CN101312966A

CN101312966A - Benzothiazole cyclobutyl amine derivatives and their use as histamine-3 receptors ligands

Info

Publication number: CN101312966A
Application number: CNA2006800436476A
Authority: CN
Inventors: M·D·科沃特; M·孙; C·赵; G·Z·郑
Original assignee: Abbott Laboratories
Current assignee: AbbVie Inc
Priority date: 2005-09-22
Filing date: 2006-09-19
Publication date: 2008-11-26
Also published as: UA94242C2

Abstract

Compounds of formula (I) are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

Description

Benzothiazole cyclobutyl amine derivatives and as the application of histamine-3 receptors ligand

Background of invention

The application requires the U.S. Provisional Patent Application No.60/719 of submission on September 22nd, 2005,516 interests, and this application is all incorporated the application into the form of incorporated by reference.

Technical field

The application relates to the benzothiazole cyclobutyl amine compound, contains this compound compositions, prepares the method for this compound, and with the method for this compound and combination treatment illness and obstacle.

Description of Related Art

Histamine is well-known neuronal activity conditioning agent.At least four analogued histamine acceptors have been reported in the document, so-called histamine-1, histamine-2, histamine-3 and histamine-4.An analogued histamine acceptor that is called histamine-3 acceptor is considered to work in the neurotransmission of central nervous system.

Histamine-3 (H ₃) acceptor is to be identified (Nature, 302:832-837 (1983)) by pharmacology on the histaminergic nerve tip the earliest, it is regulated central nervous system there and unifies among the peripheral organ, and particularly lung, cardiovascular system are unified in the gi tract, the release of neurotransmitter.It has been generally acknowledged that H ₃Acceptor is to be distributed in the presynaptic on the histaminergic nerve tip, and is distributed in and has other activity on the neurone of (for example suprarenal gland can activity, cholinergic activity, serotonergic activity and dopaminergic activity).H ₃The existence of acceptor is by selectivity H ₃The development of receptor stimulant and antagonist be confirmed (Nature, 327:117-123 (1987); Leurs and Timmerman compile " The History ofH ₃Receptor:a Target for New Drugs ", Elsevier (1988)).

H ₃The activity of acceptor can be by using H ₃Receptors ligand is modified and is regulated.This receptor can show antagonist, inverse agonist, agonist or partial agonist activity.For example, with H ₃Acceptor with and memory and the process of cognition, neurological process, cardiovascular function, blood glucose regulation and other systematicness active relevant illness and obstacle be associated.Although existing various demonstration H ₃The compound of receptor modulating activities, but preferably can provide for H ₃Acceptor shows the active more compound that also can be incorporated in the pharmaceutical composition that is applicable to methods of treatment.

Brief summary of the invention

The present invention relates to benzothiazole cyclobutyl amine, more particularly, the benzothiazole cyclobutyl amine derivatives of formula (I):

Or its pharmaceutically useful salt, ester, acid amides, prodrug or radiolabeled form, wherein:

M is 0 or 1;

R ₁And R ₂In one of be hydrogen, acyl group, acyloxy, alkenyl, alkoxyl group; alkoxyalkoxy group, alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl; alkyl, alkyl-carbonyl, alkyl sulphonyl, alkynyl, amide group; carboxyl, cyano group, cycloalkyl, fluoroalkyl, halogenated alkoxy; alkylhalide group, halogen, hydroxyl, hydroxyalkyl; sulfydryl, nitro, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b), N (R _14a) SO ₂(R _14b), formula-L ₂-R ₆Group or formula-L _3a-R _6a-L _3b-R _6bGroup;

R ₁And R ₂In another be selected from hydrogen, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl, fluoroalkyl, alkylthio ,-SO ₂N (R _14a) (R _14b) and-N (R _14a) SO ₂(R _14b);

R _3aAnd R _3bBe selected from hydrogen independently of one another, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl, fluoroalkyl, alkylthio ,-SO ₂N (R _14a) (R _14b) and-N (R _14a) SO ₂(R _14b);

R ₄And R ₅Be selected from alkyl independently of one another, fluoroalkyl, hydroxyalkyl, alkoxyalkyl and cycloalkyl; Perhaps R ₄And R ₅The nitrogen-atoms that connects with them forms a non-aromatic ring;

R ₆Be selected from aryl, heterocyclic radical and Heterocyclylalkyl;

R _6aBe selected from aryl and heterocyclic radical;

R _6bBe selected from aryl and heterocyclic radical;

L is a key or alkylidene group;

L ₂Be selected from a key ,-O-, alkylidene group ,-C (=0)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-and-N (R ₁₅)-;

L _3aAnd L _3bBe selected from a key independently of one another ,-O-, alkylidene group ,-C (=0)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-and-N (R ₁₅)-;

R ₁₀Be selected from hydrogen, cyano group, fluorine, hydroxyl and alkyl;

R _14aAnd R _14bWhen occurring, all be selected from hydrogen, alkyl and cycloalkyl independently of one another at every turn;

R ₁₅Be selected from hydrogen, alkyl, acyl group, carbalkoxy and (R _14a) (R _14b) NC (O)-; With

R _AAnd R _BBe independently selected from hydrogen, alkyl, acyl group, alkylhalide group, carbalkoxy, cycloalkyl and formyl radical.

Another aspect of the present invention relates to the pharmaceutical composition that contains The compounds of this invention.This based composition can be used according to method of the present invention, normally as being used for the treatment of or prevention and H ₃The part of the illness that receptor active is relevant and the treatment plan of obstacle.

Another aspect of the present invention relates to selectivity and regulates H ₃The method of receptor active.This method can be used for H in treatment or prevention and the Mammals ₃Acceptor is regulated relevant illness and obstacle.More particularly, this method can be used for treating or preventing the illness relevant with cognitive process, neurological process, cardiovascular function and body weight with memory and the method for obstacle.Therefore, compound of the present invention and composition can be used as treatment or prevention H ₃The drug use of the disease that acceptor is regulated.

Of the present invention relating in one aspect to again can be used as the radiolabeled drugs composition that radioligand uses.The formula of radio-labeling form (I) compound can provide with the form of the present composition, uses according to method of the present invention, is generally used for evaluation or diagnosis and H ₃Receptor related illness and obstacle for example are used for medical imaging.More particularly, the isotropic substance of the emission positron of The compounds of this invention can be used for the medical imaging among the PET (positron emission tomography art), wherein can measure histamine H ₃The degree that the location of acceptor and these acceptors are occupied by part.In this purposes, The compounds of this invention has at least one and is selected from ¹¹C, ¹⁸F, ¹⁵O and ¹³The isotopic atom of the emission positron of N.The compounds of this invention can also mix the isotropic substance that is used for sPECT imaging (single photon emission computerized tomography(SPECT)), for example ¹²³I.

Also considered to prepare the method for The compounds of this invention.

These compounds contain these compound compositions, prepare the method for compound, by using the method for this compounds for treating or prevention illness and obstacle, the radio-labeling form of this compound, and the composition that contains this compound radio-labeling form will further specify in this article.

Detailed Description Of The Invention

The definition of term

When some term uses in this manual, be meant describe in detail below to give a definition.

Term used herein " acyl group " is meant the alkyl that this paper that the carbonyl by this paper definition is connected with parent molecular moiety defines.The representative example of acyl group includes, but not limited to ethanoyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.

Term used herein " acyloxy " is meant the acyl group of this paper definition that is connected with parent molecular moiety by a Sauerstoffatom.The representative example of acyloxy includes, but not limited to acetoxyl group, propionyloxy and isobutyl acyloxy.

Term used herein " alkenyl " is meant and contains 2-10 carbon, preferred 2,3,4,5 or 6 carbon, and contain the straight or branched hydrocarbon of at least one carbon-to-carbon double bond.The representative example of alkenyl includes, but not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.

" alkoxyl group " used herein speech is meant the alkyl of definition herein that is connected with parent molecule by a Sauerstoffatom.The representative example of alkoxyl group includes, but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy, tert.-butoxy, pentyloxy and hexyloxy.

Term used herein " alkoxyalkoxy group " is meant the alkoxyl group of definition herein that is connected with parent molecular moiety by another alkoxyl group that defines herein.The representative example of alkoxyalkoxy group includes, but not limited to uncle's fourth oxygen methoxyl group, 2-ethoxy oxyethyl group, 2-methoxyethoxy and methoxy methoxy base.

Term used herein " alkoxyalkyl " is meant the alkoxyl group of definition herein that is connected with parent molecular moiety by an alkyl that defines herein.The representative example of alkoxyalkyl includes, but not limited to the tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.

Term used herein " carbalkoxy " is meant the alkoxyl group of this paper definition that is connected with parent molecular moiety by the carbonyl that defines herein.The representative example of carbalkoxy includes, but not limited to methoxycarbonyl, ethoxycarbonyl and tertbutyloxycarbonyl.

Term used herein " Alkoximino " is meant the alkoxyl group of definition herein that is connected with parent molecular moiety by the imino-that defines herein.The representative example of Alkoximino includes, but not limited to oxyethyl group (imino-) methyl and methoxyl group (imino-) methyl.

Term used herein " alcoxyl alkylsulfonyl " is meant the alkoxyl group of definition herein that is connected with parent molecular moiety by the alkylsulfonyl that defines herein.The representative example of alcoxyl alkylsulfonyl includes, but not limited to methoxy alkylsulfonyl, ethoxy alkylsulfonyl and the third oxygen alkylsulfonyl.

Term used herein " alkyl " is meant and contains 1-10 carbon atom, the straight or branched hydrocarbon of preferred 1,2,3,4,5 or 6 carbon atom.The representative example of alkyl comprises, but be not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, n-heptyl, n-octyl, n-nonyl and positive decyl.Each carbon atom of alkyl is replaced by hydrogen or 0,1 or 2 substituting group being selected from following group: acyl group, acyloxy, alkoxyl group, alkoxyalkoxy group, alkoxyalkyl; carbalkoxy, Alkoximino, alcoxyl alkylsulfonyl, alkyl-carbonyl, alkyl sulphonyl; amido, carboxyl, cyano group, cycloalkyl; fluoroalkyl, formyl radical, halogenated alkoxy, alkylhalide group; halogen, hydroxyl, hydroxyalkyl, sulfydryl; nitro, oxygen base, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl and (NR _AR _B) alkylsulfonyl.

Term " alkylidene group " is meant the straight or branched hydrocarbon deutero-divalent group by 1-10 carbon atom.The representative example of alkylidene group includes, but not limited to-CH ₂-,-CH (CH ₃)-,-C (CH ₃) ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-CH ₂CH ₂CH ₂CH ₂-and-CH ₂CH (CH ₃) CH ₂-.

Term used herein " alkylamino " is meant the alkyl of definition herein that is connected with parent molecule by the NH group.The representative example of alkylamino includes, but not limited to methylamino-, ethylamino, isopropylamino and fourth amino.

Term used herein " alkyl-carbonyl " is meant the alkyl of definition herein that is connected with parent molecule by the carbonyl that defines herein.The representative example of alkyl-carbonyl includes, but not limited to methyl carbonyl, ethyl carbonyl, sec.-propyl carbonyl, n-propyl carbonyl etc.

Term used herein " alkyl sulphonyl " is meant the alkyl of definition herein that is connected with parent molecular moiety by the alkylsulfonyl that defines herein.The representative example of alkyl sulphonyl includes, but not limited to methylsulfonyl and ethylsulfonyl.

Term used herein " alkylthio " is meant the alkyl of definition herein that is connected with parent molecular moiety via sulphur atom.The representative example of alkylthio includes, but not limited to methylthio group, ethylmercapto group, uncle's butylthio and own sulfenyl.

Term used herein " alkynyl " is meant and contains 2-10 carbon atom, preferred 2,3,4 or 5 carbon atoms, and contain the straight or branched alkyl of at least one carbon-to-carbon triple bond.The representative example of alkynyl includes, but not limited to ethynyl, 1-proyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.

Term used herein " amido " is meant amino, alkylamino or the dialkyl amido that is connected with parent molecular moiety by the carbonyl that defines herein.The representative example of amido includes, but not limited to aminocarboxyl, amino-carbonyl, dimethylamino carbonyl and ethyl amino-carbonyl.

Term used herein " amino " refers to-NH ₂Group.

Term used herein " aryl " refers to phenyl, aryl bicyclic or three cyclophane bases.Aryl bicyclic is connected with parent molecular moiety via any carbon atom that is included in this aryl bicyclic.The representative example of aryl bicyclic includes, but not limited to dihydro indenyl, indenyl, naphthyl, dihydro naphthyl and tetralyl.Three cyclophane bases are three cyclophane basic rings such as anthracene or phenanthrene systems for example, with Cycloalkylfused aryl bicyclic, with cycloalkenyl group condensed aryl bicyclic, or with phenyl condensed aryl bicyclic.Three cyclophane bases are connected with parent molecular moiety via any carbon atom that is included in this three cyclophanes base.The representative example of three cyclophane basic rings includes, but not limited to anthryl, phenanthryl, Azulene base, dihydro anthryl, fluorenyl and tetrahydrochysene phenanthryl.

The carbon atom of aryl of the present invention is replaced or randomly independently is selected from one or more substituting groups replacements of following group by hydrogen: acyl group, acyloxy, alkenyl, alkoxyl group, alkoxyalkoxy group; alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl, alkyl; alkyl-carbonyl, alkyl sulphonyl, alkynyl, amido, carboxyl; cyano group, cycloalkyl, fluoroalkyl, formyl radical, halogenated alkoxy; alkylhalide group, halogen, hydroxyl, hydroxyalkyl; sulfydryl, nitro, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b) and N (R _14a) SO ₂(R _14b).At this aryl is the situation of phenyl, and substituent number is 0,1,2,3,4 or 5.At this aryl is the situation of aryl bicyclic, and substituent number is 0,1,2,3,4,5,6,7,8 or 9.When this aryl was three cyclophane bases, substituent number was 0,1,2,3,4,5,6,7,8 or 9.

Term used herein " aralkyl " is meant the aryl of definition herein that is connected with parent molecular moiety via the alkyl that defines herein.The representative example of aralkyl includes, but not limited to benzyl, 2-styroyl and 3-hydrocinnamyl.

Term used herein " carbonyl " refers to-C (=O)-group.

Term used herein " carboxyl " refers to-CO ₂The H group, it can be with ester group-CO ₂The form of-alkyl is protected.

Term used herein " cyano group " be meant via carbon be connected with parent molecular moiety-the CN group.

Term used herein " benzonitrile base " be meant via phenyl be connected with parent molecular moiety-the CN group, include but not limited to 4-benzonitrile base, 3-benzonitrile base and 2-benzonitrile base.

Use term " cycloalkyl " to be meant the saturated cyclic hydrocarbons that contains 3-8 carbon atom herein.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.

0,1 or 2 substituting group that each carbon atom of cycloalkyl of the present invention is selected from following group replaces:

Acyl group herein, acyloxy, alkenyl, alkoxyl group, alkoxyalkoxy group; alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl, alkyl; alkyl-carbonyl, alkyl sulphonyl, alkynyl, amido, carboxyl; cyano group, cycloalkyl, fluoroalkyl, formyl radical, halogenated alkoxy; alkylhalide group, halogen, hydroxyl, hydroxyalkyl; sulfydryl, nitro, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b) and N (R _14a) SO ₂(R _14b).

Term used herein " naphthene base carbonyl " is meant the cycloalkyl of definition herein that is connected with parent molecular moiety via the carbonyl that defines herein.The representative example of naphthene base carbonyl includes, but not limited to cyclopropyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl and suberyl carbonyl.

Ding Yi term " dialkyl amido " is meant two alkyl that independently define that are connected with parent molecular moiety via a nitrogen-atoms herein herein.The representative example of dialkyl amido includes, but not limited to dimethylamino, diethylamino, ethylmethylamino and butyl methyl amino.

Term used herein " fluorine " refers to-F.

Term used herein " fluoroalkyl " be meant via herein the definition alkyl be connected with parent molecular moiety at least one define herein fluorine-based.The representative example of fluoroalkyl includes, but not limited to methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group and 2,2,2-trifluoroethyl.

Term used herein " fluoroalkyl " be meant via herein the definition alkoxyl group be connected with parent molecular moiety at least one define herein fluorine-based.The representative example of fluoroalkyl includes, but not limited to fluoro methoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups, seven fluorine propoxy-and 2,2,2-trifluoro ethoxy.

Term used herein " formyl radical " refers to-C (O) H group.

" halogen " used herein or " halogen " refer to Cl, Br, I or F.

Term used herein " halogenated alkoxy " refers at least one halogen atom that defines that the alkoxyl group by definition herein is connected with parent molecular moiety herein.The representative example of halogenated alkoxy includes, but not limited to 2-fluorine oxyethyl group, trifluoromethoxy and five fluorine oxyethyl groups.

Term used herein " alkylhalide group " is meant at least one halogen atom of definition herein that is connected with parent molecular moiety via the alkyl that defines herein.The representative example of alkylhalide group includes, but not limited to chloromethyl, 2-fluoro ethyl, trifluoromethyl, pentafluoroethyl group and 2-chloro-3-fluorine amyl group.

Term used herein " heterocycle " refers to contain at least one heteroatomic aromatics or non-aromatics circular base group.The example of aromatic heterocycle is for example following further heteroaryl of definition.Non-aromatic heterocyclic is to contain at least one heteroatomic non-aromatics circular base group; The example of non-aromatic heterocyclic group or non-aromatic heterocyclic is further definition below.Heterocycle is connected with parent molecular moiety via a carbon atom, or in the heterocyclic situation that includes the divalence nitrogen-atoms that connects the room, this heterocycle can be connected with parent molecular moiety by nitrogen-atoms.In addition, heterocycle can exist with the form of tautomer.

Ding Yi heteroaryl refers to contain one or more heteroatomic aromatic rings that independently are selected from nitrogen, oxygen or sulphur herein, or its tautomer.This class ring can be monocycle or dicyclo as what further specify herein.Heteroaryl ring is via carbon or nitrogen-atoms and parent molecule position, or and L ₂, L _3aOr L _3bConnect, wherein L ₂, L _3aOr L _3bSuc as formula the definition in (I).

Term used herein " bicyclic heteroaryl " or " 5-or 6 yuan of heteroaryl rings " refer to contain 1,2,3 or 4 the heteroatomic 5 or 6 yuan of aromatic ring that independently is selected from nitrogen, oxygen or sulphur, or its tautomer.The example of these rings includes, but not limited to one of them carbon by an O or S atom alternate ring; 1,2 or 3 N atoms are arranged in a suitable manner the formation aromatic ring; Two carbon atoms in the ring are by an O or S atom and a N atom alternate ring.These rings can include, but not limited to wherein, and 1-4 ring carbon atom contained 5 yuan of rings of sulphur, oxygen or a nitrogen-atoms by 6 yuan of aromatic rings of nitrogen-atoms alternate in the ring; 5 yuan of rings that contain 1-4 nitrogen-atoms; And 5 yuan of rings that contain an oxygen or sulphur and 1-3 nitrogen-atoms.The representative example of 5 to 6 yuan of heteroaryl rings comprises, but be not limited to furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiadiazoles ketone group, thiadiazine ketone group, oxadiazole base, oxadiazole ketone group, oxadiazine ketone group, thiazolyl, thienyl, triazinyl, triazolyl, pyridazine ketone group, pyriconyl and pyrimidine ketone group.

Term used herein " bicyclic heteroaryl " or " 8-12 unit ring heteroaryl ring " are meant 8,9,10,11 or 12 yuan of bicyclic aromatic rings that contain at least 3 two keys, and annular atoms wherein comprises one or more heteroatomss that independently are selected from oxygen, sulphur and nitrogen.The representative example of bicyclic heteroaryl ring comprises indyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, benzisothiazole base, benzoisoxazole base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, pteridyl, purine radicals, naphthyridinyl, cinnolines base, thieno-[2,3-d] imidazolyl, 1,5-dihydrobenzo [b] [1,4] diaza

-2-ketone group and pyrrolo-pyrimidine radicals.

No matter heteroaryl of the present invention is monocycle or dicyclo, all can be replaced by hydrogen, and the one or more substituting groups that perhaps randomly independently are selected from following group replace: acyl group; acyloxy, alkenyl, alkoxyl group, alkoxyalkoxy group; alkoxyalkyl, carbalkoxy, alkoxyimino; the alcoxyl alkylsulfonyl, alkyl, alkyl-carbonyl; alkyl sulphonyl, alkynyl, amido; carboxyl, cyano group, cycloalkyl; fluoroalkyl, formyl radical, halogenated alkoxy; alkylhalide group, halogen, hydroxyl; hydroxyalkyl, sulfydryl, nitro; the oxygen base, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b) and N (R _14a) SO ₂(R _14b).Bicyclic heteroaryl or 5 or 6 yuan of heteroaryl rings are replaced by 0,1,2,3,4 or 5 substituting group.Bicyclic heteroaryl or 8-12 unit bicyclic heteroaryl ring are replaced by 0,1,2,3,4,5,6,7,8 or 9 substituting group.Heteroaryl of the present invention can exist with tautomeric forms.

Term used herein " non-aromatic heterocyclic " refers to the monocycle or the dicyclo of 4-12 unit, wherein contains at least one saturated carbon atom, also contains 1,2,3,4 or 5 heteroatoms that independently is selected from nitrogen, oxygen and sulphur.4 yuan or 5 yuan of rings can have 0 or 1 two key.6 yuan of rings can have 0,1 or 2 two key.7 or 8 yuan of rings can have 0,1,2 or 3 two key.Non-aromatic heterocycle of the present invention can connect by carbon atom or nitrogen-atoms.This non-aromatic heterocycle can exist with tautomeric form.Nitrogenous heterocyclic representative example comprises, but be not limited to nitrogen heterocyclic heptyl, azelidinyl, nitrogen heterocyclic propyl group, nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl, dihydro-thiazolyl, dihydropyridine base and parathiazan base.The representative example of unazotized non-aromatic heterocyclic includes, but not limited to alkyl dioxin, dithiane base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl and [1,3] dioxolane base.

Non-aromatic heterocyclic of the present invention is replaced by hydrogen, or randomly independently is selected from 0,1,2,3,4,5,6,7,8 or 9 substituting group replacement of following group: acyl group, acyloxy; alkenyl, alkoxyl group, alkoxyalkoxy group; alkoxyalkyl, carbalkoxy, alkoxyimino; the alcoxyl alkylsulfonyl, alkyl, alkyl-carbonyl; alkyl sulphonyl, alkynyl, amido; carboxyl, cyano group, cycloalkyl; fluoroalkyl, formyl radical, halogenated alkoxy; alkylhalide group, halogen, hydroxyl; hydroxyalkyl, sulfydryl, nitro; the oxygen base, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b) and N (R _14a) SO ₂(R _14b).

Other example of heterogeneous ring compound includes, but not limited to isoindoline-1, the 3-diketone, (z)-1H-benzo [e] [1,4] diaza

-5 (4H)-ketone, and pyrimidine-2,4 (1H, 3H)-diketone, benzo [d] thiazole-2 (3H)-ketone, pyridine-4 (1H)-ketone, imidazolidin-2-one, 1H-imidazoles-2 (3H)-ketone, pyridazine-3 (2H)-ketone, tetrahydropyrimidine-2 (1H)-ketone and 1H-benzo [d] imidazoles-2 (3H)-ketone.

" Heterocyclylalkyl " used herein speech is meant the heterocyclic group of definition herein that is connected with parent molecular moiety by the alkyl that defines herein.The representative example of Heterocyclylalkyl includes, but not limited to 2-thenyl, 2-thiophene ethyl, 2-furans ethyl and furfuryl.

Term used herein " hydroxyl " refers to-the OH group.

Term used herein " hydrocarbon alkyl " refers at least one hydroxyl that defines that is connected with parent molecular moiety by the alkyl that defines herein herein.The representative example of hydroxyalkyl includes, but not limited to methylol, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyl amyl group and 2-ethyl-4-hydroxyl heptyl.

Term " hydroxy-protective group " is meant that a kind of substituting group of untoward reaction does not take place the protection hydroxyl between synthesis phase.The example of hydroxy-protective group comprises; but be not limited to; methoxymethyl, benzyloxymethyl, 2-methoxy (ethoxy) ylmethyl, 2-(trimethyl silyl) ethoxyl methyl, benzyl, trityl group, 2; 2,2-three chloroethyls, the tertiary butyl, trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene radical acetal, acetone contract benzylidene glycol, annular ortho ester, methoxyl group methylene radical, annular carbonic ether and annular boric acid ester.Compound and alkali (for example triethylamine) and a kind of reagent react of hydroxyl protecting group by hydroxyl is connected on the hydroxyl, and this reagent is selected from alkyl halide, trifluoromethanesulfonic acid alkyl ester, trialkylsilkl halogenide, trialkylsilkl triflate, dialkyl aryl silyl triflate or alkyl chloroformate, CH ₂I ₂Or a kind of dihalo-boric acid ester, methyl iodide for example, benzyl iodide, triethylsilyl triflate, Acetyl Chloride 98Min., benzyl chloride or methylcarbonate.Protecting group also can be connected on the hydroxyl with acid and the reaction of a kind of alkyl acetal by the compound of hydroxyl.

Herein Ding Yi term " imino-" refer to-C (=NH)-group.

Term used herein " sulfydryl " refers to-the SH group.

Term " (NR used herein _AR _B) alkyl " and be meant by herein the definition alkyl be connected with parent molecular moiety-NR _AR _BGroup.R _AAnd R _BBe independently selected from hydrogen, alkyl, acyl group, cycloalkyl and formyl radical.(NR _AR _B) representative example of alkyl includes, but not limited to 2-(methylamino-) ethyl, 2-(dimethylamino) ethyl, 2-(amino) ethyl, 2-(ethyl methylamino-) ethyl etc.

Term used herein " N (R _AR _B) carbonyl " and be meant that carbonyl via definition herein is connected with parent molecular moiety define herein-NR _AR _BGroup.(NR _AR _B) representative example of carbonyl includes, but not limited to aminocarboxyl, (methylamino-) carbonyl, (dimethylamino) carbonyl, (ethyl methylamino-) carbonyl etc.

Term " (NR used herein _AR _B) alkylsulfonyl " and be meant that alkylsulfonyl via definition herein is connected with parent molecular moiety define herein-NR _AR _BGroup.(NR _AR _B) representative example of alkylsulfonyl includes, but not limited to amino-sulfonyl, (methylamino-) alkylsulfonyl, (dimethylamino) alkylsulfonyl and (ethyl methylamino-) alkylsulfonyl.

Term used herein " N (R _14a) SO ₂(R _14b) ", be meant an amino that is connected with parent fraction again further with herein the definition a R _14aGroup and one the and (R of definition herein _14b) SO that connects of group ₂Group connects.-N (R _14a) SO ₂(R _14b) representative example include, but not limited to N-methyl Toluidrin.

Term " SO used herein ₂N (R _14a) (R _14b) " be meant one and SO ₂N (the R that group connects _14a) (R _14b) group, it is connected on the parent fraction via this alkylsulfonyl.-SO ₂N (R _14a) (R _14b) representative example include, but not limited to (dimethylamino) alkylsulfonyl and N-cyclohexyl-N-methylsulfonyl.

Term used herein " nitro " refers to-NO ₂Group.

Term used herein " nitrogen-protecting group group " refers to be used for protect between synthesis phase nitrogen-atoms that those groups of untoward reaction do not take place.Nitrogen-protecting group group comprises carbamate, acid amides, N-benzyl derivative and imine derivative.Preferred nitrogen-protecting group group is ethanoyl, benzoyl, benzyl, carbobenzoxy-(Cbz) (Cbz), formyl radical, benzenesulfonyl, valeryl, tertbutyloxycarbonyl (Boc), tertiary butyl acetal, trifluoroacetyl group and trityl group.Nitrogen-protecting group group is connected on primary amino or the secondary amino group by containing amino compound and alkali (for example triethylamine) and a kind of reagent react, and this reagent is selected from alkyl halide, trifluoromethanesulfonic acid alkyl ester, dialkyl group acid anhydrides ((alkyl-O-C=O) for example ₂The alkyl acid anhydrides of O representative), diaryl acid anhydrides ((aryl-OC=O) for example ₂O), acyl halide, alkyl chloroformate, heteroaryl-alkylsulfonyl halides, aryl sulfonyl halide or halogen-CON (alkyl) ₂, for example Acetyl Chloride 98Min., Benzoyl chloride, bromotoluene Carbobenzoxy Chloride, formyl fluoride, benzene sulfonyl chloride, the pivalyl chloride, (tertiary butyl-O-C=O) ₂O, trifluoroacetic anhydride and trityl group chlorine.

Term used herein " oxygen base " refer to (=O).

Term used herein " alkylsulfonyl " refers to-S (O) ₂-group.

Term used herein " antagonist " comprises and has described and just stops acceptor by H ₃Receptor stimulant (as histamine) activatory compound also comprises the compound that is called " inverse agonist ".Inverse agonist is not only to stop acceptor by H ₃Receptor stimulant (for example histamine) activation, but also suppress H ₃The compound of acceptor intrinsic activity.

Term used herein " radioactively labelled substance " refers to a kind of The compounds of this invention, wherein at least a atom is radioactive atom or radio isotope, this radioactive atom or isotropic substance are spontaneously launched gamma-rays or high energy particle, for example alpha-particle or beta-particle, or positron.The example of this radioactive atom includes, but not limited to ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F, ³⁵S, ¹²³I and ¹²⁵I.

Compound of the present invention

The compounds of this invention can have the chemical formula of describing in the brief summary of the invention (I).

In formula (I) compound, m is 0 or 1.Preferred m is 0.

L is a key or alkylidene group.L is a key preferably.

R in formula (I) compound ₁And R ₂In one be hydrogen, acyl group, acyloxy, alkenyl, alkoxyl group, alkoxyalkoxy group, alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl, alkyl, alkyl-carbonyl, alkane alkylsulfonyl, alkynyl, amido, carboxyl, cyano group, cycloalkyl, fluoroalkyl, halogenated alkoxy, alkylhalide group, halogen, hydroxyl, hydroxyalkyl, sulfydryl, nitro, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-N (R _A) alkane alkylsulfonyl, (NR _14aR _14b) alkylsulfonyl, or formula-L ₂-R ₆Or-L _3a-R _6a-L _3b-R _6bGroup.R ₁Or R ₂Another group of representative is hydrogen, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl, fluoroalkyl, alkylthio, SO ₂N (R _14a) (R _14b) or N (R _14a) SO ₂(R _14b), R wherein _14aAnd R _14bBe hydrogen, alkyl or cycloalkyl independently of one another, be more preferably hydrogen or alkyl, particularly methyl.Work as R ₁Or R ₂Be not-L ₂-R ₆Or-L _3a-R _6a-L _3b-R _6bThe time, preferred group is a hydrogen.

Preferred R ₁Be-L ₂-R ₆Or-L _3a-R _6a-L _3b-R _6bAnd R ₂Be hydrogen, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl and fluoroalkyl.More preferably R ₁Be-L ₂-R ₆

L ₂Be selected from a key ,-O-, alkylidene group ,-C (=O)-.-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-and-N (R ₁₅)-.Preferred L ₂It is a key.

Preferred R ₆It is a heterocyclic radical.For R ₆The example of suitable heterocyclic radical comprises, but be not limited to, furyl, imidazolyl isoxazolyl, isothiazolyl oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, the thiadiazoles ketone group, thiadiazine ketone group; oxadiazole base; oxadiazole ketone group; oxadiazine ketone group, thiazolyl, thienyl, triazinyl, triazolyl, the pyridazine ketone group, pyriconyl, the pyrimidine ketone group, indyl, benzothienyl, benzofuryl, indazolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, the benzisothiazole base, the benzoisoxazole base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, pteridyl, purine radicals, naphthyridinyl, the cinnolines base, thieno-[2,3-d] imidazolyl, 1,5-dihydrobenzo [b] [1,4] diaza

-2-ketone group, pyrrolo-pyrimidine radicals, nitrogen heterocyclic heptyl, azelidinyl, nitrogen heterocyclic propyl group, nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl, dihydro-thiazolyl, dihydropyridine base, parathiazan base, alkyl dioxin, dithiane base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl and [1,3] dioxolane base.

For R ₆, preferred heterocyclic radical is pyrazolyl, pyrimidyl, pyrimidine ketone group, pyridyl, pyridazine ketone group and quinolyl, wherein each ring all is selected from 0,1 or 2 substituting group replacement of methoxyl group and methyl.

L _3aAnd L _3bBe selected from a key independently of one another ,-O-, alkylidene group ,-C (=O)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-and-N (R ₁₅)-.Preferred L _3aIt is a key.L _3bAlso key preferably.

R _6aThe preferred aryl groups at place is a cyano-phenyl.Preferred R _6aIt is a heterocyclic radical.For R ₆, the example of suitable heterocyclic radical includes, but not limited to pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, pyridazine ketone group, pyriconyl, pyrimidine ketone group, pyrrolidyl, pyrrolinyl and quinolyl.For R _6a, preferred heterocyclic radical is pyrazolyl, pyrimidyl, pyrimidine ketone group, pyridyl, pyridazine ketone group and quinolyl, wherein each ring all is selected from 0,1 or 2 substituting group replacement of methoxyl group and methyl.

R _6bThe preferred aryl groups at place is the benzonitrile base.Preferred R6b is a heterocyclic radical.For R _6bThe example of suitable heterocyclic radical comprises, but be not limited to, furyl, imidazolyl isoxazolyl, isothiazolyl oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, the thiadiazoles ketone group, thiadiazine ketone group; oxadiazole base; oxadiazole ketone group; oxadiazine ketone group, thiazolyl, thienyl, triazinyl, triazolyl, the pyridazine ketone group, pyriconyl, the pyrimidine ketone group, indyl, benzothienyl, benzofuryl, indazolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, the benzisothiazole base, the benzoisoxazole base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, pteridyl, purine radicals, naphthyridinyl, the cinnolines base, thieno-[2,3-d] imidazolyl, pyrrolo-pyrimidine radicals, the nitrogen heterocyclic heptyl, azelidinyl, the nitrogen heterocyclic propyl group, the nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl, dihydro-thiazolyl, the dihydropyridine base, parathiazan base alkyl dioxin, the dithiane base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl and [1,3] dioxolane base.For R _6bPreferred heterocyclic radical is pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, pyridazine ketone group, pyriconyl, pyrimidine ketone group, pyrrolidyl, pyrrolinyl and quinolyl, and wherein each ring all is selected from 0,1 or 2 substituting group replacement of methoxyl group and methyl.

R _3aAnd R _3bBe independently of one another hydrogen, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl, fluoroalkyl, alkylthio ,-SO ₂N (R _14a) (R _14b) or-N (R _14a) SO ₂(R _14b).R _3aAnd R _3bHydrogen preferably all.

In an embodiment, R ₄And R ₅Be alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl independently of one another.In this embodiment, R ₄And R ₅Preferably alkyl or hydroxyalkyl, particularly methyl, ethyl, propyl group and hydroxyethyl.For R ₄And R ₅, selected group does not need identical.

Or, R ₄And R ₅The nitrogen-atoms that is connected with them forms a non-aromatic ring altogether.This non-aromatic ring can be any nitrogenous non-aromatic ring.Be fit to wherein R ₄And R ₅The example of non-aromatic ring that forms this embodiment of a ring altogether includes, but not limited to have the non-aromatic ring of following chemical formula:

Q ₁Be O, S ,-N (R ₂₀)-or C;

Q ₂Be-N (R ₂₀)-or C;

Q ₃Be N or C;

R ₂₀Be selected from hydrogen, alkyl and alkyl-carbonyl;

p ¹And p ²Be 1,2 or 3 independently of one another;

q ¹, q ², q ³, q ⁴And q ⁵Be 0,1 or 2 independently of one another; With

r ¹, r ²And r ³Be 1 or 2 independently of one another;

Wherein each carbon atom on the ring all replaces by hydrogen or by 0,1 or 2 substituting group, and these substituting groups all are independently selected from following radicals at every turn when occurring: hydroxyl, fluorine, alkyl, hydroxyalkyl, fluoroalkyl, cycloalkyl, cyano group, fluoroalkyl, alkoxyalkyl, alkoxyl group, alkylhalide group and-N (R _21a) (R _21b), R wherein _21aAnd R _21bBe selected from hydrogen, alkyl and alkyl-carbonyl independently of one another.

The preferred R that forms ₄And R ₅The group of ring have chemical formula (a) or (b).More particularly, R ₄And R ₅The nitrogen-atoms that connects with their forms nitrogen heterocyclic heptyl, azelidinyl, nitrogen heterocyclic propyl group, nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl and hexahydropyrrolo also [3,4-b] pyrryl, wherein each group all is selected from 0,1 or 2 substituting group replacement of alkyl, hydroxyalkyl, hydroxyl, fluorine and fluoroalkyl.

The ring of preferred formula (a) is piperidines, tetramethyleneimine, 4-fluorine piperidines, 4-hydroxy piperidine, pipecoline, (2R)-crassitude ring and (2S)-crassitude ring.

