentioned experimental test embodiment 1-36, wherein the specific combination of measuring in the presence of the 1mM Sufrexal is 90%.All title compounds of embodiment 1-36 all show the Ki value of being less than or equal to 1uM.The title compound of embodiment 8 shows the Ki of 5nM.The title compound of embodiment 31 shows the Ki of 2nM.The title compound of embodiment 23 shows the Ki of 1nM.

Embodiment illustrates the preparation method of compound of the present invention.Fusing point is not proofreaied and correct, and the NMR data are reported with ppm, with reference to the deuterium lock signal of sample solvent.

Embodiment

Embodiment 1

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-3,4-dihydro-1H-quinoline -2-ketone

A.6-(2-chloracetyl)-4-methyl-3,4-dihydro-1H-quinoline-2-one-

With 4-methyl-3; 4-dihydro-1H-quinoline-2-one-(4.38g; 0.027mol; according to J.Org.Chem.; method preparation in 1958,23,1330) under vigorous stirring, adds aluminum chloride (16.68 grams (g); 0.125mol) and chloracetyl chlorine (3.58ml is 0.045mol) in the mixture in dithiocarbonic anhydride (190ml).Reaction mixture refluxed 2 hours, cool to room temperature.The decant solvent, resistates is used cold water treatment under vigorous stirring.Collecting precipitation washes with water and obtains 6.29g (98%).MS(APCl)：(M+1) ⁺＝238。

B.6-(2-chloroethyl)-4-methyl-3,4-dihydro-1H-quinoline-2-one-

In nitrogen to be cooled to 0 ℃ the steps A product (6.29g, 0.026mol) and trifluoroacetic acid (20ml, add in mixture 0.26mol) in batches triethyl silicane (9.57ml, 0.095mol).Reaction mixture heated 20 minutes down at 40-45 ℃, at room temperature stirred subsequently 16 hours.In the stratified frozen water of solution impouring and hexane, vigorous stirring several hours.Collect the precipitation that forms, water and hexane wash obtain 4.51g (78%).MS(APCl)：(M+1) ⁺＝224。

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

Under vigorous stirring with the product (1.61g of step B, 7.20mmol), 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (1.15g, 4.80mmol, according to J.Med.Chem., 1986,29,359 preparations), yellow soda ash (1.12g, 10.5mmol) and sodium iodide (150mg) at 1: 1 (v/v) water: 1, the mixture in the 4-diox (60ml) refluxed 44 hours.Concentrated reaction mixture, resistates distributes between water and methylene dichloride.The organic layer dried over mgso is filtered and is concentrated.Crude product obtains white crystalline solid through quick post (silica gel 60,230-400 order, ethyl acetate) wash-out purifying, collects back washing with acetone, output=744mg (40%).MS(APCl)：(M+1) ⁺＝391，(M-1) ⁺＝389。 ¹H-NMR(DMSO-d ₆，δ)：9.99(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.7Hz)，7.25(m，1H)，7.05(s，1H)，6.98(d，1H，J＝6.1Hz)，6.73(d，1H，J＝8.1Hz)，3.45(t，4H，J＝4.6，5.1Hz)，2.98(q，1H，J＝7.1，6.4，6.8Hz)，2.66(t，2H，J＝3.4，5.1Hz)，2.60(t，4H，J＝4.9，4.9Hz)，2.51(m，3H)，2.17(dd，1H，J＝7.1，7.1Hz)，1.13(d，3H，J＝6.8Hz)。TLC:R _f=0.21 ethyl acetate (EtOAc).CHN:C ₂₃H ₂₆N ₄O ₂Calculated value, C:70.75%, H:6.71%, N:14.35%; Experimental value, C:70.80%, H:6.67%, N:14.15%.HPLC:Chiralpak AD, 250 * 4.6mm; Mobile phase, 10% ethanol (EtOH) in hexane; Flow, 0.50ml/min; Peak 1:RT=35.19min (52%), peak 2:RT=38.72min (48%).

The method of describing in the preparation of embodiment 1 step C is used to prepare the compound of embodiment 2 and 3.

Embodiment 2

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4S-methyl-3.4-dihydro-1H-quinoline -2-ketone

By 3-piperazine-1-base-benzo [d] isoxazole (1.0g, 4.17mmol) and 6-(2-chloroethyl)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(1.40g, 6.26mmol, US 5 according to promulgation on September 27th, 1994,350,747 preparations) the preparation title compound obtains 517mg (32%) behind purifying.MS(APCl)：(M+1) ⁺＝391；(M-1) ⁺＝389。 ¹H-NMR(DMSO-d ₆，δ)：9.99(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.7Hz)，7.25(m，1H)，7.05(s，1H)6.98(d，1H，J＝6.1Hz)，6.73(d，1H，J＝8.1Hz)，3.45(t，4H，J＝4.6，5.1Hz)，2.98(q，1H，J＝7.1，6.4，6.8Hz)，2.66(t，2H，J＝3.4，5.1Hz)，2.60(t，4H，J＝4.9，4.9Hz)，2.51(m，3H)，2.17(dd，1H，J＝7.1，7.1Hz)，1.13(d，3H，J＝6.8Hz)。TLC：R _f＝0.22(EtOAc)。CHN:C ₂₃H ₂₆N ₄O ₂Calculated value, C:70.75%, H:6.71%, N:14.35%; Experimental value, C:70.54%, H:6.74%, N:14.25%.HPLC:ChiralCel OD-H, 5um, 250 * 4.6mm; Mobile phase, 20% Virahol (IPA) in hexane; Flow, 0.30ml/min; Peak RT=63.07min (98.66%).Specific rotation: [a] D ²⁵=+4 ° (MeOH, c=11.4mg/ml).

Embodiment 3

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4R-methyl-3,4-dihydro-1H-quinoline -2-ketone

By 3-piperazine-1-base-benzo [d] isoxazole (1.0g, 4.17mmol) and 6-(2-chloroethyl)-4R-methyl-3,4-dihydro-1H-quinoline-2-one-(1.40g, 626mol, US 5 according to promulgation on September 27th, 1994,350,747 preparations) the preparation title compound obtains 443mg (27%) behind purifying.MS(APCl)：(M+1) ⁺＝391；(M-1) ⁺＝389。 ¹H-NMR(DMSO-d ₆，δ)：9.99(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.7Hz)，7.25(m，1H)，7.05(s，1H)，6.98(d，1H，J＝6.1Hz)，6.73(d，1H，J＝8.1Hz)，3.45(t，4H，J＝4.6，5.1Hz)，2.98(q，1H，J＝7.1，6.4，6.8Hz)，2.66(t，2H，J＝3.4，5.1Hz)，2.60(t，4H，J＝4.9，4.9Hz)，2.51(m，3H)，2.17(dd，1H，J＝7.1，7.1Hz)，1.13(d，3H，J＝6.8Hz)。TLC：R _f＝0.20(EtOAc)。CHN:C ₂₃H ₂₆N ₄O ₂Calculated value, C:70.75%, H:6.71%, N:14.35%; Experimental value, C:70.35%, H:6.83%, N:14.20%.HPLC:ChiralCel OD-H, 5um, 250 * 4.6mm; Mobile phase, 20%IPA (hexane); Flow, 0.30ml/min; Peak RT=73.81min (98.53%).Specific rotation: [a] 25=-60 (MEOH, c=7.1mg/ml).

Embodiment 4

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.1,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

In nitrogen to the 4-methyl-3 that is cooled to 0 ℃, 4-dihydro-1H-quinoline-2-one-(4.0g, 0.025mol, according to J.Org.Chem., the preparation of 1958,23,1330 method) in the solution of anhydrous tetrahydro furan (THF) in (60ml), under vigorous stirring, slowly adds sodium hydride (NaH) (60% mineral oil dispersion liquid, 1.12g, 0.05mol).After adding, reaction mixture stirred 10 minutes, and the adding methyl iodide (3.08ml, 0.05mol).Reaction mixture at room temperature stirred 2 hours, the water quencher.The aqueous mixture dichloromethane extraction, the organic extract dried over mgso is filtered and is concentrated and obtains oily matter, and it need not to be further purified and uses output=4.38g (100%).MS(APCl)：(M+1) ⁺＝176。

B.6-(2-chloracetyl)-1,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the method for describing in embodiment 1 steps A, by the compound of steps A preparation (4.38g, 0.025mol) and chloroacetyl chloride (3.58ml 0.045mol) prepares title compound and obtains 6.29g (100%) beige solid.MS(APCl)：(M+1) ⁺＝252；(M-1) ⁺＝250。

C.6-(2-chloroethyl)-1,4-dimethyl-3.4-dihydro-1H-quinoline-2-one-

According to the method that embodiment 1 step B describes, (6.29g, 0.025mol) the preparation title compound obtains 4.51g (76%) orange, crystallization when leaving standstill by above-mentioned steps B compound.MS(APCl)：(M+1) ⁺＝238；(M+3) ⁺240。

D.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4-dimethyl-3,4-dihydro-1H- The quinoline-2-one-hydrochloride

According to the described method of embodiment 1 step C, by 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (and 400mg, 1.66mmol) and the compound of embodiment 4 step C preparation (592mg, 2.49mmol) preparation title compound.(EtOAc) wash-out obtains oily matter to crude product for silica gel 60,230-400 order, and it is dissolved in the anhydrous diethyl ether, and the 4.0N hydrochloric acid (HCl) that solution is used in the diox is handled with the deposited salt hydrochlorate output=281mg (38%) through quick post.MS(APCl)：(M+1) ⁺＝405。 ¹H-NMR(DMSO-d ₆，δ)：11.10(br?s，1H)，8.01(d，1H，J＝8.1Hz)，7.58(t，2H，J＝1.9，3.2Hz)，7.30(m，1H)，7.12(s，2H)，7.02(d，1H，J＝8.1Hz)，4.11(br?d，2H，J＝13.7Hz)，3.62(br?d，2H，J＝12Hz)，3.50(dd，2H，J＝6.1，11.7Hz)，3.32(br?s，3H)，3.26(m，4H)，3.01(m，3H)，2.59(dd，1H，J＝5.4，5.6Hz)，2.29(dd，1H，J＝7.3，7.1Hz)，1.13(d，3H，J＝6.8Hz)。TLC:R _f=0.20 (free alkali, EtOAc) .CHN:C ₂₄H ₂₈N ₄O ₂1.1HCl calculated value, C:64.83%, H:6.60%, N:12.60%; Experimental value, C:64.62%, H:6.52%, N:12.05%.

Embodiment 5

6-[2-(the 4-benzo [d] isoxazole-3-base piperazine-1-yl)-ethyl]-4,4-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.3-methyl but-2-ene acid phenyl amide

(219.78g, methyl-(301.14g, 2.54mol is Aldrich) at 500 milliliters of (ml) chloroform (CHCl for the but-2-ene acyl chlorides 2.36mol) to drip 3-in room temperature in the solution in the 3L anhydrous chloroform to aniline ₃) in solution.After adding, filter reaction mixture, filtrate is used dried over mgso with 1.0N HCl solution washing, filters and be condensed into oily matter, leaves standstill curing, output=235.89g (53%).MS(APCl)：(M+1) ⁺＝176。

B.4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

(234.80g 1.34mol) is heated to 120 ℃ to the compound that above-mentioned steps A is prepared in oil bath, add several parts of aluminum chloride (excessive).Reaction is monitored with TLC, stops heating after the raw material total overall reaction.Behind the cool to room temperature, add 3 liters of (L) methylene dichloride and make solution.Organic mixture is slowly used water treatment under vigorous stirring, until obtaining abundant quencher.Separate organic layer, use dried over mgso, filter and concentrate, crude product is through chromatogram purification (SiO ₂, 9: 1 hexanes: EtOAc) obtain 98g (42%).MS(APCl)：(M+1) ⁺＝176。

C.6-(2-chloracetyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

(73.6g 0.42mol) takes Reed that-Kerafyrm thatch acylation reaction according to the method described in the embodiment 2 and obtains 96.2g (91%) product the compound of above-mentioned steps B preparation.MS(APCl)：(M+1) ⁺＝252。

D.6-(2-chloroethyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

(3.0g 0.012mol) obtains 2.09g (73%) product according to the reduction that the described method of embodiment 1 step B is carried out ketone to the compound of above-mentioned steps C preparation.MS(APCl)：(M+1) ⁺＝238；(M+3) ⁺＝240；(M-1) ⁺＝236。

E.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4,4-dimethyl-3,4-dihydro-1H- Quinoline-2-one-

[(1.0g, 4.17mmol) (1.49g, 6.26mmol) reaction obtains 304mg (18%) oily matter, crystallization when leaving standstill to d] isoxazole hydrochlorate behind the purifying with the compound of above-mentioned steps D preparation with 3-piperazine-1-base-benzo according to the method for embodiment 1 step 1.MS(APCl)：(M+1) ⁺＝405；(M-1) ⁺＝403。 ¹H-NMR(DMSO-d ₆，δ)：10.02(s，1H)，7.96(d，1H，J＝7.8Hz)，7.54(d，2H，J＝3.9Hz)，7.26(m，1H)，7.14(s，1H)，6.99(d，1H，J＝7.8Hz)，6.74(d，1H，J＝8.1Hz)，3.45(br?s，4H)，2.69(m，2H)，2.61(br?s，4H)，2.54(m，2H)，2.29(s，2H)，1.18(s，6H)。TLC：R _f＝0.27(EtOAc)。CHN:C ₂₄H ₂₈N ₄O ₂Calculated value, C:71.26%, H:6.98%, N:13.85%; Experimental value, C:70.86%, H:7.10%, N:13.65%.

Embodiment 6

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4,4-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

A.1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

(2.0g, 0.0114mol) reaction obtains 1.63g (76%) oily matter to the compound that embodiment 5 step B is prepared according to embodiment 6 described methods behind purifying.MS(APCl)：(M+1) ⁺＝190。

B.6-(2-chloracetyl)-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

As described in example 1 above, (1.63g 8.61mmol) takes the reaction of Reed that-Kerafyrm thatch and obtains 2.29g (100%) oily matter the compound of above-mentioned steps A preparation, and it slowly solidifies.MS(APCl)：(M+1) ⁺＝266；(M-1) ⁺＝264。

C.6-(2-chloroethyl)-1,44-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

(2.29g 8.61mmol), behind column purification fast, obtains 1.88g (87%) oily matter, crystallization when leaving standstill according to the ketone of the method described in the embodiment 2 reduction above-mentioned steps B.MS(APCl)：(M+1) ⁺＝252；(M+3) ⁺＝254。

D.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,4,4-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-hydrochloride

(400mg, 1.66mmol) compound with above-mentioned steps C preparation reacts, and behind quick column purification, obtains transparent oily matter to make 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate according to the preparation method described in the embodiment 3.Oily matter is dissolved in the anhydrous diethyl ether, and the 4.0NHCl that solution is used in the diox handles, precipitation 255mg (34%) hydrochloride.MS(APCl)：(M+1) ⁺＝419。 ¹H-NMR(DMSO-d ₆，δ)：11.0(br?s，1H)，8.03(d，1H，J＝8.1Hz)，7.61(s，2H)，7.33(m，1H)，7.22(s，1H)，7.16(d，1H，J＝8.5Hz)，7.06(d，1H，J＝8.3Hz)，4.13(br?d，2H，J＝13.7Hz)，3.64(br?d，2H，J＝12Hz)，3.51(m，2H)，3,33(br?s，3H)，3.28(m，4H)，3.05(br?s，2H)，2.41(s，2H)，1.19(s，6H)。TLC:Rf=0.35 (free alkali, EtOAc) .CHN:C ₂₈H ₃₀N ₄O ₂The HCl calculated value, C:65.99%, H:6.87%, N:12.31%; Experimental value, C:65.62%, H:6.89%, N:12.23%.

Embodiment 7

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-3,4-dihydro-1H-quinoline -2-ketone

A.6-(2-chloracetyl)-3-methyl-3.4-dihydro-1H-quinoline-2-one-

According to J.Med.Chem., the 3-methyl-3 of the method preparation of describing in 1986,29,1832,4-dihydro-1H-quinoline-2-one-takes Reed that-Kerafyrm thatch acidylate according to the method for describing in embodiment 1 steps A with chloroacetyl chloride, obtains required solid product.MS(APCl)：(M+1) ⁺＝238。

B.6-(2-chloroethyl)-3-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the method for describing among the embodiment 1 step B, the product of above-mentioned steps A is handled with triethyl silicane and is obtained required solid product in trifluoroacetic acid.MS(APCl)：(M+1) ⁺＝224。

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

Adopt the method for embodiment 3, [(500mg is 2.08mmol) with the described compound (699mg of above-mentioned steps B for d] isoxazole hydrochlorate with 3-piperazine-1-base-benzo, 3.13mmol) reaction, obtain title compound, it goes out white crystalline solid by solution precipitation, output=371mg (46%).MS(APCl)：(M+1) ⁺＝391；(M-1) ⁺＝389。 ¹H-NMR(DMSO-d ₆，δ)：9.95(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.7Hz)，7.26(m，1H)，7.01(s，1H)，6.97(d，1H，J＝8.1Hz)，6.72(d，1H，J＝8.1Hz)，3.45(t，5H，J＝4.6，4.9Hz)，2.85(dd，1H，J＝5.9，5.9Hz)，2.66(t，2H，J＝6.6，8.8Hz)，2.60(t，4H，J＝4.2，5.1Hz)，2.53(m，3H)，1.07(d，3H，J＝6.8Hz)。TLC：R _f＝0.44(1∶9MeOH∶EtOAc)。CHN:C ₂₃H ₂₆N ₄O ₂0.8H ₂The O calculated value, C:68.23%, H:6.87%, N:13.84%; Experimental value, C:67.63%, H:6.43%, N:13.71%.

Embodiment 8

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.6-(2-chloracetyl)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to J.Med.Chem., 1986,29; 3 of the method preparation of describing in 1832,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-; take Reed that-Kerafyrm thatch acidylate according to the method for describing in embodiment 1 steps A with chloroacetyl chloride, obtain required solid title compound.MS(APCl)：(M+1) ⁺＝252。

B.6-(2-chloroethyl)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-

The compound for preparing among the above-mentioned steps A obtains title compound solid with the triethyl silicane processing according to the method described in the embodiment 1 step B in trifluoroacetic acid.MS(APCl)：(M+1) ⁺＝238。

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-3,4-dihydro-1H- Quinoline-2-one-

According to the described method of embodiment 1 step C, with 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (500mg, 2.08mmol) with above-mentioned steps B in prepare compound (743mg, 3.13mmol) reaction obtains title compound, by solution precipitation ash discharge white crystalline solid, output=407mg (48%).MS(APCl)：(M+1) ⁺＝405；(M-1) ⁺＝403。 ¹H-NMR(DMSO-d ₆，δ)：9.91(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.9Hz)，7.26(m，1H)，6.98(d，2H，J＝8.1Hz)，6.72(d，2H，J＝7.8Hz)，3.45(t，4H，J＝4.4，5.1Hz)，2.67(m，4H)，2.60(t，4H，J＝4.6，4.9Hz)，2.52(m，2H)，1.01(s，6H)。TLC：R _f＝0.59(1∶9MeOH∶EtOAc)。CHN:C ₂₄H ₂₈N ₄O ₂Calculated value 0.5H ₂O, C:69.71%, H:7.07%, N:13.55%; Experimental value, C:69.09%, H:6.72%, N:13.36%.

Embodiment 9

6-[2-4-benzo [d] isoxazole-3-base-piperazine-1-base-ethyl]-3,4-dimethyl-1H-quinoline-2-one-system Be equipped with

A.6-(2-chloracetyl)-34-dimethyl-1H-quinoline-2-one-

According to the method described in embodiment 1 steps A, 3,4-dimethyl-1H-quinoline-2-one-(Chem.Pharm.Bull., 1983,31,2986) takes Reed that-Kerafyrm thatch acidylate with chloroacetyl chloride, obtains the title compound solid.MS(APCl)：(M+1) ⁺＝250。

B.6-(2-chloroethyl)-3,4-dimethyl-1H-quinoline-2-one-

According to the method described in the embodiment 1 step B, the compound in trifluoroacetic acid among the above-mentioned steps A is handled with triethyl silicane and is obtained the title compound white crystalline solid.MS(APCl)：(M+1) ⁺＝236。

C.6-[2-(the 4-benzo [d] isoxazole-3-base piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one- Hydrochloride

Adopt the described method of embodiment 1 step C, [(1.0g is 4.17mmol) with compound (1.48g, 6.26mmol) reaction of above-mentioned steps B preparation for d] isoxazole hydrochlorate with 3-piperazine-1-base-benzo, obtain title compound, it goes out amorphous solid (730mg) by solution precipitation.This solid suspension is added in 4N HCl in the dioxane until no longer decomposing in boiling methyl alcohol.Filter out remaining nonsoluble, concentrated filtrate.Resistates obtains hydrochloride oldlace powder with washing with acetone, output=707mg (39%).MS(APCl)：(M+1) ⁺＝403；(M-1) ⁺＝401。 ¹H-NMR(DMSO-d ₆，δ)：11.64(s，1H)，10.94(brs，1H)，8.02(d，1H，J＝8.1Hz)，7.61(m，3H)，7.33(m，2H)，7.22(d，1H，J＝8.3Hz)，4.13(br?d，2H，J＝13.4Hz)，3.64(brd，2H，J＝12.2Hz)，3.50(br?t，2H，J＝11，12Hz)，3.41(m，2H)，3.29(m，2H)，3.13(m，2H)，2.39(s，3H)，2.08(s，3H)。

Embodiment 10

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.6-(2-chloracetyl)-3,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the method described in embodiment 1 steps A, 3,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(J.Chem.Soc.Perkin1,1981,2912) take Reed that-Kerafyrm thatch acidylate with chloroacetyl chloride and obtain the title compound solid.MS(APCl)：(M+1) ⁺＝252。

B.6-(2-chloroethyl)-3,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-3,4-dihydro-1H- Quinoline-2-one-

According to the method described in the embodiment 1 step C, 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (1.50g, 6.26mmol) with above-mentioned steps B in the compound (2.23g for preparing, 9.39mmol) reaction, passing through quick post (silica gel 60,230-400 order, 1: 4 hexane: EtOAc) behind the wash-out, obtain title compound canescence amorphous solid, yield=1.35g (53%).MS(APCl)：(M+1) ⁺＝405；(M-1) ⁺＝403。 ¹H-NMR(DMSO-d ₈，δ)：9.95(s，1H)，7.95(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.9Hz)，7.26(m，1H)，7.04(s，1H)，6.98(m，1H)，6.73(d，1H，J＝7.8Hz)，3.45(t，4H，J＝4.6，4.9Hz)，2.67(m，3H)，2.60(t，4H，J＝4.9，4.9Hz)，2.48(m，2H)，2.22(m，1H)，1.10(d，3H，J＝7.1Hz)，0.99(q，3H，J＝6.8，7.1，8.8Hz)。TLC：R _f＝0.28(EtOAc)。CHN:C ₂₄H ₂₈N ₄O ₂Calculated value, C:71.26%, H:6.98%, N:13.85%; Experimental value, C:71.11%, H:7.04%, N:13.75%.

Embodiment 11

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,3,3,4,4-pentamethyl--3,4-dihydro -1H-quinoline-2-one-

A.6-(2-chloracetyl)-1,3,34,4-pentamethyl--3.4-dihydro-1H-quinoline-2-one-

According to the method described in embodiment 1 steps A, 1,3; 3,4,4-pentamethyl--3; 4-dihydro-1H-quinoline-2-one-(4.21g, 0.0193mol, J.Chem.Soc.; (C), 1971,3769) with chloroacetyl chloride (2.78ml; 0.0348mol) take Reed that-Kerafyrm thatch acidylate; obtain title compound oily matter, solidify gradually when it stirs in aqueous solution, output=5.65g (99%).MS(APCl)：(M+1) ⁺＝294；(M-1) ⁺＝292；(M+3) ⁺＝296。

B.6-(2-chloroethyl)-1,3,3,4,4-pentamethyl--3,4-dihydro-1H-quinoline-2-one-

(5.65g, reduction 0.0192mol) is in that (4: 1 hexanes: EtOAc) behind the wash-out, obtain oily matter, it is crystallization when leaving standstill for silica gel 60,230-400 order by quick post to carry out ketone among the above-mentioned steps A according to the method described in the embodiment 1 step B.Output=4.71g (88%).MS(APCl)：(M+1) ⁺＝280；(M+3) ⁺＝282。

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1,3,3,4,4-pentamethyl--3,4-two Hydrogen-1H-quinoline-2-one-

Method according to embodiment 1 step C, 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (1.0g, 4.17mmol) with the compound of as above step B preparation (1.15g, 4.11mmol) reaction obtains 773mg (42%) title compound, it goes out white amorphous solid by solution precipitation.MS(APCl)：(M+1) ⁺＝447。 ¹H-NMR(DMSO-d ₆，δ)：7.96(d，1H，J＝8.1Hz)，7.54(d，2H，J＝3.9Hz)，7.26(m，1H)，7.16(s，1H)，7.11(d，1H，J＝8.3Hz)，6.96(d，1H，J＝8.1Hz)，3.45(br?s，4H)，3.24(s，3H)，2.72(m，2H)，2.62(br?s，4H)，2.55(t，2H，J＝8.3，6.3Hz)，1.05(m，12H)。TLC：R _f＝0.53(EtOAc)。CHN:C ₂₇H ₃₄N ₄O ₂0.5H ₂The O calculated value, C:71.18%, H:7.74%, N:12.30%; Experimental value, C:70.74%, H:7.46%, N:12.16%.

Embodiment 12

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3,4-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

A.6-(2-chloracetyl)-3,3,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

According to the method for embodiment 1 steps A, 3,3; 4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(5.0g, 0.0264mol; J.Am Chem.Soc.; 1956,78,2242) with chloroacetyl chloride (3.79ml; 0.0475mol) take Reed that-Kerafyrm thatch acidylate; obtain title compound, amorphous yellow solid, output=7.02g (100%).MS(APCl)：(M+1) ⁺＝266；(M-1) ⁺＝264；(M+3) ⁺＝268。

B.6-(2-chloroethyl)-3,3,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

According to the method for embodiment 2, (7.02g 0.0264mol) obtains title compound to the ketone of compound, yellow amorphous solid, output=5.12g (77%) among the reduction above-mentioned steps A.MS(APCl)：(M+1) ⁺＝252；(M-1) ⁺＝250；(M+3) ⁺＝254。

C.6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,3,4-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-

Method according to embodiment 1 step C, 3-piperazine-1-base-benzo [d] isoxazole hydrochlorate (1.0g, 4.16mmol) with the compound (1.57g of above-mentioned steps B preparation, 6.24mmol) reaction, obtain title compound, it is through quick post (silica gel 60,230-400 order, 4: 1EtOAc: wash-out hexane) obtains white crystalline solid with washing with acetone again.Output=803mg (46%).MS(APCl)：(M+1) ⁺＝419；(M-1) ⁺＝417。 ¹H-NMR(DMSO-d ₆，δ)：9.91(s，1H)，7.95(d，1H，J＝8.3Hz)，7.54(d，2H，J＝3.9Hz)，7.25(m，1H)，7.00(s，1H)，6.97(d，1H，J＝8.1Hz)，6.71(d，1H，J＝8.1Hz)，3.45(t，4H，J＝4.6，5.1Hz)，2.67(m，3H)，2.60(t，4H，J＝4.4，4.9Hz)，2.52(m，2H)，1.01(d，3H，J＝7.1Hz)，0.98(d，6H，J＝8.5Hz)。TLC：R _f＝0.41(EtOAc)。CHN:C ₂₅H ₃₀N ₄O ₂Calculated value, C:71.74%, H:7.22%, N:13.39%; Experimental value, C:71.71%, H:7.28%, N:13.24%.

Embodiment 13

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-4-methyl-3,4-dihydro-1H-quinoline-2-one-

A.3-piperazine-1-base-1H-indazole hydrochloride

In the sealing stainless steel vessel with 3-chloro-1H-indazole (15.72g, 0.103mol, Aldrich) and piperazine (mixture Aldrich) heated 14 hours at 250 ℃ for 46g, 0.534mol.The thickness resistates distributes between 1.0N aqueous NaOH (NaOH) solution and methylene dichloride, separates organic layer, uses dried over mgso, and filters.The 4.0N hydrochloric acid (HCl) that filtrate is used in the diox is handled, and precipitates green glue.The decant solvent, the gummy residue thing is dissolved in the water, is settled out a small amount of disubstituted indazole base piperazine (1.45g, MS (APCl): (M+1) ⁺=319).Filter out precipitation, filtrate concentrating obtains green amorphous solid, output=19.03g (77%).MS(APCl)：(M+1) ⁺＝203；(M-1) ⁺＝201。

B.6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-4-methyl-3,4-dihydro-1H-quinoline-2- Ketone

According to the method described in the embodiment 1 step C, with 3-piperazine-1-base-1H-indazole hydrochloride (2.0g, 9.9mmol) with the compound (2.22g of embodiment 1 step B preparation, 9.9mmol) reaction obtains title compound, it is by quick post (silica gel 60,230-400 order, the 10%MeOH of 5% methyl alcohol (MeOH) in ethyl acetate (EtOAc)-in EtOAc) wash-out purifying, obtain canescence, amorphous solid with the MeOH washing again.Output=685mg (18%).MS(APCl)：(M+1) ⁺＝390；(M-1) ⁺＝388。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，9.98(s，1H)，7.70(d，1H，J＝8.3Hz)，7.31(d，1H，J＝8.3Hz)，7.24(t，1H，J＝6.6，7.8Hz)，7.04(s，1H)，6.99(d，1H，J＝8.1Hz)，6.93(t，1H，J＝7.1，7.1Hz)，6.73(d，1H，J＝7.8Hz)，3.29(br?s，4H)，2.98(q，1H，J＝6.6，6.6，6.6Hz)，2.68(br?t，2H，J＝6.6，8.5Hz)，2.61(br?s，4H)，2.51(m，2H)，2.17(dd，1H，J＝7.1，7.1Hz)，1.14(d，3H，J＝6.8Hz)。TLC:R _f=0.16 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₃H ₂₇N ₅O0.25C ₄H ₈O ₂Calculated value, C:70.05%, H:7.10%, N:17.02%; Experimental value, C:69.54%, H:6.90%, N:17.32%.

Alkylation described in the embodiment 1 step C is used as the general method of synthetic following indazole analogue:

Embodiment 14

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-4,4-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

By 3-piperazine-1-base-1H-indazole hydrochloride (382mg, 1.60mmol) and the compound (571mg of embodiment 5 step D preparation, 2.40mmol) the preparation title compound, the product that obtains is through quick post (silica gel 60, the 230-400 order, 8%MeOH/EtOAc) the wash-out purifying obtains the canescence foam solid, output=221mg (34%).MS(APCl)：(M+1) ⁺＝404；(M-1) ⁺＝402。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，10.02(s，1H)，7.70(d，1H，J＝8.3Hz)，7.31(d，1H，J＝8.3Hz)，7.24(t，1H，J＝6.8，8.3Hz)，7.14(s，1H)，6.98(d，1H，J＝6.4Hz)，6.93(t，1H，J＝7.8，7.1Hz)，6.74(d，1H，J＝8.1Hz)，3.28(br?s，4H)，2.68(br?t，2H，J＝6.3，8.5Hz)，2.61(br?s，4H)，2.51(br?t，2H，J＝8.5，7.1Hz)，2.28(s，2H)，1.18(s，6H)。TLC:R _f=0.25 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₄H ₂₉N ₅O0.2C ₄H ₈O ₂Calculated value, C:70.73%, H:7.32%, N:16.63%; Experimental value, C:70.22%, H:7.19%, N:16.45%.

Embodiment 15

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline Quinoline-2-ketone

By the compound of the steps A of embodiment 13 preparation (700mg, 2.93mmol) and the compound for preparing among the embodiment 6 step C (1.11g, 4.40mmol) preparation title compound.(3%MeOH/EtOAc-5%MeOH/EtOAc) wash-out obtains oily matter to crude product for silica gel 60,230-400 order, and it is crystallization when leaving standstill, output=430mg (35%) through quick post.MS(APCl)：(M+1) ⁺＝418；(M-1) ⁺＝416。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，7.70(d，1H，J＝8.1Hz)，7.31(d，1H，J＝8.3Hz)，7.24(t，1H，J＝6.8，8.3Hz)，7.19(s，1H)，7.12(d，1H，J＝8.1Hz)，6.99(d，1H，J＝8.3Hz)，6.93(t，1H，J＝7.3，7.3Hz)，3.30(br?s，4H)，3.23(s，3H)，2.73(t，2H，J＝7.3，8.1Hz)，2.62(br?s，4H)，2.54(t，2H，J＝8.1，6.8Hz)，2.38(s，2H)，1.18(s，6H)。TLC:R _f=0.26 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₅H ₃₁N ₅The O calculated value, C:71.91%, H:7.48%, N:16.77%; Experimental value, C:71.49%, H:7.57%, N:16.47%.

Embodiment 16

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3-methyl-3,4-dihydro-1H-quinoline-2-one-

By the compound of embodiment 13 steps A preparations (2.0g, 9.9mmol) and the compound of embodiment 7 step B preparation (2.21g, 9.9mmol) preparation title compound.The quick post of product warp (silica gel 60, the 230-400 order, 5%MeOH/EtOAc-10%MeOH/EtOAc) wash-out purifying, however obtain white with washing with acetone, amorphous solid, output=670mg (17%).MS(APCl)：(M+1) ⁺-390；(M-1) ⁺＝388。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，9.94(s，1H)，7.70(d，1H，J＝8.3Hz)，7.31(d，1H，J＝8.3Hz)，7.24(t，1H，J＝7.1，8.1Hz)，7.01(s，1H)，6.97(d，1H，J＝8.1Hz)，6.93(t，1H，J＝7.8，7.1Hz)，6.72(d，1H，J＝8.1Hz)，3.30(brs，4H)，2.85(dd，1H，J＝5.9，5.6Hz)，2.66(t，2H，J＝7.3，8.5Hz)，2.61(br?s，4H)，2.51(m，4H)，1.07(d，3H，J＝6.8Hz)。TLC:R _f=0.24 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₃H ₂₇N ₅The O calculated value, C:70.93%, H:6.99%, N:17.98%; Experimental value, C:70.58%, H:6.74%, N:17.81%.

Embodiment 17

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3,3-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

By the compound of embodiment 13 steps A preparations (2.0g, 9.9mmol) and the compound of embodiment 8 step B preparation (2.35g, 9.9mmol) preparation title compound.(5%MeOH/EtOAc-10%MeOH/EtOAc) the wash-out purifying obtains white with washing with acetone to product then for silica gel 60,230-400 order, amorphous solid, output=675mg (17%) through quick post.MS(APCl)：(M+1) ⁺＝404；(M-1) ⁺＝402。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，9.91(s，1H)，7.70(d，1H，J＝8.1Hz)，7.31(d，1H，J＝8.3Hz)，7.24(t，1H，J＝7.1，8.1Hz)，6.98(d，2H，J＝8.3Hz)，6.93(t，1H，J＝7.8，7.1Hz)，6.73(d，1H，J＝7.8Hz)，3.28(br?s，4H)，2.66(m，4H)，2.61(br?s，4H)，2.51(br?t，2H，J＝8.5，6.8Hz)，1.00(s，6H)。TLC:R _f=0.22 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₄H ₂₉N ₅The O calculated value, C:71.44%, H:7.24%, N:17.36%; Experimental value, C:71.24%, H:7.16%, N:17.12%.

Embodiment 18

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

By the compound of embodiment 13 steps A preparations (1.0g, 4.19mmol) and the compound of embodiment 10 step B preparation (1.50g, 6.29mmol) preparation title compound.(3%MeOH/EtOAc-5%MeOH/EtOAc) wash-out obtains title compound white to crude product for silica gel 60,230-400 order, foam solid, output=781mg (46%) through quick post.MS(APCl)：(M+1) ⁺＝404；(M-1) ⁺＝402。 ¹H-NMR(DMSO-d ₆，δ)：11.94(s，1H)，9.96(d，1H，J＝13.2Hz)，7.70(d，1H，J＝8.1Hz)，7.31(d，1H，J＝8.3Hz)，7.23(t，1H，J＝6.8，8.3Hz)，7.01(m，2H)，6.93(t，1H，J＝7.8，7.1Hz)，6.72(t，1H，J＝7.8，7.1Hz)，3.28(br?s，4H)，2.91(m，1H)，2.67(m，2H)，2.61(br?s，4H)，2.54(m，2H)，2.22(m，1H)，1.10(d，2H，J＝7.1Hz)，0.98(q，4H，J＝6.3，7.1，8.8Hz)。TLC:R _f=0.24 (1: 9MeOH: EtOAc, fluorescence).CHN:C ₂₄H ₂₉N ₅O0.6H ₂The O calculated value, C:69.57%, H:7.35%, N:16.90%; Experimental value, C:69.22%, H:6.92%, N:16.58%.

Prepare 1 of embodiment 19 and 20 with the method for describing among the embodiment 1 step C, the similar thing of 2-benzisothiazole.

Embodiment 19

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-13,3,4,4-pentamethyl--3,4-dihydro -1H-quinoline-2-one-hydrochloride

By the compound of 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (1.0g, 3.91mmol, J.Med.Chem., 1986,29,359) and embodiment 11 step B preparation (1.64g, 5.86mmol).(3: 7 hexanes: EtOAc) wash-out obtains transparent oily matter to crude product for silica gel 60,230-400 order through quick post.This oily matter is dissolved in the methylene dichloride, and the 4.0N HCl that solution is used in the diox handles deposited salt hydrochlorate, white amorphous solid, output=1.05g (54%).MS(APCl)：(M+1) ⁺＝463。 ¹H-NMR(DMSO-d ₆，δ)：11.20(brs，1H)，8.11(d，1H，J＝8.1Hz)，8.08(d，1H，J＝8.3Hz)，7.57(t，1H，J＝7.1，7.1Hz)，7.44(t，1H，J＝7.3，7.1Hz)，7.21(s，1H)，7.16(d，1H，J＝8.1Hz)，7.04(d，1H，J＝8.3Hz)，4.07(brd，2H，J＝13.4Hz)，3.65(br?d，2H，J＝11.5Hz)，3.50(brt，2H，J＝12.2，11.9Hz)，3.37(m，4H)，3.32(s，3H)，3.06(m，2H)，1.07(br?s，12H)。TLC：R _f＝0.49(EtOAc)。CHN:C ₂₇H ₃₄N ₄The OS1.1HCl calculated value, C:64.50%, H:7.04%, N:11.14%; Experimental value, C:64.05%, H:7.07%, N:11.00%.

Embodiment 20

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3,4-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

By 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (1.0g, 3.91mmol) and embodiment 12 step B in prepare compound (1.48g, 5.86mmol) preparation title compound.Title compound obtains white by precipitating in the solution, amorphous solid, output=1.22g (72%).MS(APCl)：(M+1) ⁺＝435；(M-1) ⁺＝433。 ¹H-NMR(DMSO-d ₆，δ)：9.91(s，1H)，8.02(d，2H，J＝8.3Hz)，7.52(t，1H，J＝7.3，7.1Hz)，7.40(t，1H，J＝7.1，7.3Hz)，7.00(s，1H)，6.97(d，1H，J＝8.1Hz)，6.71(d，1H，J＝8.1Hz)，3.41(br?s，4H)，2.60(m，9H)，1.01(d，3H，J＝7.1Hz)，0.98(d，6H，J＝8.3Hz)。CHN:C ₂₅H ₃₀N ₄OS0.8H ₂The O calculated value, C:66.87%, H:7.09%, N:12.48%; Experimental value, C:66.34%, H:6.75%, N:12.28%.

Embodiment 21

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

A.3-methyl-but-2-ene acid neighbour-toluamide

In the 0.25M solution of cold neighbour-Tolylamine (5.0ml, 46.85mmole, 1 equivalent) in anhydrous THF and pyridine (2 equivalent), drip pure 3,3-dimethyl-acrylate chloride, vigorous stirring.Filtering reacting solution, filtrate is used H with EtOAc (equal-volume) dilution ₂O (3 *), 1NHCl (2 *), saturated sodium bicarbonate (Na ₂CO ₃) (1 *), salt solution (1 *) washing, dry (MgSO ₄), be concentrated into solid.Title product and its terminal olefine mixture of isomers were as 1: 1 mixture separation.MS(APCl)＝190.1[M+H] ⁺。

B.4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

1, add aluminum chloride (AlCl in the solution in the 2-dichlorobenzene (50ml) to 3-methyl-but-2-ene acid neighbour-toluamide (7.27g, 38.41mmole, 1 equivalent) ₃) (30.73g, 230.49mmole, 6 equivalents), be heated to 50-70 ℃.When reaction reaches about 50 ℃, acutely discharge HCl (g).After HCl release obviously stops, making reaction continue additional 10 minutes, with postcooling.The cooling reactant is in the impouring cold water.Multiphase mixture CH ₂Cl ₂(3 * 100ml) extractions, dry (MgSO ₄), be concentrated into orange.Obtain above-mentioned title compound (5.357g, 28.31mmole, 74% yield) with MPLC (30%EA/Hex) purifying. ¹H?NMR(400mHz，CDCl ₃)δ8.43(s，1H)，7.16(d，J＝7.5Hz，1H)，7.04(d，J＝7.5Hz，1H)，6.96(t，J＝7.5Hz，1H)，2.48(s，2H)，2.30(s，3H)，1.32(s，6H)。

C.6-(2-chloro-ethanoyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

To 4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(3.545g, 18.71mmole, 1 equivalent) is at CS ₂Add chloroacetyl chloride (2.23ml, 28.06mmole, 1.5 equivalents) in the solution (200ml), once add aluminum chloride (9.98g, 74.84mmole, 4 equivalents) subsequently.Reactant reflux 1 hour, after this, reaction is finished in tlc (TLC) and MS demonstration.After cooling, the decant solvent, all the other resistatess are with cold water hydrolysis carefully.Filter out the precipitation that obtains, 50 ℃ under hivac drying obtain title compound brown solid (4.79g, 18.03mmole, 96% yield).Purity 100% under 254nm; LCMS (APCl) 266.3[M+H] ⁺ ¹H NMR (400mHz, CDCl ₃) δ 7.89 (bs, 1H), 7.81 (s, 1H) 7.67 (s, 1H), 4.65 (s, 2H), 2.52 (s, 2H), 2.32 (s, 3H), 1.36 (s, 6H).

D.6-(2-chloro-ethyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

To 6-(chloromethyl carbonyl)-4,4,8-trimethylammonium-3, the solution of 4-dihydro-1H-quinoline-2-one-(4.79g, 18.03mmole, 1.0 equivalents) in trifluoroacetic acid (100ml) adds triethyl silicane (7.20ml, 45.08mmole, 2.5 equivalents), totally be heated to 60 ℃.After 2 hours, reaction is finished in TLC (30%EtOAc/ hexane (Hex)) and MS demonstration.Cooled reaction solution, impouring are being used CH on ice ₂Cl ₂(after 3 * 100ml) extractions, dry (MgSO ₄) and be concentrated into oily matter, crude product obtains title compound white solid (3.23g, 12.84mmole, 71% yield) with MPLC (30%EtOAc/Hex) purifying.Purity 100% under 254nm; LCMS (APCl) 252.2[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ 7.41 (bs, 1H), 6.99 (s, 1H), 6.89 (s, 1H), 3.67 (t, J=7.3Hz, 2H), 2.98 (t, J=7.3Hz, 2H), 2.46 (s, 2H), 2.21 (s, 3H), 1.30 (s, 6H).

E.6-2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-

With 6-(chloromethyl carbonyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(2.200g, 8.739mmole, 1.0 equivalent), yellow soda ash (1.158g, 10.924mmole, 1.25 equivalents), sodium iodide (0.131g, 0.874mmole, catalytic amount) and the 3-piperazine-multiphase mixture of 1-base-benzo [d] isoniazthiolane hydrochlorate (3.353g, 13.110mmole, 1.5 equivalents) in acetonitrile (35ml) that adds under microwave-assisted, be heated to 150 ℃ 30 minutes.Reaction mixture water (100ml), CH ₂Cl ₂(100ml) dilution, layering.Water layer CH ₂Cl ₂(2 *, 50ml) extraction, organic layer sal epsom (MgSO ₄) drying, concentrate resistates MPLC (25%EA/CH ₂Cl ₂----50%EA gradient 20 minutes kept 20 minutes----100%EA gradients 20 minutes) purifying.Obtain the title compound white crystalline solid, 63% yield, 30% raw material (6-(2-chloro-ethyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-) that reclaims. ¹H?NMR(400mHz，CDCl ₃)δ7.90(d，1H，J＝7.94Hz)，7.80(d，1H，J＝7.94Hz)，7.46(t，1H，J＝7.94Hz)，7.34(t，1H，J＝7.94Hz)，7.02(s，1H)，6.91(s，1H)，4.78(s，1H)，3.69-3.55(m，4H)，2.86-2.59(m，8H)，2.45(s，2H)，2.21(s，3H)，1.30(s，6H)。

F.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-, mesylate

(319.77g 0.735mol) is dissolved in the tetrahydrofuran (THF) (3.0 liters), and solution is heated to 60 ℃, and (74.25g, 0.773mol) (note: heat release), the reaction mixture vigorous stirring is until cool to room temperature to add methylsulfonic acid in 5 minutes with free alkali.Collecting precipitation, water (6 liters) recrystallization.Yield=333 grams (85%), ¹H-NMR (CDCl ₃, δ): 11.69 (brs, 1H), 7.84 (cm, 2H), 7.52 (cm, 1H), 7.48 (br s, 1H), 7.41 (cm, 1H), 7.06 (br s, 1H), 6.96 (br s, 1H), 4.16 (m, 2H), 4.00 (m, 2H), 3.64 (m, 2H), 3.13-3.28 (cm, 6H), 2.91 (s, 3H), 2.45 (s, 2H), 2.21 (s, 3H), 1.30 (s, 6H).CHN: calculated value C ₂₆H ₃₄N ₄O ₄S ₂: C, 58.84%; H, 6.46%; N, 10.56%; S, 12.08%; Experimental value, C, 58.83%; H, 6.29%; N, 10.44%; S, 12.37%.