The ring of a kind of preferred formula (b) is

Q ₂Be-N (R ₂₀)-; Q wherein ₁, q ₂, q ₃And q ₄Be 1, R ₂₀It is hydrogen or alkyl.In another embodiment, q ₁Be 0, q ₂Be 2, q ₃And q ₄Be 1.

Another embodiment of the present invention is formula (II) compound:

R wherein ₁, R ₂, R _3a, R _3b, R ₄And R ₅As described in to formula (I) compound.In an embodiment, R ₁Be-L ₂-R ₆, R ₂Be hydrogen, R _3aAnd R _3bAll be hydrogen, R ₄And R ₅Form a non-aromatic ring altogether.In another embodiment, R ₁Be hydrogen, R ₂Be-L ₂-R ₆, R _3aAnd R _3bAll be hydrogen, R ₄And R ₅Form a non-aromatic ring altogether.

Another embodiment of the present invention is formula (III) compound:

The proper group of each position in formula (I) compound, for example, R ₁, R ₂, R _3a, R _3b, R ₄And R ₅, and by the integer that m represents, in all embodiments, all can irrespectively be determined with other the locational replacement of this compound.The preferred group that imagination is represented by a variable, for example R ₁Be-L ₂R ₆(L wherein ₂Be to R ₁The group of definition, R ₆Be heterocyclic radical), can be incorporated in formula (I) compound of preferred group, for example R wherein with another variable ₄And R ₅Be before to R ₄And R ₅Formula (I) compound of described formula (d) group.

An embodiment that is considered as a part of the present invention includes, but not limited to following formula (I) compound, and wherein m is 0, and L is a key, L ₂Be a key ,-O-, alkylidene group ,-C (=O)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-or-N (R ₁₅)-, be R wherein _14a, R _14bAnd R ₁₅As before to the definition of formula (I) compound, R ₆It is heterocyclic radical.

An embodiment that is considered as a part of the present invention includes, but not limited to wherein that m is 0, and L is a key, R ₆It is heterocyclic formula (I) compound.

An embodiment that is considered as a part of the present invention includes, but not limited to following formula (I) compound, and wherein m is 0, L ₂Be a key ,-O-, alkylidene group ,-C (=O)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a) C (O)-or-N (R ₁₅)-, be R wherein _14a, R _14bAnd R ₁₅As before to the definition of formula (I) compound, R ₆Be heterocyclic radical, R ₄And R ₅Form one as altogether before to R ₄And R ₅Described structural formula (a) and (b) or non-aromatic ring (c).

Another specific embodiments that is considered as a part of the present invention includes, but not limited to such formula (I) compound, and wherein m is 0, L ₂Be a key, R ₆Be heterocyclic radical, R ₄And R ₅Form one as altogether before to R ₄And R ₅Described structure (a) and (b) or non-aromatic ring (c).

Another specific embodiments that is considered as a part of the present invention includes, but not limited to such formula (I) compound, and wherein m is 0, and L is a key, R ₆Be heterocyclic radical, R ₄And R ₅Form one as altogether before to R ₄And R ₅Described structure (a), (c) or non-aromatic ring (d).

Another embodiment of preferred compound is such formula (I) compound, wherein R ₁Or R ₂Be L ₂R ₆, L ₂Be a key, R ₆Have formula (e) structure:

R wherein ₁₆And R ₁₇Be selected from hydrogen, alkyl, alkylhalide group, cycloalkyl, alkoxyalkyl, aryl and heteroaryl independently of one another; Perhaps R ₁₆And R ₁₇Form a 3-7 unit ring with the carbon atom that they connected; V is 1,2,3,4,5 or 6, and all other variable is all with identical to the definition of formula (I) compound.

The specific embodiments that is considered as a part of the present invention also includes, but not limited to formula (I) compound that limited, for example:

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 6-(2,6-lutidine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyridin-4-yl-1, the 3-benzothiazole;

Instead-and 6-(6-methoxypyridine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyridin-3-yl-1, the 3-benzothiazole;

Instead-and 3-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) quinoline;

Instead-and 6-(6-fluorine pyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 4-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) cyanobenzene;

Instead-2-{3-[(2S)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 6-(2,6-lutidine-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 6-(6-methoxypyridine-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 3-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) quinoline;

Suitable-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-6-(2,6-lutidine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Suitable-2-{3-[(2S)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Suitable-6-(2,6-lutidine-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-and 2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone;

Instead-and 6-methyl-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone;

Instead-the 5-methyl isophthalic acid-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone;

Instead-the 3-methyl isophthalic acid-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone;

Instead-and 2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone;

Instead-and 6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone;

Instead-the 5-methyl isophthalic acid-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone;

Instead-the 3-methyl isophthalic acid-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone;

Suitable-the 6-pyrimidine-5-base 2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Suitable-6-(2-methoxy pyrimidine-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Suitable-2-(3-piperidines-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-6-(2-methoxy pyrimidine-5-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Suitable-2-(3-azepan-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-2-(3-morpholine-4-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-(2S)-and 1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol;

Suitable-((2S)-1-{3-[6-(2-methoxy pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl } tetramethyleneimine-2-yl) methyl alcohol;

Suitable-2-{3-[(3aR, 6aR)-hexahydropyrrolo [3,4-b] pyrroles-5 (1H)-yl also] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-2-{3-[(3aR, 6aR)-hexahydropyrrolo [3,4-b] pyrroles-5 (1H)-yl also] cyclobutyl }-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole;

Suitable-2-{3-[(2R)-and pipecoline-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Suitable-N-sec.-propyl-N-methyl-N-I3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine;

Suitable-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] and piperidin-4-yl } methyl alcohol;

Instead-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] piperidin-4-yl } methyl alcohol;

Instead-and 2-(3-piperidines-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 6-(2,6-lutidine-3-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(6-methoxypyridine-3-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone;

Suitable-2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone;

Instead-and 6-methyl-2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone;

Instead-3-methyl isophthalic acid-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H)-ketone;

Instead-and 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and N-sec.-propyl-N-methyl-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine;

Instead-and N-sec.-propyl-N-{3-[6-(2-methoxy pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine;

Instead-and N-sec.-propyl-N-{3-[6-(6-methoxypyridine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine;

Instead-and N-sec.-propyl-N-{3-[6-(2-methoxypyridine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine;

Instead-and N-{3-[6-(2,6-lutidine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-N-sec.-propyl-N-methylamine;

Instead-and 2-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone;

Instead-2-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl-1,3-benzothiazole-6-yl)-6-methyl pyridazine-3 (2H)-ketone;

Instead-1-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl-1,3-benzothiazole-6-yl)-3-picoline-2 (1H)-ketone;

Instead-1-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl-1,3-benzothiazole-6-yl)-5-picoline-2 (1H)-ketone;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 6-pyrimidine-5-base-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(2,6-lutidine-3-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-(6-methoxypyridine-3-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 2-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone;

Instead-and 6-methyl-2-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone;

Instead-5-methyl isophthalic acid-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H)-ketone;

Instead-3-methyl isophthalic acid-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H)-ketone;

Instead-and 2-(3-azepan-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 2-(3-morpholine-4-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-2-{3-[(2S)-and 2-(methyl fluoride) tetramethyleneimine-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-(2S)-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol;

Instead ((2S)-1-{3-[6-(2,6-lutidine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl } tetramethyleneimine-2-yl } methyl alcohol;

Instead-2-[3-(pipecoline-1-yl) cyclobutyl]-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-and 2-(the 3-hexahydropyrrolo is [3,4-b] pyrroles-5 (1H)-basic ring butyl also)-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole;

Instead-and 6-(2,6-lutidine-3-yl)-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-1, the 3-benzothiazole;

Instead-(3R)-and 1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] piperidines-3-alcohol;

Instead-and N-ethyl-N-propyl group-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine;

Instead-diethyl-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine;

Instead-diethyl-3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } amine;

Instead-3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } the methyl propylamine;

Instead-3-[6-(2,6-lutidine-3-yl) benzothiazole-2-yl] cyclobutyl } the methyl propylamine;

Instead-methyl-3-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzothiazole-2-yl] cyclobutyl } propylamine;

Instead-2-(ethyl-and 3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } amino) ethanol;

Instead-2-(3-[6-(2,6-lutidine-3-yl) benzothiazole-2-yl] and cyclobutyl } ethylamino) ethanol;

6-pyrimidine-5-base-2-(3-tetramethyleneimine-1-ylmethyl cyclobutyl) benzothiazole;

Instead-and 5-(2,6-lutidine-3-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole;

Instead-and 5-(2,4-dimethoxypyridin-5-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole;

Instead-and 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole;

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzothiazole;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(2,6-lutidine-3-yl)-1, the 3-benzothiazole;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1, the 3-benzothiazole;

Instead-and 2-(3-nitrogen heterocyclic heptan-1-basic ring butyl)-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole;

Instead-and 2-(3-nitrogen heterocyclic heptan-1-basic ring butyl)-6-(2,6-lutidine-3-yl)-1, the 3-benzothiazole;

Instead-and 2-(3-nitrogen heterocyclic heptan-1-basic ring butyl)-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1, the 3-benzothiazole;

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] ethanamide;

Suitable-2-chloro-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] ethanamide;

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide;

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyramide;

Suitable-cyclopropane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-cyclobutane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-Cyclopentane carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-hexahydrobenzoic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-furans-the 2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-4-cyano group-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] benzamide;

Suitable-4-cyano group-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] benzsulfamide;

Suitable-thiophene-2-sulfonic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-thiophene-2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyl carbamate;

Suitable-morpholine-the 4-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-pyrazine-the 2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl]-2-thiene-3-yl-ethanamide;

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl]-3-thiophene-2-base propionic acid amide;

Suitable-3-furans-2-base-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide;

Suitable-pyrimidine-5-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-and 4-cyano group-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] benzamide

Instead-and N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide;

Instead-and N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyramide;

Anti--[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyl carbamate;

Instead-cyclopropane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-cyclobutane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-Cyclopentane carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-hexahydrobenzoic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-furans-2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-morpholine-4-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-pyrimidine-5-carboxylic acid's [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Instead-pyrazine-2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides;

Racemize-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] pyrimidine-5-base amine;

Racemize-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] pyrimidine-2-base amine;

Racemize-(5-bromo pyrimi piperidine-2-yl)-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] amine;

Racemize-(5-picoline-2-yl)-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] amine;

Racemize-6-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-base is amino] the cigarette nitrile;

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-base nitrogen heterocyclic din-2-ketone;

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-base pyrrolidin-2-one;

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-phenylpiperidines-2-ketone;

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1, the 3-benzothiazole-high pyrrolidin-2-one of 6-base;

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-sec.-propyl-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-cyclopropyl-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-phenyl-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-thiazol-2-yl-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-benzyl-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N-(2-styroyl)-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

N, N-dimethyl-2-{ is anti--3-[(S)-and pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide;

(tetramethyleneimine-1-yl)-2-(anti--3-[(S)-and pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-ketone;

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-base-3-methylpyrrolidin-2-ketone;

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-Ji oxazolidine-2-ketone;

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-base-3-Methylimidazole alkane-2-ketone;

Instead-6-bromine 2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl]-1, the 3-benzothiazole;

Instead-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl]-1, the 3-benzothiazole;

Suitable-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl]-1, the 3-benzothiazole;

Suitable-6-bromo-2-(3-tetramethyleneimine-1-basic ring butyl]-1, the 3-benzothiazole;

Suitable-6-bromo-2-) 3-piperidines-1-basic ring butyl]-1, the 3-benzothiazole;

Suitable-2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Suitable-(2S)-and 1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol;

Suitable-tertiary butyl (3aR, 6aR)-5-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also;

Suitable-6-bromo-2-{3-[(2R)-pipecoline-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Suitable-N-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl]-N-sec.-propyl-N-methylamine;

Suitable-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] and piperidin-4-yl } methyl alcohol;

Instead-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] piperidin-4-yl } methyl alcohol;

Instead-and 6-bromo-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-N-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl]-N-sec.-propyl-N-methylamine;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Instead-and 6-bromo-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Instead-and 6-bromo-2-(3-morpholine-4-basic ring butyl)-1, the 3-benzothiazole;

Instead-6-bromo-2-{3-[(2S)-2-(methyl fluoride) tetramethyleneimine-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Instead-(2S)-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol;

Instead-and 6-bromo-2-[3-(pipecoline-1-yl) cyclobutyl]-1, the 3-benzothiazole;

Instead-and tertiary butyl 5-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also;

Instead-and 6-bromo-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl] 1, the 3-benzothiazole;

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] diethylamine;

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] methyl-propyl amine;

Instead-and 2-{[3-(6-bromo benzothiazole-2-yl) cyclobutyl] ethylamino } ethanol;

6-bromo-2-(3-tetramethyleneimine-1-ylmethyl cyclobutyl) benzothiazole; With

Instead-5-chloro-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl benzothiazole.

Preferred formula (I), (II) or (III) compound comprise at least:

Instead-and 2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone; With

Suitable-2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone.

The compound title is specified with AUTONOM name software, and (Frankfurt Germany) provides this software, and it is by MDL InformationSystems GmbH (preceding title Beilstein Informationssysteme) The part of ULTRA 6.0.2 version software group.

Can there be the steric isomer that asymmetric center or chiral centre are wherein arranged in The compounds of this invention.These steric isomers form " R " or " S " type according to the substituent configuration around the chiral carbon atom.Term used herein " R " and " S " are at IUPAC 1974Recommendations forSection E, Fundamental Sterochemistry, in Pure Appl.Chem., 1976, defined configuration among the 45:13-30.The present invention has considered various steric isomers and composition thereof, and they are comprised within the scope of the present invention clearly.Steric isomer comprises enantiomorph and diastereomer, and the mixture of enantiomorph or diastereomer.Each steric isomer of The compounds of this invention can be set out synthetic the preparation by the commercially available initiator that contains asymmetric center or chiral centre, or the preparation racemic mixture, carries out well known to those of ordinary skill in the art disassembling then.The example of these disassembling methods has: (1) is attached to the mixture of enantiomorph on a kind of chirality assistant agent, utilize recrystallization or chromatography that the non-enantiomer mixture that forms is separated, and randomly from this assistant agent, discharge optically pure product, as Furniss, Hannaford, Smith and Tatchell, " Vogel ' s Textbook of Practical Organic Chemistry ", 5th edition (1989), Longman Scientific﹠amp; Technical, ESSex CM 202JE, described in the England, perhaps directly separate the mixture of optical antipode on chiral chromatographic column (2), perhaps (3) fractional recrystallization method.

The compounds of this invention can exist with the form of cis or trans-isomer(ide), and wherein the substituting group on the ring can all be connected the same side (cis) of ring each other, or is connected the both sides, opposite (trans) of ring.For example, tetramethylene can exist with cis or transconfiguration, and can exist with the form of the mixture of single isomer or cis and trans-isomer(ide).Each cis or the trans-isomer(ide) of The compounds of this invention can utilize the selectivity organic transformation, by the synthetic preparation of commercially available initiator, perhaps utilize the purifying mixture with cis and trans-isomer(ide), are prepared into the individual isomer form.These methods are that those of ordinary skills know, and can comprise utilizing recrystallization or chromatography with isomer separation.

Should be understood that The compounds of this invention can have tautomeric form and geometrical isomer, these also constitute a part of the present invention.Should be understood that also The compounds of this invention can exist with the form of isotope-isomerism thing, wherein atom can have different weight, for example hydrogen and neon, perhaps ¹²C and ¹³C.

The preparation method of The compounds of this invention

Contact is following is used for the synthetic schemes and the method for means of example explanation preparation The compounds of this invention, can understand The compounds of this invention better.

The abbreviation of using in the explanation of scheme and embodiment subsequently is: BINAP, 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene; Boc, butoxy carbonyl; EtOAc, ethyl acetate; HPLC, high pressure liquid chromatography; IPA, Virahol; Me, methyl; MeOH, methyl alcohol; Ms, methylsulfonyl; Pd, palladium; TBu, the tertiary butyl; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran (THF); Ts, p-toluenesulfonyl, rt, room temperature or envrionment temperature are preferably 20-30 ℃.Microwave heating is finished in the commodity microwave device.

The compounds of this invention can prepare with multiple synthetic method.Representational method is shown in, but is not limited to, among the scheme 1-5.

Scheme 1

Formula (3) compound, wherein m, R ₁, R ₂, R _3a, R _3b, R ₄, R ₅, L is suc as formula the definition in (1), can be by preparation described in the scheme 1.The acyl chlorides of formula (1) can be buy or with the known method preparation of those of ordinary skills, when its usefulness formula (2) compound treatment, can obtain formula (3) compound as the representative of The compounds of this invention.

Scheme 2

The formula of nitrile group-containing (4) compound can obtain the carboxylic acid of formula (5) during with sodium-hydroxide treatment in the aqueous solution.The carboxylic acid cpd of formula (5) can obtain the chloride of acid of formula (6) when handling with SULPHURYL CHLORIDE or oxalyl chloride.The benzothiazole compound of formula (6) compound condensation with formula (2a) compound treatment time formation formula (7).The R of formula (2a) compound _3a, R _3bIdentical with definition in the formula (1), X wherein ₁And X ₂In at least one is chlorine, iodine or bromine, another be hydrogen, acyl group, acyloxy, alkenyl, alkoxyl group, alkoxyalkoxy group, alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl, alkyl, alkyl-carbonyl, alkyl sulphonyl, alkynyl, amido, carboxyl, cyano group, cycloalkyl, fluoroalkyl, halogenated alkoxy, alkylhalide group, halogen, hydroxyl, hydroxyalkyl, sulfydryl, nitro, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b), N (R _14a) SO ₂(R _14b).Formula (7) compound can obtain the cyclobutanone compound of formula (8) with perosmic anhydride or potassium osmate and sodium periodate processing the time.Formula (8) compound with hydride reducer (such as but not limited to 3-sec-butyl lithium borohydride (L-Selectride)) reduction, obtains formula (9) compound in solvent (such as but not limited to THF).Formula (9) compound is handled with trifluoromethanesulfanhydride anhydride, methylsulfonyl chloride or toluene sulfonyl chloride in the presence of alkali (such as but not limited to salt of wormwood, triethylamine, diisopropylethylamine etc.), uses formula R subsequently ₄R ₅The amine of NH is handled, wherein R ₄And R ₅Definition in the cotype (1) obtains formula (10) compound.

The a variety of suitable and formula R that are easy to get are arranged ₄R ₅The amine of NH, wherein R ₄And R ₅Definition in the cotype (1).These amine R ₄R ₅The example of NH is, but is not limited to the amine of listing in the table 1.

Table 1

The formula R that is easy to get ₄R ₅The example of the amine of NH

Formula (10) compound that can utilize the Suzuki reaction will contain X1 group (I, Br or Cl) transforms an accepted way of doing sth (11) compound.Similarly, the Suzuki reaction can will contain X ₂Formula (10) compound of group (I, Br or Cl) transforms an accepted way of doing sth (12) compound.This Suzuki reaction is a kind of halogen compounds, and formula (10) compound for example is with formula R _x-B (OR) ₂Boric acid or the reaction between the boric acid ester compound, wherein R _XBe aryl, heteroaryl, heterocyclic radical, alkyl, alkenyl or cycloalkyl, R is a hydrogen or alkyl, and this for example is reflected at metal catalyst, but is not limited to, palladium diacetate, PdCl ₂(PPh ₃) ₂Or Pd (PPh ₃) ₄Carry out under existing, can randomly add a kind of palladium part, for example 2-(dicyclohexyl phosphino-) biphenyl, tributylphosphine or three (2-furyl) phosphine, and a kind of alkali are such as but not limited to K ₃PO ₄Or Na ₂CO ₃The aqueous solution or KF.Or, can use tetramethyl ethylene ketone boric acid ester reagent, for example following formula

The compound of representative replaces boric acid or ester in the Suzuki reaction.At following document: N.Miyauraet al., can find the description to this method in the document of quoting in Chem.Rev.95:2457 (1995) or this article.

A variety of aryl, heteroaryl and heterocyclic boronic acids and boric acid ester are arranged, they or commercial goods, or can described in the scientific literature of Synthetic Organic Chemistry, prepare.Be used for the synthetic boric acid of formula (I) compound and the representative instance of boric acid ester reagent and be shown in table 2.

Table 2

The example of boric acid and boric acid ester reagent

Boric acid or boric acid ester	Commercial source, chemical abstracts number (CAS#), or reference
Boric acid or boric acid ester		2-pyrimidone-5-boric acid	CAS#373384-19-1
2-methoxy pyrimidine-5-boric acid	Frontier Scientific，Inc.，Logan，UT，USA	2-pyrimidone-5-boric acid	CAS#373384-19-1
2-methoxy pyrimidine-5-boric acid	Frontier Scientific，Inc.，Logan，UT，USA	1H-pyrimidine-2,4-diketone-5-boric acid	Specs，Fleminglaan，the Netherlands CAS#70523-22-7；Schinazi，Raymond F.； Prusoff，William H.，Synthesis of 5- (dihydroxyboryl)-2′-deoxyuridine and related boron-containing pyrimidines， Journal of Organic Chemistry(1985)， 50(6)，841-7.
Pyridine-3-boric acid	CAS#1692-25-7，Frontier Scientific，Inc.， Logan，UT，USA	1H-pyrimidine-2,4-diketone-5-boric acid

2,4-dimethoxypyridin-5-boric acid	CAS#89641-18-9，Frontier Scientific，Inc.， Logan，UT，USA
2,4-dimethoxypyridin-5-boric acid	CAS#89641-18-9，Frontier Scientific，Inc.， Logan，UT，USA	2-methoxyl group-5-pyridine boric acid	Digital Specialty Chemicals，Dublin，NH； CAS#163105-89-3；New shelf-stable halo- and alkoxy-substituted pyridylboronic acids and their Suzuki cross-coupling reactions to yield heteroarylpyridines，Parry，Paul R.； Bryce，Martin R.；Tarbit，B rian，Department of Chemistry，Synthesis(2003)，(7)，1035- 1038；Functionalized Pyridylboronic Acids and Their Suzuki Cross-Coupling Reactions To Yield Novel Heteroarylpyridines，Parry，Paul R.；Wang， Changsheng；Batsanov，Andrei S.；Bryce， Martin R.；Tarbit，Brian，Journal of Organic Chemistry(2002)，67(21)，7541-7543.
Pyrimidine-5-boric acid	CAS#109299-78-7，S.Gronowitz，et al.， ″On the synthesis of various thienyl-and selenienylpyrimidines″，Chem.Scr. 26(2)：305-309(1986).	2-methoxyl group-5-pyridine boric acid
Pyrimidine-5-boric acid		Pyrimidine-5-boric acid, pinacol ester	Umemoto，et al.，Angew.Chem.Int.Ed. 40(14)：2620-2622(2001).
2-picoline-5-boric acid hydrate	SYNCHEM OHG Heinrich-Plett-Strassse 40；Kassel，D- 34132；Germany；CAS#659742-21-9	Pyrimidine-5-boric acid, pinacol ester	Umemoto，et al.，Angew.Chem.Int.Ed. 40(14)：2620-2622(2001).
2-picoline-5-boric acid hydrate		3,6-dihydro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-2H-pyrans	CAS#287944-16-5；Murata，Miki；Oyama， Takashi；Watanabe，Shinji；Masuda， Yuzuru，Synthesis of alkenylboronates via palladium-catalyzed borylation of alkenyl triflates(or iodides)with pinacolborane. Synthesis(2000)，(6)，778-780.
3, and 6-dihydro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-	CAS#286961-14-6；A versatile synthesis of 4-aryltetrahydropyridines via palladium

Base)-1 (2H)-pyridine carboxylic acid-1,1-dimethyl ethyl ester	mediated Suzuki cross-coupling with cyclic vinyl boronates，Eastwood，Paul R.， Discovery Chemistry，Aventis Pharma， Essex，UK.，Tetrahedron Letters(2000)， 41(19)，3705-3708.
		(5-cyano group-3-pyridyl) boric acid	CAS#497147-93-0； Chemstep Institut du PIN-University Bordeaux 1 351 cours de la liberation Talence Cedex，33450 France
Thianthrene-1-boric acid	Aldrich Chemical Company，Inc.	(5-cyano group-3-pyridyl) boric acid
Thianthrene-1-boric acid	Aldrich Chemical Company，Inc.	Benzoxazole-5-boric acid	Cat#110831，Asymchem Laboratories， Inc.
Benzothiazole-5-boric acid	Cat#1464，Digital Specialty Chemicals， Inc.	Benzoxazole-5-boric acid	Cat#110831，Asymchem Laboratories， Inc.
Benzothiazole-5-boric acid	Cat#1464，Digital Specialty Chemicals， Inc.	4-methyl-7-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-3,4-dihydro-2H-1,4-benzoxazine	Cat#CC13539CB，Acros Organics USA
10-methyl-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-10H-thiodiphenylamine	Kraemer，C.S.；et.al.Synthesis 2002，9， 1163-1170.		Cat#CC13539CB，Acros Organics USA
	Kraemer，C.S.；et.al.Synthesis 2002，9， 1163-1170.	(1,4-dihydro-4,4-dimethyl-2-oxygen-2H-3,1-benzoxazine-6-yl) boric acid	Zhang，P.；et.al.J.Med.Chem，2002，45， 4379-4382.

Formula R _X-B (OR) ₂With

Boric acid or boric acid ester can be by following arbitrary method from corresponding R _XHalogenide or triflate preparation: (1) carries out metal exchange with organolithium reagent, subsequently with boric acid alkyl ester or the addition of tetramethyl ethylene ketone boric acid ester, or (2) with for example, but be not limited to two (tetramethyl ethylene ketone base) two boron (CAS#73183-34-3) or two (tetramethyl ethylene ketone) borane cross-couplings.The reference of describing first method is

B.T.O′Neill，et al.，Organic Letters，2：4201(2000)；M.D.Sindkhedkar，et al.，Tetrahedron，57：2991(2001)；W.C.Black，et al.，J.Med.Chem.，42：1274(1999)；R.L.Letsinger et al.，J.Amer.Chem.Soc.，81：498-501(1959)；and F.I.Carroll et al.，J.Med.Chem.，2229-2237(2001)。

The reference of describing second method is:

T.Ishiyama et al.，Tetrahedron，57：9813-9816(2001)；T.Ishiyama et al.，J.Org.Chem.，60：7508-7510(1995)；and Takagi et al.，Tetrahedron Letters，43：5649-5651(2002)。

At O.Baudoin etc., J.Org.Chem., described other method of preparation boric acid and boric acid ester among the 65:9268-9271 (2000), wherein aryl or heteroaryl halogenide or triflate have been handled in the Yu diox in the presence of triethylamine and acid chloride (II) with dialkoxy borane (for example tetramethyl ethylene ketone boric acid ester).

Or, utilizing other couling process, for example Stille coupling is by using formula (R _y) ₃S _nR _xOrganic WU alkane (R wherein _yBe alkyl or aryl, R _xBe aryl, heteroaryl, heterocyclic radical, alkyl or alkenyl, or cycloalkyl) in the presence of palladium source (for example three (dibenzalacetones) close two palladiums (CAS#52409-22-0) or palladium diacetate (CAS#3375-31-3)) and part (for example three (2-furyl) phosphines (CAS#5518-52-5) or triphenylarsine (CAS#603-32-7)), handles, formula (10) compound can be transformed an accepted way of doing sth (11) and (12) compound.This reaction can carried out in solvent (for example DMF) to about 150 ℃ temperature from about 25 ℃.These methods are described in for example J.K.Stille, Angew Chem.Int.Ed.25:508 (1986) and T.N.Mitchell, and Synthesis is in 803 (1992).

A lot of WU alkane have the commercial goods or description are arranged in the literature, but also can pass through aryl halide, trifluoromethanesulfonic acid aryl ester, heteroaryl halogenide and trifluoromethanesulfonic acid heteroaryl ester and formula ((R _X) ₃S _n) ₂Six alkyl, two WU alkane in the palladium source as Pd (Ph ₃P) ₄There are prepared in reaction, wherein R down _XIt is alkyl or aryl.The example of six alkyl, two WU alkane includes, but not limited to hexamethyl two WU alkane (CAS#661-69-8).These methods are at for example Krische, et.al., and Helvetica ChimicaActa 81 (11): 1909-1920 (1998) and Benaglia, et al., Tetrahedron Letters38:4737-4740 has description in (1997).Or aryl, heteroaryl or heterocycle organolithium and azoviolet can be used Bu ₃SnCl handles to obtain Stille reagent.These reagent can react under the Stille condition with formula (10) compound, obtain formula (11) and (12) compound.The a reference of describing the Stille reaction is A.F.Littke etc., J Amer.Chem.Soc.124:6343-6348 (2002).

Formula (11) compound, wherein m, R _3a, R _3b, R ₄And R ₅As the definition in the cotype (I), alkylthio and R ₁Be-L ₂-R ₆, L wherein ₂Be a key, R ₆Be the nitrogen heterocyclic ring that is connected with parent fraction via nitrogen-atoms, can be prepared as follows.To wherein X ₁Formula (10) compound that is I, Br or Cl is used formula H-R in the presence of alkali (such as but not limited to sodium tert-butoxide or cesium carbonate) and metal catalyst ₆Heterogeneous ring compound handle, wherein H is the hydrogen on the nitrogen-atoms that comprises in this heterocycle, described metal catalyst includes but not limited to copper metal or CuI, palladium diacetate, and can randomly use part, such as but not limited to, BINAP or tri-butyl phosphine, the result obtains formula (11) compound.Similarly, formula (10) compound (wherein m, R _3a, R _3b, R ₄And R ₅As the definition in the cotype (I), X ₂Be I, Br or Cl) use formula H-R ₆Heterogeneous ring compound (wherein H is the hydrogen that contains in heteroaryl or heterocycle on the nitrogen-atoms) handle under the same conditions, can obtain formula (12) compound.These reactions are carried out in solvent (such as but not limited to ， diox, toluene or pyridine) usually.Below be the reference of describing these methods:

J.Hartwig et al., Angew.Chem.Int.Ed.37:2046-2067 (1998); J.P.Wolfe et al., Acc.Chem.Res., 13:805-818 (1998); M.Sugahara et al., Chem.Pharm.Bull., 45:719-721 (1997); J.P.Wolfe et al., J.Org.Chem., 65:1158-1174 (2000); F.Y.Kwong et al., Org.Lett., 4:581-584 (2002); A.Klapars et al., J.Amer.Chem.Soc., 123:7727-7729 (2001); B.H.Yang et al., J.Organomet.Chem., 576:125-146 (1999); With A.Kiyomori et al., Tet.Lett., 40:2657-2640 (1999).

Formula (11) compound, wherein m, R ₃, R _3a, R _3b, R ₄And R ₅As the definition in the cotype (I), R ₁Be-L ₂-R ₆, L wherein ₂Be-NH or-N (alkyl)-, R ₆Suc as formula the definition in (I), can be prepared as follows.To wherein X ₁Be formula (10) the compound formula H of I, Br or Cl ₂N-R ₆Or HN (alkyl)-R ₆Compound and alkali (such as but not limited to sodium tert-butoxide or cesium carbonate) are being handled under heating condition in the presence of the metal catalyst, can obtain formula (11) compound, the example of described metal catalyst is, but be not limited to, copper metal or CuI, palladium diacetate, and can randomly be added with a kind of part, such as but not limited to, BINAP or tri-butyl phosphine.Similarly, formula (12) compound, wherein m, R ₃, R _3a, R _3b, R ₄And R ₅Suc as formula the definition in (I), R ₂Be-L ₂-R ₆, L wherein ₂Be-NH or-N (alkyl)-, R ₆With identical, can pass through wherein X to the definition of formula (I) compound ₂Be formula (10) compound and the formula H of I, Br or Cl ₂N-R ₆Or HN (alkyl)-R ₆Compound heats under identical condition and prepares.This reaction can be carried out in solvent such as diox, toluene or pyridine.The reference of describing these methods comprises: J.Hartwig, et al., Angew.Chem.Int.Ed., 37:2046-2067 (1998); J.P.Wolfe et al., Acc.Chem.Res., 13:805-818 (1998); J.P.Wolfe et al., J.Org.Chem., 65:1158-1174 (2000); F.Y.Kwong et al., Org.Lett., 4:581-584 (2002); With B.H.Yang et al., J.Organomet.Chem., 576:125-146 (1999).

Formula (11) compound, wherein m, R ₃, R _3a, R _3b, R ₄And R ₅As the definition in the cotype (I), R ₁Be L ₂-R ₆, L wherein ₂Be oxygen, R ₆Definition in the cotype (I) can be prepared as follows.With X wherein is formula (10) the compound formula HO-R of I, Br or Cl ₆There are heat treated down in compound and alkali (such as but not limited to sodium hydride) in metallic catalyzer (as CuI or palladium diacetate) in solvent (as toluene or N, dinethylformamide), obtain formula (11) compound.Similarly, formula (12) compound, wherein m, R ₃, R _3a, R _3b, R ₄And R ₅Definition in the cotype (I), R ₂Be L ₂-R ₆, L wherein ₂Be oxygen, R ₆Definition in the cotype (I) can be passed through wherein X ₂Be formula (10) compound and the formula HO-R of I, Br or Cl ₆Compound adds hot preparation under identical condition.The reference of describing these methods comprises: J.Hartwig et al., Angew.Chem.Int.Ed., 37:2046-2067 (1998); K.E.Torraca et al., J.Amer.Chem.Soc., 123:10770-10771 (2001); S.Kuwabe et al., J.Amer.Chem.Soc., 123:12202-12206 (2001); K.E.Toracca et al., J.Am.Chem.Soc., 122:12907-12908 (2000); R.Olivera et al., Tet.Lett., 41:4353-4356 (2000); J.-F.Marcoux et al., J.Am.Chem.Soc., 119:10539-10540 (1997); A.Aranyos et al., J.Amer.Chem.Soc., 121:4369-4378 (1999); T.Satoh et al., Bull.Chem.Soc.Jpn., 71:2239-2246 (1998); J.F.Hartwig, Tetrahedron Lett., 38:2239-2246 (1997); M.Palucki et al., J.Amer.Chem.Soc., 119:3395-3396 (1997); N.Haga et al, J.Org.Chem., 61:735-745 (1996); R.Bates et al., J.Org.Chem., 47:4374-4376 (1982); T.Yamamoto etal., Can.J.Chem., 61:86-91 (1983); A.Aranyos et al., J.Amer.Chem.Soc., 121:4369-4378 (1999); With E.Baston et al., Synth.Commun., 28:2725-2730 (1998).

Formula (11) compound, wherein m, R ₃, R _3a, R _3b, R ₄And R ₅As the definition in the cotype (I), R ₁Be L ₂-R ₆, L wherein ₂Be sulphur, R ₆Definition in cotype (I) compound can be passed through wherein X ₁Be formula (10) compound and the formula HS-R of I, Br or Cl ₆Compound adds or not with metal catalyst such as CuI or palladium diacetate, adds hot preparation in solvent such as dimethyl formamide or toluene in the presence of alkali.Similarly, formula (12) compound, wherein m, R ₃, R _3aR _3b, R ₄And R ₅Definition in the cotype (I), R ₂Be L ₂-R ₆, L wherein ₂Be sulphur, R ₆Definition in the cotype (I) can be passed through wherein X ₂Be formula (10) compound and the formula HS-R of I, Br or Cl ₆Compound adds hot preparation under the same conditions.The reference of describing these methods can find in following document:

G.Y.Liet al., J.Org.Chem., 66:8677-8681 (2001); Y.Wang et al., Bioorg.Med.Chem.Lett., 11:891-894 (2001); G.Liu et al., J.Med.Chem., 44:1202-1210 (2001); G.Y.Li et al., Angew.Chem.Int.Ed., 40:1513-1516 (2001); U.Schopfer et al., Tetrahedron, 57:3069-3074 (2001); And C.Palomo et al., Tet.Lett., 41:1283-1286 (2000); A.Pelter et al., Tet.Lett., 42:8391-8394 (2001); W.Lee et al., J.Org.Chem., 66:474-480 (2001); With A.Toshimitsu et al., Het.Chem., 12:392-397 (2001).

Scheme 3

As shown in scheme 3, formula (13) compound is used earlier formula R ₄R ₅The amine of NH is handled, and uses sodium cyanoborohydride/methyl alcohol subsequently, or sodium triacetoxy borohydride/methylene dichloride, or handles at solvent mixture (such as but not limited to methylene dichloride and ethane) with borane-pyridine complex, obtains formula (14) compound.Formula (14) compound, wherein m, R _3a, R _3b, R ₄And R ₅Definition in the cotype (I), R ₂Be selected from hydrogen, alkoxyl group, halogen, cyano group or alkylthio, X is I, Br or C1, can handle according to the condition that description formula (10) compound transforms the compound of an accepted way of doing sth (11), obtains formula (15) compound.Similarly, formula (14) compound, wherein R _3a, R _3b, R ₄And R ₅Definition in the cotype (I), R ₁Be selected from hydrogen, alkoxyl group, halogen, cyano group or alkylthio, X ₂Be I, Br or Cl, can handle, obtain formula (16) compound according to the condition of description formula (a 10) compound conversion accepted way of doing sth (12) compound.