Embodiment 22

2-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

To 6-(2-chloro-ethyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(1.5 equivalent) Zai diox/H ₂The 3-piperazine that adds yellow soda ash (2.2 equivalent), sodium iodide (catalytic amount) in the solution among the O (0.03M 1: 1) and add-1-base benzo [d] isoniazthiolane hydrochlorate (1.0 equivalent).Reaction mixture refluxed heating 24-72 hour.Reaction mixture concentrates subsequently, at H ₂O and CH ₂Cl ₂Between distribute.With organic layer drying (MgSO ₄), concentrate and obtain title compound, the 15-48% yield through chromatography (4: 1 EA/Hex) purifying.

LC/MS post: Phenomenex Develosil Combi-RP-33p, 50 * 4.6mm, length 150 * 4.6.

Embodiment 23

6-[2-(4-benzo [d] isothiazole-3-base piperazine-1-yl)-ethyl]-7-chloro-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-mesylate

A.3-methyl-but-2-ene acid (3-chloro-2-methyl-phenyl)-acid amides

0 ℃ with 3,3-diethyl acrylate chloride (21.0mL, 0.189mol) slowly add 3-chloro-2-aminotoluene (20.0mL, 0.167mol) and pyridine (17.0mL is 0.210mol) in the solution in methylene dichloride (210mL).Behind 1.5h, by slow adding saturated sodium bicarbonate solution (60mL) stopped reaction.Solution is transferred in the 500mL separating funnel layering.(2 * 100mL) strip water layer with methylene dichloride.The organic extract anhydrous sodium sulfate drying that merges filters removal of solvent under reduced pressure.The purple solid that obtains directly uses, and need not purifying.MS(APCl)：(M+1)＝224.1。

B.7-chloro-6-(2-chloro-ethanoyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

With the compound dissolution of above-mentioned steps A preparation in methylene dichloride (167mL), to reaction mixture with the speed that keeps gentle reflux slowly add aluminum chloride (91.5g, 0.686mol).After aluminum chloride adds, connect reflux exchanger, the reaction mixture refluxed heating.Behind 1.5h, TLC shows does not have residual raw materials.(20.0mL, 0.250mol), mixture refluxed 4 hours more slowly to add chloroacetyl chloride.With reaction mixture impouring frozen water (1000mL), with methylene dichloride (4 * 300mL) extractions.Merge organic extract,, use anhydrous sodium sulfate drying, removal of solvent under reduced pressure with sodium chloride solution (200mL) washing.The solid that obtains is directly used in next step, need not purifying.MS(APCl)：(M+1) ⁺＝300.1，(M+3) ⁺＝302.1。

C.7-chloro-6-(2-chloro-ethyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

In trifluoroacetic acid (168.0mL), (59.0mL, 0.369mol), reaction mixture is heated to 60 ℃ in nitrogen to add triethyl silicane in solution with the compound dissolution of above-mentioned steps B preparation.Behind 5.5h, reaction mixture is to room temperature, and stirred reaction mixture spends the night.With reaction mixture impouring frozen water (350mL), reaction flask cleans with methyl alcohol (50mL).The mixture vigorous stirring forms precipitation, crosses filter solid, develops with hexane subsequently.Solid by hot methyl tertiary butyl ether (MTBE) (600mL) recrystallization obtain the light brown solid of title compound (36.0345g, 0.126mol, 75% 4 step portion's yield).MS(APCl)：(M-1) ⁺＝286.1，(M+1) ⁺＝288.1。 ¹H?NMR(400mHz，CDCl ₃)δ7.50(br?s，1H)，7.06(s，1H)，3.71(t，J＝7.2Hz，2H)，3.16(t，J＝7.2Hz，2H)，2.45(s，2H)，2.30(s，3H)，1.30(s，6H)。

D.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-chloro-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Product (the 5.0016g of above-mentioned steps C, 17.476mmol), 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (4.4811g, 17.520mmol), salt of wormwood (4.8299g, 34.946mmol) and potassiumiodide (0.2903g, mixture 1.749mmol) in acetonitrile (29.0mL) in CEM MARS5 microwave reactor 200 ℃ the reaction 1 hour.Reaction mixture is cooled to room temperature, and dilute with water also filters.Solid water and hexane wash, the solid that obtains MPLC[silica gel, 100% methylene dichloride (CH ₂Cl ₂)-3%MeOH/CH ₂Cl ₂, 1 hour, remain on 3%MeOH/CH then ₂Cl ₂] purifying obtains 5.6591g, (12.065mmol, 69%) title compound canescence crystalline solid.LC-MS(APCl)：(M-1) ⁺＝469.1，(M+1) ⁺＝471.0。

E.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-chloro-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-mesylate

(0.139mL, (1.0042g is 2.141mmol) in the hot solution of tetrahydrofuran (THF) (THF) in (35.0mL) 2.142mmol) to add the product of above-mentioned steps D with methylsulfonic acid.Title compound almost begins crystallization immediately.With the sluggish cool to room temperature, after 2 hours, collect the tenderly white look solid of title compound 1.0813g (1.913mmol, 89%).Need not to be further purified. ¹H?NMR(400mHz，CDCl ₃)δ1.31(s，6H)，2.29(s，3H)，2.44(s，2H)，2.90(s，3H)，3.17-3.29(m，4H)，3.32-3.40(m，2H)，3.70(d，J＝11.3Hz，2H)，3.97(t，J＝12.1Hz，2H)，4.17(d，J＝14.4Hz，2H)，7.33(s，1H)，7.41(t，J＝8.0Hz，1H)，749-7.55(m，2H)，7.84(t，J＝7.8Hz，2H)，11.67(br?s，1H)。Ultimate analysis C ₂₅H ₂₉ClN ₄OS-CH ₄O ₃S calculated value: C, 55.26; H, 5.89; N, 9.91; Experimental value: 54.86; H, 5.83; N, 9.65.

Embodiment 24

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-hydrochloride

A.3-methyl-but-2-ene acid (3-fluoro-2-methyl-phenyl)-acid amides

(2.30mL, 20.197mmol) with 3,3-dimethyl acryloyl chloride (2.50mL, 22.457) preparation title compound need not purifying, semi-solid direct use that obtains by 3-fluoro-2-aminotoluene to use the method described in embodiment 23 steps A.MS(APCl)：(M+1) ⁺＝208.1。

B.6-(2-chloro-ethanoyl)-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

Use the method for embodiment 23 step B by the compound of above-mentioned steps A, aluminum chloride (11.04g, 82.796mmol) and chloroacetyl chloride (2.40mL 30.005mmol) prepares title compound.Product is by the crystallization of hot EtOAc/ hexane, and mother liquor is with MPLC (silica gel, 100%CH ₂Cl ₂-3%MeOH/CH ₂Cl ₂, 1 hour, remain on 3%MeOH/CH subsequently ₂Cl ₂) purifying.Identical in batches by LC-MS two, merging obtains 4.6617g (16.430mmol, 81% three goes on foot altogether) title compound white solid.MS(APCl)：(M+1) ⁺＝284.2。 ¹H?NMR(400mHz，CDCl ₃)δ7.7.9(d，J＝7.3Hz?1H)，7.74(brs，1H)，4.69(d，J＝3.2Hz，2H)，2.50(s，2H)，2.20(s，3H)，1.34(s，6H)。

C.6-(2-chloro-ethyl)-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

Adopt the method described in the embodiment 23 step C, by 6-(2-chloro-ethanoyl)-7-fluoro-4,4; 8-trimethylammonium-3; 4-dihydro-1H-quinoline-2-one-(46.56g, 0.164mol), triethyl silicane (55.0mL, 0.344mol) and trifluoroacetic acid (78.0mL) preparation title compound.Reaction is cleaned with methyl alcohol (70mL) with frozen water (400mL) quencher, flask.Form white solid, cross filter solid, use hexane wash.Solid obtains 19.7280g (73.137mmol, 45%) title compound white solid by hot acetonitrile/MTBE recrystallization.MS(APCl)：(M+1) ⁺＝270.1；(M+3) ⁺＝272.0。1H?NMR(400Hz，CDCl ₃)δ1.29(s，6H)，2.14(d，J＝1.8Hz，3H)，2.45(s，2H)，3.04(t＝7.3Hz，2H)，3.68(t，J＝7.3Hz，2H)，6.97(d，J＝7.8Hz，1H)，7.68(s，1H)。

D.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-hydrochloride

With 6-(2-chloro-ethyl)-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(0.7499g, 2.780mmol), 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.7834g, 3.036mmol), salt of wormwood (0.8456g, 6.118mmol) and potassiumiodide (0.0495g, mixture 0.298mmol) in acetonitrile (7.0mL) in CEM MARS5 microwave reactor 150 ℃ the reaction 1 hour.Reaction mixture is cooled to room temperature, and water (70mL) dilution is with methylene dichloride (2 * 75mL) extractions.Merge organic extract, use anhydrous sodium sulfate drying, filter and removal of solvent under reduced pressure.The solid that obtains MPLC purifying (solid water and hexane wash).The solid that obtains MPLC (silica gel, 100%CH ₂Cl ₂-3%MeOH/CH ₂Cl ₂, 1H remains on 3%MeOH/CH then ₂Cl ₂) purifying obtains title compound and step C product mixtures.This mixture is dissolved in the methylene dichloride, and the 4M hydrochloric acid that slowly is added in the diox precipitates until product.Separate title compound (0.3137g, 0.660mmol, 53% two steps altogether) white solid.MS (APCl): (M+1, free alkali) ⁺=439.2. ¹H?NMR(400mHz，CDCl ₃)δ1.29(s，6H)，2.12(d，J＝1.6Hz，3H)，2.44(s，2H)，3.19(s，4H)，3.32(s，2H)，3.59(s，2H)，4.17(m，4H)，7.12(d，J＝7.6Hz，1H)，7.38-7.45(m，2H)，7.49-7.54(m，1H)，7.84(t，J＝8.8Hz，2H)，13.2(brs，1H)。Ultimate analysis C ₂₄H ₂₇FN ₄OS.HCl.0.75H ₂O.0.10CH ₂Cl ₂Calculated value: 58.24; H, 6.02; N, 11.27; H ₂O, 2.72, experimental value: 57.84; H, 6.17; N, 10.98; H ₂O, 2.57.

Embodiment 25

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-mesylate

A.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Product (the 2.2896g of embodiment 24 step C, 8.488mmol), 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (2.4295g, 8.489mmol), salt of wormwood (2.3472g, 16.983mmol) and potassiumiodide (0.1406g, mixture 0.847mmol) in acetonitrile (14.0mL) in CEM MARS5 microwave reactor 175 ℃ the reaction 20 minutes.With the reaction mixture cool to room temperature, dilute with water filters the solid, water and the hexane wash that obtain.LC-MS measures solid purity＞98%.White solid obtains 3.2518g (7.185mmol, 85%) title compound white solid 50 ℃ of dryings under vacuum.LC-MS＞98% is pure.MS(APCl)：(M+1) ⁺＝453.2。

B.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7-fluoro-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-mesylate

With methylsulfonic acid (0.144mL, 2.219mmol) product (1.0054g, 2.221mmol) solution in THF (25.0mL) of adding above-mentioned steps A.Title compound begins crystallization immediately, the slow cool to room temperature of reaction mixture.After 3 hours, cross filter solid and obtain the tenderly white look solid of 1.1945g (2.177mmol, 98%) title compound.LC-MS (APCl): (M+1, free alkali) ⁺=452.8. ¹H?NMR(400mHz，CDCl ₃)δ1.29(s，6H)，1.79-1.89(m，1H)，2.11(d，J＝1.4Hz，3H)，2.44(s，2H)，2.89(s，3H)，3.15-3.26(m，5H)，3.58-3.78(m，8H)，3.92-4.03(m，2H)，4.09-4.19(m，2H)，7.16(d，J＝8.0Hz，1H)，7.34(s，1H)，7.37-7.43(m，1H)，7.48-7.54(m，1H)，7.83(d，J＝7.6Hz，1H)，7.85(d，J＝7.6Hz，1H)，11.67(br?s，1H)。Ultimate analysis C ₂₅H ₂₉FN ₄OS.CH ₄O ₃S calculated value: C, 56.91; H, 6.06; N, 11.66. experimental value: C, 56.60; H, 6.07; N, 9.91.

Embodiment 26

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-8-ethyl-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

A.3-methyl-but-2-ene acid (2-ethyl-phenyl)-acid amides

Adopt the described method of embodiment 5A by 2-ethylaniline and 3, the preparation of 3-dimethyl acryloyl chloride.Separate purity 100% at 254nm; LCMS (APCl): 204[M+H] ⁺

B.8-ethyl-4,4-dimethyl-34-dihydro-1H-quinoline-2-one-

Adopt the preparation method of embodiment 5B, prepare by embodiment 26A.Separate purity 100% at 254nm; LCMS (APCl): 204[M+H] ⁺

C.6-(2-chloro-ethanoyl)-8-ethyl-4.4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

Adopt of the title compound preparation of the described method of embodiment 1A, separate purity 100% at 254nm by embodiment 26B; LCMS (APCl): 280[M+H] ⁺

D.6-(2-chloro-ethyl)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

Adopt the preparation method of embodiment 1B, by the title compound preparation of embodiment 26C.Separate purity 100% at 254nm; LCMS (APCl): 266[M+H] ⁺

E.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-8-ethyl-4,4-dimethyl-3,4- Dihydro-1H-quinoline-2-one-

Adopt the preparation method of embodiment 25A, by title compound and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate preparation of embodiment 26D.Separate purity 100% at 254nm; LCMS (APCl): 273[M+H] ⁺1H NMR (400mHz, δ ppm 1.23 (t, J=7.62Hz, 3H) 1.31 (s of chloroform-D), 6H) 2.46 (s, 2H) 2.53 (q, J=7.68Hz, 2H) 2.61-2.72 (m, 2H) 2.72-2.88 (m, 6H) 3.60 (s, 4H) 6.93 (d, J=1.95Hz, 1H) 7.03 (d, J=1.76Hz, 1H) 7.32-7.39 (m, 2H) 7.45 (d, J=7.81Hz, 1H) 7.81 (d, J=8.21Hz, 1H) 7.90 (d, J=7.81Hz, 1H).CHN:C ₂₆H ₃₂N ₄O ₁S ₁Calculated value C:69.61%, H:7.19%, N:12.49%; Experimental value, C:69.51%, H:7.32%, N:12.30%.

Embodiment 27

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-8-chloro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-hydrochloride

A.3-methyl-but-2-ene acid (2-chloro-phenyl)-acid amides

Adopt the described method of embodiment 5A, by 2-chloroaniline and 3, the preparation of 3-dimethyl acryloyl chloride.1H NMR (400mHz, chloroform) δ ppm 1.92 (s, 3H) 2.22 (s, 3H) 5.76 (s, 1H) 6.99 (t, J=7.82Hz, 1H) 7.25 (t, J=7.82Hz, 1H) 7.34 (d, J=8.06Hz, 1H) 7.53 (s, and 1H) 8.43 (d, J=7.82Hz, 1H).

B.8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

Adopt the preparation method of embodiment 5B, by the title compound preparation of embodiment 27A.1H NMR (400mHz, chloroform) δ ppm 1.32 (s, 6H) 2.49 (s, and 2H) 6.98 (t, J=7.93Hz, 1H) 7.20 (d, J=7.81Hz, 1H) 7.24 (dd, J=9.40,1.34Hz, 1H) 7.88 (s, 1H).

C.8-chloro-6-(2-chloro-ethanoyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

Use the preparation method of embodiment 5C, by the title compound preparation of embodiment 27B.1H NMR (400mHz, the δ ppm 1.37 of chloroform-D) (s, 6H) 2.54 (s, 2H) 4.60 (s, 2H) 7.84 (s, 1H) 7.86 (s, and 1H) 8.01 (s, 1H).

D.8-chloro-6-(2-chloro-ethyl)-4,4-dimethyl-3.4-dihydro-1H-quinoline-2-one-

Use the preparation method of embodiment 1B, prepare by embodiment 27C title compound.Separate purity 100% at 254nm; LCMS (APCl): 273[M+H] ⁺

E.6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-8-chloro-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-hydrochloride

According to the preparation method of embodiment 25A,, separate purity 100% at 254nm by embodiment 27D title compound and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate preparation; LCMS (APCl): 455[M+H] ⁺1H?NMR(400mHz，DMSO-d ₆)δppm?1.22(s，6H)2.37(s，2H)2.99-3.07(m，2H)3.33-3.50(m，5H)3.57-3.67(m，2H)4.02-4.12(m，2H)7.20(d，J＝1.71Hz，1H)7.26(d，J＝1.71Hz，1H)7.42-7.47(m，1H)7.54-7.59(m，1H)8.09(d，J＝8.30Hz，1H)8.11(d，J＝8.30Hz，1H)9.55(s，1H)11.01(s，1H)。CHN:C ₂₄H ₂₇N ₄O ₁S ₁1.20HCl calculated value, C:57.79%, H:5.70%, N:11.23%; Experimental value, C:58.10%, H:5.78%, N:10.84%.

Embodiment 28

6-[2-(the different azoles of 4-benzo [d]-3-base-piperazine-1-yl)-ethyl]-8-ethyl-4,4-dimethyl-3.4-dihydro -1H-quinoline-2-one-

According to the preparation method of embodiment 25A, [preparation of d] isoxazole hydrochlorate separates purity 100% at 254nm by embodiment 26D title compound and 3-piperazine-1-base-benzo; LCMS (APCl): 433[M+H] ⁺1H NMR (400mHz, δ ppm 1.23 (t, J=7.62Hz, 3H) 1.31 (s of chloroform-D), 6H) 2.45 (s, 2H) 2.53 (q, J=7.55Hz, 2H) 2.61-2.70 (m, 2H) 2.70-2.83 (m, 6H) 3.56-3.67 (m, 4H) 6.92 (d, J=1.76Hz, 1H) 7.02 (d, J=1.76Hz, 1H) 7.21 (ddd, J=8.06,6.40,1.56Hz, 1H) 7.39 (s, 1H) 7.43-7.50 (m, 2H) 7.68 (d, J=8.01Hz, 1H).CHN:C ₂₆H ₃₂N ₄O ₁S ₁0.51CH ₂Cl ₂Calculated value, C:66.91%, H:6.99%, N:11.77%; Experimental value, C:66.57%, H:7.20%, N:11.88%.

Adopt the method for embodiment 25A, obtain embodiment 29-38 with the title compound of embodiment 21D and suitable aryl piperazines analogue.

Embodiment 29

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

[d] isoxazole hydrochlorate separates purity 100% at 254nm to use 3-piperazine-1-base-benzo; LCMS (APCl): 419[M+H] ⁺1H NMR (400mHz, δ ppm 1.30 (s, 6H) 2.20 (s, 3H) 2.45 (s of chloroform-D), 2H) 2.60-2.68 (m, 2H) 2.69-2.81 (m, 6H) 3.57-3.65 (m, 4H) 6.90 (d, J=1.22Hz, 1H) 7.01 (d, J=1.47Hz, 1H) 7.21 (ddd, J=8.06,6.35,1.71Hz, 1H) 7.33 (s, 1H) 7.43-7.50 (m, 2H) 7.68 (d, J=8.06Hz, 1H) .CHN:C ₂₅H ₃₀N ₄O ₂Calculated value, C:71.74%, H:7.32%, N:13.39%; Experimental value, C:71.30%, H:7.14%, N:13.11%.

Embodiment 30

6-{2-[4-(5-methoxyl group-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4, the 8-trimethylammonium -3,4-dihydro-1H-quinoline-2-one-

Use 4-(5-methoxyl group-benzo [a] isothiazole-3-yl)-piperazine (J.Med.Chem., 1991,34,3316), separate purity 100% at 254nm; LCMS (APCl): 465[M+H] ⁺1H NMR (400MHz, 8 ppm 1.31 (s, 6H) 2.22 (s, 3H) 2.46 (s of chloroform-D), 2H) 2.63-2.73 (m, 2H) 2.74-2.85 (m, 6H) 3.51-3.65 (m, 4H) 3.89 (s, 3H) 6.92 (s, 1H) 7.03 (d, J=1.37Hz, 1H) 7.14 (dd, J=8.79,2.34Hz, 1H) 7.25 (d, J=2.54Hz, 2H) 7.43 (s, 1H) 7.68 (d, J=8.79Hz, 1H).

Embodiment 31

6-{2-[4-(7-methoxyl group-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4, the 8-trimethylammonium -3,4-dihydro-1H-quinoline-2-one-

Use 4-(7-methoxyl group-benzo [d] isothiazole-3-yl)-piperazine (J.Med.Chem., 1991,34,3316), separate purity 100% at 254nm; LCMS (APCl): 465[M+H]+.1H NMR (400MHz, δ ppm 1.31 (s, 6H) 2.23 (s of chloroform-D), 3H) 2.45 (s, 2H) 2.61-2.70 (m, 2H) 2.71-2.81 (m, 6H) 3.54-3.64 (m, 4H) 3.96 (s, 3H) 6.82 (d, J=7.61Hz, 1H) 6.91 (s, 1H) 7.02 (s, 1H) 7.29 (t, J=7.91Hz, 1H) 7.47 (d, J=7.81Hz, and 1H) 7.81 (s, 1H).

Embodiment 32

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine, separate purity 100% at 254nm; LCMS (APCl): 453[M+H] ⁺1H NMR (400mHz, 8 ppm 1.32 (s, 6H) 2.22 (s, 3H) 2.47 (s, 2H) 2.61-2.96 (m of chloroform-D), 8H) 3.50-3.80 (m, 4H) 6.92 (s, 1H) 7.03 (s, 1H) 7.33 (s, 1H) 7.48-7.57 (m, 1H) 7.75 (dd, J=8.91,4.76Hz, 1H).

Embodiment 33

6-{2-[4-(5-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(5-fluoro-benzo [d] isoxazole-3-base)-piperazine, separate purity 100% at 254nm; LCMS (APCl): 437[M+H] ⁺1H NMR (400mHz, δ ppm 1.31 (s, 6H) 2.22 (s, 3H) 2.46 (s of chloroform-D), 2H) 2.65 (m, 2H) 2.73 (s, 3H) 2.78 (m, 3H) 3.57 (s, 4H) 6.90 (d, J=1.22Hz, 1H) 7.01 (d, J=1.46Hz, 1H) 7.22 (dd, J=9.03,2.68Hz, 1H) 7.33 (dd, J=8.30,2.20Hz, 1H) 7.40 (dd, J=9.03,3.66Hz, 1H) 7.48 (s, 1H).

Embodiment 34

6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(6-fluoro-benzo [d] isoxazole-3-base)-piperazine (EP-494817A1), separate purity 100% at 254nm; LCMS (APCl): 437[M+H] ⁺1H NMR (400mHz, δ ppm 1.31 (s, 6H) 2.22 (s, 3H) 2.46 (s of chloroform-D), 2H) 2.62-2.68 (m, 2H) 2.70-2.81 (m, 6H) 3.54-3.64 (m, 4H) 6.90 (d, J=1.22Hz, 1H) 6.97 (td, J=8.78,2.20Hz, 1H) 7.01 (d, J=1.46Hz, 1H) 7.13 (dd, J=8.54,1.95Hz, 1H) 7.52 (s, 1H) 7.63 (dd, J=8.79,5.12Hz, 1H).

Embodiment 35

6-{2-[4-(5-chloro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(5-chloro-benzo [d] isoxazole-3-base)-piperazine (J.Med.Chem., 1986,29,359), separate purity 100% at 254nm; LCMS (APCl): 453[M+H] ⁺1H NMR (400MHz, δ ppm 1.30 (s, 6H) 2.21 (s, 3H) 2.45 (s, 2H) 2.60-2.68 (m of chloroform-D), 2H) 2.68-2.81 (m, 6H) 3.52-3.62 (m, 4H) 6.89 (s, 1H) 7.00 (s, 1H) 7.35-7.48 (m, 3H) 7.65 (d, J=1.71Hz, 1H).

Embodiment 36

6-{2-[4-(7-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(7-fluoro-benzo [d] isothiazole-3-yl)-piperazine, separate purity 100% at 254nm; LCMS (APCl): 453[M+H] ⁺1H NMR (400mHz, δ ppm 1.31 (s, 6H) 2.21 (s of chloroform-D), 3H) 2.46 (s, 2H) 2.61-2.69 (m, 2H) 2.71-2.81 (m, 6H) 3.54-3.64 (m, 4H) 6.91 (s, 1H) 7.02 (s, 1H) 7.10-7.18 (m, 1H) 7.29-7.40 (m, 2H) 7.68 (d, J=8.06Hz, 1H).

Embodiment 37

6-{2-[4-(6-methyl-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4- Dihydro-1H-quinoline-2-one-

Use 4-(the different azoles of 6-methyl-benzo [d]-3-yl)-piperazine, separate purity 100% at 254nm; LCMS (APCl): 433[M+H] ⁺1H NMR (400MHz, δ ppm 1.30 (s, 6H) 2.20 (s of chloroform-D), 3H) 2.45 (s, 2H) 2.46 (s, 3H) 2.60-2.66 (m, 2H) 2.69-2.73 (m, 4H) 2.73-2.79 (m, 2H) 3.56-3.62 (m, 4H) 6.89 (d, J=1.22Hz, 1H) 6.99-7.03 (m, 2H) 7.23 (s, 1H) 7.34 (s, 1H) 7.53 (d, J=8.30Hz, 1H).

Embodiment 38

6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Use 4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperazine (FR-2761067A1), separate purity 100% at 254nm; LCMS (APCl): 452[M+H] ⁺1H NMR (400MHz, δ ppm1.30 (s, 6H) 1.99-2.26 (m, 10H) 2.45 (s of chloroform-D), 2H) 2.57-2.65 (m, 4H) 2.74-2.80 (m, 2H) 3.12-3.24 (m, 3H) 6.90 (s, 1H) 7.01 (s, 1H) 7.15 (td, J=8.67,2.20Hz, 1H) 7.37 (s, 1H) 7.56 (dd, J=8.18,2.08Hz, 1H) 7.94 (dd, J=8.91,4.76Hz, 1H).

Carry out the N-alkylation described in the title compound of embodiment 32 such as the embodiment 39-44 preparation.

Embodiment 39

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-1,4,4,8-tetramethyl--3,4- Dihydro-1H-quinoline-2-one-hydrochloride

To 6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3 adds potassium tert.-butoxide (1.5 equivalent) in the solution of 4-dihydro-1H-quinoline-2-one-(1 equivalent) in anhydrous THF, totally be heated to 40 ℃ 10 minutes.In stirred solution, add methyl iodide (1.5 equivalent), reaction mixture in air-tight bottle, be heated to 60 ℃ 16 hours.After cooling, reaction mixture water and EtOAc dilution, layering.Water layer washs with EtOAc, dry (MgSO ₄) organic layer, concentrate resistates chromatography (4%MeOH/DCM) purifying.Using 1N HCl ether (Et ₂O) during solution-treated, product is isolating 1, the 4-dioxane solution.Separate purity 100% at 254nm; LCMS (APCl): 467[M+H] ⁺1H NMR (400MHz, δ ppm 1.23 (s, 6H) 2.31 (s, 3H) 2.38 (s of chloroform-D), 2H) 3.11-3.32 (m, 8H) 3.52-3.64 (m, 2H) 4.01-4.10 (m, 2H) 4.10-4.24 (m, 2H) 6.96 (d, J=4.15Hz, 2H) 7.30 (td, J=8.55,2.20Hz, 1H) 7.45 (dd, J=8.79,2.20Hz, 1H) 7.79 (dd, J=9.04,4.64Hz, 1H) 13.45 (s, 1H).

With 6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-and suitable alkyl halide are raw material, prepare the title compound of embodiment 40-44 according to embodiment 39 described methods.

Embodiment 40

1-ethyl-6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4,4, the 8-front three Base-3,4-dihydro-1H-quinoline-2-one-hydrochloride

Separate purity 100% at 254nm; LCMS (APCl): 481[M+H] ⁺1H NMR (400MHz, δ ppm 1.09 (t, the J=7.20Hz of chloroform-D), 3H) 1.24 (s, 6H) 2.29 (s, 3H) 2.35 (s, 2H) 3.13-3.28 (m, 6H) 3.54-3.63 (m, 2H) 3.95 (q, J=7.08Hz, 2H) 4.01-4.08 (m, 2H) 4.12-4.21 (m, 2H) 6.94 (d, J=1.47Hz, 1H) 6.98 (d, J=1.95Hz, 1H) 7.30 (td, J=8.61,2.32Hz, 1H) 7.44 (dd, J=8.79,1.95Hz, 1H) 7.79 (dd, J=8.79,4.64Hz, 1H) 13.40 (s, 1H).

Embodiment 41

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-4.4,8-trimethylammonium-1-third Base-3,4-dihydro-1H-quinoline-2-one-hydrochloride

Separate purity 100% at 254nm; LCMS (APCl): 495[M+H] ⁺1H NMR (400MHz, δ ppm 0.84 (t, the J=7.45Hz of chloroform-D), 3H) 1.24 (s, 6H) 1.48 (hextet, J=7.42Hz, 2H) 2.29 (s, 3H) 2.35 (s, 2H) 3.13-3.28 (m, 6H) 3.59 (d, J=11.23Hz, 2H) 3.77-3.86 (m, 2H) 4.04 (d, J=14.41Hz, 2H) 4.11-4.12 (m, 2H) 6.93 (d, J=1.71Hz, 1H) 6.97 (d, J=1.71Hz, 1H) 7.30 (td, J=8.61,2.32Hz, 1H) 7.44 (dd, J=8.91,2.32Hz, 1H) 7.79 (dd, J=8.91,4.52Hz, 1H) 13.39 (s, 1H).

Embodiment 42

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-1-sec.-propyl-4,4,8-three Methyl-3,4-dihydro-1H-quinoline-2-one-hydrochloride

Separate purity 100% at 254nm; LCMS (APCl): 495[M+H] ⁺

Embodiment 43

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl-1-methoxymethyl-4,4,8- Trimethylammonium-3,4-dihydro-1H-quinoline-2-one-hydrochloride

Separate purity 100% at 254nm; LCMS (APCl): 497[M+H] ⁺1H NMR (400MHz, δ ppm 1.27 (s, 6H) 2.28 (s, 3H) 2.37 (s of chloroform-D), 2H) 3.13-3.28 (m, 8H) 3.50 (t, J=5.74Hz, 2H) 3.59 (d, J=11.23Hz, 2H) 4.01-4.20 (m, 6H) 6.93 (s, 1H) 6.98 (d, J=1.22Hz, 1H) 7.30 (td, J=8.61,2.32Hz, 1H) 7.44 (dd, J=8.79,2.20Hz, 1H) 7.79 (dd, J=8.79,4.64Hz, 1H) 13.39 (s, 1H).

Embodiment 44

1-(2-oxyethyl group-ethyl)-6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-second Base }-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-hydrochloride

Separate purity 100% at 254nm; LCMS (APCl): 525[M+H] ⁺1H NMR (400MHz, δ ppm 0.94 (t, J=6.96Hz, 3H) 1.22 (s, 6H) 2.23 (s of chloroform-D), 3H) 2.32 (s, 2H) 3.07-3.22 (m, 6H) 3.26 (q, J=6.92Hz, 2H) 3.47 (t, J=5.86Hz, 2H) 3.54 (d, J=11.23Hz, 2H) 3.96-4.16 (m, 6H) 6.87 (s, 1H) 6.93 (s, 1H) 7.25 (td, J=8.55,2.20Hz, 1H) 7.39 (dd, J=8.91,2.32Hz, 1H) 7.74 (dd, J=8.79,4.40Hz, 1H) 13.34 (s, 1H).

Embodiment 45

6-[2-(4-benzo [B] thiene-3-yl--piperazine-1-yl)-ethyl]-4S-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the method for describing among the embodiment 2, by 1-benzo [b] thiene-3-yl-piperazine hydrochloride (500mg, 1.96mmol; J.Med.Chem., 1992,35,2712) and 6-(2-chloroethyl)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(658mg, 2.94mmol) preparation.(EtOAc) wash-out obtains orange to crude product for silica gel 60,230-400 order, and it is dissolved among the EtOAc, and the 4.0N HCl that solution is used in the diox handles deposited salt hydrochlorate canescence, amorphous solid, output=262mg (30%) by quick post.MS(APCl)：(M+1) ⁺＝406；(M-1) ⁺＝404。 ¹H-NMR(DMSO-d ₆，δ)：10.51(br?s，1H)，10.09(s，1H)，7.92(d，1H，J＝6.6Hz)，7.78(d，1H，J＝7.8Hz)，7.37(m，2H)，7.10(d，2H，J＝8.1Hz)，7.05(d，1H，J＝8.3Hz)，6.81(d，1H，J＝8.1Hz)，3.64(m，4H)，3.35(m，4H)，3.06(m，5H)，2.55(dd，1H，J＝5.9，6.1Hz)，2.20(dd，1H，J＝7.1，7.1Hz)，1.17(d，3H，J＝7.1Hz)。CHN:C ₂₄H ₂₇N ₃O 1HCl calculated value, C:65.22%, H:6.38%, N:9.51%; Experimental value, C:64.76%, H:6.50%, N:9.07%.Specific rotation: [a] ₂₅ ^D=-4.16 ° (DMSO, c=4.81mg/ml).

Embodiment 46

6-[2-(4-benzo [B] thiene-3-yl--piperazine-1-yl)-ethyl]-4R-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the method described in the embodiment 3, by 1-benzo [b] thiene-3-yl-piperazine hydrochloride (600mg, 2.06mmol; J.Med.Chem., 1992,35,2712) and 6-(2-chloroethyl)-4R-methyl-3,4-dihydro-1H-quinoline-2-one-(692mg, 3.09mmol) preparation.(EtOAc) wash-out obtains the yellow crystal solid to crude product for silica gel 60,230-400 order, output=319mg (38%) by quick post.MS(APCl)：(M+1) ⁺＝406；(M-1) ⁺＝404。 ¹H-NMR(DMSO-d ₆，δ)：9.98(s，1H)，7.87(d，1H，J＝6.6Hz)，7.69(d，1H，J＝6.6Hz)，7.33(m，2H)，7.04(s，1H)，6.98(d，1H，J＝7.6Hz)，6.87(s，1H)，6.73(d，1H，J＝7.8Hz)，3.03(m，4H)，2.65(m，10H)，2.17(dd，1H，J＝7.1，6.8Hz)，1.14(d，3H，J＝6.8Hz)。CHN:C ₂₄H ₂₇N ₃The OS calculated value, C:71.08%, H:6.71%, N:10.36%; Experimental value, C:70.82%, H:6.92%, N:10.13%.Specific rotation: [α] ₂₅ ^D=+4.40 (DMSO, c=10mg/ml).Chirality HPLC:ChiralCel OD-H, 5m, 250 * 4.6mm; Mobile phase, the IPA/ hexane; Flow, 0.30ml/min; Peak RT=47.61min (99.96%).

Embodiment 47

6-{2-[4-(the 6-fluorobenzene is [B] thiene-3-yl-also)-piperazine-1-yl]-ethyl }-4S-methyl-3,4-dihydro-1H- Quinoline-2-one-

According to the method described in the embodiment 2, (the 6-fluorobenzene is [b] thiene-3-yl-piperazine hydrochloride (562mg, 2.06mmol also by 1-; J.Med.Chem., 1992,35,2712) and 6-(2-chloroethyl)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(692mg, 3.09mmol) preparation.(2%MeOH/EtOAc) wash-out obtains oily matter to crude product for silica gel 60,230-400 order, and it is crystallization when leaving standstill, output=258mg (30%) by quick post.MS(APCl)：(M+1) ⁺＝424；(M-1) ⁺＝422。 ¹H-NMR (CDCl ₃, δ): 7.64 (m, 2H), 7.44 (d, 1H, J=8.8Hz), 7.04 (m, 3H), 6.65 (d, 1H, J=7.8Hz), 6.55 (s, 1H), 3.15 (m, 5H), 2.77 (m, 9H), 2.39 (dd, 1H, J=7.3,7.3Hz), 1.28 (d, 3H, J=7.1Hz) .CHN:C ₂₄H ₂₆FN ₃The OS calculated value, C:68.06%, H:6.19%, N:9.92%; Experimental value, C:67.80%, H:6.12%, N:9.57%.Specific rotation: [α] ₂₅ ^D=-0.8 ° of (CH ₂Cl ₂, c=5mg/ml).Chirality HPLC:ChiralCel OD-H, 5m, 250 * 4.6mm; Mobile phase, the IPA/ hexane; Flow, 0.30ml/min; Peak RT=32.41min (99.97%).

Embodiment 48

6-{2-[4-(the 6-fluorobenzene is [B] thiene-3-yl-also)-piperazine-1-yl]-ethyl }-4R-methyl-3,4-dihydro-1H- Quinoline-2-one-

According to the method described in the embodiment 3, (the 6-fluorobenzene is [b] thiene-3-yl-piperazine hydrochloride (562mg, 2.06mmol also by 1-; J.Med.Chem., 1992,35,2712) and 6-(2-chloroethyl)-4R-methyl-3,4-dihydro-1H-quinoline-2-one-(692mg, 3.09mmol) preparation.(2%MeOH/EtOAc) wash-out obtains oily matter to crude product for silica gel 60,230-400 order, and it is crystallization when leaving standstill, with cold acetone washing, output=180mg (21%) by quick post.MS(APCl)：(M+1) ⁺＝424；(M-1) ⁺＝422。 ¹H-NMR(CDCl ₃，δ)：7.64(m，2H)，7.44(d，1H，J＝8.8Hz)，7.04(m，3H)，6.65(d，1H，J＝8.1Hz)，6.56(s，1H)，3.15(m，5H)，2.78(m，9H)，2.39(dd，1H，J＝7.3，7.3Hz)，1.29(d，3H，J＝7.1Hz)。CHN:C ₂₄H ₂₆FN ₃The OS calculated value, C:68.06%, H:6.19%, N:9.92%; Experimental value, C:67.86%, H:6.18%, N:9.78%.Specific rotation: [α] ₂₅ ^D=+3.2 ° of (CH ₂Cl ₂, c=5mg/ml).Chirality HPLC:ChiralCel OD-H, 5m, 250 * 4.6mm; Mobile phase, IPA in hexane; Flow, 0.30ml/min; Peak RT=34.51min (99.97%).

Embodiment 49

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.6-(3-chloro-propionyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

With 4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(10g 57.1mmol) is dissolved in the 60ml dithiocarbonic anhydride, slowly add aluminum chloride (15.0g, 112mmol) and the 3-chlorpromazine chloride (7.0mL, 84.4mmol).Reactant is heated to backflow, stirs 3 hours.Decant dithiocarbonic anhydride, reaction flask cools off in ice bath.Slowly add ice and water until all aluminium reactions, form precipitation.Stirred reaction mixture 1 hour filters out precipitation, washs with massive laundering.Vacuum-drying 6-(3-chloro-propionyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(14.34g).MS(APCl)：266[M+H] ⁺。

B.6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

With 6-(3-chloro-propionyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(6.0g) is dissolved in the trifluoroacetic acid (13.9mL), is cooled to 0 ℃, slowly adds triethyl silicane (10.8mL), and mixture at room temperature stirred 3 days.In mixture impouring frozen water, use the hexane layering, vigorous stirring 30 minutes.Filter out the precipitation of generation, wash with water, vacuum-drying obtains 6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield 100%; MS (APCl): 252[M+H] ⁺

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro-1H- Quinoline-2-one-

(0.160g) dilutes in 10mL water with anhydrous sodium carbonate, add 6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.300g, 1.19mmol), 3-piperazine-1-base-benzisothiazole (0.390g, 1.78mmol) and acetonitrile (10mL).Mixture refluxes and stirred 48 hours, and after cooling 1 hour, solution dilutes with ethyl acetate, washes with water.Organic extract sodium sulfate (Na ₂SO ₄) drying, concentrate with vacuum-drying and obtain 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.030g).MS(APCl)：435[M+H] ⁺。 ¹H?NMR(400MHz，CDCl ₃)δ8.23(s，1H)，7.85(d，J＝8.1Hz，1H)，7.76(d，J＝8.1Hz，1H)，7.4(t，J＝8.1Hz，1H)，7.29(t，J＝8.1Hz，1H)，7.09(s，1H)，6.95(dd，J＝1.7，1.9Hz，1H)，6.66(d，J＝7.81Hz，1H)，3.55(s，4H)，2.66(s，4H)，2.58(t，J＝7.5，7.8Hz，2H)，2.44(s，4H)，1.81(m，2H)，1.28(s，6H)。

Embodiment 50

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4,4-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (2.50g), 6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(2.0g, 7.94mmol) and 3-piperazine-1-base-indazole hydrochloride (2.0g, 8.38mmol) preparation 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.200g6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-propyl group }-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.MS(APCl)：418[M+H] ⁺。 ¹H?NMR(400MHz，CDCl ₃)δ9.13(s，1H)，7.66(d，J＝8.3Hz，1H)，7.58(s，1H)，7.3(s，1H)，7.0(m，3H)，6.62(d，J＝7.81Hz，1H)，3.4(s，4H)，2.6(m，5H)，2.44(s，3H)，1.84(m，2H)，1.54(s，2H)，1.28(s，6H)。

Embodiment 51

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-chloro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

A.7-chloro-6-(3-chloro-propionyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in embodiment 49 steps A; with 7-chloro-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(1.00g; 4.77mmol), aluminum chloride (2.54g, 19.1mmol) and 3-chlorpromazine chloride (0.47mL, 5.66mmol) preparation 7-chloro-6-(3-chloro-propionyl)-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 76% obtains 7-chloro-6-(3-chloro-propionyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.MS(APCl)：300[M+H] ⁺。

B.7-chloro-6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; with 7-chloro-6-(3-chloro-propionyl)-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(1.05g; 3.49mmol), trifluoroacetic acid (1.86mL, 24.1mmol) and triethyl silicane (0.939mL, 5.88mmol) preparation 7-chloro-6-(3-chloro-propyl group)-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 26% obtains 7-chloro-6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.260g).MS(APCl)：286[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-chloro-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (0.097g), 7-chloro-6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.200g, 0.698mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.229g, 1.04mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.084g 7-chloro-6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl): 469[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ8.16(s，1H)，7.85(d，J＝8.1Hz，1H)，7.76(d，J＝8.3Hz，1H)，7.4(t，J＝8.1Hz，1H)，7.3(t，J＝8.1Hz，1H)，7.1(s，1H)，6.76(s，1H)，3.57(s，4H)，2.7(m，6H)，2.45(t，J＝7.1，7.5Hz，3H)，2.43(s，3H)，1.84(m，2H)，1.27(s，6H)。

Embodiment 52

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-7-chloro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

According to the general method described in the embodiment 49, with anhydrous sodium carbonate (0.022g), 7-chloro-6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.046g, 0.162mmol) and 3-piperazine-1-base-benzo [d] isoxazole (0.033g, 0.162mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-7-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.014g 7-chloro-6-[3-(4-benzoisoxazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.MS(APCl)：453[M+H] ⁺ ^。1HNMR(400MHz，CDCl ₃)δ8.23(s，1H)，7.6(d，J＝8.1Hz，1H)，7.39(t，J＝7.8，8.5Hz，2H)，7.13(t，J＝6.8，7.8Hz，1H)，7.07(s，1H)，6.74(s，1H)，3.5(s，4H)，2.66(m，6H)，2.6(s，4H)，1.77(m，2H)，1.25(s，6H)。

Embodiment 53

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline -2-ketone

A.6-(3-chloro-propionyl)-4-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in embodiment 49 steps A; with 4-methyl-3; 4-dihydro-1H-quinoline-2-one-(10.0g; 62.0mmol), aluminum chloride (15.0g; 112.5mmol) and 3-chlorpromazine chloride (7.2mL; 86.8mmol) preparation 6-(3-chloro-propionyl)-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 50% obtains 6-(3-chloro-propionyl)-4-methyl-3,4-dihydro-1H-quinoline-2-one-(7.79g).MS(APCl)：251[M+H] ⁺。