Scheme 4

Scheme 4 represents to obtain from formula (9) compound another approach of formula (11) compound, wherein R _3a, R _3b, R ₄And R ₅Identical with definition in the formula (I), X is I, Br or Cl.Formula (9) compound with boric acid or ester and palladium catalyst processing, obtains formula (18) compound under the Suzuki condition.Formula (18) compound is handled in methylene dichloride with trifluoromethanesulfanhydride anhydride and alkali (such as but not limited to salt of wormwood), uses formula R subsequently ₄R ₅The amine of NH and alkali (such as but not limited to salt of wormwood) are handled, and obtain formula (11) compound.Similarly, wherein m, R _3a, R _3b, R ₄And R ₅Identical with definition in the formula (I), and X ₂Be formula (9) compound of I, Br or Cl, when under the Suzuki reaction conditions, handling, can obtain formula (19) compound with boric acid or ester and palladium.Formula (19) compound is used formula R again after handling in methylene dichloride with trifluoromethanesulfanhydride anhydride and alkali (such as but not limited to salt of wormwood) ₄R ₅The amine of NH and alkali (such as but not limited to salt of wormwood) are handled, can production (12) compound.

Scheme 5

Described in scheme 5, formula (8) compound is understood production (21) compound with the solution-treated of negatively charged ion that contains isocyano-methyl-phosphorous acid diethyl ester (being produced by the phosphonate reagent of formula (20)) and alkali (such as but not limited to sodium hydroxide or sodium methylate) time.The application of this reaction method is described in Moskal etc., Recl.Trav.Pay Chem B.Vol.106-(5), and 137-141 (1987) and Yan etc., J.Medical Chemistry, Vol.37 (16) is among the 2619-2622 (1994).The hydrolysis under acidic conditions of formula (21) compound, the aldehyde of production (22).The aldehyde cpd of formula (22) is being used amine R ₄R ₅NH (R wherein ₄And R ₅Identical with definition in the formula (I)) handle, use sodium cyanoborohydride/methyl alcohol subsequently, or sodium triacetoxy borohydride/methylene dichloride, or borane-pyridine complex/methylene dichloride obtains formula (23) compound during with the methanol mixture processing.Formula (23) compound is handled according to the condition of describing the Suzuki reaction in the scheme 2, obtains formula (24) or (25) compound, and this depends on X ₁Or X ₂Suitable replacement.

Scheme 6

Described in scheme 6, wherein X is a bromine or iodine, and R ₂, R _3aAnd R _3bFormula (26) compound of definition in the cotype (I) is with formula 27 compounds (R wherein ₁Or formula-L ₂-R ₆Group, or formula-L _3a-R _6a-L _3b-R _6bGroup, L ₂And L _3aBe a key, R ₆And R _6aBe the heterocycle that contains active nitrogen, as pyridazine-3 (2H)-ketone or pyridine-2 (1H)-ketone, L _3bAnd R _6aDefinition in the cotype (I)) in the presence of copper powder, cupric iodide, salt of wormwood and pyridine, during heat treated, obtains formula (28) compound.Formula (28) compound carries out oxidation, for example, but is not limited to, the known Dess-Martin pentavalent of those skilled in the art iodine superoxide ([87413-09-0], Aldrich Chemical Company) oxidation, Swern oxidation or Jones oxidation can obtain formula (29) compound.Formula (29) compound formula R ₃R ₄The amine of NH is handled, and adds sodium cyanoborohydride subsequently, obtains formula (30) compound.Or the reductive agent that is used for formula (13) compound is transformed an accepted way of doing sth (14) compound described in the scheme 3 also can be used for this conversion reaction.When formula (29) compound is handled with sodium borohydride or other appropriate reductant well known by persons skilled in the art, can obtain formula (31) compound.Formula (31) compound is handled at alkali (such as but not limited to salt of wormwood) with trifluoromethanesulfanhydride anhydride, uses formula R subsequently ₃R ₄Pressing of NH handled, and obtains formula (32) compound.Formula (30) and formula (32) compound all are the representatives of The compounds of this invention, but contain different three-dimensional chemical configurations.

Tetramethylene nitrile compound (4) can be obtained or can have been bought by known approach.For example 3-methylene radical tetramethylene formonitrile HCN (CAS#15760-35-7) can be by Maybridge Plc, Trevillett, Tintagel, Cornwall, PL34 OHW, United Kingdom and Ryan Scientific, Inc., P.O.Box 845, Isle of Palms, SC 29451, and USA has bought.1-methyl-3-methylene radical tetramethylene formonitrile HCN (CAS#32082-16-9) can utilize

" Methods of preparing 2-and 3-functionally substitutedmethylenecyclobutanes via the cycloaddition of allene with acrylic acid derivatives " by Men ' shchikov, V.A. (Otkrytoe Aktsionernoe Obshchestvo " VserossiiskiiNauchno-Issledovatel ' skii Institut Organicheskogo Sinteza ", Russia) and method described in the Russ P application RU 2000-103966 obtain, last document can be found by changing digest 137:310640.At " Cyclbutane Carboxamide Inhibitors of FungalMelanin:Biosynthesis and their Evaluation as Fungicides " Jennings, et al.Bioorganic﹠amp; The synthetic of 1-methyl-3-methylene radical tetramethylene formonitrile HCN also described among Medicinal Chemistry 8 (2000) 897-907, the document has also been described 3-methylene radical-1-(trifluoromethyl) tetramethylene formonitrile HCN, 1-chloro-3-methylene radical tetramethylene formonitrile HCN synthetic, and the 1-that has described synthetic compound (4) replaces the universal method of analogue.1-chloro-3-methylene radical tetramethylene formonitrile HCN is available Bienfait etc. also, Tetrahedron (1991), and 47 (38), method obtains described in the 8167-76.Chlorinated compound, 1-chloro-3-methylene radical tetramethylene formonitrile HCN for example, to fluorine cpd, for example the conversion of 1-fluoro-3-methylene radical tetramethylene formonitrile HCN is well-known, for example handles with fluoride ion.Compound (4) can utilize scheme 1-5 and method described here to transform the The compounds of this invention of an accepted way of doing sth (5) compound and general formula (I).

The also available currently known methods of cyclobutane-carboxylic acid compound (5) obtains or can buy.For example, at Della et al., Journal of the American Chemical Society (1994), 116 (14), 1-hydroxyl-3-methylene radical cyclobutane-carboxylic acid has been described among the 6159-6166.At Jennings, et al.Bioorganic﹠amp; Other formula (5) compound has been described among Medicinal Chemistry 8 (2000) 897-907,1-methyl-3-methylene radical cyclobutane-carboxylic acid and 1-ethyl-3-methylene radical cyclobutane-carboxylic acid for example, it is a kind of with commercially available 3-methylene radical cyclobutane-carboxylic acid (CAS#15760-35-7 that this reference provides, can be from Ryan Scientific, Inc., PO BOX 845, Isle of Palms, SC, 29451, USA and other source obtain) change into the universal method of the 3-methylene radical cyclobutane-carboxylic acid that 1-miscellaneous replaces.In this conversion reaction, 3-methylene radical cyclobutane-carboxylic acid is handled deprotonation with alkali (for example diisopropylaminoethyl lithium or other alkali) in solvent such as THF, handle with electrophilic reagent then.Suitable electrophilic reagent is iodoethane, TosMIC (toluene methyl-isocyanide), CNBr etc.

The ester of cyclobutane-carboxylic acid compound (5) can obtain with currently known methods, or the commercial goods is arranged, and they can be hydrolyzed into cyclobutane-carboxylic acid compound (5) under alkaline condition (NaOH) or acidic conditions (HCl).For example, 1-cyano group-3-methylene radical cyclobutane-carboxylic acid methyl esters (CAS#116546-99-7) can be used to hydrolysis and forms 1-cyano group-3-methylene radical cyclobutane-carboxylic acid.

The 2-amino-benzene mercaptan compound of formula (2) can obtain or can buy with several different methods.The example of compound (2) comprises that (CAS#860766-72-9 sees Zincke to 2-amino-5-(dimethylamino) benzenethiol, Th.; Muller, Joh.Marburg, Ber. (1913), 46,775-86); 2-amino-(CAS#859032-36-3 sees Takahashi to 5-chloro-3-anisole thiolate hydrochlorate, Torizo; Shibasaki, Juichiro; Okada, Jutaro.Synthesese of heterocycliccompounds of nigrogen, L.Yakugaku Zasshi (1951), 71,41-4), Herz, Richard; 2-amino-5-(phenylamino) benzenethiol (CAS#858833-38-2 sees Friedlaender, Paul.Aryl mercaptan derivatives. (1923), DE 491224); 4-amino-3-sulfydryl cyanobenzene (CAS#802559-53-1, see Bogert, Marston T, Husted, Helen G.Thiazoles.XVIII.Synthesis of 2-phenylbenzothiazole-5-carboxylic acid andderivatives.Journal of the American Chemical Society (1932) 54,3394-7); 2-amino-(CAS#785727-27-7 sees 5-phenetole mercaptan

Wilde，Richard G.；Billheimer，Jeffrey T.；Germain，Sandra J.；Gillies，Peter J.；Higley，C.Anne；Kezar，Hollis S.，III；Maduskuie，Thomas P.；Shimshick，Edward S.；Wexler，Ruth R.Acyl CoA：cholesterol acyltransferase(ACAT)inhibitors：ureasbearing heterocyclic groups bioisosteric for an imidazole.Bioorganic&MedicinalChemistry Letters(1995)，5(2)，167-72)；

2-amino-5-(piperidines-1-base alkylsulfonyl) benzenethiol (CAS#749216-22-6 can be by Enamine, 23Alexandra Matrosova Street, and Kiev, 01103 buys); 3-amino-4-Thiosalicylic acid methyl esters (being described among Dannley et al.Canadian J.Chem.vol.43 (1965) 2610-2612); 2-amino-5-benzyloxy benzenethiol is described in Sugano, and et al.Bioorg.Med.Chem Lett.vol.6 (1996) is among the pp 361-366.

In addition, the 2-amino-benzene mercaptan compound of formula (2) can be described in embodiment 1a, and by the alkaline hydrolysis of benzo [d] thiazole-2 (3H)-ketone, or acidic hydrolysis obtains.Reported many kinds of benzos [d] thiazoles-2 (3H)-ketone, its preparation method is that the technician in organic synthesis field is known.The example for preparing the universal method of benzo [d] thiazole-2 (3H)-ketone from aniline compound (itself has multiple commercial goods) can find following document:

" Development of a Manufacturing Process for Sibenadet Hydrochloride, the ActiveIngredient of Viozan " Giles, et al.Organic Process Research﹠amp; Development, vol.8 (4), 628-642 (2004), with " Synthesis and Evaluation of Non-Catechol D-1and D-2Dopamine Receptor Agonists:Benzimidazol-2-one, Benzoxazol-2-one, and theHighly Potent Benzothiazol-2-one 7-Ethylamines " Weinstock, et al., Journal ofMedicinal Chemistry (1987), 30, pp1166-1176.

Compound of the present invention can separate and purifying with the method that the organic synthesis those skilled in the art know with intermediate.The example that is used to separate with the ordinary method of purifying compounds can comprise, but be not limited to, at solid carrier such as silica gel, aluminum oxide or have chromatographic separation on the silica gel of deriving of alkyl silane group, perhaps after randomly using the activated carbon pre-treatment under high temperature or low temperature recrystallization, tlc, under various different pressures, distill, distillation and development under the vacuum, as " Vogel ' sTexbook of Practical Organic Chemistry ", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, Pub.Longman Scientific﹠amp; Technical, Essex CM 202JE is described in the England.

The compounds of this invention has at least one basic nitrogen atom, therefore can form desired salt with acid treatment.For example, compound can be under room temperature or higher temperature and acid-respons, obtains sedimentary desired salt, and collects in cooled and filtered.The acid that is fit to this reaction comprises, but be not limited to, tartrate, lactic acid, succsinic acid, and amygdalic acid, α-phenyl-lactic acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, naphthene sulfonic acid, Phenylsulfonic acid, carbonic acid, fumaric acid, toxilic acid, glyconic acid, acetate, propionic acid, Whitfield's ointment, hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, oxysuccinic acid, toluylic acid, aspartic acid, L-glutamic acid etc.

Composition of the present invention

The present invention also provides the pharmaceutical composition that contains with pharmaceutically acceptable carrier bonded treatment significant quantity formula (I) compound.Said composition contains the The compounds of this invention of preparing with one or more nontoxic pharmaceutically acceptable carrier.This pharmaceutical composition can be mixed with and be used for oral solid or liquid form, is used for non-enteron aisle injection or is used for rectal administration.

Term used herein " pharmaceutically acceptable carrier " is meant the preparation assistant agent of avirulent inert solid, semisolid or liquid filler, thinner, capsule material or any kind.Some examples that can be used as the material of pharmaceutically acceptable carrier are sugar, for example lactose, dextrose plus saccharose; Starch, for example corn and potato starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum; Theobroma oil and suppository wax; Oils is as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols, for example propylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; Ringer solution; Ethanol; Phosphate buffered saline buffer, the compatible lubricant that other is nontoxic is as sodium lauryl sulphate and Magnesium Stearate; According to preparation those skilled in the art's judgement fully, can also add tinting material, releasing agent, Drug coating, sweeting agent, flavour agent and flavouring agent, sanitas and oxygenant in the composition.

Pharmaceutical composition of the present invention can be oral to people and other Mammals, in the rectum, non-enteron aisle, brain pond, intravaginal, intraperitoneal, part (with powder, paste or drops form), through cheek or oral cavity or the administration of nose internal spraying.Term used herein " non-enteron aisle " be meant comprise that intravenously, intramuscular, intraperitoneal, breastbone are interior, subcutaneous, the administering mode of intra-arterial injection and infusion.

The pharmaceutical composition of non-enteron aisle injection comprises pharmaceutically useful aseptic aqueous solution or non-aqueous solution, dispersion, and suspension or emulsion, and be used for recombinating and form the aseptic Injectable solution or the sterilized powder of dispersion.The example of suitable water and nonaqueous carrier, thinner, solvent or vehicle comprises water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc., with its suitable mixture), vegetables oil (for example sweet oil) and injectable organosilane ester, for example ethyl oleate, or its suitable mixture.By using dressing (for example Yelkin TTS), keep needed size of particles in the situation of dispersion, and use tensio-active agent, can make composition keep suitable flowability.

These compositions can also contain assistant agent, for example sanitas, wetting agent, emulsifying agent and dispersion agent.By adding various sterilant and anti-mycotic agent, for example, p-Hydroxybenzoate, butylene-chlorohydrin, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.May preferably also comprise isotonic agent, for example sugar, sodium-chlor etc.Use the reagent of delayed absorption, for example aluminum monostearate and gelatin can make the absorption of injectable medicament forms prolong.

In some situations, for the absorption of prolong drug, the absorption of the medicine of usually wish to slow down subcutaneous or intramuscularly.This can realize by the crystal of use poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be relevant with crystalline size and crystal formation.Or, by with medicine dissolution or be suspended in the oily carrier delayed absorption of the medicament forms of realizing parenterai administration.

In the suspensoid, except active compound, can also contain suspension agent, for example, ethoxylation isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, monohydrate alumina, wilkinite, agar, tragacanth gum and their mixture.

If wish, perhaps for more effective distribution, The compounds of this invention can be incorporated in slowly-releasing or the target delivery systme, for example, polymeric matrix, liposome and microballoon.They can utilize by the filter filtration of resistance bacterium or add disinfectant in aseptic solids composition form and sterilize, and this solids composition can be dissolved in aseptic water or other the injectable sterile media before use at once.

Injectable depot formulation form is to make by forming the micro encapsulation matrix of medicine in biodegradable polymkeric substance such as polylactide-glycolide copolymer.According to the person's character of the ratio of medicine and polymkeric substance and used concrete polymkeric substance, speed that can control drug release.Other biodegradable examples of polymer comprises poly-(ortho ester) and poly-acid anhydrides.Injectable depot formulation also prepares by pharmaceutical pack being rolled in liposome compatible with bodily tissue or the microemulsion.

Injectable formulation can utilize the filter that flows through the resistance bacterium or mix sterilant and sterilize in aseptic solids composition, and this solids composition can dissolve or be dispersed in the aseptic injectable medium before use at once.

Injectable formulation, for example, aseptic injectable water or oil-based suspension can use suitable dispersion agent or wetting agent and suspension agent to prepare according to already known processes.Aseptic injectable formulation also can be outside a kind of nontoxic, enteron aisle injectable sterile solution, suspension or emulsion in acceptable diluent or the solvent, for example solution in 1,3 butylene glycol.Among operable acceptable vehicle and solvent, comprise water, Ringer solution (U.S.P) and isoosmotic sodium chloride solution.In addition, aseptic nonvolatile oils is used as solvent or suspension medium usually.For this reason, any non-irritating nonvolatile oil be can use, synthetic monoglyceride or diester comprised.In addition, lipid acid such as oleic acid can be used for preparing injectable formulation.

The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, but one or more compounds of the present invention mix with at least a inert pharmaceutical carrier (for example Trisodium Citrate or Lin Suanergai) and/or following substances: a) filler or extender, for example starch, lactose, sucrose, glucose, N.F,USP MANNITOL and Whitfield's ointment; B) tackiness agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting agent, for example glycerine; D) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash; E) dissolving retarding agent, for example paraffin; F) absorb accelerator, for example quaternary ammonium compound; G) wetting agent, for example hexadecanol and Zerol; H) absorption agent, for example kaolin and wilkinite; And i) lubricant, talcum for example, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.In the situation of capsule, tablet and pill, can also comprise buffer reagent in the formulation.

The solids composition of similar type also can be used as filler and is used in the soft or hard-filled gelatin capsule that uses lactose and high molecular weight polyethylene glycol.

Solid dosages such as tablet, dragee, capsule, pill and granule can be prepared into and have dressing and shell, for example other dressing of knowing of enteric coating and medicine formulation art.They can randomly contain opalizer, and can be only to exist in the mode that delays, and perhaps preferably exist, and certain part of enteron aisle discharges composition of active components.The example that can be used for the material that active medicine delays to discharge comprises polymkeric substance and wax.

The composition that is used for rectum or vagina administration is suppository preferably, it can prepare by The compounds of this invention is mixed with suitable nonirritant carrier such as theobroma oil, polyoxyethylene glycol or suppository wax, these carriers are solid at ambient temperature, but under body temperature, be liquid, thereby fusing and discharge active compound in rectum or vaginal canal.

The liquid dosage form of oral administration comprises pharmaceutically useful emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except active compound, can also contain inert diluent usually used in this field in the liquid dosage form, for example, water or other solvent, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil are (particularly, oleum gossypii seminis, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), the fatty acid ester of glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and anhydrous sorbitol, and their mixture.

Except that inert diluent, oral compositions also can comprise auxiliary, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, flavour agent and flavouring agent.

The formulation that is used for The compounds of this invention part or transdermal administration comprises ointment, paste, ointment, lotion, gelifying agent, powder, solution, sprays, inhalation or patch.Needed The compounds of this invention is being mixed with a kind of pharmaceutically useful carrier and any required sanitas or buffer reagent in the time may needing under the aseptic condition.Ophthalmic preparation, ear drop, eye ointment, powder and solution also are considered and belong within the scope of the present invention.

Ointment, paste, ointment and gelifying agent, except active compound of the present invention, can also contain animal and plant fat, oil, wax, paraffin, starch, tragacanth gum, derivatived cellulose, polyoxyethylene glycol, polysiloxane, wilkinite, silicic acid, talcum and zinc oxide, or their mixture.

Powder and sprays except The compounds of this invention, can also contain lactose, talcum, silicic acid, aluminium hydroxide, Calucium Silicate powder and Silon, or the mixture of these materials.Sprays also can contain propelling agent commonly used, for example chlorofluorocarbon in addition.

The compounds of this invention also can be with the form administration of liposome.As known in the art, liposome is generally derived by phosphatide or other lipid matter and is formed.Liposome is by brilliant formation of single or multiple lift hydrating fluid that is dispersed in the aqueous medium.Can use on any nontoxic, the physiology that can form liposome and can accept and metabolizable lipid.The present composition of liposome form except The compounds of this invention, can also contain stablizer, sanitas etc.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), separately uses or uses together.

The method that forms liposome is known in the art.For example see Prescott, Ed., Methodsin cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), each page after P33 reaches.

The formulation that is used for the The compounds of this invention topical comprises powder, sprays, ointment and inhalation.With active compound under aseptic condition with pharmaceutically useful carrier and when needed any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are considered and belong within the scope of the present invention.The water-based liquid composition that contains The compounds of this invention is also within considering.

The compounds of this invention can use with the form from inorganic or the pharmaceutically useful salt of organic acid deutero-, ester or acid amides." pharmaceutically useful salt, ester and acid amides " used herein speech, be meant carboxylate salt, amino acid addition salt, zwitter-ion, ester and the acid amides of formula (1) compound, they are fit to contact use with the tissue of people and rudimentary animal in the scope of reliable medical judgment, and there are not undue toxicity, pungency, transformation reactions etc., have rational profit/evil ratio, and effective to its predetermined purposes.

Term " pharmaceutically useful salt " is meant and is being fit to contact the salt that uses with the tissue of people and rudimentary animal in the medical judgment scope reliably that they do not have undue disposition, pungency, transformation reactions etc., have rational profit/evil ratio.Pharmaceutically useful salt is known in the art.These salt can be during the final separation of The compounds of this invention and purifying in-situ preparing, or prepare respectively with the appropriate organic reaction by alkali functional group freely.

Representational acid salt comprises, but be not limited to acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isetionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, embonate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.The preferred salt of The compounds of this invention is tartrate and hydrochloride.

In addition, the nitrogen-containing group of alkalescence can be with for example following reagent be quaternized: elementary alkyl halide, as methyl, ethyl, propyl group and butyl muriate, bromide and iodide; Sulfuric acid dialkyl, for example methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, for example decyl, dodecyl, tetradecyl and octadecyl chlorination thing, bromide and iodide; Aralkyl halide, for example benzyl and styroyl bromination thing and other.Thereby obtain water or the molten or dispersible products of oil.

The example that can be used for forming the acid of pharmaceutically useful acid salt comprises mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid, for example oxalic acid, toxilic acid, succsinic acid and citric acid.

The alkalescence additive salt can be during the last separation of The compounds of this invention and purifying the part and suitable alkali by containing carboxylic acid, the for example oxyhydroxide of pharmaceutically acceptable metallic cation, carbonate or supercarbonate, or with organic primary amine, secondary amine or tertiary amine, react in-situ preparing.Pharmaceutically useful salt comprises, but be not limited to, based on basic metal or alkaline-earth metal cationic salt such as lithium, sodium, potassium, calcium, magnesium and aluminium for example, and avirulent quaternary ammonium and amine positively charged ion, comprise the salt of ammonium, tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine etc.Other typical organic amine that can be used to form base addition salt comprises quadrol, thanomin, diethanolamine, piperidines and piperazine.

Terminology used here " pharmaceutically useful ester " refers to the ester of the The compounds of this invention of hydrolysis in vivo, and comprises easy those esters that stay parent compound and salt thereof that decompose in human body.The example of pharmaceutically useful non-toxic ester of the present invention comprises C ₁-C ₆Alkyl ester and C ₅-C ₇Cycloalkyl ester, but preferred C ₁-C ₄Alkyl ester.The ester of formula (1) compound can prepare according to ordinary method.For example, these esters can pass through compound and the acid or alkyl carboxylic acid (for example acetate) reaction of hydroxyl, or react with acid and aryl carboxylic acid (for example phenylformic acid), are connected on the hydroxyl.Situation at carboxy-containing acid group's compound, pharmaceutically useful ester is to pass through this compound and alkali (for example triethylamine) and alkyl halide, trifluoromethanesulfonic acid alkyl ester by the compound that contains the carboxylic acid group to react, for example with methyl-iodide, benzyl iodide, the preparation of cyclopentyl Iod R.They can also be by this compound and the reaction of acid (for example hydrochloric acid) and alkyl carboxylic acid (for example acetate), or with sour and aryl carboxylic acid (for example phenylformic acid) prepared in reaction.

Term used herein " pharmaceutically useful acid amides " is meant by ammonia, C ₁-C ₆Primary amine and C ₁-C ₆The of the present invention avirulent acid amides that dialkylamine is derived and formed.In the situation of secondary amine, amine also can be 5 or 6 yuan of heterocyclic forms that contain a nitrogen-atoms.Preferably from ammonia deutero-acid amides, C ₁-C ₃Alkyl primary amide and C ₁-C ₂Dialkyl group secondary amide.The acid amides of formula (1) compound can prepare according to ordinary method.Pharmaceutically useful acid amides is reacted and prepares by containing this amino compound and alkyl acid anhydrides, aryl acid anhydrides, acyl halide or aryl halide by the compound that contains primary amine or secondary amine group.In the situation of carboxy-containing acid group's compound, pharmaceutically useful ester by the compound that contains this hydroxy-acid group by this compound and alkali (for example triethylamine), amine aqua (for example dicyclohexyl carbodiimide or carbonyl dimidazoles) and alkylamine, dialkylamine (for example methylamine, diethylamine, piperidines) prepared in reaction.They also can be by The compounds of this invention and acid (for example sulfuric acid) and alkyl carboxylic acid (for example acetate), or with sour and aryl carboxylic acid (for example phenylformic acid), the prepared in reaction that under dehydration conditions, (for example adds molecular sieve).The present composition can comprise the The compounds of this invention of pharmaceutically useful prodrug forms.

Term used herein " pharmaceutically useful prodrug " or " prodrug ", those prodrugs of expression The compounds of this invention, they are fit to contact use with the tissue of people and rudimentary animal within the scope of reliable medical judgment, and there are not undue toxicity, pungency, transformation reactions etc., have rational profit/evil ratio, and effective to its intended purpose.Prodrug of the present invention can pass through for example hydrolysis in blood in vivo, transforms the parent compound of an accepted way of doing sth (I) fast.At T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, V.14 of the ACS Symposium Series and Edward B.Roche, ed., Biorever-Sible Carriers in Drug Design, among the American Pharmaceutical Association and Pergamon Press (1987) sufficient discussion is arranged, above-mentioned document is incorporated the application into the form of reference.

That the present invention has considered chemosynthesis or the pharmaceutically active compound by a bio-transformation accepted way of doing sth (I) compound in vivo.

Method of the present invention

Compound of the present invention and composition can be used for treating and preventing some disease and the obstacle of humans and animals.Regulate an important consequence of the ability of the histamine-effect of 3-acceptor in cell as The compounds of this invention, the compound of describing among the present invention can influence the physiological process of humans and animals.In this way, compound of describing among the present invention and composition can be used for treating and preventing to be subjected to the disease and the obstacle of histamine-3 acceptor adjusting.Usually, the treatment of this class disease and obstacle or prevention can be by individually, or with as another active medicine of the part of treatment plan jointly, take compound of the present invention, and histamine-3 acceptor of optionally regulating in the Mammals carries out.

The compounds of this invention, those that include but not limited to enumerate in an embodiment, has avidity for histamine-3 acceptor, therefore The compounds of this invention can be used for treatment and for example following disease of prevention or symptom: attention deficit hyperinetic disorder (ADHD), attention deficit, dementia, with memory and study defective diseases associated, schizophrenia, the schizophrenia cognitive defect, kakergasia in cognitive defect and the mental disorder, alzheimer's disease, the mild cognitive damage, epilepsy, epileptic seizures, rhinallergosis, asthma, motion sickness, dizzy, Meniere, vestibular disorder, dizzy, obesity, diabetes, type ii diabetes, the X syndromes, insulin resistance syndrome, metabolic syndrome, pain, comprise neuropathic pain, neuropathy, somnopathy, narcolepsy, pathologic is drowsiness, trouble with jet lag, drug abuse, mood alteration, the bipolarity obstacle, dysthymia disorders, obsession, Tourette syndrome, Parkinson's disease and medullary thyroid carcinoma, melanoma and polycystic ovary syndrome.Histamine-3-receptor modulators, and therefore The compounds of this invention are in prevention or treat ability aspect these diseases, by being confirmed below with reference to the example of finding in the document.

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment attention deficit hyperactivity disorder (ADHD) and attention deficit can be confirmed by following document:

Cowart，et al.J.Med.Chem.2005，48，38-55；Fox，G.B.，et al.″Pharmacological Properties of ABT-239：II.Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition andSchizophrenia of a Potent and Selective Histamine H ₃ Receptor Antagonist″，Journalof Pharmacology and Experimental Therapeutics(2005)313，176-190；″Effects ofhistamine H ₃ receptor ligands GT-2331 and ciproxifan in a repeated acquisitionavoidance response in the spontaneously hypertensive rat pup.″Fox，G.B.，et al.Behavioural Brain Research(2002)，131(1，2)，151-161；Yates，et al.JPET(1999)289，1151-1159″Identification and Pharmacological Characterization of a Series ofNew 1H-4-Substituted-Imidazoyl Histamine H ₃Receptor Ligands″；Ligneau，et al.Journal of Pharmacology and Experimental Therapeutics(1998)，287，658-666；Tozer，M.Expert Opinion Therapeutic Patents(2000)10，p.1045；M.T.Halpern，″GT-2331″Current Opinion in Central and Peripheral Nervous System InvestigationalDrugs(1999)1，pages 524-527；Shaywitz et al.，Psychopharmacology，82：73-77(1984)；Dumery and Blozovski，Exp.Brain Res.，67：61-69(1987)；Tedford et al.，J.Pharmacol.Exp.Ther.，275：598-604(1995)；Tedford et a1.，Soc.Neurosci.Abstr.，22：22(1996)；and Fox，et al.，Behav.Brain Res.，131：151-161(2002)；Glase，S.A.，et al.″Attention deficit hyperactivity disorder：pathophysiology and design of newtreatments.″Annual Reports in Medicinal Chemistry(2002)，3711-20；Schweitzer，J.B.，and Holcomb，H.H.″Drugs under investigation for attention-deficit hyperactivitydisorder″Current Opinion in Investigative Drugs(2002)3，p.1207。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and treatment is dull-witted and with the ability of the disease of memory and study defective, can be confirmed by following document:

″Two novel and selectivenonimidazole H ₃ receptor antagonists A-304121 and A-317920：II.In vivo behavioraland neurophysiological characterization.″Fox，G.B.，et al.Journal of pharmacologyand experimental therapeutics(2003 Jun)，305(3)，897-908；″Identification of novelH ₃ receptor(H ₃R)antagonist with cognition enhancing properties in rats.″Fox，G.B.；Inflammation Research(2003)，52(Suppl.1)，S31-S32；Bernaerts，P.，et al.″Histamine H ₃ antagonist thioperamide dose-dependently enhances memoryconsolidation and reverses amnesia induced by dizocilpine or scopolamine in a one-trial inhibitory avoidance task in mice″Behavioural Brain Research 154(2004)211-219；Onodera，et al.Nauyn-Schmiedebergs′Arch.Pharmacol.(1998)，357，508-513；Prast，et al.Brain Research(1996)734，316-318；Chen，et al.Brain Research(1999)839，186-189″Effects of histamine on MK-801-induced memory deficits In radialmaze performance in rats″；P8ssani，et al.″Central histaminergic system andcognition″Neuroscience and Biobehavioral Reviews(2000)24，p107-113。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment schizophrenia, schizoid cognitive defect and cognitive defect can be confirmed by following document:

Fox，G.B.，et al.″Pharmacological Properties of ABT-239：II.Neurophysiological Characterization andBroad Preclinical Efficacy in Cognition and Schizophrenla of a Potent and SelectiveHistamine H ₃ Receptor Antagonist″，Journal of Pharmacology and ExperimentalTherapeutics(2005)313，176-190and by″Enhancement of prepulse inhibition ofstartle in mice by the H ₃ receptor antagonists thioperamide and ciproxifan.″Browman，Kaitlin E.，et al.Behavioural Brain Research(2004)，153(1)，69-76；″H ₃receptor blockade by thioperamide enhances cognition in rats without inducinglocomotor sensitization.″；Komater，V.A.，et al.Psychopharmacology(Berlin，Germany)(2003)，167(4)，363-372；AA Rodrigues，FP Jansen，R Leurs，HTimmerman and GD Prell″Interaction of clozapine with the histamine H ₃ receptor inrat brain″British Journal of Pharmacology(1995)，114(8)，pp.1523-1524；Passani，etal.″Central histaminergic system and cognition″Neuroscience and BiobehavioralReviews(2000)24，p107-113；Morriset，S.，et al.″Atypical Neuroleptics EnhanceHistamine Turnover in Brain Via 5-Hydroxytryptamine _2A Receptor Blockade″Journalof Pharmacology and Experimental Therapeutics(1999)288，pages 590-596。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of the kakergasia in the treatment psychosis, alzheimer's disease and mild cognitive damage can be confirmed by following document:

Meguro，et al.Pharmacology，Biochemistry and Behavior(1995)50(3)，321-325；Esbenshade，T.，et al.″Pharmacological and behavioral properties of A-349821，aselective and potent human histamine H3 receptor antagonist″BiochemicalPharmacology 68(2004)933-945；Huang，Y.-W.，et al.″Effect of the histamine H3-antagonist clobenpropit on spatial memory deficits induced by MK-801 as evaluatedby radial maze in Sprague-Dawley rats″Behavioural Brain Research 151(2004)287-293；Mazurkiewicz-Kwilecki and Nsonwah，Can.J.Physiol.Pharmacol.(1989)67，p.75-78；P.Panula，et al.，Neuroscience(1997)82，993-997；Haas，et al.，Behav.B rain Res.(1995)66，p.41-44；De Almeida and Izquierdo，Arch.Int.Pharmacodyn.(1986)，283，p.193-198；Kamei et al.，Psychopharmacology，(1990)102，p.312-318；Kamei and Sakata，Jpn.J.Pharmacol.(1991)，57，p.437-482；Schwartz et al.，Psychopharmacology，The Fourth Generation of Progress.Bloomand Kupfer(eds).Raven Press，New York，(1995)397；and Wada，et al.，Trends inNeurosci.(1991)14，p.415。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment epilepsy and epileptic seizures can be confirmed by following document:

Harada，C.，et al.″Inhibitory effect of iodophenpropit，a selectivehistamine H3 antagonist，on amygdaloid kindled selzures″Brain Research Bulletin(2004)63p，143-146；as well as by Yokoyama，et al.，Eur.J.Pharmacol.(1993)234，p.129-133；Yokoyama，et al.European Journal of Pharmacology(1994)260，p.23；Yokoyama and linuma，CNS Drugs(1996)5，p.321；Vohora，Life Sciences(2000)66，p.297-301；Onodera et al.，Prog.Neurobiol.(1994)42，p.685；Chen，Z.，et al.″Pharmacological effects of carcinine on histaminergic neurons in the brain″British Journal of Pharmacology(2004)143，573-580；R.Leurs，R.C.Vollinga andH.Timmerman，″The medicinal chemistry and therapeutic potential of ligands of thehistamine H ₃ receptor″，Progress in Drug Research(1995)45，p.170-165；Leurs andTimmerman，Prog.Drug Res.(1992)39，p.127；H.Yokoyama and K.linuma，″Histamine and Seizures：Inplications for the treatment of epilepsy″，CNS Drugs，5(5)：321-330(1995)；and K.Hurukami，H.Yokoyama，K.Onodera，K.linuma and T.Watanabe，“AQ-0145，A newly developed histamine H ₃ antagonist，decreasedseizure susceptibility of electrically induced convulsions in mice″，Meth.Find.Exp.Clin.Pharmacol.，17(C)：70-73(1995)；Yawata，et al.″Role of histaminergic neuronsin development of epileptic seizures in EL mice″Molecular Brain Research 132(2004)13-17。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment rhinallergosis and asthma can be confirmed by following document:

McLeod，R.L.，Mingo，G.G.，Herczku，C.，DeGennaro-Culver，F.，Kreutner，W.，Egan，R.W.，Hey，J.A.，“Combined histamine H1and H3receptorblockade produces nasal decongestion in an experimental model of nasalcongestion″Am.J.Rhinol.(1999a)13，p.391-399；McLeod，Robble L.；Egan，Robert W.；Cuss，Francis M.；Bolser，Donald C.；Hey，John A.(Allergy，Schering-Plough Research Institute，Kenilworth，NJ，USA.)Progress In Respiratory Research(2001)，31(in New Drugs for Asthma，Allergyand COPD)，pp.133-136；A.DelaunoisA.，et al.，″Modulation of acetylcholine，capsaicin and substance P effects byhistamine H ₃ receptors in isolated perfused rabbit lungs，″European Journal ofPharmacology(1995)277，p.243-250；Dimitriadou，et al.，″Functional relationshipbetween mast cells and C-sensitive nerve fibres evidenced by histamine H ₃-receptormodulation in rat lung and spleen，″Clinical Science(1994)，87，p.151-163。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and treatment motion sickness, dizziness, Meniere, vestibular disorder and dizzy ability can be confirmed by following document:

Pan，et al.Methods and Findings in Clinical Pharmacology(1998)，20(9)，771-777；O′Neill，et al.Methods and Findings in Clinical Pharmacology(1999)21(4)，285-289；and by R.Leurs，R.C.Vollinga and H.Timmerman，″The medicinal chemistry and therapeuticpotential of ligands of the histamine H ₃ receptor，″Progress in Drug Research(1995)，45，p.170-165，Lozada，et al.“Plasticity of histamine H ₃ receptor expressionand binding in the vestibular nuclei after labyrinthectomy in rat″BioMedCentralNeuroscience 2004，5：32。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment of obesity, diabetes, type ii diabetes, X syndromes, insulin resistance syndrome and metabolic syndrome can be confirmed by following document:

Hancock，A.A.″Antiobesity effects of A-331440，a novel non-imidazole histamine H3 receptor antagonist″European Journal of Pharmacology(2004)487，183-197；Hancock，A.A.，et al.″Histamine H ₃ antagonists in models ofobesity″Inflamm.res.(2004)53，Supplement 1 S47-S48；as well as by E.Itoh，M.Fujimiay，and A.Inui，″Thioperamide，A histamine H ₃ receptor antagonist，powerfullysuppresses peptide YY-induced food intake in rats，″Biol.Psych.(1999)45(4)，p.475-481；S.I.Yates，et al.，″Effects of a novel histamine H ₃ receptor antagonist，GT-2394，on food intake and weight gain in Sprague-Dawley rats，″Abstracts，Society forNeurosclence，102.10：219(November，2000)；and C.Bjenning，et al.，″Peripherallyadministered ciproxifan elevates hypothalamic histamine levels and potently reducesfood lntake in the Sprague Dawley rat，″Abstracts，International Sendai HistamineSymposium，Sendai，Japan，#P39(November，2000)；Sakata T；et al.″Hypothalamicneuronal histamine modulates ad libitum feeding by rats.″Brain research(1990Dec24)，537(1-2)，303-6。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment pain (comprising neuropathic pain and neuropathy) can be confirmed by following document:

Malmberg-Aiello，Petra；Lamberti，Claudia；Ghelardini，Carla；Giotti，Alberto；Bartolini，Alessandro.British Journal ofPharmacology(1994)，111(4)，1269-1279；Hriscu，Anisoara；Gherase，Florenta；Pavelescu，M.；Hriscu，E.″Experimental evaluation of the analgesic efficacy of someantihistamines as proof of the histaminergic receptor involvement in pain.″Farmacia，(2001)，49(2)，23-30，76。

The compounds of this invention includes but not limited to the compound enumerated among the embodiment, and the ability of treatment somnopathy (comprising that narcolepsy and pathologic are drowsiness) and trouble with jet lag can be by being confirmed in the following document:

Barbier，A.J.，et al.″Acute wake-promoting actions of JNJ-5207852，a novel，diamine-based H ₃antagonist″British Journal of Pharmacology(2004)1-13；Monti et al.，Neuropsychopharmacology(1996)15，31-35；Lin et al.，Brain Res.(1990)523，p.325-330；Monti，et al.，Neuropsychopharmacology(1996)15，p.31-35；Ligneau，etal.Journal of Pharmacology and Experimental Therapeutics(1998)，287，658-666；Sakai，et al.，Life Sci.(1991)48，p.2397-2404；Mazurkiewicz-Kwilecki and Nsonwah，Can.J.Physiol.Pharmacol.，(1989)67，p.75-78；P.Panula，et al.，Neuroscience(1998)44，465-481；Wada，et al.，Trends in Neuroscience(1991)14，p.415；andMonti，et al.，Eur.J.Pharmacol.(1991)，205，p.283；Dvorak，C.，et al.″4-Phenoxypiperidines：Potent，Conformationally Restricted，Non-Imidazole HistamineH ₃ Antagonists″Journal of Medicinal Chemistry(2005)48，2229-2238。

The compounds of this invention includes but not limited to the compound enumerated among the embodiment, has the ability of medicine abuse.Amphetamine is a kind of stimulant of human abuse.Locomotor activity in it and the medicine irritation animal of similarly being abused has been found that H ₃The motion hormesis that the inhibition of antagonist Thioperamide is brought out by Amphetamine, so H ₃Antagonist is applicable to the medicine abuse probably, confirms as following document:

Clapham J.；KilpatrickG.J.″Thioperamide，the selective histamine H ₃ receptor antagonist，attenuatesstimulant-induced locomotor activity in the mouse″，European journal ofpharmacology(1994)，259(2)，107-14。

The compounds of this invention includes but not limited to the compound enumerated among the embodiment, and the ability of treatment mood alteration, bipolarity obstacle, dysthymia disorders, obsession and Tourette syndrome can be confirmed by following document:

Lamberti，et al.British Journal of Pharmacology(1998)123，1331-1336；Perez-Garcia C，et.al.，Psychopharmacology(Berlin)(1999)142(2)：215-20。

The compounds of this invention includes but not limited to the compound enumerated among the embodiment, and the ability of treatment Parkinson's disease (a kind of disease, patient's defectiveness aspect the ability of first motion wherein, and the dopamine level of brain is low) can be confirmed by following document:

Sánchez-Lemus，E.，et al.″Histamine H ₃receptor activation inhibits dopamine D ₁ receptor-induced cAMP accumulation in ratstriatal slices″Neuroscience Letters(2004)364，p.179-184；Sakai，et al.，Life Sci.(1991)48，2397-2404；Fox，G.B.，et al.″Pharmacological Properties of ABT-239：IINeurophysiological Characterization and Broad Preclinical Efficacy in Cognition andSchizophrenia of a Potent and Selective Histamine H ₃ Receptor Antagonist″Journalof Pharmacology and Experimental Therapeutics，313：176-190，2005；Chen，Z.，etal.″Pharmacological effects of carcinine on histaminergic neurons in the brain″British Journal of Pharmacology(2004)143，573-580。

The compounds of this invention includes but not limited to the compound enumerated in an embodiment, and the ability of treatment medullary thyroid carcinoma, melanoma, polycystic ovary syndrome can be confirmed by following document:

Polish Med.Sci.Mon.(1998)4(5)：747；Adam Szelag，″Role of histamine H ₃-receptors in the proliferation ofneoplastic cells in vitro，″Med.Sci.Monitor(1998)4(5)：747-755；and C.H.Fitzsimons，et al.，″Histamine receptors signalling in epidermal tumor cell lines withH-ras gene alterations，″Inflammation Res.(1998)47(Suppl 1)：S50-S51。

The compounds of this invention is specially adapted to treat and prevent to influence memory or cognitive illness or obstacle, for example alzheimer disease, attention-deficit hyperactivity disease, schizophrenia or schizoid cognitive defect.

The actual dose level of activeconstituents can change in the pharmaceutical composition of the present invention, so that obtain can realizing for specific patient, composition and mode of administration the active compound quantity of desirable treatment response.Selected dosage level will depend on the activity of concrete compound, route of administration, the severity of the illness of being treated and subject patient's situation and previous medical history.But the common practice of this area is, the compound dosage during the beginning medication is lower than the level for realizing that desirable result of treatment is required, and increased dosage amount gradually is up to reaching desirable effect.

When be used in above or other treatment in the time, can use a kind of The compounds of this invention of the treatment significant quantity of pure form or pharmaceutically useful salt, ester, acid amides or prodrug forms (when these forms exist).Or The compounds of this invention can be with the form administration of pharmaceutical composition, wherein contain the compound considered to some extent and with one or more pharmaceutically useful carriers of its bonded.The The compounds of this invention of phrase " treatment significant quantity " is meant enough treats the compound quantity of disease with the rational profit/evil ratio that is applicable to any therapeutic treatment.Yet should be clear, total per daily dose of compound of the present invention and composition will be determined in the scope of reliable medical judgment by the responsibility doctor.For any specific patient, concrete treatment effective dose level depends on multiple factor, comprises the severity of the disease of being treated and this disease; The activity of used particular compound; The concrete composition that uses; Patient's age, body weight, general health situation, sex and diet; Administration time and approach, and the drainage rate of used particular compound; The treatment time length; With used specific compound associating or the medicine that uses simultaneously; And well-known similar factor in the medical field.For example, those skilled in the art know that the dosage of compound will be lower than for reaching the required level of desirable curative effect during the beginning medication, and increased dosage amount is until realizing desirable curative effect gradually.

In order to treat or preventing disease, of the present invention total per daily dose that people or rudimentary animal are used can be about 0.0003-30mg/Kg/ days.For oral administration, more preferred dose can be about 0.0003-1mg/Kg/ days.If desired, this effective per daily dose can be divided into a plurality of dosage so that administration; Therefore, unit-dose composition can comprise these multiple dosess or inferior multiple doses to form per daily dose.

Compound of the present invention and composition also can be used as diagnostic tool and use.(for example histamine is for histamine H by endogenic ligand for acceptor in PET (positron emission tomography art) and the sPECT detection humans and animals ₃Acceptor) or the ability of the degree that occupies of medicine (for example medicine of the influence of clinical use and brain histamine levels) be widely known by the people.This has constituted the application that PET renders a service as the pharmacology intervention of biological marker mensuration medicine.The problem and the application that are used for the positron radiation part of these purposes are extensively commented, for example see

″PET ligands for assessing receptor occupancy in vivo″Burns，et al.Annual Reports in Medicinal Chemistry(2001)，36，267-276；″Ligand-receptor interactions as studied by PET：implications for drug development″ byJarmo Hietala，Annals of Medicine(Helsinki)(1999)，31(6)，438-443；″Positronemission tomography neuroreceptor imaging as a tool in drug discovery，researchand development″Burns，et al.Current Opinion in Chemical Biology(1999)，3(4)，388-394。

With ¹¹C, ¹⁸The isotropic substance synthetic The compounds of this invention of F or other emission positron is the part instrument that is fit to PET; The reagent of many emission positron is synthesized, existing commodity, and be known in the art.The The compounds of this invention that is particularly suitable for this usefulness be can by with ¹¹CH ₃One of I reaction bonded ¹¹CH ₃Those compounds of I group.In addition, the The compounds of this invention that is particularly suitable for this usefulness in addition can by with ¹⁸The reaction of F fluorine anion will ¹⁸The F group is attached to those compounds in the compound. ¹¹CH ₃The combination of I can be used according to for example embodiment 51 described methods ¹¹CH ₃Use among the I replacement embodiment 51 ¹²CH ₃I carries out.In a comparable manner, R wherein ₆, R _6aOr R _6bBe pyrazoles-4-base or pyrazoles-2-base formula (I) compound can with alkali and ¹¹CH ₃I handles, and preparation is used for the part of PET research.In order to incite somebody to action ¹⁸F is attached in The compounds of this invention or the composition, wherein R ₄R ₅N is that formula (I) compound of 4-hydroxy piperidine or 4-hydroxymethyl-pyrrolidine can use methylsulfonic acid acid anhydride or trifluoromethanesulfanhydride anhydride and alkali to handle in inert solvent (as methylene dichloride), and formed compound (mesylate or fluoroform sulphonate) can be used with Synthetic Organic Chemistry or the known method of medicinal chemistry those skilled in the art ¹⁸The F-fluorochemical is handled.Being suitable as the The compounds of this invention that part is used for PET research is to contain ¹⁸F and ¹¹The isotopic The compounds of this invention of C includes but not limited to:

Instead-6-(1-( ¹¹C) methyl isophthalic acid H-pyrazoles-4-yl)-and 2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole;

Instead-2-{3-[(2S)-2-(( ¹⁸F) tetramethyleneimine-1-yl methyl fluoride)] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole;

Instead-2-[3-(4-( ¹⁸F) cyclobutyl fluorine piperidines-1-yl)]-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole;

Instead-6-(2,6-lutidine-3-yl)-2-[3-(4-( ¹⁸F) cyclobutyl fluorine piperidines-1-yl)]-1, the 3-benzothiazole;

Instead-methyl-3-[6-(1-( ¹¹C) benzothiazole-2-yl methyl isophthalic acid H-pyrazoles-4-yl)] cyclobutyl } propylamine;

Instead-6-(1-( ¹¹C) methyl isophthalic acid H-pyrazoles-4-yl)-and 2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole;

Instead-2-[3-(4-( ¹⁸F) cyclobutyl fluorine piperidines-1-yl)]-6-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzothiazole; With

Instead-2-[3-(4-(fluorine piperidines-1-yl) cyclobutyl]-6-(1-( ¹¹C) benzothiazole methyl isophthalic acid H-pyrazoles-4-yl).

Can understand Compounds and methods for of the present invention better with reference to following examples, these embodiment are used for example explanation, rather than to the restriction of scope of the present invention.

Reference example

Reference example 1

3-methylene radical cyclobutane-carboxylic acid

With 3-methylene radical tetramethylene formonitrile HCN (CAS#15760-35-7,33.84g, 0.368mol), sodium hydroxide (38g, 0.95mol) and water (50mL) mix and to be incorporated in 110 ℃ of heating 30 minutes, obtain two-phase mixture.(the 40wt.% aqueous solution, 0.7mL), organic phase becomes brown to add tetrabutylammonium hydroxide.Had gas to emit in 10 minutes, the two-phase thorough mixing that becomes obtains the homogeneous solution of light brown.Continue heating 2 days at 110 ℃.Mixture is cooled to room temperature, is cooled to 0 ℃ then.Add concentrated hydrochloric acid very slowly so as with pH regulator to 0.5-1.0.Formed white slurry, with extracted with diethyl ether (500mL * 2).With organic layer drying (Na ₂SO ₄) and concentrate, obtain oily matter.With this oily matter distillation, collect 108-110 ℃ of cut, obtain colourless liquid (27.74g, productive rate 68%).

1H NMR(300MHz，CDCl ₃)δppm 4.77-4.88(m，2H)，3.10-3.24(m，1H)，2.86-3.09(m，4H).

Reference example 2

3-methylene radical tetramethylene acyl chlorides

In a 50mL round-bottomed flask of water condenser that dropping funnel and band drying tube be housed, add above preparation carboxylic acid (26.19g, 0.234mol).Dropwise add thionyl chloride (20.5mL, 0.281mol, 1.2 equivalents).With mixture heating up backflow (90 ℃ of oil bath temperatures) 3 hours, be cooled to room temperature then.Change condenser into still head, with this mixture underpressure distillation.Collect transparent colourless liquid (23g, productive rate 75%) at 43-45 ℃.

1H NMR(300MHz，CDCl ₃)δppm 4.85-4.93(m，2H)，3.50-3.63(m，1H)，2.95-3.19(m，4H).

Embodiment

Embodiment 1

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 1A

2-amino-5-bromo benzothiazole

With 6-bromo-2-[4-morpholinodithio quinoline ketone (4.65g, 20.0mmol) and sodium hydroxide (15.4g 0.385mol) mixes in 40mL water.This mixture of stirring 100 ℃ of heating, became transparent solution then to form slurry in 30 minutes under the room temperature.This mixture is continued stirring at 100 ℃ spend the night, be cooled to room temperature subsequently.Refrigerative is used the pH regulator to 6 of acetate (22mL) with solution simultaneously in ice bath.Filter and collect the solid that forms, wash with water 3 times, vacuum-drying obtains the 4.60g title compound.

¹H NMR(300MHz，DMSO-d ₆)δppm 7.23(s，1H)，6.98(d，J＝7.80Hz，1H)，6.59(d，J＝8.82Hz，1H)，5.41(br，2H).MS：(M+H) ⁺＝203/205，(M+H) ⁺＝406.

Embodiment 1B

6-bromo-2-(3-methylene radical cyclobutyl) benzothiazole

Weigh embodiment 1A product (1.0g 4.90mmol) puts into the 100mL round-bottomed flask, add the tosic acid pyridine (0.37g, 1.47mmol).Flask placed under high vacuum spend the night.Add successively p-Xylol (50mL) and triethylamine (0.68mL, 4.9mmol).Mixture is stirred fast at 50 ℃, obtain almost transparent solution.In 15 minutes, dropwise add 3-methylene radical tetramethylene carbonyl chlorine (0.64g, 4.9mmol) (according to document JACS, 1959,81, the preparation of the method for 2723-2728) solution in 10mL dimethylbenzene then.Temperature rises to 140 ℃, keeps 7 hours.After mixture is cooled to room temperature, add ethyl acetate (100mL).The solution that forms is washed with saturated solution of sodium bicarbonate, with organic layer drying (Na ₂SO ₄), concentrate, obtain oily matter.Crude product obtains title compound (1.03g, 75%) with chromatography purification (20% hexanes/ch).

¹H NMR(300MHz，CDCl ₃)δppm 7.98(d，J＝2.03Hz，1H)，7.83(d，J＝8.82Hz，1H)，7.55(dd，J＝8.82，2.03Hz，1H)，4.83-4.98(m，2H)，3.83-4.04(m，1H)，3.10-3.35(m，4H).MS：(M+H) ⁺＝279/281.

Embodiment 1C

3-(6-bromo benzothiazole-2-yl) cyclobutanone

With the product of embodiment 1B (931mg, 3.33mmol) and perosmic anhydride (28mg, catalyzer) be dissolved in 30mL THF and the 15mL water.This solution is cooled to 0 ℃.Branch aliquot adding sodium periodate (1.5g, 7.0mmol).Mixture at room temperature stirred spend the night, the reaction of this solution of water quencher is with dichloromethane extraction 3 times.The organic phase that merges obtains crude product with dried over sodium sulfate and concentrated.Through chromatogram purification (20% hexanes/ch), obtain title compound (710mg, 76%).

¹H NMR(500MHz，CDCl ₃)δppm 8.00(d，J＝1.87Hz，1H)，7.84(d，J＝8.74Hz，1H)，7.59(dd，J＝8.73，1.87Hz，1H)，3.96-4.10(m，1H)，3.54-3.76(m，4H).MS：(M+H) ⁺＝281/283

Embodiment 1D

Suitable-3-(6-bromo benzothiazole-2-yl) cyclobutanol

(710mg 2.52mmol) is dissolved among the anhydrous THF of 50ml, is cooled to 0 ℃ with the product of embodiment 1C.Slowly add 3-sec-butyl lithium borohydride (1.0M THF solution, 3.02ml, 3.02mmol).Mixture was stirred 10 minutes at 0 ℃, be warmed to room temperature then 30 minutes.With 1N sodium hydroxide (20ml) quencher reaction, use ethyl acetate extraction 3 times.Organic phase is merged, use dried over sodium sulfate, obtain crude product, the not purified next step that is used for.

Embodiment 1E

Instead-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

The product of embodiment 1D (2.52mmol) is dissolved in the anhydrous methylene chloride (20ml).Add successively salt of wormwood (696mg, 5.04mmol) and trifluoromethanesulfanhydride anhydride (551 μ l, 3.27mmol).Mixture was at room temperature stirred 2 hours, (1.74g 12.6mmol), adds 2-(R)-crassitude L-tartrate subsequently (according to R.Altenbach etc. to add another part salt of wormwood then, WO 2004043458 and Y.Pu etc., Orgnic Process Research﹠amp; Development, 9 (1) 45-50, the preparation of step described in 2005) (1.18g, 5.04mmol).Formed mixture at room temperature stirs and spends the night, and dichloromethane extraction 3 times are used in water quencher reaction then.Organic layer is merged,, concentrate with the salt washing.Crude product obtains 394mg (45%) title compound with column chromatography purifying (0.5% ammonium hydroxide and 5% ethanol/methylene).

¹H NMR(400MHz，CDCl ₃)δppm7.97(d，J＝1.84Hz，1H)，7.83(d，J＝8.90Hz，1H)，7.55(dd，J＝8.75，1.99Hz，1H)，3.75′-3.88(m，1H)，3.40-3.56(m，1H)，3.00-3.10(m，1H)，2.61-2.79(m，3H)，2.42-2.57(m，2H)，2.23-2.37(m，1H)，1.88-2.02(m，1H)，1.77-1.88(m，1H)，1.61-1.76(m，1H)，1.39-1.54(m，1H)，1.11(d，J＝6.14Hz，3H).MS：(M+H) ⁺＝351/353.

Embodiment 1F

Product (the 40mg of embodiment 1E, 0.114mmol), pyrimidine-5-boric acid (CAS#109299-78-7) (21mg, 0.169mmol), dichloro two (triphenyl phosphine) closes palladium (II) (8mg, 0.01mmol) and salt of wormwood (47mg, 0.34mmol) solution in the 1ml Virahol spends the night in 85 ℃ of following heated and stirred.Dichloromethane extraction 3 times are used in water quencher reaction then.The organic phase that merges is washed with salt, uses dried over sodium sulfate, filters and concentrates.Crude product with column chromatography purifying (with 0.35% ammonium hydroxide and 3.5% ethanol/methylene wash-out), is obtained 33mg (productive rate 82%) title compound.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)，9.02(s，2H)，8.12(d，J＝8.59Hz，1H)，8.06(d，J＝1.84Hz，1H)，7.67(dd，J＝8.44，1.99Hz，1H)，3.83-3.94(m，1H)，3.46-3.62(m，1H)，2.99-3.14(m，1H)，2.64-2.85(m，3H)，2.43-2.64(m，2H)，2.23-2.40(m，1H)，1.89-2.03(m，1H)，1.78-1.91(m，1H)，1.67-1.78(m，1H)，1.42-1.56(m，1H)，1.14(d，J＝4.91Hz，3H).MS：(M+H) ⁺＝351.

Embodiment 2

Instead-and 6-(2,6-lutidine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Embodiment 2A

2,6-dimethyl-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls) pyridine

To the 3-bromo-2 that is cooled to-78 ℃, (5.10g, 27.4mmol) solution in anhydrous diethyl ether (160ml) dropwise adds n-Butyl Lithium (4.1ml, 10M hexane solution) to the 6-lutidine under nitrogen atmosphere, and stirs 45 minutes at-78 ℃.Under-78 ℃, dropwise add 2-isopropoxy-4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentanes (10.2g, the 54.8mmol) solution in the 20ml ether, and-78 ℃ of stirrings 3 hours.With this mixture of 10ml Virahol quencher, it is warmed to room temperature.Add 150ml NaCl saturated aqueous solution.Water phase separated is also used dichloromethane extraction (100ml * 6).The organic phase that merges dry and concentrate after obtain light brown oily title compound (6.29g, 98.4%).

¹H NMR(300MHz，CDCl ₃)δppm 7.92(d，J＝7.46Hz，1H)6.96(d，J＝7.80Hz，1H)2.73(s，3H)2.53(s，3H)1.34(s，12H).MS：(M+H) ⁺＝234.

Embodiment 2B

Title compound is according to the step of embodiment 1F, with product replacement pyrimidine-5-boric acid preparation of embodiment 2A.

¹H NMR(400MHz，CDCl ₃)δppm8.02(d，J＝8.29Hz，1H)7.76(d，J＝1.84Hz，1H)7.46(d，J＝7.67Hz，1H)7.39(dd，J＝8.44，1.69Hz，1H)7.07(d，J＝7.67Hz，1H)3.82-3.93(m，1H)3.47-3.58(m，1H)2.98-3.13(m，1H)2.64-2.84(m，3H)2.59(s，3H)2.50(s，3H)2.43-2.59(m，2H)2.26-2.40(m，1H)1.89-2.03(m，1H)1.78-1.88(m，1H)1.61-1.75(m，1H)1.40-1.54(m，1H)1.13(t，J＝5.37Hz，3H).MS：(M+H) ⁺＝378.

Embodiment 3

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to the step of embodiment 1F, and with 2,6-dimethoxy-5-pyrimidine boric acid (CAS#89641-18-9) replaces pyrimidine-5-boric acid preparation.

¹H NMR(400MHz，CDCl ₃)δppm 8.32(s，1H)8.02(d，J＝8.59Hz，1H)7.97(d，J＝1.84Hz，1H)7.57(dd，J＝8.44，1.69Hz，1H)4.06(s，3H)4.05(s，3H)3.82-3.92(m，1H)3.45-3.59(m，1H)3.02-3.13(m，1H)2.65-2.82(m，3H)2.47-2.62(m，2H)2.25-2.41(m，1H)1.90-2.02(m，1H)1.77-1.89(m，1H)1.67-1.76(m，1H)1.53-1.66(m，1H)1.14(d，J＝5.83Hz，3H).MS：(M+H) ⁺＝411.

Embodiment 4

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, with 2-methoxy pyrimidine-5-boric acid (Frontier Scientific, Inc., Logan, UT, USA) replacement pyrimidine-5-boric acid preparation.

¹H NMR(500MHz，CDCl ₃)δppm 8.77(s，2H)8.08(d，J＝8.42Hz，1H)7.98(d，J＝1.56Hz，1H)7.57(dd，1H)4.09(s，3H)3.83-3.95(m，1H)3.50-3.62(m，1H)3.03-3.15(m，1H)2.67-2.85(m，2H)2.46-2.64(m，2H)2.29-2.40(m，1H)1.92-2.03(m，1H)1.82-1.89(m，1H)1.65-1.79(m，1H)1.44-1.63(m，2H)1.15(s，3H).MS：(M+H) ⁺＝381.

Embodiment 5

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyridin-4-yl-1, the 3-benzothiazole

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with pyridine-4-boric acid.

¹HNMR(500MHz，CDCl ₃)δppm 8.69(d，J＝6.24Hz，2H)8.12(d，J＝1.87Hz，1H)8.08(d，J＝8.42Hz，1H)7.73(dd，J＝8.42，1.87Hz，1H)7.56(dd，J＝4.52，1.72Hz，2H)3.85-3.93(m，1H)3.49-3.59(m，1H)3.01-3.13(m，1H)2.69-2.84(m，2H)2.46-2.61(m，2H)2.28-2.42(m，1H)1.92-2.01(m，1H)1.79-1.88(m，1H)1.69-1.78(m，1H)1.57-1.66(m，1H)1.45-1.55(m，1H)1.14(d，J＝5.62Hz，3H).MS：(M+H) ⁺＝350.

Embodiment 6

Instead-and 6-(6-methoxypyridine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with 2-methoxypyridine-5-boric acid.

¹H NMR(300MHz，CDCl ₃)δppm8.00(d，J＝8.48Hz，1H)7.87(d，J＝2.03Hz，1H)7.67(dd，J＝9.15，2.71Hz，1H)7.56(d，J＝2.71Hz，1H)7.49(dd，J＝8.48，2.03Hz，1H)6.70(d，J＝9.15Hz，1H)3.82-3.95(m，1H)3.65(s，3H)3.48-3.60(m，1H)3.01-3.21(m，1H)2.65-2.87(m，2H)2.45-2.64(m，2H)2.28-2.44(m，1H)1.92-2.05(m，1H)1.62-1.91(m，3H)1.46-1.60(m，1H)1.15(s，3H).MS：(M+H) ⁺380.

Embodiment 7

Instead-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyridin-3-yl-1, the 3-benzothiazole

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with pyridine-3-boric acid.

¹HNMR(300MHz，CDCl ₃)δppm 8.91(d，J＝1.70Hz，1H)8.62(dd，J＝4.92，1.53Hz，1H)8.02-8.15(m，2H)7.89-7.97(m，1H)7.68(dd，J＝8.48，1.70Hz，1H)7.34-7.44(m，1H)3.79-3.96(m，1H)3.46-3.62(m，1H)3.02-3.16(m，1H)2.65-2.88(m，2H)2.47-2.63(m，2H)2.27-2.44(m，1H)1.64-2.06(m，4H)1.41-1.59(m，1H)1.14(t，J＝6.95Hz，3H).MS：(M+H) ⁺＝350.

Embodiment 8

Instead-and 3-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) quinoline

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with 3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycles, penta-2-yl) quinoline (CAS#171364-85-5).

¹H NMR(300MHz，CDCl ₃)δppm 9.24(d，J＝2.37Hz，1H)8.37(d，J＝2.03Hz，1H)8.08-8.23(m，3H)7.91(d，J＝7.46Hz，1H)7.82(dd，J＝8.48，1.70Hz，1H)7.72-7.79(m，1H)7.61(t，J＝7.46Hz，1H)3.87-4.00(m，1H)3.46-3.64(m，1H)3.01-3.15(m，1H)2.73-2.83(m，2H)2.58-2.69(m，2H)2.32-2.45(m，1H)1.70-2.12(m，5H)1.55(s，3H).MS：(M+H) ⁺＝400.

Embodiment 9

Instead-and 6-(6-fluorine pyridin-3-yl)-2-{3-[(2R)-2-picoline alkane-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls) pyridine (can be obtained by Aldrich).

¹H NMR(300MHz，CDCl ₃)δppm8.48(d，J＝2.71Hz，1H)8.07(d，J＝8.48Hz，1H)7.98-8.04(m，2H)7.62(dd，J＝8.48，2.03Hz，1H)7.04(dd，J＝8.48，2.71Hz，1H)3.84-3.97(m，1H)3.46-3.68(m，1H)2.95-3.22(m，1H)2.68-2.87(m，2H)2.51-2.64(m ，2H)2.24-2.44(m，1H)1.47-2.08(m，5H)1.17(s，3H).MS：(M+H) ⁺＝368.

Embodiment 10

Instead-and 4-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) cyanobenzene

Title compound replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F with 4-benzonitrile ylboronic acid.

¹H NMR(300MHz，CDCl ₃)δppm8.05-8.06(m，2H)7.75(s，4H)7.68(dd，J＝8.82，1.70Hz，1H)3.83-3.94(m，1H)3.46-3.58(m，1H)3.01-3.15(m，1H)2.65-2.86(m，2H)2.45-2.63(m，2H)2.27-2.42(m，1H)1.65-2.03(m，4H)1.42-1.57(m，1H)1.14(d，J＝6.10Hz，3H).MS：(M+H) ⁺＝374.

Embodiment 11

Instead-2-{3-[(2S)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 11A

Instead-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound replaces 2-(R)-crassitude preparation according to step described in the embodiment 1E with 2-(S)-crassitude.

¹HNMR(500MHz，CDCl ₃)δppm7.98(d，J＝1.87Hz，1H)7.82(d，J＝8.74Hz，1H)7.56(dd，J＝8.73，2.18Hz，1H)3.87(t，J＝9.83Hz，1H)3.65-3.80(m，1H)3.22-3.39(m，1H)2.82-3.00(m，3H)2.69-2.78(m，1H)2.56-2.66(m，2H)2.04-2.14(m，1H)1.89-2.03(m，1H)1.78-1.89(m，1H)1.61-1.72(m，1H)1.27(d，J＝4.37Hz，3H).MS：(M+H) ⁺＝351/353.

Embodiment 11B

Title compound replaces the preparation of embodiment 1E product according to step described in the embodiment 1F with embodiment 11A product.

¹H NMR(500MHz，CDCl ₃)δppm9.24(s，1H)8.97-9.08(s，2H)8.12(d，J＝8.54Hz，1H)8.07(d，J＝1.53Hz，1H)7.67(dd，J＝8.54，1.83Hz，1H)3.86-3.96(m，1H)3.49-3.68(m，1H)3.03-3.21(m，1H)2.69-2.87(m，3H)2.53-2.66(m，2H)2.26-2.44(m，1H)1.94-2.08(m，1H)1.80-1.94(m，1H)1.68-1.81(m，1H)1.53-1.64(m，1H)1.16(s，3H).MS：(M+H) ⁺＝351.

Embodiment 12

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound use the product of the product replacement embodiment 1E of embodiment 11A, and with 2,6-dimethoxy-5-pyrimidine boric acid replaces pyrimidine-5-boric acid to prepare according to the step described in the embodiment 1F.

¹H NMR(500MHz，CDCl ₃)δppm8.32(s，1H)8.02(d，J＝8.54Hz，1H)7.98(d，J＝1.53Hz，1H)7.57(dd，J＝8.39，1.68Hz，1H)4.06(s，3H)4.05(s，3H)3.83-3.95(m，1H)3.51-3.72(m，1H)3.10-3.29(m，1H)2.68-2.80(m，3H)2.40-2.65(m，3H)1.49-2.13(m，4H)1.10-1.27(s，3H).MS：(M+H) ⁺＝411.

Embodiment 13

Instead-and 6-(2,6-lutidine-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, replaces the product of embodiment 1E and replaces pyrimidine-5-boric acid to prepare with the product of embodiment 2A with the product of embodiment 11A.

¹H NMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.24Hz，1H)7.77(d，J＝1.22Hz，1H)7.46(d，J＝7.63Hz，1H)7.40(dd，J＝8.39，1.68Hz，1H)7.07(d，J＝7.63Hz，1H)3.83-3.95(m，1H)3.49-3.65(m，1H)3.04-3.18(m，1H)2.69-2.83(m，3H)2.59(s，3H)2.53(s，3H)2.39-2.63(m，3H)1.95-2.03(m，1H)1.81-1.94(m，1H)1.69-1.80(m，1H)1.58-1.68(m，1H)1.16(s，3H).MS：(M+H) ⁺＝378.

Embodiment 14

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound still replaces the product of embodiment 1E according to the preparation of step described in the embodiment 1F with the product of embodiment 11A, and replaces pyrimidine-5-boric acid with 2-methoxy pyrimidine-5-boric acid.

¹H NMR(500MHz，CDCl ₃)δppm 8.77(s，2H)8.08(d，J＝8.42Hz，1H)7.98(d，J＝1.87Hz，1H)7.60(dd，J＝8.58，1.72Hz，1H)4.09(s，3H)3.84-3.98(m，1H)3.47-3.65(m，1H)2.99-3.18(m，1H)2.66-2.80(m，2H)2.44-2.62(m，2H)2.27-2.44(m，1H)1.92-2.04(m，1H)1.80-1.92(m，1H)1.67-1.78(m，1H)1.44-1.64(m，2H)1.14(s，3H).MS：(M+H) ⁺＝378.

Embodiment 15

Instead-and 6-(6-methoxypyridine-3-yl)-2-(3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl)-1, the 3-benzothiazole

Title compound still replaces the product of embodiment 1E according to the preparation of step described in the embodiment 1F with the product of embodiment 11A, and replaces pyrimidine-5-boric acid with 6-methoxyl group-3-pyridine boric acid.

¹H NMR(500MHz，CDCl ₃)δppm8.43(d，J＝2.18Hz，1H)8.03(d，J＝8.42Hz，1H)7.97(d，J＝1.56Hz，1H)7.83(dd，J＝8.58，2.65Hz，1H)7.61(dd，J＝8.42，1.56Hz，1H)6.84(d，J＝8.73Hz，1H)4.00(s，3H)3.81-3.92(m，1H)3.47-3.58(m，1H)2.97-3.15(m，1H)2.66-2.85(m，2H)2.44-2.64(m，2H)2.26-2.39(m，1H)1.92-2.03(m，1H)1.79-1.89(m，1H)1.67-1.77(m，1H)1.46-1.64(m，2H)1.14(d，J＝5.30Hz，3H).MS：(M+H) ⁺＝380.

Embodiment 16

Instead-and 3-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) quinoline

Title compound uses the product of embodiment 11A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid to prepare with 3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls) quinoline according to step described in the embodiment 1F.

¹H NMR(500MHz，CDCl ₃)δppm9.24(d，J＝2.50Hz，1H)8.37(d，J＝2.50Hz，1H)8.09-8.21(m，3H)7.90(d，J＝8.11Hz，1H)7.81(dd，J＝8.42，1.87Hz，1H)7.71-7.78(m，1H)7.54-7.66(m，1H)3.82-3.99(m，1H)3.46-3.64(m，1H)2.98-3.16(m，1H)2.65-2.86(m，2H)2.42-2.64(m，2H)2.28-2.41(m，1H)1.92-2.05(m，1H)1.81-1.89(m，1H)1.69-1.78(m，1H)1.44-1.63(m，2H)1.16(s，3H).MS：(M+H) ⁺＝400.

Embodiment 17

Suitable-2-{3-[(2R)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 17A

Suitable-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

(500mg 1.77mmol) is dissolved in 6ml methylene dichloride and the 4ml ethanol with the product of embodiment 1C.Adding 2-(R)-crassitude (1.04g, 4.43mmol), the toluene extract in 50% sodium hydroxide), at room temperature stirred 30 minutes.Add then borane-pyridine (358 μ l, 3.54mmol).Mixture at room temperature stirred spend the night,, use dichloromethane extraction with saturated solution of sodium bicarbonate quencher reaction.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filter, and concentrating under reduced pressure, the crude product that obtains obtains 45mg (productive rate 9%) title compound with column chromatography purifying (0.4% ammonium hydroxide and 4% ethanol/methylene).

¹H NMR(500MHz，CDCl ₃)δppm7.98(d，J＝1.83Hz，1H)7.80(d，J＝8.85Hz，1H)7.54(dd，J＝8.54，1.83Hz，1H)3.54-3.65(m，1H)3.15-3.29(m，1H)3.00-3.13(m，1H)2.73-2.86(m，1H)2.56-2.69(m，2H)2.32-2.57(m，3H)1.92-2.05(m，1H)1.79-1.90(m，1H)1.67-1.78(m，1H)1.46-1.57(m，1H)1.17(s，3H).MS：(M+H) ⁺＝351/353.

Embodiment 17B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 17A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.03-8.13(m，2H)7.65(dd，J＝8.44，1.69Hz，1H)3.57-3.74(m，1H)3.17-3.31(m，1H)3.01-3.12(m，1H)2.76-2.88(m，1H)2.61-2.70(m，1H)2.44-2.59(m，3H)2.30-2.40(m，1H)1.91-2.05(m，1H)1.78-1.89(m，1H)1.67-1.79(m，1H)1.44-1.62(m，1H)1.17(s，3H).MS：(M+H) ⁺＝351.

Embodiment 18

Suitable-6-(2,6-lutidine-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, replaces the product of embodiment 1E and prepares with product replacement pyrimidine-5-boric acid of embodiment 2A with the product of embodiment 17A.

¹H NMR(400MHz，CDCl ₃)δppm7.99(d，J＝8.29Hz，1H)7.76(d，J＝1.84Hz，1H)7.45(d，J＝7.67Hz，1H)7.38(dd，J＝8.44，1.69Hz，1H)7.06(d，J＝7.36Hz，1H)3.57-3.70(m，1H)3.14-3.29(m，1H)2.99-3.13(m，1H)2.73-2.85(m，1H)2.59(s，3H)2.49(s，3H)2.28-2.67(m，5H)1.91-2.01(m，1H)1.77-1.88(m，1H)1.59-1.73(m，1H)1.43-1.53(m，1H)1.15(s，3H).MS：(M+H) ⁺＝378.

Embodiment 19

Suitable-2-{3-[(2S)-and 2-methylpyrrolidin-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 19A

Suitable-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

(500mg 1.77mmol) is dissolved in 6ml methylene dichloride and the 4ml ethanol, adds 2-(S)-crassitude (1.04g, 4.43mmol, the toluene extract in 50% sodium hydroxide) then, and solution was at room temperature stirred 30 minutes with the product of embodiment 1C.(358 μ l 3.54mmol), at room temperature stir mixture and to spend the night to add borane-pyridine.With the reaction of going out of saturated solution of sodium bicarbonate collection, usefulness dichloromethane extraction 3 times.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrates, and the crude product that obtains obtains 98mg (productive rate 16%) title compound with column chromatography (0.4% ammonium hydroxide and 4% ethanol/methylene) purifying.

¹H NMR(500MHz，CDCl ₃)δppm7.98(d，J＝2.14Hz，1H)7.80(d，J＝8.85Hz，1H)7.54(dd，J＝8.54，1.83Hz，1H)3.54-3.65(m，1H)3.15-3.29(m，1H)3.00-3.12(m，1H)2.74-2.85(m，1H)2.58-2.68(m，1H)2.43-2.56(m，3H)2.30-2.39(m，1H)1.92-2.02(m，1H)1.78-1.89(m，1H)1.70-1.76(m，1H)1.44-1.59(m，1H)1.16(s，3H).MS：(M+H) ⁺＝351/353.

Embodiment 19B

Suitable-2-{3-{ (2S)-2-methylpyrrolidin-1-yl } cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

The title bonded replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 19A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.00-8.13(m，2H)7.65(dd，J＝8.44，1.69Hz，1H)3.58-3.75(m，1H)3.15-3.28(m，1H)3.00-3.12(m，1H)2.75-2.86(m，1H)2.60-2.71(m，1H)2.43-2.58(m，3H)2.30-2.42(m，1H)1.91-2.05(m，1H)1.76-1.90(m，1H)1.66-1.76(m，1H)1.40-1.56(m，1H)1.16(s，3H).MS：(M+H) ⁺＝351.

Embodiment 20

Suitable-6-(2,4-dimethoxypyridin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, and with embodiment 19A product replacement embodiment 1E product with 2,6-dimethoxy-5-pyrimidine boric acid replaces pyrimidine-5-boric acid preparation.

¹H NMR(400MHz，CDCl ₃)δppm8.31(s，1H)7.91-8.03(m，2H)7.55(dd，J＝8.44，1.69Hz，1H)4.06(s，3H)4.05(s，3H)3.55-3.70(m，1H)3.15-3.29(m，1H)3.02-3.14(m，1H)2.72-2.88(m，1H)2.60-2.71(m，1H)2.43-2.56(m，3H)2.30-2.40(m，1H)1.91-2.02(m，1H)1.79-1.88(m，1H)1.66-1.77(m，1H)1.44-1.55(m，1H)1.16(s，3H).MS：(M+H) ⁺＝411.

Embodiment 21

Suitable-6-(2,6-lutidine-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is used the product of embodiment 19A to replace embodiment 1E product, and is replaced pyrimidine-5-boric acid to prepare with the product of embodiment 2A according to step described in the embodiment 1F.

¹H NMR(400MHz，CDCl ₃)δppm7.99(d，J＝8.29Hz，1H)7.76(d，J＝1.53Hz，1H)7.45(d，J＝7.67Hz，1H)7.38(dd，J＝8.44，1.69Hz，1H)7.06(d，J＝7.67Hz，1H)3.58-3.70(m，1H)3.16-3.30(m，1H)3.00-3.13(m，1H)2.69-2.86(m，1H)2.59-2.68(m，1H)2.59(s，3H)2.49(s，3H)2.42-2.52(m，3H)1.91-2.03(m，1H)1.78-1.87(m，1H)1.67-1.77(m，1H)1.42-1.57(m，1H)1.16(s，3H).MS：(M+H) ⁺＝378.

Embodiment 22

Instead-and 2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone

Product (30mg with embodiment 1E, 0.085mmol), 3 (2H)-pyridazinones (CAS#504-30-3) (16mg, 0.17mmol), copper (11mg, 0.17mmol) and salt of wormwood (71mg, 0.51mmol) in the pyridine (1ml) of the degassing, mix, mixture heating up is refluxed spend the night.Dichloromethane extraction 3 times are used in water quencher reaction.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filter, and concentrating under reduced pressure, the crude product that obtains obtains 23mg (productive rate 74%) title compound with column chromatography purifying (0.35% ammonium hydroxide and 3.5% ethanol/methylene).

¹H NMR(500MHz，CDCl ₃)δppm8.15(m，1H)8.05(m，1H)7.92(dd，J＝3.74，1.87Hz，1H)7.69(dd，J＝8.73，2.18Hz，1H)7.20-7.32(m，1H)7.08(dd，J＝9.51，1.72Hz，1H)3.86-3.99(m，1H)3.58-3.70(m，1H)3.15-3.27(m，1H)3.01-3.13(m，1H)2.74-2.87(m，1H)2.28-2.71(m，4H)1.90-2.03(m，1H)1.79-1.90(m，1H)1.66-1.78(m，1H)1.44-1.65(m，1H)1.16(s，3H)MS：(M+H) ⁺＝367.

Embodiment 23

Instead-and 6-methyl-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl } 1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone

Title compound replaces the preparation of 3 (2H)-pyridazinones according to the step described in the embodiment 22 with 6-methyl-3 (2H)-pyridazinone (CAS#13327-27-0).

¹H NMR(500MHz，CDCl ₃)δppm 8.12(d，J＝1.87Hz，1H)8.01(d，J＝8.74Hz，1H)7.68(dd，J＝8.73，2.18Hz，1H)7.16(d，J＝9.36Hz，1H)7.00(d，J＝9.67Hz，1H)3.55-3.70(m，1H)3.15-3.25(m，1H)3.02-3.14(m，1H)2.74-2.84(m，1H)2.59-2.69(m，1H)2.45-2.56(m，2H)2.40(s，3H)2.30-2.37(m，1H)1.91-2.02(m，1H)1.78-1.87(m，1H)1.69-1.77(m，1H)1.55-1.67(m，1H)1.46-1.52(m，1H)1.16(d，J＝1.87Hz，3H).MS：(M+H) ⁺＝381.

Embodiment 24

Instead-the 5-methyl isophthalic acid-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone

Title compound replaces the preparation of 3 (2H)-pyridazinones according to step described in the embodiment 22 with 5-methyl-2 (1H)-pyridone (CAS#1003-68-5).

¹H NMR(500MHz，CDCl ₃)δppm8.03(m，1H)7.88(d，J＝1.87Hz，1H)7.42(dd，J＝8.58，2.03Hz，1H)7.25-7.32(m，1H)7.15(s，1H)6.62(d，J＝9.36Hz，1H)3.57-3.69(m，1H)3.15-3.25(m，1H)3.01-3.11(m，1H)2.73-2.83(m，1H)2.58-2.67(m，1H)2.42-2.54(m，2H)2.31-2.39(m，1H)2.12(s，3H)1.91-2.03(m，1H)1.78-1.89(m，1H)1.66-1.75(m，1H)1.56-1.65(m，1H)1.44-1.53(m，1H)1.15(d，J＝4.06Hz，3H).MS：(M+H) ⁺＝380.

Embodiment 25

Instead-the 3-methyl isophthalic acid-(2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone

Title compound replaces the preparation of 3 (2H)-Da piperazine ketone according to step described in the embodiment 22 with 3-methyl-2-pyridone (CAS#1003-56-1).

¹H NMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.42Hz，1H)7.89(d，J＝2.50Hz，1H)7.42(dd，J＝8.73，2.18Hz，1H)7.21-7.33(m，2H)6.18(t，J＝6.71Hz，1H)3.57-3.67(m，1H)3.15-3.25(m，1H)3.01-3.11(m，1H)2.74-2.83(m，1H)2.58-2.65(m，1H)2.43-2.55(m，2H)2.29-2.40(m，1H)2.20(s，3H)1.90-2.01(m，1H)1.80-1.89(m，1H)1.66-1.75(m，1H)1.46-1.62(m，2H)1.15(s，3H).MS：(M+H) ⁺＝380.

Embodiment 26

Instead-and 2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone

Title compound is used the product of the product replacement embodiment 1E of embodiment 11A, preparation according to the step described in the embodiment 22.

¹H NMR(500MHz，CDCl ₃)δppm8.15(d，J＝2.18Hz，1H)8.03(d，J＝8.73Hz，1H)7.92(dd，J＝3.74，1.56Hz，1H)7.69(dd，J＝8.73，2.18Hz，1H)7.23-7.30(m，1H)7.08(dd，J＝9.51，1.72Hz，1H)3.58-3.68(m，1H)3.16-3.26(m，1H)3.01-3.11(m，1H)2.75-2.84(m，1H)2.59-2.68(m，1H)2.45-2.57(m，2H)2.31-2.41(m，1H)1.92-2.01(m，1H)1.79-1.90(m，1H)1.68-1.76(m，1H)1.47-1.62(m，2H)1.16(s，3H).MS：(M+H) ⁺＝367.

Embodiment 27

Instead-and 6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone

Title compound is used the product of the product replacement embodiment 1E of embodiment 11A according to step described in the embodiment 22, and replaces the preparation of 3 (2H)-pyridazinones with 6-methyl-3 (2H)-pyridazinone.

¹H NMR(500MHz，CDCl ₃)δppm8.12(m，1H)8.00(m，1H)7.67(dd，J＝8.73，1.87Hz，1H)7.16(m，1H)7.01(m，1H)3.57-3.67(m，1H)3.15-3.24(m，1H)3.02-3.11(m，1H)2.73-2.86(m，1H)2.56-2.68(m，1H)2.45-2.55(m，2H)2.41(s，3H)2.30-2.37(m，1H)1.92-2.04(m，1H)1.77-1.87(m，1H)1.67-1.74(m，1H)1.44-1.61(m，2H)1.15(s，3H).MS：(M+H) ⁺＝381.

Embodiment 28

Instead-the 5-methyl isophthalic acid-(2-{3-[2S]-2-methylpyrrolidin-1-yl } cyclobutyl)-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone

Title compound is used the product of the product replacement embodiment 1E of embodiment 11A according to step described in the embodiment 22, and replaces the preparation of 3 (2H)-pyridazinones with 5-methyl-2 (1H)-pyridone.

¹H NMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.42Hz，1H)7.88(d，J＝2.18Hz，1H)7.42(dd，J＝8.58，2.03Hz，1H)7.28(dd，J＝9.36，2.50Hz，1H)7.15(s，1H)6.62(d，J＝9.36Hz，1H)3.59-3.69(m，1H)3.15-3.25(m，1H)3.01-3.10(m，1H)2.77-2.85(m，1H)2.60-2.67(m，1H)2.33-2.56(m，3H)2.12(s，3H)1.93-2.03(m，1H)1.79-1.88(m，1H)1.68-1.77(m，1H)1.45-1.64(m，2H)1.16(s，3H).MS：(M+H) ⁺＝380.

Embodiment 29

Instead-the 3-methyl isophthalic acid-(2-{3-[(2S)-2-methylpyrrolidin-1-yl] cyclobutyl }-1,3-benzothiazole-6-yl) pyridine-2 (1H)-ketone

Title compound is used the product of the product replacement embodiment 1E of embodiment 11A according to step described in the embodiment 22, and replaces the preparation of 3 (2H)-pyridazinones with 3-methyl-2-pyridone.

¹H NMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.74Hz，1H)7.89(d，J＝1.87Hz，1H)7.42(dd，J＝8.73，2.18Hz，1H)7.25-7.31(m，2H)6.18(t，J＝6.86Hz，1H)3.57-3.68(m，1H)3.15-3.25(m，1H)3.02-3.10(m，1H)2.72-2.85(m，1H)2.59-2.68(m，1H)2.44-2.53(m，2H)2.31-2.43(m，1H)2.20(s，3H)1.91-2.02(m，1H)1.79-1.88(m，1H)1.65-1.76(m，1H)1.44-1.64(m，2H)1.15(s，3H).MS：(M+H) ⁺＝380.

Embodiment 30

Suitable-6-pyrimidine-5-base-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Embodiment 30A

Suitable-6-bromo-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

(100mg, 0.354mmol) solution in 2ml methyl alcohol adds tetramethyleneimine (295 μ l 3.54mmol), at room temperature stirred mixture 1 hour to the product of embodiment 1C.(56mg, 0.891mmol), the mixture of formation at room temperature stirs and spends the night to add sodium cyanoborohydride.Dichloromethane extraction 3 times are used in water quencher reaction.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters, and concentrates, and the crude product that obtains obtains 65mg (55%) title compound with column chromatography (0.5% ammonium hydroxide and 5% ethanol/methylene) purifying.

¹H NMR (400MHz, CDCl ₃) for cis-isomeride δ ppm7.97 (d, J=1.84Hz, 1H) 7.80 (d, J=8.90Hz, 1H) 7.54 (dd, J=8.75,1.99Hz, 1H) 3.56-3.66 (m, 1H) 3.05-3.19 (m, 1H) 2.55-2.75 (m, 6H) 2.41-2.53 (m, 2H) 1.75-1.92 (m, 4H) .MS:(M+H) ⁺=337/339.

Embodiment 30B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 30A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.08(d，J＝8.59Hz，1H)8.05(d，J＝1.53Hz，1H)7.65(dd，J＝8.59，1.84Hz，1H)3.59-3.74(m，1H)3.02-3.16(m，1H)2.66-2.79(m，2H)2.51-2.63(m，4H)2.38-2.49(m，2H)1.84(s，4H).MS：(M+H) ⁺＝337.

Embodiment 31

Suitable-6-(2-methoxy pyrimidine-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound use the product of the product replacement embodiment 1E of embodiment 30A, and 2-methoxy pyrimidine-5-boric acid replaces pyrimidine-5-boric acid preparation according to step described in the embodiment 1F.

¹H NMR(400MHz，CDCl ₃)δppm8.77(s，2H)8.04(d，J＝8.90Hz，1H)7.98(d，J＝1.23Hz，1H)7.58(dd，J＝8.44，1.99Hz，1H)4.08(s，3H)3.60-3.72(m，1H)3.04-3.14(m，1H)2.65-2.78(m，2H)2.51-2.63(m，4H)2.38-2.51(m，2H)1.84(s，4H).MS：(M+H) ⁺＝367.

Embodiment 32

Suitable-2-(3-piperidines-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 32A

Suitable-6-bromo-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound replaces 2-(R)-crassitude preparation according to step described in the embodiment 17A with piperidines.

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝1.87Hz，1H)7.79(d，J＝8.73Hz，1H)7.53(dd，J＝8.73，1.87Hz，1H)3.50-3.61(m，1H)2.79(s，1H)2.61-2.71(m，2H)2.23-2.43(m，6H)1.52-1.71(m，6H).MS：(M+H) ⁺＝351/353.

Embodiment 32B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 32A.

¹H NMR(500MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.08(d，J＝9.05Hz，1H)8.05(d，J＝1.25Hz，1H)7.64(dd，J＝8.42，1.87Hz，1H)3.56-3.68(m，1H)2.80-2.88(m，1H)2.66-2.77(m，2H)2.22-2.47(m，6H)1.52-1.74(m，6H).MS：(M+H) ⁺＝351.

Embodiment 33

Suitable-6-(2-methoxy pyrimidine-5-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound is used the product of the product replacement embodiment 1E of embodiment 32A according to step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid.

¹H NMR(500MHz，CDCl ₃)δppm8.77(s，2H)8.04(d，J＝8.42Hz，1H)7.98(s，1H)7.58(dd，J＝8.42，1.87Hz，1H)4.08(s，3H)3.55-3.68(m，1H)2.79-2.91(m，1H)2.66-2.77(m，2H)2.23-2.49(m，6H)1.52-1.73(m，6H).MS：(M+H) ⁺＝381.

Embodiment 34

Suitable-2-(3-azepan-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 34A

Suitable-2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole

Title compound still replaces 2-(R)-crassitude with hexamethylene imine according to the preparation of step described in the embodiment 17A.

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝1.87Hz，1H)7.80(d，J＝8.74Hz，1H)7.53(dd，J＝8.58，2.03Hz，1H)3.45-3.57(m，1H)3.02-3.15(m，1H)2.64-2.73(m，2H)2.48-2.62(m，4H)2.20-2.37(m，2H)1.51-1.75(m，8H).MS：(M+H) ⁺＝365/367.

Embodiment 34B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 34A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.09(d，J＝8.29Hz，1H)8.05(d，J＝1.23Hz，1H)7.65(dd，J＝8.44，1.69Hz，1H)3.45-3.67(m，1H)3.04-3.21(m，1H)2.67-2.77(m，2H)2.46-2.65(m，4H)2.26-2.43(m，2H)1.53-1.78(m，8H).MS：(M+H) ⁺＝365.

Embodiment 35

Suitable-2-(3-morpholine-4-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 35A

Suitable-6-bromo-2-(3-morpholine-4-basic ring butyl)-1, the 3-benzothiazole

Title compound prepares for 2-(R)-crassitude with morpholino according to step described in the embodiment 17A.

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝1.87Hz，1H)7.81(d，J＝8.74Hz，1H)7.54(dd，J＝8.58，2.03Hz，1H)4.01(d，J＝15.29Hz，1H)3.68-3.80(m，2H)3.51-3.62(m，1H)3.14(d，J＝13.73Hz，1H)2.81-2.98(m，2H)2.64-2.72(m，1H)2.25-2.48(m，4H)1.58(s，2H).MS：(M+H) ⁺＝353/355.

Embodiment 35B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 35A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.10(d，J＝8.29Hz，1H)8.06(d，J＝1.53Hz，1H)7.66(dd，J＝8.29，1.84Hz，1H)3.60-3.87(m，3H)2.80-3.01(m，1H)2.66-2.78(m，2H)2.30-2.51(m，4H)1.58(s，4H).MS：(M+H) ⁺＝353.

Embodiment 36

Suitable-(2S)-and 1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol

Embodiment 36A

Suitable-(2S)-and 1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol

Title compound replaces the tetramethyleneimine preparation according to step described in the embodiment 30A with the L-pyrrolidine carbinol.

¹H NMR(400MHz，CDCl ₃)δppm7.97(d，J＝2.15Hz，1H)7.81(d，J＝8.59Hz，1H)7.55(dd，J＝8.59，1.84Hz，1H)3.50-3.63(m，2H)3.39(dd，J＝10.59，3.22Hz，1H)3.22-3.32(m，1H)3.00-3.13(m，1H)2.70-2.84(m，2H)2.58-2.70(m，1H)2.34-2.53(m，3H)1.86-2.01(m，1H)1.68-1.82(m，3H).MS：(M+H) ⁺＝367/369.

Embodiment 36B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the compound of embodiment 36A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.10(d，J＝8.90Hz，1H)8.05(d，J＝1.23Hz，1H)7.66(dd，J＝8.44，1.99Hz，1H)3.53-3.68(m，2H)3.38-3.46(m，1H)3.26-3.35(m，1H)3.02-3.14(m，1H)2.74-2.86(m，2H)2.63-2.73(m，1H)2.40-2.57(m，3H)1.86-1.99(m，1H)1.71-1.84(m，2H)1.49-1.70(m，1H).MS：(M+H) ⁺＝367.

Embodiment 37

Suitable-((2S)-1-{3-[6-(2-methoxy pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl } tetramethyleneimine-2-yl) methyl alcohol

Title compound is used the product of the product replacement embodiment 1E of embodiment 36A according to step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid.

¹H NMR(400MHz，CDCl ₃)δppm8.77(s，2H)8.06(d，J＝8.59Hz，1H)7.98(d，J＝1.53Hz，1H)7.59(dd，J＝8.59，1.84Hz，1H)4.08(s，3H)3.55-3.68(m，J＝7.67Hz，2H)3.36-3.47(m，1H)3.25-3.35(m，1H)3.03-3.14(m，1H)2.72-2.87(m，2H)2.61-2.72(m，1H)2.40-2.54(m，3H)1.87-2.01(m，1H)1.69-1.85(m，2H)1.51-1.70(m，1H).MS：(M+H) ⁺＝397.

Embodiment 38

Suitable-2-{3-[(3aR, 6aR)-hexahydropyrrolo [3,4-b] pyrroles-5 (1H)-yl also] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 38A

Suitable-tertiary butyl (3aR, 6aR)-5-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also

Title compound is according to step described in the embodiment 30A, with hexahydropyrrolo also [3,4-b] pyrroles-1-carboxylic acid tert-butyl ester (according to Q.Li etc. at J.Med.Chem; 39 (16), 3070-3088, the preparation of method described in 1996) replace tetramethyleneimine to prepare.

¹H NMR(400MHz，CDCl ₃)δppm7.97(d，J＝1.53Hz，1H)7.81(d，J＝8.59Hz，1H)7.54(dd，J＝8.59，1.84Hz，1H)4.13-4.28(m，2H)3.50-3.63(m，2H)3.33-3.46(m，2H)2.93-3.01(m，1H)2.78-2.88(m，1H)2.27-2.71(m，6H)1.90-2.02(m，1H)1.66-1.78(m，1H)1.45-1.48(s，9H).MS：(M+H) ⁺＝478/480.

Embodiment 38B

Suitable-tertiary butyl (3aR, 6aR)-5-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also

Title compound replaces the compound of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 38A.

¹H NMR(500MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.09(d，J＝8.42Hz，1H)8.05(d，J＝1.25Hz，1H)7.65(dd，J＝8.42，1.87Hz，1H)4.15-4.30(m，2H)3.53-3.71(m，2H)3.35-3.49(m，2H)2.95-3.07(m，1H)2.81-2.91(m，1H)2.58-2.76(m，3H)2.29-2.52(m，3H)1.91-2.03(m，1H)1.68-1.80(m，1H)1.39-1.52(s，9H).MS：(M+H) ⁺＝478.

Embodiment 38C

Be the preparation title compound, the product of embodiment 38B is mixed with 1: 1 mixture of TFA and methylene dichloride.After 2 hours, removal of solvent under reduced pressure, resistates alkalizes with saturated solution of sodium bicarbonate, uses dichloromethane extraction 3 times.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrating under reduced pressure.Resistates obtains title compound with column chromatography (0.5% ammonium hydroxide and 5% ethanol/methylene) purifying.

¹H NMR(500MHz，CDCl ₃)δppm9.19-9.26(s，1H)9.01(s，2H)8.09(d，J＝8.54Hz，1H)8.05(d，J＝1.53Hz，1H)7.65(dd，J＝8.54，1.83Hz，1H)3.81-3.92(m，1H)3.60-3.71(m，1H)3.03-3.12(m，1H)2.95-3.03(m，1H)2.87-2.95(m，1H)2.72-2.79(m，1H)2.64-2.71(m，2H)2.50-2：62(m，3H)2.32-2.46(m，3H)1.91-2.00(m，1H)1.57-1.67(m，1H).MS：(M+H) ⁺＝378.

Embodiment 39

Suitable-2-{3-[(3aR, 6aR)-hexahydropyrrolo [3,4-b] pyrroles-5 (1H)-yl also] cyclobutyl }-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole

Embodiment 39A

Suitable-tertiary butyl (3aR, 6aR)-5-{3-[6-(2-methoxy pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl } hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also

Title compound is used the product of the product replacement embodiment 1E of embodiment 38A according to step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid.

¹H NMR(500MHz，CDCl ₃)δppm8.77(s，2H)8.05(d，J＝8.42Hz，1H)7.97(s，1H)7.58(dd，J＝8.42，1.56Hz，1H)4.14-4.29(m，2H)4.08(s，3H)3.54-3.70(m，2H)3.34-3.49(m，2H)2.93-3.05(m，1H)2.77-2.91(m，1H)2.52-2.75(m，3H)2.28-2.50(m，3H)1.90-2.02(m，1H)1.66-1.81(m，1H)1.46(s，9H).MS：(M+H) ⁺＝508.

Embodiment 39B

Suitable-2-{3-[(13aR, 6aR)-hexahydropyrrolo [3,4-b] pyrroles-5 (1H)-yl also] cyclobutyl }-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole

Title compound replaces the product preparation of embodiment 38B according to step described in the embodiment 38C with the product of embodiment 39A.

¹H NMR(500MHz，CDCl ₃)δppm8.77(s，2H)8.05(d，J＝8.54Hz，1H)7.97(s，1H)7.58(dd，J＝8.54，1.83Hz，1H)4.08(s，3H)3.85-3.98(m，1H)3.60-3.70(m，1H)3.08-3.16(m，1H)2.90-3.02(m，2H)2.73-2.81(m，1H)2.61-2.71(m，2H)2.49-2.60(m，3H)2.31-2.47(m，3H)1.93-2.05(m，1H)1.58-1.74(m，1H).MS：(M+H) ⁺＝408.

Embodiment 40

Suitable-2-{3-[(2R)-and pipecoline-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 40A

Suitable-6-bromo-2-{3-[(2R)-pipecoline-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound replaces the tetramethyleneimine preparation according to step described in the embodiment 30A with 2-(R)-methyl piperidine (can be buied by Clariant).

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝2.18Hz，1H)7.80(d，J＝8.73Hz，1H)7.53(dd，J＝8.58，2.03Hz，1H)3.43-3.57(m，1H)3.07-3.18(m，1H)2.67-2.81(m，2H)2.51-2.66(m，2H)2.37-2.50(m，2H)2.27-2.38(m，1H)2.08(m，1H)1.50-1.68(m，4H)1.29-1.42(m，1H)1.06(d，J＝4.99Hz，3H).MS：(M+H) ⁺＝365/367.

Embodiment 40B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 40A.

¹H NMR(400MHz，CDCl ₃)δppm9.17(s，1H)9.15(s，2H)8.39(s，1H)8.11(d，J＝8.59Hz，1H)7.89(dd，J＝8.29，1.53Hz，1H)3.92-4.13(m，2H)3.75-3.90(m，2H)3.52-3.63(m，1H)3.03-3.18(m，1H)2.83-3.01(m，3H)2.66-2.83(m，2H)1.83-2.06(m，2H)1.56-1.80(m，2H)1.41(dd，J＝18.72，6.75Hz，3H).MS：(M+H) ⁺＝365.

Embodiment 41

Suitable-N-sec.-propyl-N-methyl-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine

Embodiment 41A

Suitable-N-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl]-N-sec.-propyl-N-methylamine

Title compound replaces the tetramethyleneimine preparation according to step described in the embodiment 30A with the sec.-propyl methylamine.

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝1.87Hz，1H)7.80(d，J＝8.42Hz，1H)7.53(dd，J＝8.58，2.03Hz，1H)3.47-3.58(m，1H)3.12-3.23(m，1H)2.89-3.01(m，1H)2.60-2.71(m，2H)2.23-2.38(m，2H)2.12(s，3H)1.01(d，J＝6.55Hz，6H).MS：(M+H) ⁺＝339/341.

Embodiment 41B

Suitable-N-sec.-propyl-N-methyl-N-[3-(6-pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl] amine

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 41A.

¹H NMR (400MHz, solvent) δ ppm9.17 (s, 1H) 9.15 (s, 2H) 8.39 (d, J=1.53Hz, 1H) 8.11 (d, J=8.59Hz, 1H) 7.89 (dd, J=8.59,1.84Hz, 1H) 3.96-4.10 (m, 1H) 3.77-3.91 (m, 1H) 3.60-3.78 (m, 1H) 2.86-3.07 (m, 3H) 2.69-2.82 (m, 1H) 2.71 (s, 3H) 1.36 (dd, J=30.84,6.29Hz, 6H) .MS:(M+H) ⁺=339.

Embodiment 42

Suitable-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] and piperidin-4-yl } methyl alcohol

Embodiment 42A

Suitable-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] and piperidin-4-yl } methyl alcohol

Title compound replaces the tetramethyleneimine preparation according to step described in the embodiment 30A with the 4-piperidine carbinols.

¹H NMR(500MHz，CDCl ₃)δppm7.97(d，J＝1.83Hz，1H)7.80(d，J＝8.85Hz，1H)7.54(dd，J＝8.70，1.98Hz，1H)3.54-3.60(m，1H)3.51(d，J＝6.41Hz，2H)2.94(d，J＝10.37Hz，2H)2.77-2.86(m，1H)2.65-2.72(m，2H)2.26-2.35(m，2H)1.73-1.87(m，4H)1.47-1.57(m，2H)1.23-1.34(m，2H).MS：(M+H) ⁺＝381/383.

Embodiment 42B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 42A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.02(s，2H)8.03-8.12(m，2H)7.65(dd，J＝8.59，1.84Hz，1H)3.60-3.71(m，1H)3.53(d，J＝6.44Hz，2H)3.04-3.17(m，2H)2.61-3.03(m，6H)2.46-2.59(m，2H)1.91-2.04(m，1H)1.73-1.89(m，2H)1.52-1.67(m，1H)1.34-1.49(m，1H).MS：(M+H) ⁺＝381.

Embodiment 43

Instead-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] piperidin-4-yl } methyl alcohol

Embodiment 43A

Instead-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] piperidin-4-yl } methyl alcohol

The product (0.177mmol) of embodiment 1D is dissolved in the anhydrous methylene chloride (2ml), add successively salt of wormwood (50mg, 0.362mmol) and trifluoromethanesulfanhydride anhydride (40 μ l, 0.238mmol).Mixture was at room temperature stirred 2 hours, add successively then another part salt of wormwood (100mg, 0.724mmol) and the 4-piperidine carbinols (61mg, 0.530mmol).The mixture that forms at room temperature stirs and spends the night, and dichloromethane extraction 3 times are used in water quencher reaction then.Organic layer is merged,, use dried over sodium sulfate, concentrate with the salt washing.Crude product obtains 29mg (43%) title compound with column chromatography (0.3% ammonium hydroxide and 3% ethanol/methylene) purifying.

¹H NMR(500MHz，CDCl ₃)δppm7.98(d，J＝1.83Hz，1H)7.83(d，J＝8.54Hz，1H)7.56(dd，J＝8.54，1.83Hz，1H)3.74-3.86(m，1H)3.52(d，J＝6.10Hz，2H)3.08-3.19(m，1H)2.95(d，J＝10.68Hz，2H)2.51-2.62(m，4H)1.79(d，J＝10.68Hz，4H)1.48-1.59(m，2H)1.25-1.38(m，2H).MS：(M+H) ⁺＝381/383.

Embodiment 43B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 43A.

¹H NMR(400MHz，CDCl ₃)δppm9.24(s，1H)9.02(s，2H)8.11(d，J＝8.29Hz，1H)8.06(d，J＝1.53Hz，1H)7.67(dd，J＝8.59，1.84Hz，1H)3.86-3.94(m，1H)3.54(t，J＝6.44Hz，2H)3.30-3.51(m，3H)3.15-3.24(m，2H)2.84-2.98(m，2H)2.63-2.76(m，2H)1.97-2.12(m，2H)1.77-1.90(m，2H)1.44-1.68(m，2H).MS：(M+H) ⁺381.

Embodiment 44

Instead-and 2-(3-piperidines-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 44A

Instead-and 6-bromo-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with piperidines.

¹H NMR(400MHz，CDCl ₃)δppm7.97(d，J＝2.15Hz，1H)7.82(d，J＝8.59Hz，1H)7.55(dd，J＝8.59，1.84Hz，1H)3.73-3.87(m，1H)3.05-3.18(m，1H)2.49-2.66(m，4H)2.19-2.44(m，4H)1.55-1.71(m，4H)1.39-1.54(m，2H).MS：(M+H) ⁺＝351/353.

Embodiment 44B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 44A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝8.29Hz，1H)8.06(d，J＝1.53Hz，1H)7.66(dd，J＝8.29，1.84Hz，1H)3.80-3.94(m，1H)3.09-3.21(m，1H)2.56-2.68(m，4H)2.27-2.42(m，4H)1.58-1.70(m，4H)1.42-1.55(m，2H).MS：(M+H) ⁺＝351.

Embodiment 45

Instead-and 6-(2,6-lutidine-3-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, and the product of usefulness embodiment 44A replaces the product among the embodiment 1E, and replaces pyrimidine-5-boric acid preparation with the product of embodiment 2A.

¹HNMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.24Hz，1H)7.76(s，1H)7.47(d，J＝7.63Hz，1H)7.40(dd，J＝8.54，1.53Hz，1H)7.08(d，J＝7.63Hz，1H)3.83-3.92(m，1H)3.42-3.53(m，1H)2.92-3.04(m，1H)2.62-2.74(m，3H)2.60(s，3H)2.50(s，3H)2.08(s，4H)1.71-1.83(m，4H)1.50-1.61(m，2H).MS：(M+H) ⁺＝378.

Embodiment 46

Instead-and 6-(6-methoxypyridine-3-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound is used the product of the product replacement embodiment 1E of embodiment 44A according to step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with 6-methoxypyridine-3-boric acid.

¹HNMR(500MHz，CDCl ₃)δppm8.43(d，J＝2.44Hz，1H)8.03(d，J＝8.54Hz，1H)7.97(d，J＝1.53Hz，1H)7.84(dd，J＝8.70，2.59Hz，1H)7.62(dd，J＝8.54，1.83Hz，1H)6.85(d，J＝8.54Hz，1H)4.00(s，3H)3.82-3.93(m，1H)3.36-3.48(m，1H)2.87-2.98(m，2H)2.52-2.71(m，4H)2.08(s，2H)1.67-1.82(m，4H)1.48-1.58(m，2H).MS：(M+H) ⁺＝380.

Embodiment 47

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Title compound still replaces embodiment 1E compound and replaces pyrimidine-5-boric acid with 2-methoxy pyrimidine-5-boric acid with embodiment 44A compound according to the preparation of step described in the embodiment 1F.

¹H NMR(500MHz，CDCl ₃)δppm8.78(s，2H)8.07(d，J＝8.54Hz，1H)7.98(d，J＝1.53Hz，1H)7.60(dd，J＝8.39，1.68Hz，1H)4.09(s，3H)3.80-3.92(m，1H)3.07-3.24(m，1H)2.55-2.73(m，4H)2.26-2.47(m，4H)1.57-1.80(m，4H)1.43-1.53(m，2H).MS：(M+H) ⁺＝381.

Embodiment 48A

Instead-and 2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone

Title compound replaces the product preparation of embodiment 1E according to method described in the embodiment 22 with the product of embodiment 44A.In this preparation, obtain two kinds and represent the cis of this tetramethylene ring and the isomer products of transconfiguration.Separate and purifying on silica gel with column chromatography, with 0.5% ammonium hydroxide and 5% ethanol/methylene wash-out, the RF value of separation and purifying TLC is 0.28 product (TLC condition: 0.5% ammonium hydroxide and 5% ethanol/methylene, silica gel), obtain pale solid mp139-140 ℃ corresponding to trans-isomer(ide).

¹H NMR(500MHz，CDCl ₃)δppm8.15(d，J＝2.14Hz，1H)8.05(d，J＝8.85Hz，1H)7.93(dd，J＝3.81，1.68Hz，1H)7.70(dd，J＝8.85，2.14Hz，1H)7.24-7.31(m，1H)7.09(dd，J＝9.46，1.83Hz，1H)3.80-3.92(m，1H)3.10-3.19(m，1H)2.53-2.70(m，4H)2.21-2.47(m，4H)1.58-1.72(m，4H)1.42-1.55(m，2H).MS：(M+H) ⁺＝367.

The other method of preparation embodiment 48A

Title compound is according to the method preparation of describing among the embodiment 1E, and still the product with embodiment 48E replaces the product of embodiment 1D and replaces 2-(R)-crassitude L-tartrate with piperidines.NMR and mass spectrum confirm and the spectrogram of the product that last method prepares coincide.