B.6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; with 6-(3-chloro-propionyl)-4-methyl-3; 4-dihydro-1H-quinoline-2-one-(5.0g; 19.8mmol), trifluoroacetic acid (9.0mL; 116.8mmol) and triethyl silicane (9.52mL; 59.6mmol) preparation 6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-obtains 6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-with 100% yield.MS(APCl)：238[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (0.50g), 6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-(0.300g, 1.42mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.62g, 2.83mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline-2-one-.The precipitation that obtains is washed with a large amount of water and acetonitrile, and vacuum-drying obtains 0.315g 6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl), 421[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ8.36(s，1H)，7.85(d，J＝8.1Hz，1H)，7.76(d，J＝8.1Hz，1H)，7.4(t，J＝7.56Hz，1H)，7.3(t，J＝7.3，7.81Hz，1H)，7.0(s，1H)，6.96(d，J＝8.6Hz，1H)，6.67(d，J＝8.1Hz，1H)，3.5(t，J＝4.39，4.88Hz，4H)，3.04(m，1H)，2.6(m，7H)，2.35(m，3H)，1.8(m，2H)，1.26(d，J＝7.1Hz，3H)。

Embodiment 54

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49, with anhydrous sodium carbonate (0.450g), 6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-(0.300g, 1.42mmol) and 3-piperazine-1-base-benzo [d] isoxazole (0.578g, 2.84mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.185g 6-[3-(4-1,2-benzisoxa azoles-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl), 405[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ7.95(s，1H)，7.6(d，J＝8.1Hz，2H)，7.4(m，2H)，7.15(m，1H)，6.99(s，1H)，6.96(d，J＝8.1Hz，1H)，6.64(d，J＝8.1Hz，1H)，3.5(t，J＝4.8，5.1Hz，3H)，3.09(m，1H)，2.66(m，8H)，2.4(m，3H)，1.8(m，2H)，1.26(d，J＝6.83Hz，3H)。

Embodiment 55

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (5.79g), 6-(3-chloro-propyl group)-4-methyl-3,4-dihydro-1H-quinoline-2-one-(3.73g, 15.7mmol) and 3-piperazine-1-base-1H-indazole hydrochloride (2.5g, 10.5mmol) preparation 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.547g 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-propyl group }-4-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 404[M+H] ⁺ ¹HNMR(400MHz，CDCl ₃)δ9.31(s，1H)，7.91(s，1H)，7.67(d，J＝8.3Hz，1H)，7.3(m，2H)，7.0(m，3H)，6.6(d，J＝7.81Hz，1H)，3.4(m，5H)，3.04(m，2H)，2.6(t，J＝4.4，5.6Hz，3H)，2.57(t，J＝7.56，7.81Hz，2H)，2.39(m，3H)，1.8(m，2H)，1.26(d，J＝7.1Hz，3H)。

Embodiment 56

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

A.6-(3-chloro-propionyl)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method in embodiment 49 steps A; with 3; 3-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(4.0g; 15.89mmol), aluminum chloride (6.4g, 48mmol) and 3-chlorpromazine chloride (1.85mL, 22.3mmol) preparation 6-(3-chloro-propionyl)-3; 3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 100% obtains 6-(3-chloro-propionyl)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.MS(APCl)：266[M+H] ⁺。

B.6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; with 6-(3-chloro-propionyl)-3; 3-dimethyl-3; 4-dihydro-1H quinoline-2-one-(5.0g; 18.8mmol), trifluoroacetic acid (10.1mL, 131mmol) and triethyl silicane (9.0mL, 56.3mmol) preparation 6-(3-chloro-propyl group)-3; 3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 100% obtains 6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-(4.99g).MS(APCl)：252[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H- Quinoline-2-one-

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (0.357g), 6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.500g, 1.99mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.566g, 2.58mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.The solid that generates washs with big water gaging and acetonitrile, and vacuum-drying obtains 0.0991g 6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 435[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ7.85(d，J＝8.1Hz，1H)，7.76(d，J＝8.1Hz，1H)，7.61(s，1H)，7.4(t，J＝7.1，7.3Hz，1H)，7.3(t，J＝7，8.1Hz，1H)，6.97(s，1H)，6.95(s，1H)，6.59(d，J＝7.81Hz，1H)，3.5(t，J＝4.6，4.8Hz，4H)，2.73(s，2H)，2.6(t，J＝4.6，4.88Hz，3H)，2.5(t，J＝7.5，7.8Hz，3H)，2.4(t，J＝7.3，7.56Hz，2H)，1.8(m，2H)，1.16(s，6H)。

Embodiment 57

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (0.358g), 6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.500g, 1.99mmol) and 3-piperazine-1-base-benzo [d] isoxazole (0.525g, 2.58mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.144g 6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl), 419[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ7.6(m，2H)，7.4(m，2H)，7.1(m，1H)，6.96(s，1H)，6.94(s，1H)，6.6(d，J＝7.81Hz，1H)，3.5(t，J＝4.88Hz，4H)，2.73(s，2H)，2.5-2.6(m，6H)，2.4(t，J＝7.3，7.5Hz，2H)，1.8(m，2H)，1.16(s，6H)。

Embodiment 58

6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-3,3-dimethyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 23, with anhydrous sodium carbonate (6.0g), 6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-(1.69g, 6.71mmol) and 3-piperazine-1-base-1H-indazole hydrochloride (2.0g, 8.38mmol) preparation 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.308g 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-propyl group }-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 418[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ9.26(s，1H)，7.7(d，J＝8.3Hz，1H)，7.5(s，1H)，7.3(m，2H)，7-7.2(m，1H)，6.97(s，1H)，6.95(s，1H)，6.59(d，J＝7.8Hz，1H)，3.47(s，4H)，2.73(s，2H)，2.65(s，3H)，2.6(t，J＝7.8Hz，2H)，2.4(s，2H)，1.8(s，2H)，1.59(s，1H)，1.16(s，6H)。

Embodiment 59

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline -2-ketone

A.6-(3-chloro-propionyl)-3-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the described general method of embodiment 49 steps A; use 3-methyl-3; 4-dihydro-1H-quinoline-2-one-(10.0g; 662mmol), aluminum chloride (16g; 120mmol) with 3-chlorpromazine chloride (7.20mL; 86.7mmol) preparation 6-(3-chloro-propionyl)-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 100% obtains 6-(3-chloro-propionyl)-3-methyl-3,4-dihydro-1H quinoline-2-one-.MS(APCl)：252[M+H] ⁺。

B.6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; use 6-(3-chloro-propionyl)-3-methyl-3; 4-dihydro-1H-quinoline-2-one-(5.50g; 21.8mmol), trifluoroacetic acid (10.5mL; 136mmol) and triethyl silicane (9.0mL; 56.0mmol) preparation 6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 100% obtains 6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-(4.99g).MS(APCl)：238[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (2.33g), 6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-(2.00g, 8.41mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (2.33g, 16.8mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-.The solid that generates washs with big water gaging and acetonitrile, and vacuum-drying obtains 0.452g 6-[3-(4-1,2-benzisothiazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 421[M+H] ⁺M.p212 ℃. ¹H?NMR(400MHz，CDCl ₃)δ7.91(s，1H)，7.86(d，J＝8.3Hz，1H)，7.76(d，J＝8.05Hz，1H)，7.40(t，J＝7.32，7.56Hz，1H)，7.30(t，J＝7.32，7.56Hz，1H)，6.97(s，2H)，6.63(d，J＝8.30Hz，1H)，3.54(s，4H)，2.9(dd，J＝5.13，4.88Hz，1H)，2.56-2.71(m，8H)，2.4(t，J＝7.08，8Hz，2H)，1.8-1.85(m，2H)，1.24(d，J＝6.58Hz，3H)。

Embodiment 60

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (0.68g), 6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-(1.17g, 4.92mmol) and 3-piperazine-1-base-benzo [d] isoxazole (1.30g, 6.39mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Resistates extracts with ethylene dichloride, with sodium sulfate (Na ₂SO ₄) drying, concentrate and obtain 0.208g 6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group]-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 405[M+H] ⁺M.p.185-187 ℃. ¹H?NMR(400MHz，CDCl ₃)δ7.66(s，1H)，7.64(s，1H)，7.4(m，2H)，7.16(m，1H)，6.97(s，2H)，6.6(m，1H)，3.5(t，J＝4.39Hz，4H)，2.9(dd，J＝5.13，5.37Hz，1H)，2.5-2.7(m，8H)，2.4(t，J＝7.3，7.5Hz，2H)，1.7-1.8(m，2H)，1.24(d，J＝6.58Hz，3H)。

Embodiment 61

6-{3-[4-1H-indazole-3-yl]-piperazine-1-yl }-propyl group }-3-methyl-3, the 4-DIHYDRO-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with anhydrous sodium carbonate (7.0g), 6-(3-chloro-propyl group)-3-methyl-3,4-dihydro-1H-quinoline-2-one-(3.73g, 15.7mmol) and 3-piperazine-1-base-1H-indazole hydrochloride (2.5g, 10.47mmol) preparation 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl]-propyl group }-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.74g 6-{3-[4-(1H-indazole-3-yl)-piperazine-1-yl with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-propyl group }-3-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 404[M+H] ⁺ ¹HNMR(400mHz，DMSO-d ₆)δ11.9(s，1H)，9.9(s，1H)，7.6(d，J＝8.05Hz，1H)，7.28(d，J＝8.30Hz，1H)，7.19(m，3H)，6.88(m，3H)，6.68(d，J＝7.81，1H)，3.26(s，4H)，2.80(dd，J＝5.86，6.0Hz，1H)，2.4-2.58(m，8H)，2.27(t，J＝7.08Hz，2H)，1.66(t，J＝7.08，7.32Hz)，1.04(d，J＝6.59Hz，3H)。

Embodiment 62

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4S-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.754g), 6-(3-chloro-propyl group)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(0.4318g, 1.82mmol, at US 5,350, in 747 by 4S-methyl-3,4-dihydro-1H-quinoline-2-one-prepares) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.597g, 2.72mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4S-methyl-3,4-dihydro-1H-quinoline-2-one-.The solid that generates washs with big water gaging and acetonitrile, and vacuum-drying obtains 0.600g6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4S-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 421.2[M+H] ⁺CHN:C ₂₄H ₂₈N ₄O ₁S ₁Calculated value, C:68.54%, H:6.71, N:13.32%; Experimental value, C:68.07%, H:6.78%, N:12.86%.

Embodiment 63

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4R-methyl-3.4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.873g), 6-(3-chloro-propyl group)-4R-methyl-3,4-dihydro-1H-quinoline-2-one-(0.500g, 2.10mmol at US5,4S-methyl-3 in 350,47,4-dihydro-1H-quinoline-2-one-preparation) and 3-piperazine-1-base benzo [d] isoniazthiolane hydrochlorate (0.692g, 3.16mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4R-methyl-3,4-dihydro-1H-quinoline-2-one-.The precipitation that generates obtains 0.256g6-[3-(4-1,2-benzisothiazole-3-base piperazine-1-yl)-propyl group with big water gaging and acetonitrile washing, vacuum-drying]-4R-methyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; LCMS (APCl) 421.2[M+H] ⁺CHN:C ₂₄H ₂₈N ₄O ₁S ₁Calculated value, C:68.54%, H:6.71, N:13.32%; Experimental value, C:68.24%, H:6.80%, N:13.01%.

Embodiment 64

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4R-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.762g), 6-(3-chloro-propyl group)-4R-methyl-3,4-dihydro-1H-quinoline-2-one-(0.1308g, 0.550mmol) and 3-piperazine-1-base benzo [d] isoxazole (0.264g, 1.10mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4R-methyl-3, the 4-1H-quinoline-2-one-.Solid obtains 0.027g 6-[3 (4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4R-methyl-3,4-dihydro-1H-quinoline-2-one-.MS(APO)：405.2[M+H] ⁺。

Embodiment 65

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4S-methyl-3,4-dihydro-1H-quinoline -2-ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.537g), 6-(3-chloro-propyl group)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(0.0923g, 0.388mmol) and 3-piperazine-1-base benzo [d] isoxazole (0.186g, 0.776mmol) preparation 6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4S-methyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.049g 6-[3-(4-1,2-benzoisoxazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4S-methyl-3,4-dihydro-1H-quinoline-2-one-.MS(APCl)：(M+H) ⁺405.2。 ¹H?NMR(400mHz，CDCl ₃)δ。

Embodiment 66

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

A.6-(3-chloro-propionyl)-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the described general method of embodiment 49 steps A; use 7-fluoro-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(1.00g; 5.18mmol), aluminum chloride (2.76g, 20.7mmol) and the 3-chlorpromazine chloride (0.664mL, 7.76mmol) preparation 6-(3-chloro-propionyl)-7-fluoro-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 84% obtains 6-(3-chloro-propionyl)-7-fluoro-4,4-dimethyl-3,4-dihydro-1H quinoline-2-one-(1.23g).MS(APCl)：284.1[M+H] ⁺。

B.6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; use 6-(3-chloro-propionyl)-7-fluoro-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(1.23g; 4.34mmol), trifluoroacetic acid (2.09mL, 25.9mmol) and triethyl silicane (1.73mL, 10.8mmol) preparation 6-(3-chloro-propyl group)-7-fluoro-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Yield with 98% obtains 6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(1.15g).MS(APCl)：270.1[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (1.20g), 6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.384g, 1.42mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.63g, 2.87mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.365g 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-7-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Purity 100% is at 254nm; MS (APCl): 453.1[M+H] ⁺

Embodiment 67

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-

A.6-(3-chloro-propyl group)-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

In nitrogen and 0 ℃, with 6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3, (embodiment 66B, 0.768g 2.85mmol) add NaH (60% oil suspension to 4-dihydro-1H-quinoline-2-one-, 0.137g, in the stirred suspension in 3.43mmol) in THF.(0.62ml 9.96mmol), is warming to room temperature, and stirring is spent the night to be added dropwise to methyl-iodide at 0 ℃.The quencher of reaction mixture water, (the salt water washing is used in 3 * 50mL) extractions with ethyl acetate.Dry (sodium sulfate) organic extract concentrates.The vacuum-drying solid obtains 6-(3-chloro-propyl group)-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro-1H quinoline-2-one-(0.7266g) with 90% yield.MS(APCl)：284.1[M+H] ⁺。

B.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-1,4,4-trimethylammonium-3,4- Hydrogen-1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (1.06g), 6-(3-chloro-propyl group)-7-fluoro-1,4,4-trimethylammonium-3, (0.7266g is 2.56mmol) with 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.842g for 4-dihydro-1H-quinoline-2-one-, 3.84mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Solid obtains 0.120g 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Prepare mesylate by solid being dissolved among THF and the MeOH and adding 1 equivalent methylsulfonic acid.Filter out precipitation, obtain 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the ether washing]-7-fluoro-1,4,4-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-mesylate.Purity 100% is at 254nm; LCMS (APCl): 467.2[M+H] ⁺

Embodiment 68

1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4-two Hydrogen-2H-quinoline-1-yl }-ethyl ketone

A.6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline

At 0 ℃, to 6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3, (embodiment 66B, 0.768g 2.85mmol) slowly add BH through adding funnel in the stirred solution in THF (20mL) to 4-dihydro-1H-quinoline-2-one- ₃.THF (1M, 38ml).Be warming to room temperature, stirring is spent the night.Reaction mixture stirred 4 hours with the quencher of aqueous carbonic acid hydrogen sodium.Filter out precipitation, (3 * 100mL) extractions, water and saturated nacl aqueous solution wash filtrate with ethyl acetate.Dry (sodium sulfate) organic extract concentrates.The solid that vacuum-drying obtains obtains 6-(3-chloropropyl)-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (0.8319g), MS (APCl): 265.1[M+H] ⁺

B.1-[6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone

To 6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (0.400g, 1.56mmol) add in the stirred solution in THF (3mL) acetate (0.30mL, 3.18mmol) and triethylamine (0.30mL).Reflux, stirring is spent the night, the quencher of reaction mixture water.(3 * 50mL) extractions are with saturated NaCl washing with ethyl acetate.Dry (sodium sulfate) organic extract concentrates.The solid vacuum-drying that generates obtains 1-[6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.376g).MS(APCl)：298.1[M+H] ⁺。

C.1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4- Dihydro-2H-quinoline-1-yl }-ethyl ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.699g), 1-[6-(3-chloro-propyl group)-7-fluoro-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.376g, 1.26mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.554g, 2.53mmol) preparation 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-7-fluoro-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.Solid obtains 0.300g 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-7-fluoro-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.Purity 100% is at 254nm; LCMS (APCl) 481.2[M+H] ⁺CHN:C ₂₇H ₃₅F ₁N ₄O ₁S ₁Calculated value C:67.4%, H:6.92, N:11.66%; Experimental value, C:67.18%, H:6.98%, N:11.48%.

Embodiment 69

1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro -2H-quinoline-1-yl }-ethyl ketone

A.6-(3-chloro-propyl group)-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline

According to the general method described in embodiment 68 steps A, with 6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(embodiment 49B, 1.50g, 5.96mmol), BH ₃.THF (1M, 30ml) and THF (25mL) preparation 6-(3-chloro-propyl group)-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline.The vacuum-drying solid obtains 6-(3-chloro-propyl group)-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (0.520).MS(APCl)：[M+H] ⁺238.1。

B.1-[6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone

According to the general method described in the embodiment 48 step B, use 6-(3-chloro-propyl group)-4,4-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (0.500g, 2.10mmol), acetate (0.39mL, 4.13mmol) and triethylamine (0.39mL) preparation 1-[6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone.Solid is with the automatic column purification of ISCO, and with 1: 1 dichloromethane/ethyl acetate, 2%MeOH wash-out, vacuum-drying obtains 1-[6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.390g).MS(APCl)：280.1[M+H] ⁺。

C.1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4-dimethyl-3,4-dihydro -2H-quinoline-1-yl }-ethyl ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.77g), 1-[6-(3-chloro-propyl group)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.390g, 1.39mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.610g, 2.79mmol) preparation 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4 dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.Solid obtains 0.108g 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.100% purity is at 254nm; LCMS (APCl) 463.2[M+H] ⁺

Embodiment 70

1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro -2H-quinoline-1-yl }-ethyl ketone

A.6-(3-chloro-propyl group)-3,3-dimethyl-1,2,3,4 ,-tetrahydrochysene-quinoline

According to the general method described in embodiment 68 steps A, with 6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-(1.70g, 6.77mmol), BH ₃.THF (1M, 30mL) and THF (20mL) preparation 6-(3-chloro-propyl group)-3,3-dimethyl-1,2,3,4-tetrahydrochysene-quinoline.The vacuum-drying solid obtains 6-(3-chloro-propyl group)-3,3-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (1.60g).MS(APCl)：[M+H] ⁺238.1。

B.1-[6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone

According to the general method described in the embodiment 68 step B, with 6-(3-chloro-propyl group)-3,3-dimethyl-1,2,3,4-tetrahydrochysene-quinoline (1.0g, 4.21mmol), acetate (0.794mL, 8.41mmol) and triethylamine (0.794mL) preparation 1-[6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 1-[6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.8002g).MS(APCl)：280.1[M+H] ⁺。

C.1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro -2H-quinoline-1-yl }-ethyl ketone

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (1.52g), 1-[6-(3-chloro-propyl group)-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl]-ethyl ketone (0.80g, 2.86mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (1.0g, 4.56mmol) preparation 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.Solid obtains 0.250g1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-ethyl ketone.Prepare mesylate by solid being dissolved among THF and the MeOH and adding 1 equivalent methylsulfonic acid.Filter out precipitation, obtain 1-{6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the ether washing]-3,3-dimethyl-3,4-dihydro-2H-quinoline-1-yl }-the ethyl ketone mesylate.Purity 100% is at 254nm; LCMS (APCl) 463.2[M+H] ⁺

Embodiment 71

6-[3 (4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-1,3,3-trimethylammonium-1,2,3, the 4-tetrahydrochysene- Quinoline

A.6-(3-chloro-propyl group)-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline

According to embodiment 67 steps A 6-(3-chloro-propyl group)-3,3-dimethyl-3, and 4-dihydro-1H-quinoline-2-one-(0.482g, 2.03mmol), NaH (60% oil suspension, 0.106g, 2.65mmol) and methyl-iodide (0.510mL, 8.19mmol) preparation 6-(3-chloro-propyl group)-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline.The vacuum-drying solid obtains 6-(3-chloro-propyl group)-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline (0.165g).MS(APCl)：252.1[M+H] ⁺。

B.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-1,3,3-trimethylammonium-1,2,3,4-four Hydrogen-quinoline

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.209g), 6-(3-chloro-propyl group)-1,3,3-trimethylammonium-1,2,3,4 tetrahydrochysenes-quinoline (0.1651g, 0.656mmol) and 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.230g, 1.05mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline.Solid obtains 0.093g 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the automatic column purification of ISCO with 80% ethyl acetate/hexane wash-out]-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline.Prepare mesylate by solid being dissolved among THF and the MeOH and adding 1 equivalent methylsulfonic acid.Filter out precipitation, obtain 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group with the ether washing]-1,3,3-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline mesylate.Purity 100% is at 254nm; LCMS (APCl) 435.1[M+H] ⁺ ¹H?NMR(400MHz，CDCl ₃)δ

Embodiment 72

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group 1-8-chloro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

A.6-(3-chloro-propionyl)-8-chloro-4,4-dimethyl-3,4-dihydro-1H-3,4-dihydro-1H-quinoline-2-one-

According to the described general method of embodiment 27 step C; use 8-chloro-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(2.0g; 9.54mmol), aluminum chloride (11.0g, 82.5mmol) and chlorpromazine chloride (2.97mL, 35.8mmol) preparation 6-(3-chloro-propionyl)-8-chloro-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Filter out precipitation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propionyl)-8-chloro-4,4-dimethyl-3,4-dihydro-1H quinoline-2-one-(0.439g).MS(APCl)：300.0[M+H] ⁺。

B.6-(3-chloro-propyl group)-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 27 step D; use 6-(3-chloro-propionyl)-8-chloro-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(0.439g; 1.46mmol), trifluoroacetic acid (0.676mL, 8.77mmol) and triethyl silicane (0.584mL, 3.86mmol) preparation 6-(3-chloro-propyl group)-8-chloro-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Filter out precipitation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propyl group)-8-fluoro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.417g).MS(APCl)：286.0[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8--4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (0.200g), 6-(3-chloro-propyl group)-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.375g, 1.31mmol) and 3-piperazine-1-base benzo [d] isoniazthiolane hydrochlorate (0.300g, 1.37mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.080g).MS(APCl)：468.2[M+H] ⁺。

Embodiment 73

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-8-chloro-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (1.5g, 29.6mmol), 6-(3-chloro-propyl group)-8-chloro-4,4 dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.375g, 1.31mmol) and 3-piperazine-1-base-benzo [d] isoxazole (0.63g, 2.63mmol) preparation 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-8-chloro-4,4 dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl) propyl group]-8-chloro-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.100g).MS(APCl)：453.2[M+H] ⁺。