The preparation of the salt of embodiment 48A

The methanol solution of title compound is handled with hydrochloric acid (1: 1 mol ratio), subsequently with solution concentration, obtains fusing point and be 256-259 ℃ solid.The methanol solution of title compound is handled with sulfuric acid (1: 1 mol ratio), subsequently with solution concentration, obtains fusing point and be 86-92 ℃ solid.The methanol solution of title compound is handled with ortho-phosphoric acid (1: 1 mol ratio), subsequently with solution concentration, obtains fusing point and be 110-113 ℃ solid.The methanol solution of title compound is handled with L-tartrate (1: 1 mol ratio), subsequently with solution concentration, obtains fusing point and be 94-97 ℃ solid.

Embodiment 48B

Suitable-2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone

Title compound prepares described in embodiment 48A, so that it is 0.32 (TLC condition: 0.5% ammonium hydroxide and 5% ethanol/methylene that separation TLC goes up the RF value, on the silica gel) another isomer corresponding with cis-isomeride, it is a pale solid, fusing point 127-128 ℃.

¹H NMR(400MHz，CDCl ₃)δppm8.14(t，J＝2.61Hz，1H)8.02(d，J＝8.59Hz，1H)7.92(dd，J＝3.68，1.53Hz，1H)7.66-7.70(m，1H)7.23-7.30(m，1H)7.08(dd，J＝9.36，1.69Hz，1H)3.52-3.65(m，1H)2.75-2.86(m，1H)2.62-2.73(m，2H)2.25-2.41(m，6H)1.55-1.66(m，4H)1.41-1.52(m，2H).MS：(M+H) ⁺＝367.

The preparation of the salt of embodiment 48B

The methanol solution of title compound is handled with hydrochloric acid (1: 1 mol ratio) and subsequently with solution concentration, obtains fusing point and be 258-261 ℃ solid.The methanol solution of title compound is handled with sulfuric acid (1: 1 mol ratio) and subsequently with solution concentration, obtains fusing point and be 105-110 ℃ solid.The methanol solution of title compound is handled with ortho-phosphoric acid (1: 1 mol ratio) and subsequently with solution concentration, obtains fusing point and be 206-209 ℃ solid.The methanol solution of title compound is handled with L-tartrate (1: 1 mol ratio) and subsequently with solution concentration, obtains fusing point and be 136-140 ℃ solid.

Another preparation method of embodiment 48B

Embodiment 48C

2-[2-(3-hydroxyl cyclobutyl)-1,3-benzothiazole-6-yl]-the 2H-pyridazin-3-one

Product (suitable-3-(6-bromo benzothiazole-2-yl) cyclobutanol) (2.25g with embodiment 1D, 7.93mmol), 3 (2H)-pyridazinone (CAS#504-30-3) (1.52g, 15.83mmol), copper (500mg, 7.93mmol), salt of wormwood (3.28g, 23.77mmol) and copper(I) iodide (I) (211mg, 1.11mmol) in the pyridine (50ml) of the degassing, mix, under vacuum, placed 15 minutes, and then charge into nitrogen.Add N, and N '-dimethyl-ethylenediamine (240 μ l, 196mg, 2.22mmol), with the mixture heating up liquid that refluxed.Dilute with water is used dichloromethane extraction 3 times.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filter, and concentrating under reduced pressure, the crude product that obtains obtains title compound with column chromatography (0.4% ammonium hydroxide and 4% ethanol/methylene) purifying.

¹H NMR(400MHz，CDCl ₃)δppm8.15(d，J＝2.15Hz，1H)8.04(d，J＝8.90Hz，1H)7.92(dd，J＝3.68，1.53Hz，1H)7.70(dd，J＝8.59，2.15Hz，1H)7.24-7.30(m，1H)7.04-7.11(m，1H)4.68-4.81(m，0.3H)4.31-4.43(m，0.7H)3.87-3.98(m，0.3H)3.39-3.51(m，0.7H)2.90-3.01(m，1.4H)2.77-2.87(m，0.6H)2.51-2.62(m，0.6H)2.33-2.45(m，2.1H)2.07(d，J＝5.22Hz，0.3H).MS：(M+H) ⁺＝300.

Embodiment 48D

2-[2-(3-oxo cyclobutyl)-1,3-benzothiazole-6-yl]-the 2H-pyridazin-3-one

(1.63g 5.45mmol) is dissolved in the 50ml anhydrous methylene chloride, adds Dess-Martin pentavalent iodine oxidising agent (3.0g, 7.07mmol, [87413-09-0]) with the product of embodiment 48C.After following 3 hours of the room temperature,, use dichloromethane extraction 3 times with the mixture dilute with water.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrating under reduced pressure, and the crude product that obtains obtains title compound with column chromatography (0.25% ammonium hydroxide and 2.5% ethanol/methylene) purifying.

¹H NMR(300MHz，CDCl ₃)δppm8.20(d，J＝2.03Hz，1H)8.07(d，J＝8.82Hz，1H)7.94(dd，J＝3.73，1.70Hz，1H)7.75(dd，J＝8.82，2.37Hz，1H)7.26-7.31(m，1H)7.09(dd，J＝9.49，1.70Hz，1H)4.01-4.15(m，1H)3.54-3.79(m，5H).MS：(M+H) ⁺＝298.

Embodiment 48E

Suitable-2-[2-(3-hydroxyl cyclobutyl)-1,3-benzothiazole-6-yl]-the 2H-pyridazin-3-one

(213mg 0.72mmol) is dissolved in 6ml methyl alcohol and the 3ml methylene dichloride product of embodiment 48D, cools off in ice bath.(60mg 1.62mmol), stirs mixture 30 minutes under this temperature, and dilute with water stirred 1 hour then, uses dichloromethane extraction 3 times to add sodium borohydride.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters, and concentrating under reduced pressure obtains title compound.

¹H NMR(300MHz，CDCl ₃)δppm8.16(d，J＝2.37Hz，1H)8.05(d，J＝8.82Hz，1H)7.93(dd，J＝3.73，1.70Hz，1H)7.70(dd，J＝8.82，2.03Hz，1H)7.25-7.30(m，1H)7.08(dd，J＝9.49，1.70Hz，1H)4.38(m，1H)3.37-3.54(m，1H)2.90-3.05(m，2H)2.31-2.46(m，2H)2.19-2.28(m，1H).MS：(M+H) ⁺＝300.

Embodiment 48B

Title compound still replaces the product of embodiment 1C according to the preparation of step described in the embodiment 30A with the product of embodiment 48D, and replaces tetramethyleneimine with piperidines.NMR and mass spectrum confirm and the spectrogram of the product that preceding method prepares coincide.

Embodiment 49

Instead-and 6-methyl-2-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone

Title compound uses the product of embodiment 44A to replace the product of embodiment 1E and replace 3 (2H)-pyridazinones to prepare with 6-methyl-3 (2H)-pyridazinone according to step described in the embodiment 22.

¹H NMR(400MHz，CDCl ₃)δppm8.12(d，J＝2.15Hz，1H)8.01(d，J＝8.90Hz，1H)7.67(dd，J＝8.90，2.15Hz，1H)7.16(d，J＝9.51Hz，1H)7.00(d，J＝9.51Hz，1H)3.52-3.64(m，1H)2.72-2.86(m，1H)2.53-2.73(m，2H)2.40(s，3H)2.24-2.38(m，4H)1.65-1.75(m，2H)1.54-1.65(m，4H)1.46(d，J＝4.91Hz，2H).MS：(M+H) ⁺＝381.

Embodiment 50

Instead-3-methyl isophthalic acid-[2-(3-piperidines-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H)-ketone

Title compound uses the product of embodiment 44A to replace the product of embodiment 1E and replace 3 (2H)-pyridazinones to prepare with 3-methyl-2-pyridone according to step described in the embodiment 22.

¹H NMR(400MHz，CDCl ₃)δppm8.02(d，J＝8.59Hz，1H)7.89(d，J＝2.15Hz，1H)7.42(dd，J＝8.75，1.99Hz，1H)7.22-7.34(m，2H)6.19(t，J＝6.75Hz，1H)3.53-3.68(m，1H)2.80-2.94(m，1H)2.51-2.91(m，3H)2.32-2.50(m，4H)2.20(s，3H)1.99-2.12(m，1H)1.58-1.73(m，4H)1.43-1.54(m，2H).MS：(M+H) ⁺＝380.

Embodiment 51

Instead-and 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole

Embodiment 51A

Instead-and 2-(3-piperidines-1-basic ring butyl)-6-(1-trityl-1H-pyrazoles-4-yl)-1, the 3-benzothiazole

Product (the 120mg of embodiment 44A, 0.34mmol), 4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-1-trityl-1H-pyrazoles (224mg, 0.51mmol), dichloro two (triphenyl phosphine) closes palladium (II) (14.0mg, 0.020mmol), 2-(dicyclohexylphosphontetrafluoroborate) biphenyl (7.0mg, 0.020mmol), yellow soda ash (1M solution, 0.51ml, 0.51mmol) and 1.5ml ethanol/diox (1: 1) under nitrogen atmosphere, cover in the sealable bottle and mix in a tool.With the bottle sealing, be placed in commodity (that is Emrys the Creator) microwave oven in 140 ℃ of heating 10 minutes.Water quencher reaction is with methylene dichloride (4 * 5ml) extractions.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrates, and the crude product that obtains obtains 138.1mg (70% productive rate) title compound with column chromatography (1% ammonium hydroxide and 10% ethanol/methylene) purifying.

¹H NMR(300MHz，CDCl ₃)δppm7.99(s，1H)，7，89(d，J＝8.31Hz，1H)，7.88(d，J＝2，03Hz，1H)，7.68(s，1H)，7.53(dd，J＝8.31，1.87Hz，1H)，7.52-7.35(m，9H)，7.19-7.23(m，6H)，3.93(m，1H)3.42(m，1H)2.61-2.73(m，2H)2.26-2.52(m，4H)1.73-1.90(m，4H)1.43-1.58(m，4H).MS：(M+H) ⁺＝581.

Embodiment 51B

Instead-and 2-(3-piperidines-1-basic ring butyl)-6-(1H-pyrazoles-4-yl)-1, the 3-benzothiazole

With the product of embodiment 51A (135.0mg, 0.23mmol) be dissolved in formic acid (88%, 2ml), stirred 2 hours under the room temperature.With the reaction mixture concentrating under reduced pressure.Solid residue is handled with saturated aqueous solution of sodium bicarbonate, with dichloromethane extraction (4 * 5ml).The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrates, and the crude product that obtains obtains 71.2mg (90.5%) title compound with column chromatography (1% ammonium hydroxide and 10% ethanol/methylene) purifying.

MS：(M+H) ⁺＝339。

Embodiment 51C

(34.0mg 0.10mmol) is dissolved among the DMF (2ml), is cooled to 0 ℃ then with the product of embodiment 51B.At N ₂Under add NaH (60%, 44.0mg, 1.1mmol), 0 ℃ of stirred reaction mixture 0.5 hour.(6.8 μ l 0.11mmol), stir reaction mixture 1 hour at 0 ℃, slowly rise to room temperature then to add methyl iodide.With saturated aqueous solution of sodium bicarbonate quencher reaction, with methylene dichloride (4 * 5ml) extractions.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters, and concentrates, and the crude product that obtains obtains 23.8mg (67.6%) title compound with column chromatography (10% ethanol/methylene) purifying.

¹H NMR(300MHz，CDCl ₃)δppm 7.94(d，J＝8.481H)7.93(d，J＝2.031H)7.80(s，1H)7.66，(s，1H)7.56(dd，J＝8.48，2.031H)3.80(s，3H)3.87(m，1H)3.27(m，1H)2.38-2.62(m，4H)1.49-1.76(m，6H).MS：(M+H) ⁺＝353.

Embodiment 52

Instead-and N-sec.-propyl-N-methyl-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine

Embodiment 52A

Instead-N-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl]-N-sec.-propyl-N-methylamine

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with the sec.-propyl methylamine.

¹H NMR(300MHz，CDCl ₃)δppm7.99(d，J＝1.36Hz，1H)7.83(d，J＝9.15Hz，1H)7.57(dd，J＝8.81，2.03Hz，1H)3.80-3.96(m，2H)3.28-3.42(m，1H)2.90-3.10(m，2H)2.58-2.77(m，2H)2.40(s，3H)1.23(d，J＝5.76Hz，6H).MS：(M+H) ⁺＝339/341.

Embodiment 52B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 52A.

¹H NMR(300MHz，CDCl ₃)δppm9.24(s，1H)9.02(s，2H)8.12(d，J＝8.48Hz，1H)8.07(d，J＝1.70Hz，1H)7.67(dd，J＝8.48，1.70Hz，1H)3.78-3.93(m，1H)3.61(m，1H)3.06(m，1H)2.67-2.81(m，1H)2.61(t，J＝9.16Hz，2H)2.11-2.26(m，2H)1.48-1.75(m，4H)0.94-1.17(m，4H).MS：(M+H) ⁺＝339.

Embodiment 53

Instead-and N-sec.-propyl-N-{3-[6-(2-methoxy pyrimidine-5-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine

Title compound uses the product of embodiment 52A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid according to step described in the embodiment 1F.

¹H NMR(500MHz，CDCl ₃)δppm8.77(s，2H)8.07(d，J＝8.42Hz，1H)7.98(d，J＝1.87Hz，1H)7.60(dd，J＝8.42，1.87Hz，2H)4.09(s，3H)3.76-3.89(m，1H)3.51-3.66(m，1H)2.95-3.05(m，1H)2.53-2.74(m，4H)2.14(s，3H)1.03(d，J＝6.55Hz，6H).MS：(M+H) ⁺＝369.

Embodiment 54

Instead-and N-sec.-propyl-N-{3-[6-(6-methoxypyridine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine

Title compound uses the product of embodiment 52A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid preparation with 6-methoxy pyrimidine-3-boric acid according to step described in the embodiment 1F.

¹HNMR(300MHz，CDCl ₃)δppm8.00(d，J＝8.48Hz，1H)7.87(d，J＝1.70Hz，1H)7.68(dd，J＝9.16，2.71Hz，1H)7.49(dd，J＝8.48，1.70Hz，1H)7.39-7.44(m，1H)6.70(d，J＝9.49Hz，1H)3.75-3.88(m，1H)3.65(s，3H)3.56-3.63(m，1H)3.00-3.16(m，1H)2.66-2.80(m，2H)2.52-2.65(m，2H)2.18(s，3H)1.05(d，J＝6.44Hz，6H).MS：(M+H) ⁺＝368.

Embodiment 55

Instead-and N-sec.-propyl-N-{3-[6-(2-methoxypyridine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-the N-methylamine

Title compound uses the product of embodiment 52A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid preparation with 2-methoxypyridine-3-boric acid according to step described in the embodiment 1F.

¹H NMR(500MHz，CDCl ₃)δppm8.19(dd，J＝4.99，1.87Hz，1H)7.97-8.05(m，2H)7.66(dd，J＝7.18，1.87Hz，1H)7.63(dd，J＝8.42，1.87Hz，1H)7.00(dd，J＝7.49，4.99Hz，1H)3.99(s，3H)3.78-3.85(m，1H)3.53-3.63(m，1H)2.92-3.09(m，1H)2.63-2.73(m，2H)2.52-2.61(m，3H)2.14(d，J＝5.93Hz，3H)0.96-1.08(m，6H).MS：(M+H) ⁺＝368.

Embodiment 56

Instead-and N-{3-[6-(2,6-lutidine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl }-N-sec.-propyl-N-methylamine

Title compound is according to step described in embodiment 1F preparation, but replaces the product of embodiment 1E and with product replacement pyrimidine-5-boric acid of embodiment 2A with the product of embodiment 52A.

MS：(M+H) ⁺＝366。

Embodiment 57

Instead-and 2-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl }-1,3-benzothiazole-6-yl) pyridazine-3 (2H)-ketone

Title compound still replaces the product of embodiment 1E according to the preparation of step described in the embodiment 22 with the product of embodiment 52A.

¹H NMR(400MHz，CDCl ₃)δppm8.14(d，J＝1.84Hz，1H)8.03(d，J＝8.59Hz，1H)7.92(dd，J＝3.68，1.53H z，1H)7.68(dd，J＝8.90，2.15Hz，1H)7.24-7.29(m，1H)7.08(dd，J＝9.51，1.53Hz，1H)3.53-3.65(m，1H)3.13-3.28(m，1H)2.90-3.06(m，1H)2.61-2.74(m，2H)2.28-2.45(m，2H)2.15(s，3H)1.04(d，J＝6.14Hz，6H).MS：(M+H) ⁺＝355.

Embodiment 58

Instead-2-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl }-1,3-benzothiazole-6-yl)-6-methyl pyridazine-3 (2H)-ketone

Title compound is according to the preparation of step described in the embodiment 22, and still the product with embodiment 52A replaces the product of embodiment 1E and replaces 3 (2H)-pyridazinones with 6-methyl-3 (2H)-pyridazinone.

¹H NMR(400MHz，CDCl ₃)δppm8.12(d，J＝1.84Hz，1H)8.01(d，J＝8.90Hz，1H)7.67(dd，J＝8.59，2.15Hz，1H)7.16(d，J＝9.51Hz，1H)7.00(d，J＝9.51Hz，1H)3.49-3.66(m，1H)3.12-3.28(m，1H)2.91-3.06(m，1H)2.61-2.75(m，2H)2.40(s，3H)2.29-2.40(m，2H)2.14(s，3H)1.03(d，J＝6.75Hz，6H).MS：(M+H) ⁺＝369.

Embodiment 59

Instead-1-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl }-1,3-benzothiazole-6-yl)-3-picoline-2 (1H)-ketone

Title compound is according to the preparation of step described in the embodiment 22, and still the product with embodiment 52A replaces the product of embodiment 1E and replaces 3 (2H)-pyridazinones with 3-methyl-2-pyridone.

¹H NMR(400MHz，CDCl ₃)δppm8.02(d，J＝8.59Hz，1H)7.89(d，J＝1.84Hz，1H)7.42(dd，J＝8.75，1.99Hz，1H)7.23-7.34(m，2H)6.18(t，J＝6.75Hz，1H)3.52-3.63(m，1H)3.12-3.27(m，1H)2.90-3.03(m，1H)2.55-2.73(m，2H)2.25-2.44(m，2H)2.20(s，3H)2.13(s，3H)1.02(d，J＝6.44Hz，6H).MS：(M+H) ⁺＝368.

Embodiment 60

Instead-1-(2-{3-[sec.-propyl (methyl) amino] cyclobutyl }-1,3-benzothiazole-6-yl)-5-picoline-2 (1H)-ketone

Title compound is according to the preparation of step described in the embodiment 22, and still the product with embodiment 52A replaces the product of embodiment 1E and replaces 3 (2H)-pyridazinones with 5-methyl-2-pyridone.

¹H NMR(400MHz，CDCl ₃)δppm8.02(d，J＝8.59Hz，1H)7.88(d，J＝2.15Hz，1H)7.42(dd，J＝8.59，1.84Hz，1H)7.26-7.30(m，1H)7.15(s，1H)6.62(d，J＝9.21Hz，1H)3.51-3.64(m，1H)3.13-3.27(m，1H)2.90-3.02(m，1H)2.62-2.72(m，2H)2.28-2.40(m，2H)2.13(s，3H)2.12(s，3H)1.02(d，J＝6.44Hz，6H).MS：(M+H) ⁺＝368.

Embodiment 61

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 61A

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole

Title compound still replaces the 4-piperidine carbinols with azetidine according to the preparation of step described in the embodiment 43A.

¹H NMR(300MHz，CDCl ₃)δppm7.97(d，J＝2.03Hz，1H)7.82(d，J＝8.48Hz，1H)7.56(dd，J＝8.48，2.03Hz，1H)3.95-4.09(m，1H)3.80-3.91(m，1H)3.55-3.75(m，2H)3.19-3.36(m，2H)2.78-2.94(m，2H)2.44-2.62(m，2H)2.05-2.23(m，2H).MS：(M+H) ⁺＝323/325.

Embodiment 61B

Title compound still replaces the product of embodiment 1E according to the preparation of step described in the embodiment 1F with the product of embodiment 61A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝8.29Hz，1H)8.05(d，J＝1.53Hz，1H)7.66(dd，J＝8.44，1.69Hz，1H)3.98-4.12(m，1H)3.60-3.74(m，1H)3.26-3.45(m，4H)2.53-2.69(m，2H)2.42-2.54(m，2H)2.16(m，2H).MS：(M+H) ⁺＝323.

Embodiment 62

Instead-and 6-pyrimidine-5-base-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Embodiment 62A

Instead-and 6-bromo-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound still replaces the preparation of 4-piperidine carbinols with tetramethyleneimine according to step described in the embodiment 43A.

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝2.03Hz，1H)7.82(d，J＝8.82Hz，1H)7.56(dd，J＝8.65，1.87Hz，1H)3.90-4.04(m，1H)3.47(d，J＝7.12Hz，1H)2.55-2.90(m，8H)1.93(m，4H).MS：(M+H) ⁺＝337/339.

Embodiment 62B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 62A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝8.59Hz，1H)8.06(d，J＝1.84Hz，1H)7.66(dd，J＝8.59，1.84Hz，1H)3.91-4.09(m，1H)3.20-3.40(m，1H)2.60-2.74(m，4H)2.50-2.58(m，4H)1.78-1.92(m，4H).MS：(M+H) ⁺＝337.

Embodiment 63

Instead-and 6-(2,6-lutidine-3-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, replaces the product of embodiment 1E and replaces pyrimidine-5-boric acid to prepare with the product of embodiment 2A with the product of embodiment 62A.

¹H NMR(300MHz，CDCl ₃)δppm8.02(d，J＝8.48Hz，1H)7.76(d，J＝1.36Hz，1H)7.45(d，J＝7.80Hz，1H)7.40(dd，J＝8.31，1.86Hz，1H)7.07(d，J＝7.80Hz，1H)3.95-4.07(m，1H)3.25-3.45(m，1H)2.59(s，3H)2.50(s，3H)2.43-2.78(m，6H)1.77-2.00(m，4H)1.47-1.68(m，2H).MS：(M+H) ⁺＝364.

Embodiment 64

Instead-and 6-(2-methoxy pyrimidine-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound uses the product of embodiment 62A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid to prepare with 2-methoxy pyrimidine-5-boric acid according to step described in the embodiment 1F.

¹H NMR(300MHz，CDCl ₃)δppm8.78(s，1H)8.07(d，J＝8.48Hz，1H)7.98(d，J＝1.70Hz，1H)7.60(dd，J＝8.48，2.03Hz，1H)4.08(s，3H)3.93-4.07(m，1H)3.26-3.45(m，1H)2.50-2.80(m，6H)1.78-1.96(m，4H)1.59(m，2H).MS：(M+H) ⁺＝367.

Embodiment 65

Instead-and 6-(2,4-dimethoxypyridin-5-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, and the product of usefulness embodiment 62A replaces the product of embodiment 1E and with 2,6-dimethoxy-5-pyrimidine boric acid replaces pyrimidine-5-boric acid to prepare.

¹H NMR(300MHz，CDCl ₃)δppm8.32(s，1H)8.02(d，J＝8.48Hz，1H)7.97(d，J＝1.70Hz，1H)7.57(dd，J＝8.65，1.86Hz，1H)4.03-4.10(s，3H)3.95-4.03(m，1H)3.26-3.42(m，1H)2.43-2.78(m，6H)1.79-1.98(m，4H)1.45-1.66(m，2H).MS：(M+H) ⁺＝397.

Embodiment 66

Instead-and 6-(6-methoxypyridine-3-yl)-2-(3-tetramethyleneimine-1-basic ring butyl)-1, the 3-benzothiazole

Title compound uses the product of embodiment 62A to replace the product of embodiment 1E and replace pyrimidine-5-boric acid preparation with 6-methoxyl group-3-pyridine boric acid according to step described in the embodiment 1F.

¹HNMR(300MHz，CDCl ₃)δppm8.43(d，J＝2.37Hz，1H)8.03(d，J＝8.48Hz，1H)7.97(s，1H)，7.83(dd，J＝8.65，2.54Hz，1H)7.61(dd，J＝8.48，2.03Hz，1H)6.85(d，J＝9.15Hz，1H)4.01-4.10(m，J＝6.78Hz，1H)4.00(s，3H)3.35-3.70(m，1H)2.68(s，6H)1.93(s，2H)1.93(s，4H)1.46-1.65(m，2H).MS：(M+H) ⁺＝366.

Embodiment 67

Instead-and 2-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 22 with the product of embodiment 62A.

¹H NMR(300MHz，CDCl ₃)δppm8.15(t，J＝1.86Hz，1H)8.04(dd，J＝8.65，7.63Hz，1H)7.89-7.95(dt，1H)7.72(td，1H)7.21-7.31(m，1H)7.04-7.15(dt，1H)4.03(m，1H)3.65(m，1H)2.46-2.77(m，6H)1.75-2.00(m，4H)1.49-1.62(m，2H).MS：(M+H) ⁺＝353.

Embodiment 68

Instead-and 6-methyl-2-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridazine-3 (2H)-ketone

Title compound uses the product of embodiment 62A to replace the product of embodiment 1E and replace the preparation of 3 (2H)-pyridazinones with 6-methyl-3 (2H)-pyridazinone according to step described in the embodiment 22.

¹H NMR(300MHz，CDGl ₃)δppm8.12(t，J＝2.03Hz，1H)8.03(t，J＝8.48Hz，1H)7.66(dd，J＝8.48，2.37Hz，1H)7.17(d，J＝9.49，1H)7.00(d，J＝9.49Hz，1H)3.56-3.72(m，1H)3.07(m，1H)2.48-2.78(m，6H)2.41(s，3H)1.87-1.96(m，2H)1.77-1.87(m，2H)1.49-1.73(m，2H).MS：(M+H) ⁺＝367.

Embodiment 69

Instead-5-methyl isophthalic acid-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H)-ketone

Title compound uses the product of embodiment 62A to replace the product of embodiment 1E and replace the preparation of 3 (2H)-pyridazinones with 5-methyl-2 (1H)-pyridone according to step described in the embodiment 22.

¹H NMR (300MHz，CDCl ₃)δppm8.03(d，J＝9.15Hz，1H)7.87-7.90(m，1H)7.44(td，J＝9.00，2.03Hz，1H)7.29(dt，J＝9.00，2.37Hz，2H)7.15(s，1H)6.63(d，J＝9.15Hz，1H)3.61-3.73(m，1H)3.03-3.16(m，1H)2.43-2.78(m，6H)2.12(s，3H)1.81-1.91(m，4H)1.51-1.61(m，2H).MS：(M+H) ⁺＝366.

Embodiment 70

Instead-3-methyl isophthalic acid-[2-(3-tetramethyleneimine-1-basic ring butyl)-1,3-benzothiazole-6-yl] pyridine-2 (1H) ketone

Title compound uses the product of embodiment 62A to replace the product of embodiment 1E and replace the preparation of 3 (2H)-pyridazinones with 3-methyl-2-pyridone according to step described in the embodiment 22.

¹H NMR(300MHz，CDCl ₃)δppm8.03(t，J＝8.31Hz，1H)7.89(d，J＝2.03Hz，1H)7.44(t，1H)7.27-7.33(m，1H)6.18(q，2H)3.55-3.75(m，1H)3.03-3.15(m，1H)2.39-2.76(m，6H)2.21(s，3H)1.79-1.99(m，4H)1.50-1.70(m，2H).MS：(M+H) ⁺＝366.

Embodiment 71

Instead-and 2-(3-azepan-1-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 71A

Instead-and 2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with hexamethylene imine.

¹H NMR(500MHz，CDCl ₃)δppm7.98(d，J＝1.83Hz，1H)7.82(d，J＝8.54Hz，1H)7.56(dd，J＝8.54，1.83Hz，1H)3.73-3.85(m，1H)3.29-3.42(m，1H)2.46-2.62(m，8H)1.52-1.74(m，8H).MS：(M+H) ⁺＝365/367.

Embodiment 71B

Title compound still replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 71A.

¹H NMR(400MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝7.98Hz，1H)8.06(d，J＝1.84Hz，1H)7.66(dd，J＝8.29，1.84Hz，1H)3.73-3.95(m，J＝6.29，6.29Hz，1H)3.34-3.50(m，1H)2.48-2.69(m，8H)1.59-1.82(m，8H).MS：(M+H) ⁺＝365.

Embodiment 72

Instead-and 2-(3-morpholine-4-basic ring butyl)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 72A

Instead-and 6-bromo-2 (3-morpholine-4-basic ring butyl)-1, the 3-benzothiazole

Title compound prepares for the 4-piperidine carbinols with morpholino according to step described in the embodiment 43A.

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝2.03Hz，1H)7.84(d，J＝8.65Hz，1H)7.56(dd，J＝8.65，1.86Hz，1H)3.82-3.92(m，1H)3.68-3.82(m，4H)3.08-3.27(m，1H)2.58(m，4H)2.31-2.49(m，4H).MS：(M+H) ⁺＝353/355.

Embodiment 72B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 72A.

¹H NMR(400MHz，CDCl ₃)δppm9.24(s，1H)8.99-9.05(s，2H)8.12(d，J＝8.59Hz，1H)8.06(d，J＝1.23Hz，1H)7.67(dd，J＝8.59，1.84Hz，1H)3.86-3.97(m，1H)3.71-3.82(m，4H)3.15-3.24(m，1H)2.35-2.67(m，8H).MS：(M+H) ⁺＝353.

Embodiment 73

Instead-2-{3-[(2S)-and 2-(methyl fluoride) tetramethyleneimine-1-yl] cyclobutyl }-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 73A

Instead-6-bromo-2-{3-[(2S)-2-(methyl fluoride) tetramethyleneimine-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 43A, replaces the preparation of 4-piperidine carbinols with S (+)-2-fluoromethylpyrrolidderivatives (CAS#460748-85-0, according at R.Alten-bach et al, the preparation of step described in the WO 2004043458).

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝1.70Hz，1H)7.83(d，J＝8.81Hz，1H)7.56(dd，J＝8.65，1.86Hz，1H)4.30-4.46(m，1H)4.14-4.29(m，1H)3.78-3.91(m，1H)3.55-3.70(m，1H)2.98-3.13(m，1H)2.82-2.95(m，1H)2.53-2.72(m，4H)2.39-2.50(m，1H)1.70-1.97(m，2H)1.50-1.59(m，2H).MS：(M+H) ⁺＝369/371.

Embodiment 73B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 73A.

¹H NMR(300MHz，CDCl ₃)δppm9.24(s，1H)9.02(s，2H)8.12(d，J＝8.48Hz，1H)8.06(d，J＝1.70Hz，1H)7.67(dd，J＝8.48，1.70Hz，1H)4.06-4.50(m，1H)3.82-4.03(m，1H)3.54-3.76(m，1H)3.00-3.18(m，1H)2.79-2.95(m，1H)2.55-2.74(m，3H)2.34-2.54(m，1H)1.70-1.97(m，2H)1.45-1.61(m，4H).MS：(M+H) ⁺＝369.

Embodiment 74

Instead-(2S)-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol

Embodiment 74A

Instead-(2S)-1-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl } methyl alcohol

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with S (+)-2-hydroxymethyl pyrrolidine.

¹H NMR(300MHz，CDCl ₃)δppm7.99(d，J＝2.03Hz，1H)7.82(d，J＝8.48Hz，1H)7.57(dd，J＝8.48，2.03Hz，1H)4.05-4.17(m，1H)3.28-3.95(m，5H)2.51-2.87(m，4H)1.70-2.18(m，4H)1.41-1.65(m，2H).MS：(M+H) ⁺＝367/369.

Embodiment 74B

Instead-(2S)-1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] tetramethyleneimine-2-yl] methyl alcohol

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 74A.

¹H NMR(300MHz，CDCl ₃)δppm9.24(s，1H)9.02(s，2H)8.11(d，J＝8.48Hz，1H)8.07(d，J＝2.03′Hz，1H)7.68(dd，J＝8.48，1.70Hz，1H)3.89-4.04(m，1H)3.55-3.74(m，2H)3.26-3.47(m，1H)2.62-2.88(m，4H)2.42-2.60(m，1H)1.72-2.08(m，5H)1.48-1.67(m，2H).MS：(M+H) ⁺＝367.

Embodiment 75

Instead-((2S)-1-{3-[6-(2,6-lutidine-3-yl)-1,3-benzothiazole-2-yl] cyclobutyl } tetramethyleneimine-2-yl) methyl alcohol

Title compound is according to step described in the embodiment 1F, replaces the product of embodiment 1E and prepares with product replacement pyrimidine-5-boric acid of embodiment 2A with the product of embodiment 74A.

¹H NMR(300MHz，CDCl ₃)δppm8.02(d，J＝8.81Hz，1H)7.77(d，J＝1.36Hz，1H)7.45(d，J＝7.80Hz，1H)7.40(dd，J＝8.48，1.70Hz，1H)7.07(d，J＝7.80Hz，1H)3.83-4.00(m，1H)3.52-3.75(m，2H)3.32-3.47(m，1H)2.99-3.17(m，1H)2.63-2.80(m，3H)2.59(s，3H)2.50(s，3H)1.70-2.08(m，5H)1.46-1.65(m，2H).MS：(M+H) ⁺＝394.

Embodiment 76

Instead-2-[3-(pipecoline-1-yl) cyclobutyl]-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 76A

Instead-and 6-bromo-2-[3-(pipecoline-1-yl) cyclobutyl]-1, the 3-benzothiazole

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with pipecoline (CAS#109-05-07).

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝1.70Hz，1H)7.83(d，J＝8.81Hz，1H)7.56(dd，J＝8.65，1.86Hz，1H)3.78-3.90(m，1H)2.81-3.11(m，2H)2.56-2.77(m，4H)1.38-1.93(m，8H)1.24(s，3H).MS：(M+H) ⁺＝365/367.

Embodiment 76B

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 76A.

¹H NMR(500MHz，CDCl ₃)δppm9.24(s，1H)8.99-9.04(m，2H)8.12(d，J＝8.24Hz，1H)8.07(d，J＝1.83Hz，1H)7.68(dd，J＝8.39，1.68Hz，1H)3.78-3.90(m，1H)3.51-3.67(m，1H)2.53-2.80(m，5H)1.61(m，6H)1.35-1.50(m，2H)1.09(s，3H).MS：(M+H) ⁺＝365.

Embodiment 77

Instead-and 2-(the 3-hexahydropyrrolo is [3,4-b] pyrroles-5 (1H)-basic ring butyl also)-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 77A

Instead-and tertiary butyl 5-[3-(6-bromo-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also

Title compound is according to step described in the embodiment 43A, with hexahydropyrrolo also [3,4-b] pyrroles-1-carboxylic acid tert-butyl ester (according to Q.Li et al., J.Med.Chem.; 39 (16), 3070-3088, the preparation of step described in 1996) replace the 4-piperidine carbinols to prepare.

¹H NMR(300MHz，CDCl ₃)δppm7.97(d，J＝1.70Hz，1H)7.82(d，J＝8.81Hz，1H)7.56(dd，J＝8.82，2.03Hz，1H)4.10-4.37(m，2H)3.85-4.02(m，1H)3.49(m 2H)3.11-3.29(m，1H)2.95-3.07(m，1H)2.79-2.94(m，1H)2.31-2.67(m，6H)1.90-2，11(m，1H)1.65-1.86(m，1H)1.46(s，9H).MS：(M+H) ⁺＝478/480.

Embodiment 77B

Instead-and tertiary butyl 5-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] hexahydropyrrolo [3,4-b] pyrroles-1 (2H)-carboxylicesters also

Title compound replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 77A.

¹H NMR(300MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝8.48Hz，1H)8.06(d，J＝1.36Hz，1H)7.67(dd，J＝8.42，1.87Hz，1H)4.15-4.30(m，1H)3.91-4.06(m，2H)3.43(m，3H)3.12-3.26(m，1H)2.79-2.92(m，1H)2.66-2.76(m，1H)2.49-2.62(m，4H)2.31-2.45(m，1H)1.90-2.08(m，1H)1.67-1.83(m，1H)1.44-1.47(m，9H).MS：(M+H) ⁺＝478.

Embodiment 77C

Title compound replaces the product preparation of embodiment 38B according to step described in the embodiment 38C with the product of embodiment 77B.

¹H NMR(300MHz，CDCl ₃)δppm9.23(s，1H)9.01(s，2H)8.11(d，J＝8.81Hz，1H)8.05(d，J＝1.36Hz，1H)7.66(dd，J＝8.48，2.03Hz，1H)3.94-4.06(m，2H)3.55-3.81(m，1H)3.14-3.27(m，2H)3.02-3.15(m，1H)2.75-2.96(m，3H)2.45-2.68(m，6H)1.96-2.13(m，1H)1.67-1.82(m，1H).MS：(M+H) ⁺＝378.

Embodiment 78

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-pyrimidine-5-base-1, the 3-benzothiazole

Embodiment 78A

Instead-and 6-bromo-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-1, the 3-benzothiazole

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with 4-fluorine piperidine hydrochlorate (can buy from ABCR).

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝2.03Hz，1H)7.83(d，J＝8.48Hz，1H)7.56(dd，J＝8.48，2.03Hz，1H)4.73(m，1H)，3.83(m，1H)3.20(m，1H)2.38-2.60(m，6H)1.92(m，4H)1.59(m，2H).MS：(M+H) ⁺＝369/371.

Embodiment 78B

Title compound replaces the product preparation of embodiment 1E according to the step described in the embodiment 1F with the product of embodiment 78A.

¹H NMR(300MHz，CDCl ₃)δppm9.24(s，1H)9.00(s，2H)8.11(d，J＝8.48Hz，1H)8.06(d，J＝1.70Hz，1H)7.67(dd，J＝8.48，1.70Hz，1H)4.65-4.80(m，1H)3.89(m，1H)3.20(m，1H)2.36-2.63(m，8H)1.93(m，4H).MS：(M+H) ⁺＝369.

Embodiment 79

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole

Title compound is used the product of the product replacement embodiment 1E of embodiment 78A according to step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid.

¹NMR(300MHz，CDCl ₃)δppm8.78(s，2H)8.07(d，J＝8.48Hz，1H)7.99(d，J＝1.70Hz，1H)7.61(dd，J＝8.48，1.70Hz，1H)4.71(m，1H)4.09(s，3H)3.90(m，1H)3.23(m，1H)2.62(m，6H)2.35(m，2H)1.93(m，4H).MS：(M+H) ⁺＝399.

Embodiment 80

Instead-and 6-(2,6-lutidine-3-yl)-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-1, the 3-benzothiazole

Title compound is used the product of the product replacement embodiment 1E of embodiment 78A according to the step described in the embodiment 1F, and replaces pyrimidine-5-boric acid preparation with the product of embodiment 2A.

¹H NMR(300MHz，CDCl ₃)δppm8.02(d，J＝8.48Hz，1H)7.77(d，J＝1.70Hz，1H)7.46(d，J＝7.80Hz，1H)7.40(dd，J＝8.48，1.70Hz，1H)7.07(d，J＝7.80Hz，1H)4.65-4.80(m，1H)3.89(m，1H)3.21(m，1H)2.36-2.63(m，8H)2.59(s，3H)2.50(s，3H)1.86-2.05(m，4H).MS：(M+H) ⁺＝396.

Embodiment 81

Instead-(3R)-and 1-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] piperidines-3-alcohol

Embodiment 81A

Suitable-3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutanol

Product (the 100mg of embodiment 1D, 0.35mmol), pyrimidine-5-boric acid (65mg, 0.53mmol), dichloro two (triphenyl phosphine) closes palladium (II) (14.8mg, 0.0021mmol), 2-(dicyclohexyl phosphino-) biphenyl (7.4mg, 0.021mmol), yellow soda ash (1M solution, 0.53ml, 0.53mmol) and 2ml ethanol/diox (1: 1) at N ₂In the air-tight bottle of tool lid, mix under the gas.With the bottle sealing, in commercial microwave oven (that is Emrys Creator), heated 10 minutes in 140 ℃.The quencher of reaction mixture water is with methylene dichloride (4 * 5ml) extractions.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrating under reduced pressure, and the crude product that obtains obtains 80.4mg (productive rate 84.6%) title compound with column chromatography (10% ethanol/methylene) purifying.

¹H NMR(300MHz，CDCl ₃)δppm9.25(s，1H)，9.03(s，2H)，8.14(d，J＝8.48Hz，1H)，8.07(d，J＝1.70Hz，1H)，7.67(dd，J＝8.48，2.03Hz，1H)，4.40(m，1H)，3.50(m，1H)，3.01(m，2H)，2.46(m，2H)，2.17(br s，1H).MS：(M+H) ⁺＝284.

Embodiment 81B

Title compound replaces the 4-piperidine carbinols according to step described in the embodiment 43A with (R)-3-hydroxyl piperidine hydrochloric acid salt (CAS#198976-43-1), and replaces embodiment 1D preparation with embodiment 81A.

¹H NMR(300MHz，CDCl ₃)δppm9.28(s，1H)9.11(s，2H)8.12(d，J＝9.0Hz，1H)8.10(s，1H)7.71(d，J＝9.0Hz，1H)4.28(m，1H)3.96(m，1H)3.83(m，1H)3.65(m，2H)3.50(m，2H)3.34-2.51(m，6H)2.60-1.07(m，4H).MS：(M+H) ⁺＝367.

Embodiment 82

Instead-and N-ethyl-N-propyl group-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine

Title compound replaces the 4-piperidine carbinols and replaces embodiment 1D preparation with embodiment 81A with N-ethyl-N-propylamine according to step described in the embodiment 43A.

¹H NMR(300MHz，CDCl ₃)δppm9.27(s，1H)9.07(s，2H)8.12(d，J＝9.0Hz，1H)8.11(s，1H)7.71(d，J＝9.0Hz，1H)4.14(m，1H)4.00(m，1H)3.22(m，1H)3.10(m，2H)2.90-2.73(m，4H)1.77(m，2H)1.36(t，3H)1.04(t，3H).MS：(M+H) ⁺＝353.

Embodiment 83

Instead-diethyl-[3-(6-pyrimidine-5-base benzothiazole-2-yl) cyclobutyl] amine

Embodiment 83A

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] diethylamine

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with diethylamine.1H NMR(300MHz，CDCl ₃)

δppm7.98(d，J＝2.03Hz，1H)，7.83(d，J＝8.82Hz，1H)，7.56(dd，J＝8.65，1.86Hz，1H)，3.74-3.87(m，1H)，3.53-3.70(m，1H)，2.45-2.82(m，6H)1.56(m，2H)1.00-1.17(m，6H).(M+H) ⁺＝341/343.

Embodiment 83B

Instead-diethyl-[3-(6-pyrimidine-5-base benzothiazole-2-yl) cyclobutyl] amine

Title compound replaces embodiment 1D preparation according to step described in the embodiment 81A with embodiment 83A.1H NMR(400MHz，CDCl ₃)

δppm9.23(s，1H)，9.01(s，2H)，8.12(d，J＝8.29Hz，1H)，8.06(d，J＝1.84Hz，1H)，7.67(dd，J＝8.59，1.84Hz，1H)，3.81-3.91(m，1H)，3.55-3.68(m，1H)，2.57-2.75(m，8H)，1.06(t，J＝6.90Hz，6H).MS：(M+H) ⁺＝339.

Embodiment 84

Instead-diethyl-3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } amine

Title compound replaces embodiment 1D and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid with embodiment 83A according to step described in the embodiment 81A.1H NMR(400MHz，CDCl ₃)

d ppm8.77(s，2H)，8.07(d，J＝8.29Hz，1H)，7.98(d，J＝1.84Hz，1H)，7.60(dd，J＝8.44，1.69Hz，1H)，4.09(s，3H)，3.79-3.91(m，1H)，3.55-3.67(m，1H)，2.53-2.80(m，8H)1.06(t，J＝6.90Hz，6H).MS：(M+H) ⁺＝369.

Embodiment 85

Instead-3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } the methyl propylamine

Embodiment 85A

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] methyl propylamine

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with N-methyl-N-propylamine.1H NMR(400MHz，CDCl ₃)

δppm7.97(d，J＝1.84Hz，1H)，7.82(d，J＝8.90Hz，1H)，7.55(dd，J＝8.75，1.99Hz，1H)，3.74-3.83(m，1H)，3.15-3.27(m，1H)，2.56(t，J＝7.06Hz，4H)，2.20-2.28(m，2H)，2.16(s，3H)，1.46-1.56(m，2H)，0.91(t，J＝7.36Hz，3H).MS：(M+H) ⁺＝339/341.

Embodiment 85B

Title compound replaces embodiment 1D according to step described in the embodiment 81A with embodiment 85A, and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid.1H NMR(400MHz，CDCl ₃)

δppm8.77(s，2H)，8.07(d，J＝8.59Hz，1H)，7.98(d，J＝1.84Hz，1H)，7.60(dd，J＝8.29，1.84Hz，1H)，4.08(s，3H)，3.80-3.90(m，1H)，3.22-3.32(m，1H)，2.57-2.66(m，4H)，2.24-2.32(m，2H)，2.19(s，3H)，1.48-1.59(m，2H)，0.92(t，J＝7.36Hz，3H).MS：(M+H) ⁺＝369.

Embodiment 86

Instead-3-[6-(2,6-lutidine-3-yl) benzothiazole-2-yl] cyclobutyl } methyl-propyl amine

Title compound is according to step described in the embodiment 81A, replaces embodiment 1D and replaces pyrimidine-5-boric acid to prepare with the product of embodiment 2A with embodiment 85A.1H NMR(500MHz，CDCl ₃)

δppm8.02(d，J＝8.54Hz，1H)，7.77(d，J＝1.22Hz，1H)，7.46(d，J＝7.93Hz，1H)，7.40(dd，J＝8.24，1.83Hz，1H)，7.07(d，J＝7.63Hz，1H)，3.82-3.91(m，1H)，3.27-3.41(m，1H)，2.68-2.77(m，2H)，2.61-2.67(m，2H)，2.59(s，3H)，2.50(s，3H)，2.31-2.39(m，2H)，2.25(s，3H)，1.53-1.63(m，2H)，0.94(t，J＝7.32Hz，3H).(M+H) ⁺＝366.

Embodiment 87

Instead-methyl-3-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzothiazole-2-yl] cyclobutyl } propylamine

Title compound is according to step described in the embodiment 81A, replaces embodiment 1D and with 1-methyl-4-(4 with embodiment 85A, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles (can buy) replacement pyrimidine-5-boric acid preparation from Boron Molecular.1H NMR(400MHz，CDCl ₃)

δppm7.94(d，J＝8.59Hz，1H)，7.92(d，J＝1.23Hz，1H)，7.80(s，1H)，7.65(s，1H)，7.56(dd，J＝8.59，1.84Hz，1H)，3.97(s，3H)，3.79-3.89(m，1H)，3.26-3.42(m，1H)，2.56-2.78(m，4H)，2.31-2.41(m，2H)，2.26(s，3H)，1.53-1.64(m，2H)，0.94(t，J＝7.36Hz，3H).(M+H) ⁺＝341.

Embodiment 88

Instead-2-(ethyl-and 3-[6-(2-methoxy pyrimidine-5-yl) benzothiazole-2-yl] cyclobutyl } amino) ethanol

Embodiment 88A

Instead-and 2-{[3-(6-bromo benzothiazole-2-yl) cyclobutyl] ethylamino } ethanol

Title compound replaces the preparation of 4-piperidine carbinols according to step described in the embodiment 43A with 2-(ethylamino) ethanol.1H NMR(400MHz，CDCl ₃)

δppm7.98(d，J＝2.15Hz，1H)，7.83(d，J＝8.59Hz，1H)，7.56(dd，J＝8.75，1.99Hz，1H)，3.72-3.80(m，1H)，3.62-3.71(m，1H)，3.58(t，J＝5.37Hz，2H)，2.53-2.68(m，8H)，1.03(t，J＝7.06Hz，3H).(M+H) ⁺＝355/357.

Embodiment 88B

Title compound replaces embodiment 1D and replaces pyrimidine-5-boric acid preparation with 2-methoxy pyrimidine-5-boric acid with embodiment 88A according to step described in the embodiment 81A.1H NMR(400MHz，CDCl ₃)

δppm8.77(s，2H)，8.07(d，J＝8.29Hz，1H)，7.98(d，J＝1.53Hz，1H)，7.60(dd，J＝8.29，1.84Hz，1H)，4.09(s，3H)，3.78-3.88(m，1H)，3.65-3.76(m，1H)，3.60(t，J＝5.52Hz，2H)，2.53-2.71(m，8H)，1.05(t，J＝7.21Hz，3H).MS：(M+H) ⁺＝385.

Embodiment 89

Instead-2-(3-[6-(2,6-lutidine-3-yl) benzothiazole-2-yl] and cyclobutyl } ethylamino) ethanol

Title compound is according to step described in the embodiment 81A, replaces embodiment 1D and replaces pyrimidine-5-boric acid to prepare with the product of embodiment 2A with embodiment 88A.1H NMR(500MHz，CDCl ₃)

δppm8.02(d，J＝8.54Hz，1H)，7.77(d，J＝1.22Hz，1H)，7.46(d，J＝7.63Hz，1H)，7.41(dd，J＝8.24，1.53Hz，1H)，7.07(d，J＝7.93Hz，1H)，3.78-3.90(m，2H)，3.71{t，J＝5..03Hz，2H)，2.79-2.88(m，4H)，2.75-2.79(m，2H)，2.65-2.71(m，2H)，2.59(s，3H)，2.50(s，3H)，1.14(t，J＝7.17Hz，3H).MS：(M+H) ⁺＝382.

Embodiment 90

6-pyrimidine-5-base-2-(3-tetramethyleneimine-1-ylmethyl cyclobutyl) benzothiazole

Embodiment 90A

[3-(6-bromo benzothiazole-2-yl) cyclobutyl] methyl alcohol

(600.o mg 2.14mmol) is dissolved among the 4ml THF, is cooled to 0 ℃, to wherein adding BH with the product of embodiment 1B ₃(1M THF solution, 5.35ml 5.35mmol), is warmed to room temperature with mixture to THF, stirs 2 hours postcooling to 0 ℃, dropwise adds 30%H successively ₂O ₂(2.5ml) with 3M NaOH.Mixture slowly is warmed to room temperature, stirred 5 hours.With salt solution quencher reaction, use dichloromethane extraction 3 times, the organic phase of merging is washed with sodium sulfite solution and salt, use dried over sodium sulfate, filter and concentrate, obtain crude product, it with chromatography (5% ethanol/methylene) purifying, is obtained title compound (268.9mg, 42.1%).

¹H NMR(300MHz，CDCl ₃)7.98(d，J＝2.0Hz，1H)7.83(d，J＝8.8Hz，1H)7.56(dd，J＝8.7，1.9Hz，1H)3.79(m，2H)3.66(m，1H)2.55-2.70(m，3H)2.42(m，1H)2.26(m，1H).MS：(M+H) ⁺＝298/300.

Embodiment 90B

6-bromo-2-(3-tetramethyleneimine-1-ylmethyl cyclobutyl) benzothiazole

Title compound still replaces the 4-piperidine carbinols and replaces embodiment 1D preparation with embodiment 90A with tetramethyleneimine according to step described in the embodiment 43A.

¹H NMR(300MHz，CDCl ₃)δppm7.98(d，J＝2.03Hz，1H)7.82(d，J＝8.48Hz，1H)7.56(dd，J＝8.48，2.03Hz，1H)3.81-3.94(m，3H)3.25-3.35(m，3H)2.76-2.92(m，4H)2.09-2.57(m，6H).MS：(M+H) ⁺＝351/353.

Embodiment 90C

Title compound still replaces the product preparation of embodiment 1E according to step described in the embodiment 1F with the product of embodiment 90B.MS：(M+H) ⁺＝351。

Embodiment 91

Instead-and 5-(2,6-lutidine-3-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole

Embodiment 91A

2-amino-4-chlorobenzene mercaptan

Title compound replaces the preparation of 6-bromo-2-[4-morpholinodithio quinoline ketone according to step described in the embodiment 1A with 5-chloro-2-[4-morpholinodithio quinoline ketone.

1H NMR (300MHz, CHLOROFORM-D) δ ppm7.03 (d, J=8.48Hz, 1H), 6.71 (d, J=2.03Hz, 1H), 6.56 (dd, J=8.31,2.20Hz, 1H), 4.43 (br, 2H) .MS:(M+H) ⁺=160, (M+H) ⁺=316 (dimers).

Embodiment 91B

5-chloro-2-(3-methylene radical cyclobutyl) benzothiazole

Title compound replaces 1A preparation (productive rate 42%) according to step described in the embodiment 1B with 91A.

1H NMR(500MHz，CHLOROFORM-D)δppm7.96(d，J＝2.18Hz，1H)，7.75(d，J＝8.42Hz，1H)，7.33(dd，J＝8.58，2.03Hz，1H)，4.88-4.95(m，1H)，4.76-4.82(m，1H)，3.90-4.00(m，1H)，3.14-3.30(m，2H)，2.90-3.12(m，2H).(M+H) ⁺＝236.

Embodiment 91C

3-(5-chloro benzothiazole-2-yl) cyclobutanone

Title compound replaces the preparation of embodiment 1B product according to step described in the embodiment 1C with embodiment 91B product.

1H NMR(500MHz，CHLOROFORM-D)δppm7.99(d，J＝1.87Hz，1H)，7.77(d，J＝8.42Hz，1H)，7.37(dd，J＝8.58，2.03Hz，1H)，4.00-4.11(m，1H)，3.56-3.75(m，4H).(M+H) ⁺＝238.

Embodiment 91D

Suitable-3-(5-chloro benzothiazole-2-yl) cyclobutanol

Title compound replaces the preparation of embodiment 1C product according to step described in the embodiment 1D with embodiment 91C product.The not purified next step that is used for of crude product.

Embodiment 91E

Instead-and 5-chloro-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole

Title compound replaces the 1D preparation according to the step described in the embodiment 1E with 91D.

1H NMR(500MHz，CHLOROFORM-D)δppm7.98(d，J＝1.83Hz，1H)，7.75(d，J＝8.54Hz，1H)，7.33(dd，J＝8.54，2.14Hz，1H)，3.78-3.88(m，1H)，3.44-3.56(m，1H)，3.01-3.11(m，1H)，2.62-2.81(m，3H)，2.44-2.58(m，2H)，2.25-2.37(m，1H)，1.91-2.01(m，1H)，1.78-1.88(m，1H)，1.67-1.76(m，1H)，1.43-1.54(m，1H)，1.13(d，J＝5.80Hz，3H).(M+H) ⁺＝307.

Embodiment 91F

In the bottle of a 4ml, add embodiment 91E product (30mg, 0.098mmol), Potassium monofluoride (19mg, 0.323mmol) and three (dibenzalacetones) close two palladiums (5.3mg, 0.0075mmol), under vacuum dry 30 minutes.Under nitrogen atmosphere, add successively embodiment 2A product (34mg, 0.147mmol) and dioxan (1ml).(10wt% hexane solution, 45 μ L 0.0147mmol), with the bottle sealing, 85 ℃ of heated overnight, heated 7 hours at 95 ℃ then to add tri-butyl phosphine at last.TLC (condition: 1% ammonium hydroxide and 10% ethanol/methylene, on the silica gel) demonstrates the new stigma except that raw material.Dichloromethane extraction 3 times are used in water quencher reaction.The organic layer that merges is washed with salt, uses dried over sodium sulfate, filters and concentrates.Crude product obtains 6mg (productive rate 16%) title compound with column chromatography (with 0.35% ammonium hydroxide and 3.5% ethanol/methylene wash-out) purifying.

1H NMR(300MHz，CHLOROFORM-D)δppm7.93(d，J＝1.36Hz，1H)，7.89(d，J＝8.14Hz，1H)，7.47(d，J＝7.80Hz，1H)，7.30(dd，J＝8.48，1.70Hz，1H)，7.08(d，J＝7.80Hz，1H)，3.80-3.94(m，1H)，3.46-3.60(m，1H)，3.02-3.15(m，1H)，2.66-2.84(m，3H)，2.60-2.61(s，3H)，2.50-2.54(s，3H)，2.26-2.40(m，2H)，1.62-2.04(m，4H)，1.43-1.58(m，1H)，1.15(d，J＝5.76Hz，3H).(M+H) ⁺＝378.

Embodiment 92

Instead-and 5-(2,4-dimethoxypyridin-5-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole

Title compound is according to the step described in the embodiment 91F, and with 2,6-dimethoxy-5-pyrimidine boric acid replaces embodiment 2A preparation.

1H NMR(400MHz，CHLOROFORM-D)δppm8.34(s，1H)，8.13(s，1H)，7.89(d，J＝8.29Hz，1H)，7.48(dd，J＝8.29，1.84Hz，1H)，4.06(s，3H)，4.05(s，3H)，3.81-3.92(m，1H)，3.46-3.61(m，1H)，2.99-3.17(m，1H)，2.63-2.86(m，3H)，2.48-2.62(m，2H)，2.27-2.41(m，1H)，1.45-2.03(m，4H)，1.14(s，3H).(M+H) ⁺＝411.

Embodiment 93

Instead-and 6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl] benzothiazole

Title compound replaces the preparation of embodiment 44 products according to step described in the embodiment 51A-C with embodiment 1E product.

1H NMR(400MHz，CHLOROFORM-D)d ppm7.90-7.98(m，2H)7.80(s，1H)7.65(s，1H)7.56(dd，J＝8.44，1.69Hz，1H)3.97(s，3H)3.80-3.92(m，1H)3.50-3.63(m，1H)3.01-3.22(m，1H)2.67-2.89(m，2H)2.50-2.64(m，2H)2.31-2.45(m，1H)1.93-2.04(m，1H)1.81-1.91(m，1H)1.65-1.81(m，2H)1.46-1.58(m，1H)1.17(d，J＝4.60Hz，3H).(M+H) ⁺＝353.

Embodiment 94

Instead-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-6-(1-methyl isophthalic acid H-pyrazoles-4-yl) benzothiazole

Title compound replaces the preparation of embodiment 44A product according to step described in the embodiment 51A-C with embodiment 78A product.

1H NMR(400MHz，CHLOROFORM-D)d ppm7.88-7.98(m，2H)7.80(s，1H)7.65(s，1H)7.56(d，J＝8.29Hz，1H)4.60-4.80(m，1H)3.97(s，3H)3.76-3.89(m，1H)3.11-3.24(m，1H)2.44-2.65(m，5H)2.25-2.39(m，2H)1.80-2.04(m，3H)1.52-1.62(m，2H).(M+H) ⁺＝371.

Embodiment 95

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, but replaces the product of embodiment 1E with the product of embodiment 61A, and with 2-methoxy pyrimidine-5-boric acid (Frontier Scientific, Inc., Logan, UT USA) replaces pyrimidine-5-boric acid to prepare.

1H NMR(300MHz，CDCl ₃)δppm8.77(s，2H)8.07(d，J＝8.48Hz，1H)7.97(d，J＝2.03Hz，1H)7.59(dd，J＝8.48，2.03Hz，1H)4.08(s，3H)3.93-4.06(m，1H)3.18-3.34(m，5H)2.49-2.61(m，1H)2.34-2.47(m，3H)2.03-2.19(m，2H).MS：(M+H) ⁺＝353.

Embodiment 96

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(2,6-lutidine-3-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, but replaces the product of embodiment 1E and with embodiment 2A product (2 with the product of embodiment 61A, 6-dimethyl-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycles, penta-2-yl) pyridine) replaces pyrimidine-5-boric acid preparation.

¹H NMR(300MHz，CDCl ₃)δppm8.01(d，J＝8.48Hz，1H)7.75(d，J＝1.36Hz，1H)7.45(d，J＝7.80Hz，1H)7.39(dd，J＝8.48，1.70Hz，1H)7.06(d，J＝7.80Hz，1H)3.96-4.08(m，1H)3.19-3.40(m，5H)2.59(s，3H)2.49(s，3H)2.37-2.56(m，4H)2.07-2.19(m，2H).MS：(M+H) ⁺＝350.

Embodiment 97

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, and still the product with embodiment 61A replaces embodiment 1E product and replaces pyrimidine-5-boric acid preparation with 1-methyl-4-1H-pyrazoles boric acid pinacol ester.

¹H NMR(300MHz，CDCl ₃)δppm7.89-7.97(m，2H)7.80(s，1H)7.65(s，1H)7.55(dd，J＝8.31，1.86Hz，1H)3.97(s，3H)3.92-4.07(m，1H)3.21-3.45(m，5H)2.36-2.62(m，4H)2.06-2.24(m，2H).MS：(M+H) ⁺＝325.

Embodiment 98

Instead-and 2-(3-azepan-1-basic ring butyl)-6-(2-methoxy pyrimidine-5-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, but with the product of embodiment 71A replace embodiment 1E product and with 2-methoxy pyrimidine-5-boric acid (Frontier Scientific, Inc., Logan, UT USA) replaces pyrimidine-5-boric acid to prepare.

¹H NMR(500MHz，CDCl ₃)δppm8.78(s，2H)8.07(d，J＝8.24Hz，1H)7.98(d，J＝1.83Hz，1H)7.59(dd，J＝8.39，1.68Hz，1H)4.09(s，3H)3.78-3.86(m，1H)3.33-3.44(m，1H)2.45-2.65(m，8H)1.58-1.75(m，8H).MS：(M+H) ⁺＝395.

Embodiment 99

Instead-and 2-(3-azepan-1-basic ring butyl)-6-(2,6-lutidine-3-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, but replaces the product of embodiment 1E and with embodiment 2A product (2 with the product of embodiment 71A, 6-dimethyl-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycles, penta-2-yl) pyridine) replaces pyrimidine-5-boric acid preparation.

¹H NMR(500MHz，CDCl ₃)δppm8.02(d，J＝8.54Hz，1H)7.76(d，J＝1.53Hz，1H)7.46(d，J＝7.63Hz，1H)7.39(dd，J＝8.24，1.83Hz，1H)7.07(d，J＝7.63Hz，1H)3.78-3.86(m，1H)3.32-3.43(m，1H)2.59(s，6H)2.45-2.56(m，8H)1.58-1.73(m，8H).MS：(M+H) ⁺＝392.

Embodiment 100

Instead-and 2-(3-azepan-1-basic ring butyl)-6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1, the 3-benzothiazole

Title compound is according to step described in the embodiment 1F, and still the product with embodiment 71A replaces embodiment 1E product and replaces pyrimidine-5-boric acid preparation with 1-methyl-4-1H-pyrazoles boric acid pinacol ester.

¹H NMR(500MHz，CDCl ₃)δppm7.89-7.97(m，2H)7.80(s，1H)7.65(s，1H)7.55(dd，J＝8.39，1.68Hz，1H)3.97(s，3H)3.74-3.83(m，1H)3.30-3.41(m，1H)2.46-2.61(m，8H)1.56-1.71(m，8H).MS：(M+H) ⁺＝367.

Embodiment 101

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] ethanamide

Embodiment 101A

Suitable-2-(3-piperidines-1-basic ring butyl) benzothiazole-6-base amine

Embodiment 44A is (anti--6-bromo-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole) (658mg, 1.875mmol), three (dibenzalacetones) close two palladiums (O) (34mg, 0.037mmol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (BINAP, 70mg, 0.113mmol) and sodium tert-butoxide (249mg 2.62mmol) packs into and seals in the pipe.This system was vacuumized 2 hours and charged into nitrogen.Add successively toluene (10ml) and benzophenone imine (409mg, 377 μ L, 2.25mmol).With the pipe of sealing in oil bath (95 ℃ of temperature) internal heating 18 hours.TLC (condition: 0.5% ammonium hydroxide and 5% ethanol/methylene, on the silica gel) confirm to react completely, two new spots are arranged.Water quencher reaction, mixture dichloromethane extraction 3 times.The organic layer drying (is used Na ₂SO ₄), filter and concentrating under reduced pressure, obtain the benzophenone imine crude product.This crude product is dissolved among tetrahydrofuran (THF) (10ml) and the 2N HCl (4ml).Stirred this mixture 2 hours under the room temperature.TLC (condition: 0.5% ammonium hydroxide and 5% ethanol/methylene, on the silica gel) indicate initiator (imines) to change into two kinds of new products fully.This mixture with 2N NaOH (6ml) alkalization, is used dichloromethane extraction 3 times.With organic layer drying (Na ₂SO ₄), filter and concentrating under reduced pressure, obtain crude product.This crude product column chromatography (0.4% ammonium hydroxide and 4% ethanol/methylene) purifying.The Rf value is 0.3 product of (TLC condition: 0.5% ammonium hydroxide and 5% ethanol/methylene, on the silica gel) is corresponding to cis-product (270mg).

¹H NMR(300MHz，CDCl ₃)δppm7.71(d，J＝8.82Hz，1H)7.08(d，J＝2.03Hz，1H)6.79(dd，J＝8.82，2.37Hz，1H)3.75(s，2H)3.42-3.57(m，1H)2.68-2.82(m，1H)2.55-2.69(m，2H)2.16-2.39(m，6H)1.52-1.65(m，4H)1.39-1.51(m，2H).MS：(M+H) ⁺＝288.

Embodiment 101B

Instead-2-(3-piperidines-1-basic ring butyl) benzothiazole-6-base amine

In above preparation, the Rf value is that 0.2 product (TLC condition: 0.5% ammonium hydroxide and 5% ethanol/methylene, on the silica gel) is corresponding to trans-isomer(ide) (100mg).

¹H NMR(300MHz，CDCl ₃)δppm7.74(d，J＝8.82Hz，1H)7.09(d，J＝2.37Hz，1H)6.80(dd，J＝8.65，2.20Hz，1H)3.67-3.83(m，3H)2.99-3.15(m，1H)2.46-2.60(m，4H)2.21-2.38(m，4H)1.53-1.68(m，4H)1.39-1.51(m，2H).MS：(M+H) ⁺＝288.

Embodiment 101C

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] ethanamide

With the product of embodiment 101A (20mg 0.070mmol) is dissolved in anhydrous methylene chloride (1.5ml), add triethylamine (35.6mg, 49 μ L, 0.35mmol) and Acetyl Chloride 98Min. (10 μ L, 0.14mmol).Mixture at room temperature stirred spend the night, then dilute with water.Water layer dichloromethane extraction, the organic layer of merging concentrate and obtain crude product.Crude product with column chromatography (0.5% ammonium hydroxide and 5% ethanol/methylene) purifying, is obtained title compound.

¹H NMR(500MHz，CDCl ₃)δppm8.39(d，J＝2.14Hz，1H)7.84(d，J＝8.54Hz，1H)7.37(s，1H)7.22(dd，J＝8.85，2.14Hz，1H)3.48-3.59(m，1H)2.72-2.83(m，1H)2.60-2.70(m，2H)2.24-2.39(m，6H)2.21(s，3H)1.54-1.64(m，4H)1.40-1.51(m，2H).MS：(M+H) ⁺＝330.

Embodiment 102

Suitable-2-chloro-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] ethanamide

Title compound is according to step described in the embodiment 101C, with the preparation of chloroacetyl chloride replacing acetyl chloride.

¹HNMR(500MHz，CDCl ₃)δppm8.38(d，J＝1.83Hz，1H)8.36(s，1H)7.90(d，J＝8.85Hz，1H)7.35(dd，J＝8.85，2.14Hz，1H)4.23(s，2H)3.49-3.61(m，1H)2.74-2.84(m，1H)2.61-2.72(m，2H)2.20-2.41(m，6H)1.54-1.63(m，4H)1.40-1.52(m，2H).MS：(M+H) ⁺＝364.

Embodiment 103

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide

Title compound is according to step described in the embodiment 101C, with the preparation of propionyl chloride replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm8.43(s，1H)7.84(d，J＝8.54Hz，1H)7.30(d，1H)7.23(dd，J＝8.54，2.14Hz，1H)3.48-3.60(m，1H)2.72-2.84(m，1H)2.61-2.70(m，2H)2.43(q，J＝7.53Hz，2H)2.22-2.38(m，6H)1.54-1.64(m，4H)1.39-1.51(m，2H)1.27(t，J＝7.63Hz，3H).MS：(M+H) ⁺＝344.

Embodiment 104

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyramide

Title compound is according to step described in the embodiment 101C, with the preparation of isobutyryl chloride replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.85(d，J＝8.54Hz，1H)7.29(s，1H)7.23(dd，J＝8.85，2.14Hz，1H)3.48-3.58(m，1H)2.71-2.82(m，1H)2.61-2.70(m，2H)2.48-2.59(m，1H)2.22-2.39(m，6H)1.54-1.64(m，4H)1.39-1.51(m，2H)1.28(d，J＝7.02Hz，6H).MS：(M+H) ⁺＝358.

Embodiment 105

Suitable-cyclopropane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound prepares for Acetyl Chloride 98Min. with the cyclopropane carbonyl chloro according to step described in the embodiment 101C.

1H NMR(500MHz，CDCl ₃)δppm8.42(s，1H)7.84(d，J＝8.54Hz，1H)7.56(s，1H)7.24(dd，J＝8.70，1.98Hz，1H)3.48-3.58(m，1H)2.73-2.81(m，1H)2.60-2.70(m，2H)2.23-2.39(m，6H)1.56-1.64(m，4H)1.49-1.56(m，1H)1.40-1.49(m，2H)1.08-1.15(m，2H)0.83-0.91(m，2H).MS：(M+H) ⁺＝356.

Embodiment 106

Suitable-cyclobutane-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound prepares for Acetyl Chloride 98Min. with tetramethylene carbonyl chloro according to step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝2.14Hz，1H)7.84(d，J＝8.85Hz，1H)7.22(dd，J＝8.54，2.14Hz，1H)7.15(s，1H)3.48-3.60(m，1H)3.13-3.23(m，1H)2.72-2.83(m，1H)2.61-2.70(m，2H)2.37-2.46(m，2H)2.19-2.36(m，8H)1.89-2.09(m，2H)1.54-1.64(m，4H)1.40-1.50(m，J＝4.88Hz，2H).MS：(M+H) ⁺＝370.

Embodiment 107

Suitable-Cyclopentane carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound prepares for Acetyl Chloride 98Min. with pentamethylene carbonyl chloro according to step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝2.14Hz，1H)7.84(d，J＝8.54Hz，1H)7.32(s，1H)7.22(dd，J＝8.85，2.14Hz，1H)3.48-3.60(m，1H)2.61-2.83(m，4H)2.22-2.40(m，6H)1.87-2.01(m，4H)1.78-1.86(m，2H)1.55-1.68(m，6H)1.40-1.50(m，2H).MS：(M+H) ⁺＝384.

Embodiment 108

Suitable-hexahydrobenzoic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound prepares for Acetyl Chloride 98Min. with hexanaphthene carbonyl chloro according to step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.84(d，J＝8.85Hz，1H)7.30(s，1H)7.22(dd，J＝8.54，2.14Hz，1H)3.47-3.59(m，1H)2.72-2.81(m，1H)2.61-2.70(m，2H)2.21-2.40(m，6H)1.93-2.02(m，2H)1.82-1.90(m，2H)1.67-1.74(m，1H)1.52-1.64(m，6H)1.40-1.50(m，2H)1.21-1.40(m，4H).MS：(M+H) ⁺＝384.

Embodiment 109

Suitable-furans-the 2-carboxylic acid [2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound is according to step described in the embodiment 101C, with the preparation of 2 furoyl chloride replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm8.53(d，J＝2.14Hz，1H)8.19(s，1H)7.90(d，J＝8.54Hz，1H)7.54(s，1H)7.40(dd，J＝8.70，2.29Hz，1H)7.24-7.31(m，1H)6.58(dd，J＝3.51，1.68Hz，1H)3.50-3.62(m，1H)2.74-2.83(m，1H)2.61-2.71(m，2H)2.24-2.41(m，6H)1.55-1.64(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝382.

Embodiment 110

Suitable-4-cyano group-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] benzamide

Title compound is according to step described in the embodiment 101C, with the preparation of 4-cyano-benzoyl chloride replacing acetyl chloride.

¹H NMR(400MHz，CDCl ₃)δppm8.50(d，J＝2.15Hz，1H)7.96-8.02(m，3H)7.92(d，J＝8.59Hz，1H)7.81(d，J＝8.59Hz，2H)7.39(dd，J＝8.75，2.30Hz，1H)3.49-3.62(m，1H)2.73-2.85(m，1H)2.62-2.73(m，2H)2.24-2.38(m，6H)1.54-1.64(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝417.

Embodiment 111

Suitable-4-cyano group-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] benzsulfamide

Title compound is according to the preparation of step described in the embodiment 101C, still with 4-cyano group benzene sulfonyl chloride replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm8.07(d，J＝8.54Hz，2H)7.94(d，J＝8.54Hz，1H)7.87-7.91(m，3H)7.51(d，J＝2.14Hz，1H)7.02(dd，J＝8.54，2.14Hz，1H)3.57-3.64(m，1H)2.76-2.86(m，1H)2.64-2.75(m，2H)2.24-2.41(m，6H)1.56-1.65(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝453.

Embodiment 112

Suitable-thiophene-2-sulfonic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound prepares described in embodiment 101C, but uses thiophene-2-SULPHURYL CHLORIDE replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm7.91(d，J＝8.85Hz，1H)7.79(dd，J＝3.97，1.22Hz，1H)7.75(dd，J＝5.03，1.37Hz，1H)7.63(d，J＝2.14Hz，1H)7.16(dd，J＝5.03，3.81Hz，2H)7.12(dd，J＝8.54，2.14Hz，1H)3.53-3.64(m，1H)2.75-2.83(m，1H)2.62-2.73(m，2H)2.23-2.39(m，6H)1.55-1.63(m，4H)1.40-1.51(m，2H).MS：(M+H) ⁺＝434.

Embodiment 113

Suitable-thiophene-2-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces Acetyl Chloride 98Min. with 2-thiophene carbonyl chloro according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.49(d，J＝2.14Hz，1H)7.90(d，J＝8.54Hz，1H)7.81(s，1H)7.63-7.69(m，1H)7.55-7.59(m，1H)7.37(dd，J＝8.54，2.14Hz，1H)7.15(dd，J＝5.03，3.81Hz，1H)3.50-3.60(m，1H)2.73-2.83(m，1H)2.61-2.72(m，2H)2.23-2.39(m，6H)1.55-1.63(m，4H)1.41-1.50(m，2H).MS：(M+H) ⁺＝398.