Embodiment 74

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

A.6-(3-chloro-propionyl)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in embodiment 49 steps A; with 4; 4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(1.0g; 5.28mmol), aluminum chloride (2.82g; 21.5mmol) and chlorpromazine chloride (0.526mL, 6.34mmol) preparation 6-(3-chloro-propionyl)-4,4; 8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Filter out the precipitation of generation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propionyl)-4,4,8-trimethylammonium-3,4-dihydro-1H quinoline-2-one-(1.27g).MS(APCl)：280.1[M+H] ⁺。

B.6-(3-chloro-propyl group)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; with 6-(3-chloro-propionyl)-4; 4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(1.27g; 4.54mmol), trifluoroacetic acid (2.1mL; 27.3mmol) and triethyl silicane (1.81mL, 11.3mmol) preparation 6-(3-chloro-propyl group)-4,4; 8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Filter out the precipitation of generation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propyl group)-4,4,8-trimethylammonium-3,4-dihydro-1H quinoline-2-one-(0.693g).MS(APCl)：266.1[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro -1H-quinoline-2-one-

According to the general method described in the embodiment 49 step C, with Anhydrous potassium carbonate (0.375g), 6-(3-chloro-propyl group)-4,4,8-trimethylammonium-3, (0.30g is 1.1mmol) with 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (0.297g for 4-dihydro-1H-quinoline-2-one-, 1.35mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(0.0896g).MS(APCl)：449.2[M+H] ⁺。

Embodiment 75

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H- Quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (1.56g, 11.3mmol), 6-(3-chloro-propyl group)-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(30g, 1.1mmol) and 3-piperazine-1-base-benzo [d] isoxazole (0.54g, 2.26mmol) preparation 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-4,4,8-trimethylammonium-3,4-dihydro-1H-quinoline-2-one-(0.257g).MS(APCl)：433.2[M+H] ⁺。

Embodiment 76

6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

A.6-(3-chloro-propionyl)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in embodiment 49 steps A; with 8-ethyl-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(2.0g; 9.84mmol), aluminum chloride (5.25g, 39.37mmol) and chlorpromazine chloride (0.98mL, 11.81mmol) preparation 6-(3-chloro-propionyl)-8-ethyl-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Filter out precipitation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propionyl)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(2.86g).MS(APCl)：294.1[M+H] ⁺。

B.6-(3-chloro-propyl group)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step B; with 6-(3-chloro-propionyl)-8-ethyl-4; 4-dimethyl-3; 4-dihydro-1H-quinoline-2-one-(2.86g; 9.74mL), trifluoroacetic acid (4.5mL, 58.4mmol) and triethyl silicane (3.89mL, 24.4mmol) preparation 6-(3-chloro-propyl group)-8-ethyl-4; 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Filter out precipitation, wash with massive laundering, vacuum-drying obtains 6-(3-chloro-propyl group)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(1.66g).MS(APCl)：280.1[M+H] ⁺。

C.6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4- Dihydro-1H-quinoline-2-one-

According to the general method described in the embodiment 49 step C, with Anhydrous potassium carbonate (1.30g), 6-(3-chloro-propyl group)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.70g, 2.5mmol) and 3-piperazine-1-base benzo [d] isoniazthiolane hydrochlorate (0.823g, 3.75mmol) preparation 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.223g).MS(APCl)：463.2[M+H] ⁺。

Embodiment 77

6-[3-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

According to the general method described in the embodiment 49C, with Anhydrous potassium carbonate (4.1g, 29.6mmol), 6-(3-chloro-propyl group)-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.700g, 2.5mmol) and 3-piperazine-1-base-benzo [d] isoxazole (1.19g, 4.96mmol) preparation 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.Solid is with the automatic column purification of ISCO, and with 4: 1 ethyl acetate/hexane wash-outs, vacuum-drying obtained 6-[3-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-propyl group]-8-ethyl-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.4225g).MS(APCl)：447.2[M+H] ⁺。

Prepare embodiment 78-87 according to following synthetic route:

Embodiment 78

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl isophthalic acid H-quinoline-2-one-

In being equipped with the open tube (8ml) of stirring rod, mix aniline (IP 901A, 1.0mmol, 338mgs), ortho-xylene (1ml) and ethanoyl ethyl acetate (1.1mmol, 140 μ l).Mixture in the aluminium heat block, be heated to 130 ℃ 2.5 hours.(TLC and MS show only residual trace aniline).With the reaction mixture cooling, be concentrated into dried (light yellow oil).Crude amide is used the 1ml vitriolization subsequently, reaction mixture sealing, be warming to 80 ℃ 1 hour.The reaction mixture cooling is in impouring water/ice.Regulate pH to neutral (～7) with 50%NaOH.Filter out precipitation, be dried to constant weight.Crude product is dissolved in 400: 8: 1 (CH ₂Cl ₂: EtOH: NH ₄OH) in, add silicagel column, through the MPLC purifying, (silicagel column 40g) uses methylene dichloride-(100: 8: 1) methylene dichloride: ethanol: ammoniacal liquor gradient elution 1 hour obtains pure products (193mgs, 47.7% yield).Crystallization is developed with acetonitrile, filters.MS(APCl)：405[M+H]。 ¹HNMR(400MHz，DMSO-D ₆)δppm2.39(d，J＝1.22Hz，3H)2.63(m，6H)2.81(m，2H)3.30(d，J＝9.52Hz，8H)3.42(m，4H)6.34(s，1H)7.20(d，J＝8.30Hz，1H)7.39(m，2H)7.53(m，2H)8.02(d，J＝8.30Hz，2H)11.50(s，1H)。

The title compound for preparing embodiment 79-87 with the method that is similar to embodiment 78.

Embodiment 79

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one-

MS(APCl)：419[M+H]。

Embodiment 80

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-ethyl-1H-quinoline-2-one-

MS(APCl)：419[M+H]。

Embodiment 81

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,2,3,5-tetrahydrochysene-pentamethylene is [c] also Quinoline-4-ketone

MS(APCl)：431[M+H]。

Embodiment 82

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-ethyl-4-methyl isophthalic acid H-quinoline-2- Ketone

MS(APCl)：433[M+H]。

Embodiment 83

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-propyl group-1H-quinoline-2-one-

MS(APCl)：433[M+H]。

Embodiment 84

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-sec.-propyl-1H-quinoline-2-one-

MS(APCl)：433[M+H]。

Embodiment 85

2-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-7,8,9,10-tetrahydrochysene-5H-phenanthridines-2- Ketone

MS(APCl)：445[M+H]。

Embodiment 86

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-Trifluoromethyl-1 H-quinoline-2-one-

MS(APCl)：459[M+H]。

Embodiment 87

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-phenyl-1H-quinoline-2-one-

MS(APCl)：467[M+H]。

Embodiment 88

9-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

A.9-(2-chloracetyl)-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

Under vigorous stirring, (1.56ml 19.6mmol) adds 1 with chloroacetyl chloride, 2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone (2.04g, 10.9mmol, Tetrahedron, 1986,42,5407) and aluminum chloride (7.27g is 54.5mmol) in the mixture in dithiocarbonic anhydride (50ml).Reaction mixture refluxed heating 2 hours is cooled to room temperature.The decant solvent, resistates is slowly handled with cold water under vigorous stirring, after quencher, collects golden amorphous solid, washes with water and drying.Yield=2.51g (87%); MS (APCl), (M+1) ⁺=264, (M-1) ⁺=262.

B.9-(2-chloroethyl)-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

(2.51g 9.52mmol) adds in 7.30ml (95.2mmol) trifluoroacetic acid, under nitrogen atmosphere stirred mixture is cooled to 0 ℃ with the product of embodiment 88A.Add triethyl silicane (3.52ml, 21.8mmol), reaction mixture remained on room temperature 15 hours 45 ℃ of heating 20 minutes in batches.In reaction mixture impouring water, use ethyl acetate extraction.The organic extract dried over mgso is filtered and is concentrated.(1: 1 hexane: EtOAc) wash-out obtains yellow oil for silica gel 60,230-400 order, crystallization when leaving standstill by quick post.Output=1.90g (80%); MS (APCl), (M+1) ⁺=250, (M+3) ⁺=253.

C.9-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

With 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (1.62g, 6.34mmol), the product (1.90g of embodiment 88B, 7.61mmol), Anhydrous potassium carbonate (1.93g, 13.9mmol) and the mixture of potassiumiodide (200mg) in acetonitrile (80ml) refluxed 48 hours.Concentrated reaction mixture, resistates distributes between methylene dichloride and water.The organic layer dried over mgso is filtered and is concentrated.Crude product by quick post (silica gel 60, the 230-400 order, EtOAc) wash-out obtain transparent, thickness oily matter, crystallization when leaving standstill.Output=1.16g (42%); MS (APCl), (M+1) ⁺=433. ¹H-NMR(DMSO-d ₆，δ)8.03(d，2H，J＝9.0Hz)，7.53(t，1H，J＝8.1，7.8Hz)，7.40(t，1H，J＝8.1，7.3Hz)，6.87(d，2H，J＝7.3Hz)，3.69(t，2H，J＝5.9，5.9Hz)，3.26-3.43(m，6H)，2.46-2.78(m，12H)，1.78(m，2H)。CHN:C ₂₅H ₂₈N ₄The OS calculated value, C, 69.41%, H, 6.52%, N, 12.95%; Experimental value C, 69.28%, H, 6.60%, N, 12.65%.

Embodiment 89

9-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,1-dimethyl-1,2,6,7-tetrahydrochysene -5H-pyrido [3,2,1-ij] quinoline-3-ketone

A.1-(3,4-dihydro-2H-quinoline-1-yl)-3-methyl-but-2-ene-1-ketone

To 1,2,3, the 4-tetrahydroquinoline (10.82ml 0.086mol) slowly adds 3 in the vigorous stirring solution in anhydrous propanone (80ml), and 3-dimethyl propylene acyl chlorides (10ml, 0.090mol).Reaction mixture refluxed 7 hours is in the rare aqueous hydrochloric acid of impouring 300ml.The aqueous mixture chloroform extraction, organic extract is concentrated into red oil.Output=15.08g (81%); MS (APCl), (M+1) ⁺=216.

B.1,1-dimethyl-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

(15.08g 0.07mol) mixes with aluminum chloride (22.54g, 0.169mol, heat release), and pure mixture discharges until HCl 90 ℃ of heating and stops with the product of embodiment 89A.After cooling, chloroform extraction is used in reaction mixture cold water quencher.The organic extract dried over mgso is filtered and is concentrated.(3: 2 hexanes: EtOAc) wash-out obtains orange red oily matter to crude product for silica gel 60,230-400 order by quick post.Yield=3.91g (26%); MS (APCl), (M+1) ⁺=216.

C.9-(2-chloracetyl)-1,1-dimethyl-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

According to the preparation method of embodiment 88A, (3.91g, 0.0182mol) taking Reed that-Kerafyrm thatch acidylate with chloroacetyl chloride, to obtain required product brown, amorphous solid for the product of embodiment 89B.Output=5.24g (99%); MS (APCl), (M+1) ⁺=292, (M-1) ⁺=290, (M+3) ⁺=294.

D.9-(2-chloroethyl)-1,1-dimethyl-1,2,6,7-tetrahydrochysene-5H-pyrido [3,2,1-ij] quinoline-3-ketone

According to the method for embodiment 88B, (5.24g 0.018mol) reduces and obtains orange, crystallization when leaving standstill by embodiment 89C product.Output=4.63g (93%); MS (APCl), (M+1) ⁺=278, (M+3) ⁺=280.

E.9-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,1-dimethyl-1,2,6,7-tetrahydrochysene -5H-pyrido [3,2,1-ij] quinoline-3-ketone

According to the described method of embodiment 88C, (849mg is 3.06mmol) with 3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate (652mg, 2.55mmol) reaction for the product of embodiment 89D.Title compound is dissolved in the methylene dichloride, and solution is used in 1, and the 4.0N HCl in the 4-diox handles with the deposited salt hydrochlorate.Output=342mg (27%); MS (APCl), (M+1) ⁺=461. ¹H-NMR(DMSO-d ₆，δ)：8.11(t，2H，J＝4.4，8.3Hz)，7.58(t，1H，J＝7.3，7.6Hz)，7.45(t，1H，J＝7.6，7.1Hz)，7.05(s，1H)，6.94(s，1H)，4.1(d，2H，J＝12.9Hz)，3.74-3.00(m，10H)，2.73-2.47(m，3H)，2.39(s，2H)，1.80(br?s，2H)，1.19(s，6H)。CHN:C ₂₇H ₃₂N ₄The OS1.3HCl calculated value, C, 63.83%, H, 6.61%, N, 11.03%; Experimental value C, 63.56%, H, 6.64%, N, 10.48%.

Embodiment 90

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-6,6-dimethyl-1,2,5,6-tetrahydrochysene pyrrole Pyridine is [3,2,1-ij] quinoline-4-ketone also

A.6,6-dimethyl-1,2,5,6-tetrahydropyridine [3,2,1-ij] quinoline-4-ketone also

To be similar to the method for embodiment 89B, with 1-(2,3-indoline-1-yl)-3-methyl-but-1-ene-1-ketone (5.0g, 0.025mol. according to embodiment 89A by 2,3-indoline and 3, the preparation of 3-dimethyl propylene acyl chlorides) obtain the title compound orange solids with aluminium reaction.Output=4.28g (85%); MS (APCl), (M+1) ⁺=202.

B.8-(2-chloracetyl)-6,6-dimethyl-1,2,5,6-tetrahydropyridine be [3,2,1-ij] quinoline-4-ketone also

According to the method described in the embodiment 88A, (4.28g 0.021mol) takes Reed that-Kerafyrm thatch acidylate and obtains title compound light brown, amorphous solid embodiment 90A.Output=5.80g (99%); MS (APCl), (M+1) ⁺=278, (M-1) ⁺=276, (M+3) ⁺=280.

C.8-(2-chloroethyl)-6,6-dimethyl-1,2,5,6-tetrahydropyridine be [3,2,1-ij] quinoline-4-ketone also

With the method described in the embodiment 88B, (5.80g 0.021mol) reduces and obtains the title compound orange, crystallization when leaving standstill embodiment 90B.Output=5.27g (95%); MS (APCl), (M+1) ⁺=264, (M+3) ⁺=266.

D.8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-6,6-dimethyl-1,2,5,6-tetrahydrochysene Pyrido [3,2,1-ij] quinoline-4-ketone

According to the described method of embodiment 88C, (1.0g is 3.79mmol) with 3-piperazine-l-base-benzo [d] isoniazthiolane hydrochlorate (808mg, 3.16mmol) reaction for the product of embodiment 90C.Title compound is dissolved in the methylene dichloride, and solution is used in 1, and the 4.0N HCl in the 4-diox handles with the deposited salt hydrochlorate.Output=482mg (32%); MS (APCl), (M+1) ⁺=447. ¹H-NMR(DMSO-d ₆，δ)8.10(dd，2H，J＝8.3，8.1Hz)，7.57(t，1H，J＝7.6，7.6Hz)，7.45(t，1H，J＝7.8，7.3Hz)，7.02(s，2H)，4.08(d，2H，J＝13.2Hz)，3.92(t，2H，J＝8.3，8.5Hz)，3.66-3.02(m，12H)，2.47(s，2H)，1.20(s，6H)。CHN:C ₂₆H ₃₀N ₄OS0.6H ₂The O calculated value, C, 63.23%, H, 6.57%, N, 11.34%; Experimental value C, 62.94%, H, 6.61%, N, 10.91%.

Embodiment 91

6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-4S-methyl-3,4-dihydro-1H-quinoline Quinoline-2-ketone

According to the method described in the embodiment 1C, by 6-fluoro-3-piperidin-4-yl-benzo [d] isoxazole hydrochlorate (500mg, 1.95mmol.J.Med.Chem., 1985,28,761) and 6-(2-chloroethyl)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(658mg, 2.94mmol, reference example 2) preparation title compound obtain amorphous solid.Output=258mg (32%); MS (APCl), (M+1) ⁺=408, (M-1) ⁺=406. ¹H-NMR(DMSO-d ₆，δ)：9.98(s，1H)，7.97(t，1H，J＝3.4，5.1Hz)，7.66(d，1H，J＝9.3Hz)，7.25(t，1H，J＝9.0，9.0Hz)，7.04(s，1H)，6.97(d，1H，J＝8.1Hz)，6.73(d，1H，J＝7.8Hz)，3.12-2.96(m，4H)，2.67-2.47(m，5H)，2.15(m，3H)，1.99(m，2H)，1.82(m，2H)，1.14(d，3H，J＝6.8Hz)。CHN:C ₂₄H ₂₆FN ₃O ₂Calculated value, C, 70.74%, H, 6.43%, N, 10.31%; Experimental value, C, 70.22%, H, 6.54%, N, 9.99%.Specific rotation [α] ^D ₂₅=-3.6 (DMSO, c=10mg/ml).

Embodiment 92

6-{2-[4-(the different azoles of 6-fluoro-benzo [d]-3-yl)-piperidines-1-yl]-ethyl }-4,4-dimethyl-3,4-dihydro -1H-quinoline-2-one-

According to the method described in the embodiment 1C, by 6-fluoro-3-piperidin-4-yl-benzo [d] isoxazole hydrochlorate (500mg, 1.95mmol.J.Med.Chem., 1985,28,761) and 6-(2-chloroethyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(699mg, 2.94mmol, embodiment 5D) the preparation title compound obtains white, amorphous solid.Output=319mg (39%); MS (APCl), (M+1) ⁺=422, (M-1) ⁺=420. ¹H-NMR(DMSO-d ₆，δ)：10.02(s，1H)，7.97(q，1H，J＝5.1，3.4，5.4Hz)，7.66(d，1H，J＝9.0Hz)，7.25(t，1H，J＝9.3，9.0Hz)，7.13(s，1H)，6.97(d，1H，J＝7.6Hz)，6.74(d，1H，J＝8.1Hz)，3.15-3.00(m，3H)，2.68(m，4H)，2.29(s，2H)，2.17-1.76(m，6H)，1.18(s，6H)。CHN:C ₂₅H ₂₈FN ₃O ₂Calculated value, C, 71.24%, H, 6.70%, N, 9.97%; Experimental value C, 70.83%, H, 6.82%, N, 9.76%.

Embodiment 93

6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperidines-1-yl]-ethyl }-4S-methyl-3, the 4-dihydro -1H-quinoline-2-one-

According to the method described in the embodiment 1C, by 6-fluoro-3-piperidin-4-yl-benzo [d] isoniazthiolane hydrochlorate (500mg, 1.83mmol, WO 0160796A1) and 6-(2-chloroethyl)-4S-methyl-3,4-dihydro-1H-quinoline-2-one-(615mg, 2.75mmol, reference example 2) and the preparation title compound, after forming hydrochloride, previously described method obtains orange glassy mass.Output=339mg (40%); MS (APCl), (M+1) ⁺=424, (M-1) ⁺=422. ¹H-NMR(DMSO-d ₆，δ)：10.38(br?s，1H)，10.08(s，1H)，8.31(q，1H，J＝4.9，3.9，4.9Hz)，8.08(d，1H，J＝9.0Hz)，7.42(t，1H，J＝8.8，9.0Hz)，7.12(s，1H)，7.05(d，1H，J＝7.8Hz)，6.80(d，1H，J＝8.1Hz)，3.66-3.00(m，10H)，2.55(dd，1H，J＝5.9，5.6Hz)，2.18(m，5H)，1.16(d，3H，J＝6.8Hz)。CHN:C ₂₄H ₂₆FN ₃The OS1.1HCl calculated value, C, 62.17%, H, 5.89%, N, 9.06%; Experimental value, C, 61.79%, H, 6.00%, N, 8.93%.Specific rotation: [α] ^D ₂₅=-5.6 (DMSO, c=10mg/ml).

Embodiment 94

6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperidines-1-yl]-ethyl }-4,4-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

According to the method described in the embodiment 1C, by 6-fluoro-3-piperidin-4-yl benzo [d] isoniazthiolane hydrochlorate (500mg, 1.83mmol, WO0160796A1) and 6-(2-chloroethyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(654mg, 2.75mmol, embodiment 5D) preparation title compound obtains white glass shape thing.Output=339mg (42%); MS (APCl), (M+1) ⁺=438, (M-1) ⁺=436. ¹H-NMR(DMSO-d ₆，δ)：10.00(s，1H)，8.18(q，1H，J＝4.9，4.1，4.9Hz)，8.01(d，1H，J＝6.8Hz)，7.33(t，1H，J＝6.6，6.6Hz)，7.11(s，1H)，6.95(d，1H，J＝8.1Hz)，6.72(d，1H，J＝8.1Hz)，3.26(m，1H)，2.99(br?d，2H，J＝11.2Hz)，2.65(t，2H，J＝7.1，8.3Hz)，2.49(m，2H)，2.26(s，2H)，2.13(brt，2H，J＝10.5，10.7Hz)，1.86(m，4H)，1.16(s，6H)。CHN:C ₂₅H ₂₈FN ₃The OS calculated value, C, 68.62%, H, 6.45%, N, 9.60%; Experimental value, C, 68.69%, H, 6.48%, N, 9.39%.

Embodiment 95-157 represents to prepare these title compounds by combinational chemistry.

Embodiment 95

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-ethanamide

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-3,4-dihydro-1H-quinoline-2-one-is diluted to 0.50M with anhydrous tetrahydro furan, packs in the 8mL bottle (0.10mmol) with transfer pipet.In quinolinone solution, add potassium tert.-butoxide (0.20mmol, 1.0M tetrahydrofuran solution).Solution at room temperature stirs half an hour.The 2-bromoacetamide is diluted to 0.50M with tetrahydrofuran (THF), at room temperature adds (0.40mmol) in the quinolinone solution.This solution stirs down at 45 ℃ and spends the night, subsequently cool to room temperature.Added additional 0.20mmol 2-bromoacetamide in second day.Reaction mixture stirs down at 45 ℃ and spends the night.Reaction mixture distributes between 2mL ethyl acetate and 2mL water, and extracted organic phase concentrates through HT-12 GeneVac.Crude product HPLC (30 * 100mm ODS-AC (18) 5u post) purifying.Separating 2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl at 254nm]-3-methyl-2-oxo-3,4-dihydro-2H-quinoline-1-yl }-ethanamide, purity 100%, LCMS (APCl) 464[M+H] ⁺

Use the combinatorial library form, according to the step described in the embodiment 95, scale with 0.10mmol, use 6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-3,4-dihydro-1H-quinoline-2-one-, 6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-, 6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-3,4-dihydro-1H-quinoline-2-one-, 6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-3,4-dihydro-1H-quinoline-2-one-, 6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one-, 6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one-, 6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1H-quinoline-2-one-and 6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,4-trimethylammonium-3,3-dihydro-1H-quinoline-2-one-and suitable alkyl halide raw material and potassium tert.-butoxide synthesize embodiment 96-157.Crude product HPLC (30 * 100mm ODS-AC (18) 5u post) purifying.

The title compound of embodiment 96-157 is by being similar to the method preparation described in the embodiment 95.

Embodiment 96

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionic acid amide

Separate purity 100% at 254nm; LCMS (APCl) 478[M+H] ⁺

Embodiment 97

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-N-phenyl-propionic acid amide

Separate purity 100% at 254nm; LCMS (APCl) 554[M+H] ⁺

Embodiment 98

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-ethyl acetate

Separate purity 100% at 254nm; LCMS (APCl) 493[M+H] ⁺

Embodiment 99

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-and 3-methyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 505[M+H] ⁺

Embodiment 100

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 3-methyl isophthalic acid-(2-oxo-2-phenyl- Ethyl)-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 525[M+H] ⁺

Embodiment 101

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(2-methoxyl group-ethyl)-3-methyl -3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 465[M+H] ⁺

Embodiment 102

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionitrile

Separate purity 100% at 254nm; LCMS (APCl) 460[M+H] ⁺

Embodiment 103

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--3-methyl-3, the 4-dihydro -1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 463[M+H] ⁺

Embodiment 104

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-2-oxo-3,4- Dihydro-2H-quinoline-1-base 1-ethanamide

Separate purity 100% at 254nm; LCMS (APCl) 478[M+H] ⁺

Embodiment 105

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl] and-3,3-dimethyl-2-oxo-3,4-two Hydrogen-2H-quinoline-1-yl }-ethyl acetate

Separate purity 100% at 254nm; LCMS (APCl) 507[M+H] ⁺

Embodiment 106

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-3,3-dimethyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 519[M+H] ⁺

Embodiment 107

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-1-(2-oxo-2-benzene Base-ethyl)-3,4-dihydro-1H-quinoline-2-one-

Separate purity 88% at 254nm; LCMS (APCl) 539[M+H] ⁺

Embodiment 108

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-methoxymethyl-3, the 3-dimethyl -3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 465[M+H] ⁺

Embodiment 109

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(2-methoxyl group-ethyl)-3,3-two Methyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 479[M+H] ⁺

Embodiment 110

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,3-dimethyl-2-oxo-3,4- Dihydro-2H-quinoline-1-yl }-propionitrile

Separate purity 100% at 254nm; LCMS (APCl) 474[M+H] ⁺

Embodiment 111

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-ethyl-3,3-dimethyl-3,4-two Hydrogen-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 449[M+H] ⁺

Embodiment 112

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--3,3-dimethyl-3,4- Dihydro-1H-quinoline-2-one-

Separate purity 100%, LCMS (APCl) 477[M+H at 254nm] ⁺

Embodiment 113

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionic acid amide

Separate purity 100% at 254nm; LCMS (APCl) 478[M+H] ⁺

Embodiment 114

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-N-phenyl-propionic acid amide

Separate purity 100% at 254nm; LCMS (APCl) 554[M+H] ⁺

Embodiment 115

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-ethyl acetate

Separate purity 100% at 254nm; LCMS (APCl) 493[M+H] ⁺

Embodiment 116

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-and 4-methyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 505[M+H] ⁺

Embodiment 117

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 4-methyl isophthalic acid-(2-oxo-2-phenyl- Ethyl)-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 525[M+H] ⁺

Embodiment 118

2-{6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionitrile

Separate purity 100% at 254nm; LCMS (APCl) 460[M+H] ⁺

Embodiment 119

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-ethyl-4-methyl-3, the 4-dihydro -1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 435[M+H] ⁺

Embodiment 120

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 4-methyl isophthalic acid-(2,2,2-three fluoro-second Base)-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 489[M+H] ⁺

Embodiment 121

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--4-methyl-3, the 4-dihydro -1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 463[M+H] ⁺

Embodiment 122

2-{6-[2-(the different azoles of 4-benzo [d]-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-ethanamide

Separate purity 89% at 254nm; LCMS (APO) 448[M+H] ⁺

Embodiment 123

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionic acid amide

Separate ， @254nm with 97% purity; LCMS (APCl) 462[M+H] ⁺

Embodiment 124

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-the N-Phenylpropionamide

Separate purity 100% at 254nm; LCMS (APCl) 538+H] ⁺

Embodiment 125

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-ethyl acetate

Separate purity 100% at 254nm; LCMS (APCl) 477[M+H] ⁺

Embodiment 126

6-[2-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-and 4-methyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 489[M+H] ⁺

Embodiment 127

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-(2-methoxyl group-ethyl)-4-methyl -3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 449[M+H] ⁺

Embodiment 128

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-4-methyl-2-oxo-3, the 4-dihydro -2H-quinoline-1-yl }-propionitrile

Separate purity 100% at 254nm; LCMS (APCl) 444[M+H] ⁺

Embodiment 129

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-ethyl-4-methyl-3, the 4-dihydro -1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 419[M+H] ⁺

Embodiment 130

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--4-methyl-3, the 4-dihydro -1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 447[M+H] ⁺

Embodiment 131

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-3,4-dimethyl-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 517[M+H] ⁺

Embodiment 132

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-[2-(2-hydroxyl-oxyethyl group)-second Base]-3,4-dimethyl-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 507[M+H] ⁺

Embodiment 133

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(2-methoxyl group-ethyl)-3 4-two Methyl isophthalic acid H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 477[M+H] ⁺

Embodiment 134

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-ethyl-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

Separate purity 100% at 254nm; LCMS (APCl) 447[M+H] ⁺

Embodiment 135

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1-(2,2,2-three fluoro- Ethyl)-the 1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 501[M+H] ⁺

Embodiment 136

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--3,4-dimethyl-1H- Quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 475[M+H] ⁺

Embodiment 137

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-2-oxo-2H- Quinoline-1-yl }-ethanamide

Separate purity 94% at 254nm; LCMS (APCl) 460[M+H] ⁺

Embodiment 138

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-2-oxo-2H- Quinoline-1-yl }-propionic acid amide

Separate purity 100% at 254nm; LCMS (APCl) 474[M+H] ⁺

Embodiment 139

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-2-oxo-2H-quinoline Quinoline-1-yl } ethyl acetate

Separate purity 100% at 254nm; LCMS (APCl) 489[M+H] ⁺

Embodiment 140

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-2-oxo-2H- Quinoline-1-base-methyl propionate

Separate purity 100% at 254nm; LCMS (APCl) 489[M+H] ⁺

Embodiment 141

6-[2-(4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-(3,3-dimethyl-2-oxo-Ding Base)-3,4-dimethyl-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 501[M+H] ⁺

Embodiment 142

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-1-(2-oxo-2-benzene Base-ethyl)-the 1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 521[M+H] ⁺

Embodiment 143

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-(2-methoxyl group-ethyl)-3,4-two Methyl isophthalic acid H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 461[M+H] ⁺

Embodiment 144

2-{6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,4-dimethyl-2-oxo-2H- Quinoline-1-base-}-propionitrile

Separate purity 96% at 254nm; LCMS (APCl) 456[M+H] ⁺

Embodiment 145

6-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-1-ethyl-3.4-dimethyl-1H-quinoline Quinoline-2-ketone

Separate purity 100% at 254nm; LCMS (APCl) 431[M+H] ⁺

Embodiment 146

6-[2-(4-benzo [d] isoxazole-3-base piperazine-1-yl)-ethyl]-3,4-dimethyl-1-(2,2,2-three fluoro-second Base)-the 1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 485[M+H] ⁺

Embodiment 147

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl] and-4,4,8-trimethylammonium-2-oxo-3,4- Dihydro-2H-quinoline-1-yl }-ethyl acetate

Separate purity 96% at 254nm; LCMS (APCl) 521[M+H] ⁺

Embodiment 148

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8-trimethylammonium-1-amyl group-3,4-two Hydrogen-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 505[M+H] ⁺

Embodiment 149

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-4,4,8 trimethylammoniums-1-(3-methyl-Ding Base)-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 505[M+H] ⁺

Embodiment 150

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl I-1-(2-ethyl-butyl)-4,4, the 8-front three Base-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 519[M+H] ⁺

Embodiment 151

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(2-oxyethyl group-ethyl)-4,4,8-three Methyl-3,4-dihydro-1H-quinoline-2-one-

Separate purity 96% at 254nm; LCMS (APCl) 507[M+H] ⁺

Embodiment 152

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-(2,2-dimethyl-propyl group)-4,4,8- Trimethylammonium-3,4-dihydro-1H-quinoline-2-one-

Separate purity 93% at 254nm; LCMS (APCl) 505[M+H] ⁺

Embodiment 153

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-cyclohexyl methyl-4,4, the 8-front three Base-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 531[M+H] ⁺

Embodiment 154

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-cyclobutylmethyl-4,4, the 8-front three Base-3,4-dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 503[M+H] ⁺

Embodiment 155

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-isobutyl--4,4,8-trimethylammonium-3,4- Dihydro-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 491[M+H] ⁺

Embodiment 156

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-butyl-4,4,8-trimethylammonium-3,4-two Hydrogen-1H-quinoline-2-one-

Separate purity 100% at 254nm; LCMS (APCl) 491[M+H] ⁺

Embodiment 157

6-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1-cyclobutyl-4,4,8-trimethylammonium-3,4- Dihydro-1H-quinoline-2-one-

Separate purity 95% at 254nm; LCMS (APCl) 489[M+H] ⁺

Embodiment 158

6-{2-[4-(5-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone (3)

With reference to such scheme, in 10mL microwave reaction bottle, mix 0.25g (0.001mol) AA, 0.35gK ₂CO ₃(2.5 equivalents, 0.0025mol), 0.18g potassiumiodide (KI) (1 equivalent, 0.001mol), 4mL CH ₃CN and 0.35g BB, and 5-fluoro-3-piperazine-1-base-benzo [d] isoxazole (1.5 equivalents, 0.0015mol).Reaction vessel in microwave reactor, be heated to 150 ℃ 5400 seconds, cool to room temperature in the impouring water, filters.The solid that generates was 60 ℃ of following vacuum-dryings 24 hours.Obtain 0.31g crude product (73% crude product yield).(YMC 30 * 100mm ODS-A 5uM C18 uses CH to this material of about 82mg with preparation property HPLC ₃CN/H ₂The O+0.05%TFA wash-out) purifying obtains the 42mg solid, through 254 and 214nM HPLC to measure purity be 100%. ¹H?NMR(400MHz，DMSO-d ₆)δppm?2.1(s，3H)，2.4(s，3H)，3.1(d，J＝8.1Hz，2H)，3.3(d，J＝7.8Hz，6H)，3.7(d，J＝6.1Hz，2H)，4.1(d，J＝4.6Hz，2H)，7.2(s，1H)，7.3(s，1H)，7.5(m，1H)，7.6(s，1H)，7.7(m，1H)，8.0(d，J＝2.4Hz，1H)，11.7(s，1H)。MS[M+H] ⁺＝421。

Embodiment 159

6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-3.4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperazine-1-yl with 6-fluoro-3-piperazine-1-base-benzo [d] isoxazole hydrochlorate]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-; HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=421.

Embodiment 160

6-{2-[4-(5-chloro-benzo [d] isoxazole-3-base)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(5-chloro-benzo [d] isoxazole-3-base)-piperazine-1-yl with 5-chloro-3-piperazine-1-base-benzo [d] isoxazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=437.

Embodiment 161

6-{2-[4-(5-methoxyl group-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-3, the 4-dimethyl -1H-quinoline-2-one-

As embodiment 158, prepare 6-{2-[4-(5-methoxyl group-benzo [d] isothiazole-3-yl)-piperazine-1-yl with 5-methoxyl group-3-piperazine-1-base-benzo [d] isothiazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-; HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=449.

Embodiment 162

6-{2-[4-(7-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(7-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl with 7-fluoro-3-piperazine-1-base-benzo [d] isoniazthiolane hydrochlorate]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] +=437.

Embodiment 163

6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl with 6-fluoro-3-piperazine-1-base-benzo [d] isothiazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=437.

Embodiment 164

6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(5-fluoro-benzo [d] isothiazole-3-yl)-piperazine-1-yl with 5-fluoro-3-piperazine-1-base-benzo [d] isothiazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=437.

Embodiment 165

6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperidines-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(6-fluoro-benzo [d] isothiazole-3-yl)-piperidines-1-yl with 6-fluoro-3-piperidin-4-yl-benzo [d] isothiazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=436.

Embodiment 166

6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperidines-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline Quinoline-2-ketone

As embodiment 158, prepare 6-{2-[4-(6-fluoro-benzo [d] isoxazole-3-base)-piperidines-1-yl with 6-fluoro-3-piperidin-4-yl-benzo [d] isoxazole]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-.HPLC: purity 100%, 254 and 214nM, MS[M+H] ⁺=420.

Embodiment 167

6-{2-[4-(1H-indazole-3-yl)-piperazine-1-yl]-ethyl }-3,4-dimethyl-1H-quinoline-2-one-

According to the method among the embodiment 1 step C, 3-piperazine-1-base-1H-indazole hydrochloride (382mg, 1.60mmol) with the compound of embodiment 9 step B preparation (259mg, 1.1mmol) reaction obtains title compound, it with amorphous solid by precipitating in the solution.The product that obtains is by quick post (silica gel 60,230-400 order, 100: 8: 1, CH ₂Cl: EtOH: NH ₄OH) the wash-out purifying obtains canescence spumescence solid, output=113mg (26%).MP：265.5-268.1℃。 ¹H-NMR(DMSO-d ₆，δ)：2.08(s，3H)，2.38(s，3H)，2.61(m，5H)，2.82(m，2H)，3.30(m，4H)，6.93(t，J＝7.45Hz，1H)，7.17(d，J＝8.30Hz，1H)，7.24(m，1H)，7.32(m，2H)，7.60(s，1H)，7.71(d，J＝7.82Hz，1H)。

Embodiment 168

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-6-methyl-3,5-dihydro-1H-furans And [3,4-c] quinoline-4-ketone

With reference to such scheme, to sodium-chlor (60%, in the oil) (42.0g, 1.05mol) at room temperature in 1 hour, add in the suspension in ether (800mL) ethyl glycollate (100g, 0.96mol).Suspension stirs half an hour subsequently, vacuum-evaporation.In the solid that obtains, add dimethyl sulfoxide (DMSO) (200mL), be cooled to 0 ℃ subsequently, under vigorous stirring, add ethyl propenoate (115.10g, 1.15mol) solution in dimethyl sulfoxide (DMSO) (100mL) in batches.Make suspension be warming to room temperature, stirred 3 hours.The aqueous sulfuric acid that reaction mixture impouring carefully is ice-cooled (5%, 300mL) in, with ether (3 * 100mL) extraction, use MgSO ₄Drying, evaporation and obtain compound 3 (70.0g, 46%) at the enterprising circumstances in which people get things ready for a trip of silica gel (hexane/ethyl acetate, 10: 1) spectrum purifying. ¹H?NMR(400MHz，CDCl ₃)δ4.55-4.40(m，2H)，4.30-4.20(m，2H)，4.10-3.95(m，2H)，3.50(t，1H)，1.15(t，3H)。

With compound 3 (18.4g, 0.11mol), ethyl glycollate (15.0g .22mol), tosic acid (2.2g, 0.01mol) and benzene (30mL) add to be equipped with in the flask of Dean-Stark and condenser.Mixture reflux 2 hours, cool to room temperature, solvent removed in vacuo.The heavy-gravity resistates dilutes with ether (100mL), solution with water, and MgSO is used in the sodium bicarbonate aqueous solution washing ₄Dry.Evaporation subsequently obtains compound 5 (14.9g, 63%). ¹H?NMR(400MHz，CDCl ₃)δ4.30-4.10(m，6H)，4.00-3.85(m，4H)，3.10(t，1H)，1.15(t，3H)。

(15.0g, 74.2mmol), NaOH (111.0mmol, 4.5g is in 10mL water) and methyl alcohol (50mL) reflux 1 hour, with the mixture cool to room temperature, vacuum is removed methyl alcohol with 5.Resistates dilute hydrochloric acid acidifying is with ethyl acetate (3 * 50mL) extractions.The extract MgSO that merges ₄Drying, evaporation obtains compound 6 (9.1g, 70%). ¹H?NMR(400MHz，DMSO-d ₆)δ12.4(br?s，1H)，4.05-3.95(m，2H)，3.90-3.85(m，4H)，3.65(d，1H)，3.55(d，1H)，3.10(t，1H)。

B.8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-6-methyl-3,5-dihydro-1H-furan Also [3, the 4-c] quinoline-4-ketone of muttering

At 0 ℃, (1.18g, (1.1 6g 11.9mmol), are warming to room temperature subsequently, stir 1 hour 6.8mmol) slowly to add oxalyl chloride in the solution in dimethyl formamide (0.1mL) and methylene dichloride (20mL) to 6.The vacuum-evaporation mixture is dissolved in the methylene dichloride (10mL).This solution add down 2 at 0 ℃ subsequently (2.0g, 3.6mmol) and triethylamine (2.5g is 24.6mol) in the mixture in methylene dichloride (20mL).Make mixture be warming to room temperature, stirred the water quencher 2 hours.Isolate organic layer, use the salt water washing, use MgSO ₄Drying concentrates and obtains compound 3 (0.71g, 24%) at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (methanol/ethyl acetate, 1: 10) purifying. ¹H?NMR(400MHz，CDCl ₃)：δ7.95-7.75(m，2H)，7.50-7.35(m，2H)，7.45(t，1H)，7.35(t，1H)，7.10-7.05(m，2H)，4.40(dd，1H)，4.15(dd，1H)4.10-4.00(m，4H)，3.95(d，1H)，3.80(d，1H)，3.65-3.55(m，4H)，3.15(dd，1H)，2.85-2.60(m，8H)，2.25(s，3H)。

With compound 3 (0.70g, 1.40mmol) and the mixture of the vitriol oil (5mL) 60 ℃ of down heating 45 minutes, with the mixture cool to room temperature, after filtration, obtain jelly in the impouring ice.With ultra sonic bath jelly is suspended in the methyl alcohol, vacuum is removed methyl alcohol.In resistates, add triethylamine (10mL), refluxed 15 minutes.The vacuum-evaporation reaction mixture obtains compd B (0.518g, 82%) at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (methanol/ethyl acetate, 10: 100) purifying. ¹H?NMR(400MHz，DMSO-D ₆)：δ10.95(s，1H)，8.05(d，2H)，7.60-7.55(m，1H)，7.50-7.40(m，1H)，7.30(s，1H)，7.20(s，1H)，5.35-5.25(m，2H)，5.00-4.95(m，2H)，3.50-3.30(m，4H)，2.90-2.55(m，8H)，2.45(s，3H)。

Embodiment 169

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-3,5-dihydro-1H-furo [3,4-C] Quinoline-4-ketone

To be similar to the method described in the foregoing description 168, by 4-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-aniline prepares title compound. ¹H?NMR(400MHz，DMSO-d ₆)δ11.80(br?s，1H)，8.20-8.00(m，2H)，7.60-7.20(m，5H)，5.25(br?s，2H)，4.95(br?s，2H)，3.60-3.40(m，4H)，2.90-2.50(m，8H)。

Embodiment 170

8-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-3,5-dihydro-1H-furo [3,4-c] Quinoline-4-ketone

With the method described in analogue the foregoing description 160, by 4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-aniline prepares title compound. ¹H?NMR(400MHz，CDCl ₃)δ11.85(s，1H)，8.15(t，2H)，7.60(t，1H)，7.55-7.35(m，4H)，5.20(br?s，2H)，5.00(br?s，2H)，3.50(br?s，4H)，2.75(t，2H)，2.60(br?s，4H)，2.40(t，2H)，1.95-1.80(m，2H)。

Embodiment 171

8-[2-(the 4-benzo [d] isoxazole-3-base-piperazine-1-yl)-ethyl]-3,5-dihydro-1H-furo [3,4-c] Quinoline-4-ketone

(20g drips oleum (20ml) in 0.14mol), mixture restir 45 minutes under uniform temp to 1-chloro-2-diphenylphosphino ethane at 0 ℃.The reaction of water (200mL) quencher carefully.With methylene dichloride (100mL) extraction, use MgSO ₄Drying obtains 2 (8.0g, 30%) by chloroform/hexane crystallization.H?NMR(400MHz，CDCl ₃)δ8.20(d，2H)，7.40(d，2H)，3.75(t，2H)，3.20(t，2H)。

With 2 (2.3g, 12.4mmol), 3 (2.0g, 8.4mmol), triethylamine (5.0g, 49.6mmol), sodium iodide (7.4g, 49.6mmol) and the mixture of acetonitrile (45mL) in microwave oven 82 ℃ of heating 1 hour.Cool to room temperature subsequently, solvent removed in vacuo.Resistates washes with water with ethyl acetate (200mL) dilution, uses MgSO ₄Dry also evaporation.Thick material obtains 4 (1.8g, 61%) with column chromatography (ethyl acetate/hexane, 50: 50) purifying. ¹H?NMR(400MHz，CDCl ₃)δ8.20(d，2H)，7.70(d，1H)，7.50-7.45(m，2H)，7.35(d，2H)，7.25(t，1H)，3.65-3.55(m，4H)，3.00-2.90(m，2H)，2.80-2.65(m，6H)。

Mixture in methyl alcohol (50.0mL) is at 40psi with 4 (0.9g, 3.0mmol, 10mL tetrahydrofuran (THF)s) and palladium/charcoal (1.6g, 10%), and hydrogenation is 10 minutes under the room temperature.By Sai Lite diatomite filtration reaction mixture, evaporated filtrate obtains 5 (0.81g, 50%) in the separation of the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (methylene dichloride). ¹HNMR(400MHz，CDCl ₃)δ7.60(d，1H)，7.45-7.35(m，2H)，7.20-7.05(m，1H)，6.95(d，2H)，6.55(d，2H)，3.60-3.45(m，6H)，2.75-2.55(m，6H)，2.55-2.45(m，2H)。

As compound 1,4,7-trioxa-spiral shell [4.4] nonane-9-carboxylic acid { 4-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-2-methyl-phenyl }-described similar approach of acid amides is used for by 5 (0.65g, 3.75mmol) and 7 (0.80g, 2.50mmol) preparation compound 7 (1.0g, 83%). ¹H?NMR(400MHz，CDCl ₃)δ7.85(s，1H)，7.70(d，1H)，7.55-7.05(m，3H)，7.40-7.15(m，4H)，4.40-3.60(m，14H)，3.15(t，1H)，2.80-2.45(m，6H)。

As compound 8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-6-methyl-3,5-dihydro-1H-furo [3,4-c] quinoline-described similar approach of 4-ketone is used for (1.0g, 2.10mmol) preparation required product compounds (0.25g, 57%) by 7. ¹H?NMR(400MHz，CDCl ₃)δ11.80(s，1H)，8.00(d，1H)，7.60(d，2H)，7.45(d，1H)，7.40-7.25(m，3H)，5.30(br?s，2H)，4.95(br?s，2H)，3.50(br?s，4H)，2.85(t，2H)，2.75-2.55(br?s，6H)。

Embodiment 172

8-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-the 2-methyl isophthalic acid, 2,3,5-tetrahydrochysene-pyrroles And [3,4-c] quinoline-4-ketone

A.N-{4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group 1-phenyl]-acrylamide

Under 0 ℃ and nitrogen, and under agitation to 4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-aniline (2.43g, 6.9mmol) contain triethylamine (0.84g, drip in the solution in 40mL methylene dichloride 8.3mmol) acrylate chloride (0.69g, 7.6mmol).Make reaction mixture be warming to room temperature, continue to stir 2 hours, add the 100mL methylene dichloride subsequently.(dried over sodium sulfate is used in 2 * 20mL) washings to mixture, concentrates and obtains little yellow viscous substance (2.80g, quantitative yield), and it is enough pure to be used for subsequent reaction with 10mL saturated sodium bicarbonate, salt solution. ¹H?NMR(400MHz，CDCl ₃)δ7.92(d，1H)，7.82(d，1H)，7.54(d，2H)，7.46(dd，1H)，7.38(dd，1H)，7.19(d，2H)，6.43(m，1H)，6.28(m，1H)，5.79(d，1H)，3.60(m，4H)，2.72(m，4H)，2.65(t，2H)，2.49(t，2H)，1.90(m，2H)。MSm/z407[C ₂₃H ₂₆N ₄OS+1]。

B.[(2-{4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-the phenyl amino formyl radical }- Ethyl)-methyl-amino]-ethyl acetate

With N-{4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-phenyl }-acrylamide (2.80g, 6.9mmol), hydrochloride ethyl sarcosnate (5.30g, 34.5mmol), triethylamine (3.48g, 34.5mmol) and 2, the mixture of 6-di-t-butyl-p-Cresol (100mg) in 60mL methyl alcohol spends the night 90 ℃ of backflows.After cooling, vacuum-evaporation methyl alcohol adds ethyl acetate (400mL) in resistates, and (dried over sodium sulfate is used in 3 * 50mL) washings, concentrates with salt solution.At the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, use methylene dichloride: methyl alcohol (95: 5) is made elutriant, obtains the little yellow oil of required product (3.18g, 88.1%), and it is directly used in afterreaction.MSm/z524[C ₂₈H ₃₇N ₅O ₃S+1]。

C.1-methyl-4-oxo-tetramethyleneimine-3-carboxylic acid 4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)- Propyl group]-phenyl }-acid amides

(0.81g 7.2mmol) is dissolved in the 15mL anhydrous tetrahydro furan, is cooled to 5-10 ℃ with ice bath with potassium tert.-butoxide.Under agitation; in this mixture, slowly be added in [(2-{4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-the propyl group]-phenyl amino formyl radical in the 15mL anhydrous tetrahydro furan }-ethyl)-methyl-amino]-ethyl acetate (3.14g, 6.0mmol).Reaction mixture stirred 4 hours under uniform temp, added 20mL water subsequently, regulated pH to 7-8 with 1N HCl.(3 * 400mL) extractions are with dried over sodium sulfate and concentrated with ethyl acetate for product.The solid that obtains carries out ultrasonic development with ether and obtains required product (2.0g, 70.0%) pale solid. ¹H?NMR(400MHz，CDCl ₃)δ8.64(br?s，1H)，7.94(d，1H)，7.81(d，1H)，7.45(m，3H)，7.38(dd，1H)，7.19(dd，2H)，3.59(m，4H)，3.50(m，1H)，3.38-3.20(m，3H)，3.01(m，1H)，2.68(m，6H)，2.50(s，3H)，2.44(dd，2H)，1.85(m，2H)。MSm/z?478[C ₂₆H ₃₁N ₅O ₂S+1]。

D.8-[3-4-benzo [d] isothiazole-3-base-piperazine-1-yl]-propyl group]-the 2-methyl isophthalic acid, 2,3,5-tetrahydrochysene-pyrroles And [3,4-c] quinoline-4-ketone

In nitrogen under agitation with 1-methyl-4-oxo-tetramethyleneimine-3-carboxylic acid { 4-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propyl group]-phenyl }-acid amides (0.81g, 1.70mmol) and Tripyrophosphoric acid (PPA, mixture 20g) 130 ℃ the heating 3 hours.After cooling, in mixture impouring frozen water, the brown jelly that filter to collect generates, and in the 100mL saturated sodium bicarbonate solution sonic treatment 1 hour, use methylene dichloride (3 * 500mL) extractions subsequently.Alkalize to pH8-8.5 with solid potassium hydroxide down ice-cooled by the filtrate that jelly obtains, use methylene dichloride (3 * 500mL) extractions subsequently.Merge all dichloromethane extracts, carry out chromatogram purification with silica gel, use methylene dichloride: methyl alcohol (4: 1) is made elutriant, obtains desired substance (0.36g, 46.2%) pale solid.mp?206-208℃。 ¹H?NMR(400MHz，CDCl ₃)δ10.60(br?s，1H)，7.94(d，1H)，7.80(d，1H)，7.48(dd，1H)，7.38(dd，2H)，7.28(m，1H)，7.21(d，1H)，4.28(dd，2H)，4.08(dd，2H)，3.60(m，4H)，2.79(t，2H)，2.68(m，7H)，2.46(t，2H)，1.95(m，2H)。MSm/z?460[C ₂₆H ₂₉N ₅OS+1]。Ultimate analysis C ₂₆H ₂₉N ₅OS calculated value: C, 67.94; H, 6.36; N, 15.24; Experimental value: C, 67.86; H, 6.00; N, 15.10.

Embodiment 173

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 2-methyl isophthalic acid, 2,3,5-tetrahydrochysene-pyrroles And [3,4-c] quinoline-4-ketone

With similar approach (embodiment 172), by 4-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl) ethyl]-aniline prepares 8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 2-methyl isophthalic acid, 2,3,5-tetrahydrochysene-pyrrolo-[3,4-c] quinoline-4-ketone.mp?205-207℃。 ¹H?NMR(400MHz，CDCl ₃)δ10.62(br?s，1H)，7.94(d，1H)，7.81(d，1H)，7.48(dd，1H)，7.39(m，2H)，7.28(m，2H)，4.25(m，2H)，4.08(m，2H)，3.61(m，4H)，2.95(m，2H)，2.79(m，4H)，2.75(m，2H)，2.70(s，3H)。MSm/z?446[C ₂₅H ₂₇N ₅OS+1]。Ultimate analysis: C ₂₅H ₂₇N ₅OS1.25H ₂O calculated value: C, 64.15; H, 6.35; N, 14.96; Experimental value: C, 63.91; H, 5.85; N, 14.76.

Embodiment 174

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-5-ethyl-1,2,3,5-tetrahydrochysene-ring penta Alkane is [c] quinoline-4-ketone also

At room temperature to 8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,2,3,5-tetrahydrochysene-pentamethylene also [c] quinoline-4-ketone (embodiment 81,0.10g, 0.23mmol) add NaH (10mg, 0.24mmol in the solution in DMF (1.5mL); Be 60% oil suspension).The suspension that obtains at room temperature stirred 30 minutes, and the adding iodoethane (40.5mg, 0.26mmol).Mixture heated 2 hours down at 50 ℃, and cool to room temperature is in the impouring trash ice.Collecting precipitation washes with water, with column chromatography (hexane: ethyl acetate: methyl alcohol; 25: 25: 1) purifying obtains solid (30mg, 29%). ¹H?NMR(400MHz，CDCl ₃)：δ7.95(d，1H)，7.85(d，1H)，7.55-7.30(m，5H)，4.40(q，2H)，3.70-3.55(m，4H)，3.20-3.10(m，2H)，3.00-2.90(m，4H)，2.85-2.70(m，6H)，2.25-2.15(m，2H)，1.35(t，3H)。

Embodiment 175

8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-the 5-methyl isophthalic acid, 2,3,5-tetrahydrochysene-ring penta Alkane is [c] quinoline-4-ketone also

Use is as being used for 8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-5-ethyl-1,2,3,5-tetrahydrochysene-pentamethylene is the similar approach of [c] quinoline-4-ketone (embodiment 174) also, by 8-[2-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-ethyl]-1,2,3,5-tetrahydrochysene-pentamethylene also [c] quinoline-4-ketone (0.40g, 0.96mmol), NaH (40mg, 1.02mmol; Be 60% oil suspension) and methyl iodide (0.14g, 1.02mmol), preparation required compound material. ¹H?NMR(400MHz，CDCl ₃)δ7.95(d，1H)，7.80(d，1H)，7.55-7.30(m，5H)，3.75(s，3H)，3.65-3.55(m，4H)，3.20-3.15(m，2H)，3.00-2.90(m，4H)，2.80-2.70(m，6H)，2.25-2.15(m，2H)。

Embodiment 176

8-[3-(4-benzo [d] isothiazole-3-base-piperazine-1-yl)-propoxy-]-1,2,3,5-tetrahydrochysene-pentamethylene is [c] also Quinoline-4-ketone methylsulfonic acid

With reference to such scheme, and with 2 (5.0g, 40.6mmol) and 3 (24mL, the 162mmol) mixture heating up to 120 in NMP (50mL) ℃ stirred 2 hours under uniform temp, at room temperature stirred and spent the night.Remove NMP by vacuum distilling, resistates is cooled to room temperature.Thick yellow solid obtains compound 4 (6.5g, 69%) by crystallization purifying in 95% ethanol. ¹H NMR (400MHz, CDCl ₃): δ 8.64 (s, 1H), 7.42 (d, 2H), 6.82 (d, 2H), 3.80 (s, 3H), 3.18 (t, 1H), in 2.50-2.30 (m, 4H), 2.15-2.05 (m, 1H), 1.95-1.80 (m, 1H), MSm/z 233.85[C ₁₃H ₁₅NO ₃+ H] ⁺

With 4 (2.0g, 8.5mmol) mixture in polyphosphoric acid (20g) is under agitation 120 ℃ of heating 2.5 hours, in refrigerative soup compound impouring ice, Tripyrophosphoric acid NaHCO ₃Neutralization.Filter out solid by water layer, wash with water several times.Thick material obtains 5 (1.0g, 55%) by 95% alcohol crystal purifying. ¹H?NMR(400MHz，DMSO-d ₆)：δ11.50(s，1H)，7.25(d，1H)，7.10(d，1H)，7.00(s，1H)，3.80(s，3H)，3.08(t，2H)，2.75(t，2H)，2.18-2.05(m，2H)，MSm/z?215.90[C ₁₃H ₁₃NO ₂+H] ⁺。

(600mg, 2.8mmol) solution in HBr (2.0mL) and AcOH (3.0mL) spends the night at 140 ℃ of reflux with 5.After cooling, in reaction mixture impouring frozen water, use NaHCO ₃With pH regulator to 4-5.(3 * 50mL) extract organism with the EtOAc that contains 5%MeOH.MgSO is used in the organism water and the salt water washing that merge ₄Dry.Filtration and evaporating solvent obtain 6 solids (300mg, 53%). ¹H?NMR(400MHz，DMSO-d ₆)：δ11.40(s，1H)，7.20(d，1H)，6.95(d，1H)，6.80(s，1H)，3.00(t，2H)，2.70(t，2H)，2.18-2.05(m，2H)，MSm/z?202.04[C ₁₂H ₁₁NO ₂+H] ^-。

(3.30g 16.4mmo1) adds K in the solution in dry DMF to 6 ₂CO ₃(9.06g 65.6mmol), adds 1 subsequently, and 3-dibromopropane 7 (8.3mL, 82mmol).Reaction mixture is 50 ℃ of heating down, and lasting stirring is spent the night.Reaction mixture is to room temperature, water (100mL) quencher.The organic compound CH that contains 5%MeOH ₂Cl ₂(3 * 100mL) extractions, the organism of merging washs with 1NNaOH, subsequently water and salt water washing.Organic layer Na ₂SO ₄Drying is filtered and vacuum concentration.Resistates is suspended in the hexane subsequently, and sonic treatment 1 minute is filtered.The additional hexane wash of solid, vacuum-drying obtain compound 8 (900mg, 17%). ¹H?NMR(400MHz，CDCl ₃)：δ11.35(br?s，1H)，7.32(d，1H)，7.18-7.10(m，1H)，6.95(s，1H)，4.18(t，2H)，3.62(t，2H)，3.18(t，2H)，3.00(t，2H)，2.28(t，2H)，2.20(t，2H)。MSm/z324.01[C ₁₅H ₁₆BrN ₄O ₂+H] ⁺。

With 8 (700mg, 2.2mmol), 9 (817mg, 3.2mmol), Nal (651mg, 4.3mmol) and triethylamine (1.5mL, 10.9mmol) the mixture reflux in acetonitrile (50.0mL) is 48 hours, cooling, the mixture vacuum concentration is to doing.Resistates is suspended in the water (50mL), and sonic treatment 5 minutes is filtered by sintered frit.The additional water rinse of solid, vacuum-drying is with chromatography (silica gel, gradient 3-5%MeOH/CH ₂Cl ₂) purifying obtains compound 10 (630mg, 63%) white solid. ¹H?NMR(400MHz，CDCl ₃)：δ10.75(br?s，1H)，7.93(d，1H)，7.80(d，1H)，7.50-7.43(m，1H)，7.40-7.35(m，1H)，7.29-7.22(m，1H)，7.10(d，1H)，6.98(s，1H)，4.10(t，2H)，3.61-3.52(m，4H)，3.15(t，2H)，3.00(t，2H)，2.80-2.72(m，4H)，2.70(t，2H)，2.29-2.20(m，2H)，2.10-2.02(m，2H)，MSm/z?460.97[C ₂₆H ₂₈N ₄O ₂S+H] ⁺。

(free alkali, 600mg 1.3mmol) are dissolved among EtOAc (20.0mL) and the MeOH (2.0mL), use MeSO with compound 10 ₃(84 μ L 1.3mmol) handle H.Reaction mixture at room temperature stirred 15 minutes, filtered out the solid of generation, with EtOAc (20mL) and Et ₂O (20mL) washing obtains brown solid 1 (610mg, 78%) 70 ℃ of following dryings in vacuum drying oven. ¹H?NMR(400MHz，DMSO-d ₆)：δ11.75(s，1H)，9.60(br?s，1H)，8.20-8.10(m，2H)，7.60(dd，1H)，7.50(dd，1H)，7.30(d，1H)，7.15(d，1H)，7.00(s，1H)，4.20-4.11(m，4H)，3.78-3.72(m，2H)，3.45-3.30(m，6H)，3.10(t，2H)，2.80(t，2H)，2.35(s，3H)，2.25-2.02(4H)。MSm/z 460.91[C ₂₆H ₂₈N ₄O ₂S+H]+, ultimate analysis C ₂₆H ₂₈N ₄O ₂S 1.5CH ₃SO ₃H calculated value: C 54.61, H 5.68, and N 9.26; Experimental value C 54.75, H 5.65, and N 8.98.

Claims

1, formula 1 compound:

Wherein X is S, O, SO, SO ₂, CH ₂Or NR ¹⁰

Y is N or CH;

Z is N or CH;

M is the integer of 1-4;

R ²And R ³Be selected from H, (C respectively ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, halogen, aryl, aryl-(C ₁-C ₄) alkyl-, heteroaryl and heteroaryl-(C ₁-C ₄) alkyl-, (C wherein ₁-C ₄) alkyl and (C ₁-C ₄) moieties of alkoxyl group can replace by 1-3 fluorine atom is optional, also can be independently by amino or hydroxyl substituent is optional replaces, aryl-(C wherein ₁-C ₄) alkyl-and heteroaryl-(C ₁-C ₄) alkyl-moieties can be replaced by 1-3 fluorine atom is optional, wherein the aryl of these groups and heteroaryl moieties can be by one or more substituting groups, preferred 0-2 substituting group is optional to be replaced, and this substituting group is selected from halogen, nitro, amino, cyano group respectively, is chosen wantonly (the C of replacement by 1-3 fluorine atom ₁-C ₆) alkyl and by the optional (C that replaces of 1-3 fluorine atom ₁-C ₆) alkoxyl group;

Or R ²And R ³One of can be with carbon that links to each other with it and and W ¹Quinolinone ring carbon form saturated or unsaturated heterocycle together, this heterocycle contains 4-7 ring element, wherein 1-3 ring element can be the heteroatoms that is selected from N, O and S, all the other ring elements are carbon, its prerequisite is to work as W ¹With R ²And R ³One of when forming ring, R ²And R ³In another does not exist;

W ¹Be CR ⁵R ⁶And W ²Be CR ⁷R ⁸, by W ¹To W ²Dotted line represent that two keys of choosing wantonly, its prerequisite are when at W ¹And W ²Between when having two key, R ⁵And R ⁷Do not exist;

Or be connected in the R of carbon atom ⁵, R ⁶, R ⁷And R ⁸Any two carbon that link to each other with their form (C ₃-C ₇) saturated or unsaturated carbocyclic, its prerequisite is W ¹Quinolinone carbon not with R ⁵, R ⁶, R ⁷And R ⁸In two form ring, and and R ²Or R ³Form ring;

With the pharmaceutically useful salt of this compound.

2, the compound of claim 1, wherein A is-(CH ₂) _mCH ₂-.

3, the compound of claim 1, wherein X is that S and Y are N.

4, be selected from the compound or the salt of following compound and their pharmacologically acceptable salt:

5, the compound of claim 1, wherein R ⁴Be H and R ²And R ³One of or both are H.

6, the compound of claim 1, wherein R ¹, R ⁵, R ⁶, R ⁷And R ⁸Be selected from H and (C respectively ₁-C ₃) alkyl.

7, be used for the treatment of Mammals, the pharmaceutical composition that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant behavior disorder with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, said composition contain in this disease of treatment or illness each compound or its pharmaceutically useful salt and the pharmaceutically useful carrier of the claim 1-6 that is significant quantity.

8, treatment is Mammals, the method that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, the prosperous first court of a feudal ruler disease (HD) of pausing, presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because multiple etiology, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, this method comprise Mammals administration to this treatment of needs effective each compound or its pharmaceutically useful salt of the claim 1-6 of amount in this disease of treatment or illness.

9, the method for claim 8, wherein disease of being treated or illness be selected from mental disorder, of short duration mental disorder that schizophrenia, Schizoaffective disease, vain hope disease, material cause, share mental disorder, because mental disorder and the schizophreniform diseases that the general medical science symptom causes.

10, the method for claim 8, wherein the compound of claim 1 or its pharmaceutically useful salt are administered for any two or more of treatment to human body and are selected from those diseases mentioned in claim 8 and the disease or the illness of symptom.

11, the method for claim 10, wherein disease of being treated or illness are to be accompanied by depressed schizophrenia.

12, the method for claim 10, wherein disease of being treated or illness are the schizophrenia that is accompanied by anxiety.

13, treatment is Mammals, the method that comprises philtrum disease or illness, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, this method comprises to described Mammals, comprises people's administration:

(a) compound of each of claim 1-6 or its pharmaceutically useful salt; With

(b) pharmaceutical active compounds of another kind of thymoleptic or anxiolytic or its pharmaceutically useful salt;

Wherein active medicine " a " and " b " are so that be combined in effectively quantity existence in this disease of treatment or the illness.

14, the pharmaceutical composition of treatment disease or illness in Mammals, described disease or illness are selected from single outbreak or the adult depressive illness of recurrent, the spirit depressing disease, depressive neurosis and neurotic depression, melancholia, constrain, comprise apocleisis, lose weight, insomnia, morning, early awakening or psychomotor postponed, atypia depression (or reactive depression), the appetite that comprises increase, drowsiness, psychomotor is exciting or excited, seasonal effect disease and the pediatrics department depression, bipolar disease or manic depression, for example bipolar I type disease, bipolar II type disease and cycloophrenia disease, behavior disease, the fissility behavior disease, scatterbrained hyperactivity disorder (ADHD), postpone relevant dyskinesias with spirit, lonely disease and behavior disease, anxiety disorders, for example be with or without the panic disease that agoraphobia, agoraphobia not have panic disease history, special phobia, for example special Zoophpbia, social anxiety, social phobia, obsessive-compulsive disorder, nervous disease, comprise nervous disease and acute nervous disease and general anxiety disease after the wound, indefinite personality disease, schizophrenia and other mental disorder, schizophreniform diseases for example, the Schizoaffective disease, the vain hope disease, of short duration mental disorder, share mental disorder, the mental disorder that has vain hope or illusion, the psycholeptic episode of anxiety, the anxiety relevant with psychosis, the psychosis emotional disorder, for example seriously adult depressive illness, the emotional disorder relevant with mental disorder, for example relevant with bipolar disease is acute mad dry and depressed, the emotional disorder relevant with schizophrenia, delirium, dull-witted and forget and other cognition or neurodegenerative disease, Parkinson's disease (PD) for example, Huntington Chorea (HD), presenile dementia, senile dementia, senilism sexual type dementia, the memory disease, carry out afunction, dull-witted and other dementia of vascular, for example because the HIV disease, head trauma, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya syndromes, or because the dementia that multiple etiology causes, movement disorders, for example motion can not, dyskinesia, comprise the sudden dyskinesia of familial, spasm, Tourette syndrome, the Scott syndromes, PALSYS and motion can not the rigidity syndromess, the outer motion disease of pyramidal tract, the movement disorders that causes of pharmacological agent for example, the Parkinson's disease that cause of tranquilizer for example, the pernicious syndromes of tranquilizer, the acute dystonia that tranquilizer causes, acute the cathisophobiaing that tranquilizer causes, slow dyskinesia and drug-induced posture that tranquilizer causes are trembled, chemical relies on and habit-formingly (for example relies on or be addicted in alcohol, heroine, Cocaine, benzodiazepines, Nicotine or phenylethyl barbituric acid) and behavior habit-forming, the gambling of for example wallowing in, and disease of eye, for example glaucoma and local asphyxia retinopathy, said composition contains:

(a) compound of each of claim 1-6 or its pharmaceutically useful salt;

(b) pharmaceutical active compounds of another kind of thymoleptic or anxiolytic or its pharmaceutically useful salt; With

(c) pharmaceutically useful carrier.

15, the method for claim 13, wherein disease of being treated or illness are schizophrenia.