Embodiment 114

Title compound is according to the preparation of step described in the embodiment 101C, still with 2-thiophen acetyl chloride replacing acetyl chloride.

¹H NMR(500MHz，CDCl ₃)δppm8.33(d，J＝1.83Hz，1H)7.82(d，J＝8.54Hz，1H)7.44(s，1H)7.33(dd，J＝4.58，1.83Hz，1H)7.15(dd，J＝8.54，2.14Hz，1H)7.01-7.09(m，2H)3.98(s，2H)3.47-3.58(m，1H)2.71-2.82(m，1H)2.64(m，2H)2.21-2.38(m，6H)1.52-1.65(m，4H)1.45(s，2H).MS：(M+H) ⁺＝412.

Embodiment 115

Suitable-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyl carbamate

Title compound is still used the isobutyl chlorocarbonate replacing acetyl chloride according to the preparation of step described in the embodiment 101C.

¹HNMR(500MHz，CDCl ₃)δppm8.18(s，1H)7.84(d，J＝8.54Hz，1H)7.19(dd，J＝8.85，2.14Hz，1H)6.72(s，1H)3.98(d，J＝6.71Hz，2H)3.48-3.59(m，1H)2.72-2.82(m，1H)2.61-2.70(m，2H)2.22-2.38(m，6H)1.94-2.05(m，1H)1.54-1.64(m，4H)1.41-1.51(m，2H)0.98(d，J＝6.71Hz，6H).MS：(M+H) ⁺＝388.

Embodiment 116

Suitable-morpholine-the 4-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces Acetyl Chloride 98Min. with 4-morpholine carbonyl chloro according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.15(d，J＝2.14Hz，1H)7.82(d，J＝8.85Hz，1H)7.17(dd，J＝8.85，2.14Hz，1H)6.51(s，1H)3.72-3.79(m，4H)3.49-3.53(m，4H)3.36-3.44(m，1H)2.72-2.80(m，1H)2.60-2.69(m，2H)2.20-2.39(m，6H)1.54-1.62(m，4H)1.39-1.51(m，2H).MS：(M+H) ⁺＝401.

Embodiment 117

Suitable-pyrazine-the 2-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Product (59mg with embodiment 101A, 0.206mmol) be dissolved in the anhydrous methylene chloride (2.0ml), add 2-pyrazine carboxylic acid (51mg, 0.412mmol), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (79mg, 0.412mmol) and the I-hydroxybenzotriazole hydrate (28mg, 0.206mmol).Mixture at room temperature stirred spend the night, then dilute with water.With 1N NaOH with the pH regulator of mixture to pH 9, hand over dichloromethane extraction 3.The organic layer that merges concentrates and obtains crude product.This crude product with column chromatography purifying (0.6% ammonium hydroxide and 6% ethanol/methylene), is obtained title compound.

¹H NMR(500MHz，CDCl ₃)δppm9.81(s，1H)9.54(d，J＝1.53Hz，1H)8.83(d，J＝2.44Hz，1H)8.66(d，J＝2.14Hz，1H)8.58-8.63(m，1H)7.94(d，J＝8.85Hz，1H)7.52(dd，J＝8.85，2.14Hz，1H)3.52-3.62(m，1H)2.74-2.84(m，1H)2.61-2.72(m，2H)2.24-2.41(m，6H)1.55-1.64(m，4H)1.40-1.52(m，2H).MS：(M+H) ⁺＝394.

Embodiment 118

Suitable-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl]-2-thiene-3-yl-ethanamide

Title compound still replaces 2-pyrazine carboxylic acid with the 3-thiophene acetic acid according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm8.34(d，J＝2.14Hz，1H)7.81(d，J＝8.54Hz，1H)7.42(dd，J＝4.88，3.05Hz，1H)7.26-7.32(m，1H)7.13(dd，J＝8.70，2.29Hz，1H)7.10(d，J＝4.88Hz，1H)3.81(s，2H)3.47-3.57(m，1H)2.73-2.81(m，1H)2.61-2.69(m，2H)2.23-2.40(m，6H)1.54-1.63(m，4H)1.40-1.50(m，2H).MS：(M+H) ⁺＝412.

Embodiment 119

Along N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl]-3-thiophene-2-base propionic acid amide

Title compound still replaces 2-pyrazine carboxylic acid with 3-(2-thienyl) propionic acid according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm8.37(d，J＝1.83Hz，1H)7.83(d，J＝8.54Hz，1H)7.23(s，1H)7.11-7.19(m，2H)6.93(dd，J＝5.03，3.51Hz，1H)6.88(d，J＝2.75Hz，1H)3.47-3.59(m，1H)3.30(t，J＝7.32Hz，2H)2.71-2.82(m，3H)2.60-2.70(m，2H)2.22-2.40(m，6H)1.54-1.65(m，4H)1.40-1.50(m，2H).MS：(M+H) ⁺＝426.

Embodiment 120

Suitable-3-furans-2-base-N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide

Title compound still replaces 2-pyrazine carboxylic acid with 3-(2-furyl) propionic acid according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm8.38(d，J＝1.53Hz，1H)7.83(d，J＝8.54Hz，1H)7.34(s，1H)7.25-7.30(m，1H)7.16(dd，J＝8.54，2.14Hz，1H)6.27-6.34(m，1H)6.09(d，J＝2.75Hz，1H)3.47-3.59(m，1H)3.10(t，J＝7.32Hz，2H)2.70-2.83(m，3H)2.60-2.69(m，2H)2.22-2.40(m，6H)1.54-1.65(m，4H)1.40-1.51(m，2H).MS：(M+H) ⁺＝410.

Embodiment 121

Suitable-pyrimidine-5-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces 2-pyrazine carboxylic acid with the 5-pyrimidine carboxylic according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm9.39(s，1H)9.25(s，2H)8.49(s，1H)7.99-8.07(m，1H)7.93(d，J＝8.85Hz，1H)7.41(dd，J＝8.85，2.14Hz，1H)3.52-3.63(m，1H)2.73-2.84(m，1H)2.63-2.73(m，2H)2.22-2.42(m，6H)1.54-1.64(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝394.

Embodiment 122

Title compound is according to step described in embodiment 101C preparation, but replaces embodiment 101A and with 4-cyano-benzoyl chloride replacing acetyl chloride with embodiment 101B.

¹H NMR(400MHz，CDCl ₃)δppm8.51(s，1H)8.00(d，J＝8.59Hz，2H)7.91-7.98(m，2H)7.78-7.84(m，2H)7.40(dd，J＝8.90，2.15Hz，1H)3.76-3.88(m，1H)3.05-3.16(m，1H)2.49-2.61(m，4H)2.23-2.37(m，4H)1.54-1.66(m，4H)1.40-1.53(m，2H).MS：(M+H) ⁺＝417.

Embodiment 123

Instead-and N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] propionic acid amide

Title compound still replaces embodiment 101A and uses the propionyl chloride replacing acetyl chloride with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.44(d，J＝1.53Hz，1H)7.87(d，J＝8.85Hz，1H)7.21-7.33(m，2H)3.74-3.85(m，1H)3.03-3.16(m，1H)2.49-2.62(m，4H)2.44(q，J＝7.63Hz，2H)2.21-2.38(m，4H)1.56-1.63(m，4H)1.41-1.52(m，2H)1.28(t，J＝7.63Hz，3H).MS：(M+H) ⁺＝344.

Embodiment 124

Instead-and N-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyramide

Title compound still replaces embodiment 101A and uses the isobutyryl chloride replacing acetyl chloride with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.87(d，J＝8.85Hz，1H)7.29(s，1H)7.24-7.26(m，1H)3.77-3.85(m，1H)3.04-3.14(m，1H)2.49-2.61(m，5H)2.22-2.37(m，4H)1.56-1.64(m，4H)1.42-1.52(m，2H)1.29(d，J＝6.71Hz，6H).MS：(M+H) ⁺＝358.

Embodiment 125

Anti--[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] isobutyl carbamate

Title compound still replaces embodiment 101A and uses the isobutyl chlorocarbonate replacing acetyl chloride with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.18(s，1H)7.87(d，J＝8.54Hz，1H)7.21(dd，J＝8.85，2.14Hz，1H)6.73(s，1H)3.98(d，J＝6.41Hz，2H)3.74-3.84(m，1H)3.04-3.13(m，1H)2.48-2.60(m，4H)2.19-2.38(m，4H)1.95-2.07(m，1H)1.55-1.68(m，4H)1.42-1.51(m，2H)0.98(d，J＝6.71Hz，6H).MS：(M+H) ⁺＝388.

Embodiment 126

Instead-cyclopropane-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces Acetyl Chloride 98Min. with the cyclopropane carbonyl chloro with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.42(s，1H)7.87(d，J＝8.85Hz，1H)7.52(s，1H)7.22-7.30(m，1H)3.74-3.85(m，1H)3.03-3.15(m，1H)2.49-2.61(m，4H)2.19-2.39(m，4H)1.57-1.64(m，4H)1.50-1.57(m，1H)1.41-1.48(m，2H)1.08-1.15(m，2H)0.82-0.94(m，2H).MS：(M+H) ⁺＝356.

Embodiment 127

Instead-cyclobutane-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces Acetyl Chloride 98Min. with tetramethylene carbonyl chloro with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.87(d，J＝8.85Hz，1H)7.24(dd，J＝8.85，2.14Hz，1H)7.16(s，1H)3.75-3.84(m，1H)3.14-3.23(m，1H)3.04-3.14(m，1H)2.50-2.61(m，4H)2.37-2.47(m，2H)2.21-2.37(m，6H)1.91-2.08(m，2H)1.56-1.64(m，4H)1.42-1.51(m，2H).MS：(M+H) ⁺＝370.

Embodiment 128

Instead-Cyclopentane carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces Acetyl Chloride 98Min. with pentamethylene carbonyl chloro with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.87(d，J＝8.85Hz，1H)7.31(s，1H)7.24(dd，J＝8.85，2.14Hz，1H)3.74-3.84(m，1H)3.03-3.13(m，1H)2.67-2.76(m，1H)2.51-2.61(m，4H)2.23-2.39(m，4H)1.88-2.01(m，4H)1.76-1.86(m，2H)1.56-1.65(m，6H)1.42-1.51(m，2H).MS：(M+H) ⁺＝384.

Embodiment 129

Instead-hexahydrobenzoic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces Acetyl Chloride 98Min. with hexanaphthene carbonyl chloro with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.46(d，J＝1.83Hz，1H)7.87(d，J＝8.85Hz，1H)7.24(dd，J＝8.85，2.14Hz，1H)3.75-3.83(m，1H)3.05-3.14(m，1H)2.50-2.60(m，4H)2.21-2.37(m，4H)1.96-2.02(m，2H)1.82-1.90(m，2H)1.69-1.76(m，1H)1.54-1.64(m，6H)1.43-1.51(m，2H)1.24-1.40(m，4H).MS：(M+H) ⁺＝398.

Embodiment 130

Instead-furans-2-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and uses the 2 furoyl chloride replacing acetyl chloride with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(500MHz，CDCl ₃)δppm8.54(d，J＝2.14Hz，1H)8.20(s，1H)7.93(d，J＝8.85Hz，1H)7.54(s，1H)7.41(dd，J＝8.54，2.14Hz，1H)7.23-7.31(m，1H)6.59(dd，J＝3.51，1.68Hz，1H)3.76-3.87(m，1H)3.05-3.18(m，1H)2.51-2.64(m，4H)2.21-2.41(m，4H)1.54-1.72(m，4H)1.40-1.52(m，2H).MS：(M+H) ⁺＝382.

Embodiment 131

Instead-morpholine-4-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces Acetyl Chloride 98Min. with 4-morpholine carbonyl chloro with embodiment 101B according to the preparation of step described in the embodiment 101C.

¹H NMR(400MHz，CDCl ₃)δppm8.16(s，1H)7.84(s，1H)7.84(s，1H)7.18(d，J＝8.59Hz，1H)6.45(s，1H)3.71-3.85(m，4H)3.45-3.56(m，4H)3.35-3.45(m，1H)3.04-3.12(m，1H)2.47-2.59(m，4H)2.21-2.38(m，4H)1.40-1.67(m，4H)1.20-1.31(m，2H).MS：(M+H) ⁺＝401.

Embodiment 132

Instead-pyrimidine-5-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A and replaces 2-pyrazine carboxylic acid with the 5-pyrimidine carboxylic with embodiment 101B according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm9.39(s，1H)9.25(s，2H)8.50(s，1H)8.05(s，1H)7.96(d，J＝8.85Hz，1H)7.43(dd，J＝8.85，2.14Hz，1H)3.77-3.88(m，1H)3.05-3.16(m，1H)2.57(t，J＝7.17Hz，4H)2.19-2.42(m，4H)1.55-1.65(m，4H)1.39-1.54(m，2H).MS：(M+H) ⁺＝394.

Embodiment 133

Instead-pyrazine-2-carboxylic acid-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] acid amides

Title compound still replaces embodiment 101A with embodiment 101B according to the preparation of step described in the embodiment 117.

¹H NMR(500MHz，CDCl ₃)δppm9.82(s，1H)9.54(d，J＝1.53Hz，1H)8.84(d，J＝2.44Hz，1H)8.66(d，J＝1.83Hz，1H)8.59-8.64(m，1H)7.97(d，J＝8.54Hz，1H)7.54(dd，J＝8.85，2.14Hz，1H)3.77-3.88(m，1H)3.05-3.18(m，1H)2.51-2.62(m，4H)2.19-2.41(m，4H)1.55-1.66(m，4H)1.41-1.52(m，2H).MS：(M+H) ⁺＝394.

Embodiment 134

Racemize-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] pyrimidine-5-base amine

Product (suitable-2-(3-piperidines-1-basic ring butyl) benzothiazole-6-base amine) (50mg with embodiment 101A, 0.174mmol), 5-bromo pyrimi piperidine (42mg, 0.264mmol), three (dibenzalacetones) close two palladiums (0) (6.5mg, 0.007mmol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-biphenyl (BINAP, 8.7mg, 0.014mmol) and sodium tert-butoxide (23mg 0.242mmol) packs into and seals in the pipe.This pipe was placed 2 hours under high vacuum, re-filled nitrogen.Add toluene (2ml), place microwave reactor in 145 ℃ of heating 15 minutes reactor.After being cooled to room temperature, the mixture dilute with water is used dichloromethane extraction 3 times.The organic layer that merges is concentrated crude product column chromatography purifying (0.4% ammonium hydroxide and 4% ethanol/methylene).The product of collecting is the mixture of cis and trans-isomer(ide).

¹HNMR(400MHz，CDCl ₃)δppm8.79(s，1H)8.50-8.56(m，2H)7.89(d，J＝8.90Hz，1H)7.58(d，J＝2.15Hz，1H)7.18(dd，J＝8.59，2.15Hz，1.H)5.83(s，1H)3.48-3.63(m，1H)2.73-2.85(m，1H)2.59-2.71(m，2H)2.23-2.39(m，6H)1.54-1.66(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝366.

Embodiment 135

Racemize-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] pyrimidine-2-base amine

The product of embodiment 44A is (anti--6-bromo-2-(3-piperidines-1-basic ring butyl)-1, the 3-benzothiazole) (100mg, 0.285mmol), 2-aminopyrimidine (35mg, 0.368mmol), three (dibenzalacetones) close two palladiums (0) (10.4mg, 0.011mmol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (BINAP, 14mg, 0.022mmol) and sodium tert-butoxide (38mg 0.400mmol) packs into and seals in the pipe.This pipe was placed high vacuum following 2 hours and re-filled nitrogen.Add toluene (2ml), place microwave reactor in 145 ℃ of heating 15 minutes reactor.After being cooled to room temperature, the mixture dilute with water is used dichloromethane extraction 3 times.The organic layer that merges under reduced pressure concentrates, crude product column chromatography purifying (0.4% ammonium hydroxide and 4% ethanol/methylene).The product of collecting is the mixture (98mg) of cis and trans-isomer(ide).

¹H NMR(400MHz，CDCl ₃)δppm8.42-8.49(m，3H)7.89(d，2H)7.37-7.46(m，2H)6.75(t，J＝4.76Hz，1H)3.75-3.86(m，0.6H)3.48-3.62(m，0.4H)3.03-3.17(m，0.6H)2.73-2.84(m，0.4H)2.48-2.72(m，4H)2.21-2.42(m，4H)1.55-1.66(m，4H)1.41-1.51(m，2H).MS：(M+H) ⁺＝366.

Embodiment 136

Racemize-(5-bromo pyrimi piperidine-2-yl)-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] amine

Title compound still replaces the 2-aminopyrimidine with 2-amino-5-bromo pyrimi piperidine according to preparation described in the embodiment 135.

¹H NMR(400MHz，CDCl ₃)δppm8.45(s，2H)8.39(dd，J＝5.83，2.15Hz，1H)7.89(dd，J＝11.81，8.75Hz，1H)7.33-7.43(m，2H)7.21-7.26(m，1H)3.76-3.85(m，0.4H)3.49-3.61(m，0.6H)3.04-3.16(m，0.4H)2.72-2.85(m，0.6H)2.50-2.71(m，4H)2.22-2.41(m，4H)1.54-1.67(m，4H)1.41-1.50(m，2H).

Embodiment 137

Racemize-(5-picoline-2-yl)-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-yl] amine

Title compound still replaces the 2-aminopyrimidine with 2-amino-5-picoline according to the preparation of step described in the embodiment 135.

¹H NMR(300MHz，CDCl ₃)δppm8.06(s，1H)7.98(d，J＝2.37Hz，1H)7.85(d，J＝8.82Hz，1H)7.35(dd，J＝8.31，2.20Hz，1H)7.22-7.28(m，1H)6.79(d，J＝8.48Hz，1H)6.46(s，1H)3.76-3.89(m，0.3H)3.48-3.61(m，0.7H)3.06-3.22(m，0.3H)2.74-2.87(m，0.7H)2.53-2.72(m，4H)2.28-2.44(m，4H)2.25(s，3H)1.53-1.71(m，4H)1.39-1.52(m，2H).MS：(M+H) ⁺＝379.

Embodiment 138

Racemize-6-[2-(3-piperidines-1-basic ring butyl) benzothiazole-6-base is amino] the cigarette nitrile

Title compound still replaces the 2-aminopyrimidine with 2-amino-5-cyano pyridine according to the preparation of step described in the embodiment 135.

¹H NMR(400MHz，CDCl ₃)δppm8.49(t，J＝2.45Hz，1H)7.90-8.04(m，2H)7.67(dd，J＝8.75，2.30Hz，1H)7.30-7.39(m，1H)6.99(s，1H)6.77(dd，J＝8.44，2.92Hz，1H)3.75-3.87(m，0.3H)3.50-3.66(m，0.7H)3.04-3.17(m，0.3H)2.75-2.85(m，0.7H)2.51-2.73(m，4H)2.22-2.40(m，4H)1.61(s，4H)1.40-1.51(m，2H).MS：(M+H) ⁺＝390.

Embodiment 139

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-base nitrogen heterocyclic din-2-ketone

Embodiment 139A

6-bromo-2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1, the 3-benzothiazole

Title compound replaces 2-(R)-crassitude preparation according to step described in the embodiment 1E with (S)-pipecoline.

¹H NMR(300MHz，CDCl ₃)：δ＝7.98ppm(d，J＝2.3Hz，1H)，7.83(d，J＝8.5Hz，1H)，7.56(dd，J＝8.5，2.3Hz，1H)，3.75(m，1H)，3.53(m，1H)，2.50-2.85(m，6H)，2.19(m，1H)，1.65(m，4H)，1.41(m，2H)，1.06(d，J＝6.8Hz，3H).MS(ESI，M+H ⁺)：365.9.

Embodiment 139B

But the embodiment 139A that in the bottle of the microwave heating that magnetic stirring bar is housed, packs into (50mg, 0.14mmol), add subsequently nitrogen heterocyclic din-2-ketone (50mg, 0.7mmol), Pd ₂(dba) ₃(3.5mg, 0.004mmol), Xantphos (9,9-dimethyl-4,5-two (diphenylphosphino) xanthene) (6.1mg, 0.011mmol, Strem Chemicals, 7Mulliken Way, Newburyport, MA 01950-4098) and CsCO ₃(65mg, 0.2mmol).To react bottle then and seal, use N with aluminium lid ₂Gas cleans 10 times at least, adds diox (2ml) through syringe then.With this mixture supersound process, in microwave oven, heated 20 minutes then in 200 ℃.Mixture is cooled to 23 ℃, filters.Removal of solvent under reduced pressure, residue chromatography (SiO ₂, ethyl acetate (0-80%)/hexane) and purifying, obtain title compound.

¹H NMR(300MHz，CDCl ₃)：δ＝7.97ppm(d，J＝2.0Hz，1H)，7.92(d，J＝8.5Hz，1H)，7.38(dd，J＝8.5，2.0Hz，1H)，3.75(m，1H)，3.71(t，J＝4.7Hz，2H)，3.46(m，1H)，3.17(t，J＝4.7Hz，2H)，2.64(m，3H)，2.51(m，3H)，2.11(m，1H)，1.64(m，4H)，1.38(m，2H)，1.01(d，J＝6.5Hz，3H).MS(ESI，M+H ⁺)：356.1.

Embodiment 140

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-base pyrrolidin-2-one

Title compound replaces the nitrogen heterocyclic din-2-ketone preparation according to step described in the embodiment 139B with pyrrolidin-2-one.

¹H NMR(300MHz，CDCl ₃)：δ＝8.29ppm(d，J＝2.3Hz，1H)，7.95(d，J＝9.1Hz，1H)，7.58(dd，J＝9.1，2.3Hz，1H)，3.94(t，J＝4.8Hz，2H)，3.74(m，1H)，3.47(m，1H)，2.48-2.73(m，8H)，2.21(m，2H)，2.11(m，1H)，1.62(m，4H)，1.38(m，1H)，1.02(d，J＝6.5Hz，3H).MS(ESI，M+H ⁺)：370.1.

Embodiment 141

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-phenylpiperidines-2-ketone

Title compound replaces the nitrogen heterocyclic din-2-ketone preparation according to step described in the embodiment 139B with piperidines-2-ketone.

¹H NMR(300MHz，CDCl ₃)：δ＝7.98ppm(d，J＝8.5Hz，1H)，7.75(d，J＝2.0Hz，1H)，7.33(dd，J＝8.5，2.0Hz，1H)，3.75(m，1H)，3.70(t，J＝6.1Hz，2H)，3.52(m，1H)，2.49-2.80(m，8H)，2.14(m，1H)，1.97(m，4H)，1.60(m，4H)，1.43(m，2H)，1.06(m，3H)，MS(ESI，M+H ⁺)：384.1.

Embodiment 142

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1, the 3-benzothiazole-high pyrrolidin-2-one of 6-base

Title compound replaces the nitrogen heterocyclic din-2-ketone preparation according to step described in the embodiment 139B with high pyrrolidin-2-one.

¹H NMR(300MHz，CDCl ₃)：δ＝7.96ppm(d，J＝8.4Hz，1H)，7.71(d，J＝2.7Hz，1H)，7.29(dd，J＝8.4，2.7Hz，1H)，3.80(m，2H)，3.76(m，1H)，3.49(m，1H)，3.73(m，2H)，2.66(m，4H)，2.50(m，2H)，2.10(m，1H)，1.86(m，6H)，1.62(m，4H)，1.41(m，1H)，1.04(m，3H).MS(ESI，M+H ⁺)：398.2.

Embodiment 143

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-methane amide

Embodiment 143A

2-{ is anti--3-[(S)-pipecoline-1-yl] cyclobutyl }-1,3-benzothiazole-6-carboxylate methyl ester

With 6-bromo-2-{ anti--3-[(S)-pipecoline-1-yl] cyclobutyl-1, (embodiment 139A, 2.0g 5.5mmol) are dissolved in methyl alcohol (60ml) to the 3-benzothiazole, then add catalyst P dCl ₂(dppf) CH ₂Cl ₂(225mg, 0.3mmol are also referred to as Palladous chloride (II)-1,1 '-two (diphenylphosphino) ferrocene, CAS#72287-26-4), heat 2 hours in 80 ℃ under CO pressure (60psi).Mixture is cooled to 23 ℃ then, filters.Removal of solvent under reduced pressure, residue chromatography (SiO ₂, the 10-80% ethyl acetate/hexane) and purifying, obtain title compound.

¹H NMR(300MHz，CDCl ₃)：δ＝8.58ppm(d，J＝1.7Hz，1H)，8.16(dd，J＝8.5，1.7Hz，1H)，8.01(d，J＝8.5Hz，1H)，4.10(m，2H)，4.00(m，1H)，3.97(s，3H)，3.72(m，1H)，3.52(m，1H)，3.49(d，J＝4.1Hz，3H)，2.76(m，4H)，1.60(m，2H)，1.40(m，2H)，1.00(m，2H).MS(ESI，M+H ⁺)：345.1.

Embodiment 143B

2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-carboxylic acid

With 2-{ anti--3-[(S)-pipecoline-1-yl] cyclobutyl-1,3-benzothiazole-6-carboxylate methyl ester (embodiment 143A, 2.0g, 5.8mmol) be dissolved in methyl alcohol (600ml), subsequently 23 ℃ add entry (300mg, 16.7mmol) and sodium methylate (1.4g, 26mmol).Reaction mixture was stirred 1 day at 23 ℃, remove and desolvate and unnecessary water.Adding 2N HCl makes mixture slightly be acid (pH～5-6), remove unnecessary water.With solid CH ₂Cl ₂/ MeOH develops after-filtration.The solvent in the filtrate, residue CH are removed in decompression ₂Cl ₂Handle and filter once more.Remove and desolvate, obtain desired product, be pale solid (2.13g, 100%).

¹H NMR(300MHz，CD ₃OD)：δ＝8.54ppm(d，J＝1.3Hz，1H)，8.11(dd，J＝8.9，1.3Hz，1H)，7.91(d，J＝8.9Hz，1H)，4.00(m，1H)，3.80(m，1H)，2.70-3.10(m，7H)，2.00(m，2H)，1.80(m，2H)，1.65(m，2H)，1.41(d，J＝6.8Hz，3H).MS(ESI，M+H ⁺)：331.0.

Embodiment 143C

2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Under 23 ℃ with 2-{ anti--3-[(S)-pipecoline-1-yl] cyclobutyl-1, ((17mg is 0.13mmol) at CH 0.062mmol) to be added to oxalyl chloride for embodiment 143B, 20mg for 3-benzothiazole-6-carboxylic acid ₂Cl ₂In the solution (1ml), subsequently in the DMF of 1 catalytic quantity.Reaction mixture was stirred 1 hour.Removal of solvent under reduced pressure and unnecessary oxalyl chloride, residual solid is dissolved in CH again ₂Cl ₂(0.5ml).In reaction flask, add then excess of ammonia (2ml, 1.2mmol)/CH ₂Cl ₂(2ml).Reaction mixture stirred spend the night, remove and desolvate, crude product obtains the product (65%) of 16mg trifluoroacetic acid salt form with HPLC purifying (C-18 post, 0.1%TFA/ acetonitrile).

¹H NMR(500MHz，CD ₃OD)：δ＝8.51ppm(m，1H)，8.01(m，2H)，4.00(m，1H)，3.80(m，1H)，3.83(m，2H)，2.80-3.15(m，5H)，2.74(m，1H)，1.94(m，3H)，1.75(m，3H)，1.41(m，3H).MS(ESI，M+H ⁺)：330.0.

Embodiment 144

N-sec.-propyl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with the 2-isopropylamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.43ppm(m，1H)，7.94-8.03(m，2H)，4.23(m，1H)，3.96(m，2H)，3.02(m，1H)，2.93(m，3H)，2.86(m，2H)，1.94(m，3H)，1.75(m，3H)，1.40(m，3H)，1.30(d，J＝6.7Hz，6H).MS(ESI，M+H ⁺)：372.1.

Embodiment 145

N-cyclopropyl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with cyclopropylamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.43ppm(m，1H)，7.93-8.02(m，2H)，4.00(m，1H)，3.82(m，2H)，3.02(m，1H)，2.90(m，4H)，2.86(m，2H)，1.94(m，3H)，1.69(m，3H)，1.40(m，3H)，0.82(m，2H)，0.67(m，2H).MS(ESI，M+H ⁺)：370.1.

Embodiment 146

N-phenyl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with aniline.

¹H NMR(300MHz，CD ₃OD)：δ＝8.57ppm(m，1H)，8.04-8.10(m，2H)，7.71(d，J＝7.6Hz，2H)，7.37(m，2H)，7.16(t，J＝7.7Hz，1H)，4.00(m，1H)，3.82(m，2H)，3.07(m，1H)，2.96(m，3H)，2.87(m，2H)，1.94(m，3H)，1.75(m，3H)，1.41(m，3H).MS(ESI，M+H ⁺)：406.1.

Embodiment 147

N-thiazol-2-yl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with thiazolamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.68ppm(m，1H)，8.17(m，1H)，8.09(m，1H)，7.53(d，J＝3.6Hz，1H)，7.19(d，J＝3.6Hz，1H)，4.00(m，1H)，3.85(m，2H)，3.10(m，1H)，2.95(m，3H)，2.76(m，2H)，1.94(m，3H)，1.73(m，3H)，1.41(m，3H).MS(ESI，M+H ⁺)：413.1.

Embodiment 148

N-benzyl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with the 2-benzylamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.48ppm(m，1H)，8.00(m，2H)，7.38(m，2H)，7.33(m，2H)，7.25(m，1H)，4.61(s，2H)，4.00(m，1H)，3.82(m，2H)，3.04(m，1H)，2.93(m，3H)，2.73(m，2H)，1.94(m，3H)，1.73(m，3H)，1.40(m，3H).MS(ES I，M+H ⁺)：420.1.

Embodiment 149

N-(2-styroyl)-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with the 2-phenylethylamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.40ppm(m，1H)，8.00(m，1H)，7.91(m，1H)，7.27(m，3H)，7.20(m，2H)，4.00(m，1H)，3.82(m，2H)，3.63(t，J＝7.0Hz，2H)，3.04(m，1H)，2.94(t，J＝7.0 Hz，2H)，2.83(m，3H)，2.75(m，2H)，1.94(m，3H)，1.73(m，3H)，1.40(m，3H).MS(ESI，M+H ⁺)：434.2.

Embodiment 150

N, N-dimethyl-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-methane amide

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with dimethylamine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.08ppm(m，1H)，8.03(m，1H)，7.58(m，1H)，4.00(m，1H)，3.83(m，2H)，3.14(s，3H)，3.08(m，1H)，3.03(s，3H)，2.90(m，3H)，2.72(m，2H)，1.92(m，3H)，1.68(m，3H)，1.40(m，3H).MS(ESI，M+H ⁺)：358.1.

Embodiment 151

(tetramethyleneimine-1-yl)-2-{ is pipecoline-1-yl instead-3-[(S)] cyclobutyl }-1,3-benzothiazole-6-ketone

Title compound replaces the ammonia preparation according to step described in the embodiment 143C with tetramethyleneimine.

¹H NMR(300MHz，CD ₃OD)：δ＝8.17ppm(m，1H)，8.03(m，1H)，7.68(m，1H)，4.00(m，1H)，3.81(m，2H)，3.63(t，J＝6.7Hz，2H)，3.49(t，J＝6.7Hz，2H)，3.08(m，1H)，2.90(m，3H)，2.75(m，2H)，1.92(m，7H)，1.68(m，3H)，1.40(m，3H).MS(ESI，M+H ⁺)：384.1.

Embodiment 152

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-base-3-methylpyrrolidin-2-ketone

Embodiment 152A

6-bromo-2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1, the 3-benzothiazole

Title compound replaces 2-(R)-crassitude preparation according to step described in the embodiment 1E with piperidines.

¹H NMR(300MHz，CDCl ₃)：δ＝7.98ppm(d，J＝2.0Hz，1H)，7.83(d，J＝8.5Hz，1H)，7.55(dd，J＝8.5，2.0Hz，1H)，3.80(m，1H)，3.09(m，1H)，2.56(m，4H)，2.30(m，4H)，1.61(m，4H)，1.47(m，2H).MS(ESI，M+H ⁺)：351.9.

Embodiment 152B

But in the bottle of the microwave heating that magnetic stirring bar is housed, add 6-bromo-2-[anti--3-(piperidines-1-yl) cyclobutyl]-1, the 3-benzothiazole (3,50mg, 0.14mmol), Pd ₂(dba) ₃(4.0mg, 0.004mmol), Xantphos (6.9mg, 0.0l2mmol) and CsCO ₃(68mg, 0.2mmol), then add 3-methylpyrrolidin-2-ketone (50mg, 0.5mmol).With aluminium lid bottle is sealed then, use N ₂Cleaning places under the inert atmosphere it, adds diox (2ml) through syringe.Ultrasonic to the reaction mixture short period of time to guarantee its inner thorough mixing, in the commodity microwave oven, heated 60 minutes then in 150 ℃.Reaction mixture is cooled to 23 ℃, filtering solid, removal of solvent under reduced pressure, residue chromatography (SiO ₂, ethyl acetate (0-80%)/hexane) and purifying, obtain the title compound (28mg, 55%) of pure products form.

¹H NMR(300MHz，CDCl ₃)：δ＝8.33ppm(d，J＝2.1Hz，1H)，7.94(d，J＝9.2Hz，1H)，7.61(dd，J＝9.2，2.1Hz，1H)，3.85(m，3H)，2.72(m，1H)，2.59(m，4H)，2.43(m，2H)，2.40(m，2H)，1.82(m，1H)，1.40-1.75(m，8H)，1.33(d，J＝7.1Hz，3H).MS(ESI，M+H ⁺)：370.1.

Embodiment 153

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-Ji oxazolidine-2-ketone

Title compound replaces the nitrogen heterocyclic din-2-ketone preparation according to the Yong of step ， described in embodiment 152B oxazolidine-2-ketone.

¹H NMR(300MHz，CDCl ₃)：δ＝8.14ppm(d，J＝2.4Hz，1H)，7.95(d，J＝9.1Hz，1H)，7.62(dd，J＝9.1，2.4Hz，1H)，4.55(m，2H)，4.15(m，2H)，3.97(m，1H)，3.70(m，2H)，3.36(m，3H)，2.70(m，4H)，1.50-2.00(m，6H).MS(ESI，M+H ⁺)：358.0.

Embodiment 154

2-[is anti--3-(piperidines-1-yl) cyclobutyl] and-1,3-benzothiazole-6-base-3-Methylimidazole alkane-2-ketone

Title compound replaces the nitrogen heterocyclic din-2-ketone preparation according to step described in the embodiment 152B with 3-Methylimidazole alkane-2-ketone.

¹H NMR(300MHz，CDCl ₃)：δ＝8.12ppm(d，J＝2.4Hz，1H)，7.89(d，J＝8.9Hz，1H)，7.65(dd，J＝8.9，2.4Hz，1H)，3.88(m，3H)，3.75(m，1H)，3.52(m，2H)，3.23(m，4H)，2.93(s，3H)，2.70(m，4H)，1.50-2.00(m，6H).MS(ESI，M+H ⁺)：371.1.

Biological activity determination

In order to determine that typical compound of the present invention is as histamine-3 receptors ligand (H ₃Receptors ligand) effectiveness (is seen European Journal of Pharmacology, 188:219-227 (1990) according to previously described method; Journal of Pharmacology and ExperimentalTherapeutics, 275:598-604 (1995); Journal of Pharmacology andExperimental Therapeutics, 276:1009-1015 (1996); And BiochemicalPharmacology, 22:3099-3109 (1973)) carried out following test.

With rat H ₃Receptor cloning and being expressed in the cell (is seen Esbenshade, et al.Journal of Pharmacology and ExperimentalTherapeutics, vol.313:165-175,2005 according to the method for former description; Esbenshade et al., BiochemicalPharmacology 68 (2004) 933-945; Krueger, et al.Journal of Pharmacologyand Experimental Therapeutics, vol.314:271-281,2005) be at war with in conjunction with test.Cytolemma is by expressing the rat histamine H ₃The C6 of acceptor or HEK 293 cells are by pressing down homogenizing preparation in phthalein enzyme, 1 μ g/ml leupeptin and the 1 μ g/ml pepstatin in TE damping fluid (50mM Tris-HCl damping fluid, pH 7.4, contain 5mM EDTA), 1mM benzenyl amidine, 2 μ g/ml on ice.With homogenizing thing under 4 ℃ centrifugal 20 minutes in 40000g.Repeat this step, with the granular precipitation resuspending that obtains in the TE damping fluid.Be divided into aliquot liquid sample, freezing until use down in-70 ℃.On the same day of measuring, film is thawed and dilute with the TE damping fluid.

With film preparation with [ ³H]-N-Alpha-Methyl histamine (0.5-1.0nM) concentration cumulative be used for H ₃There is or does not exist incubation down in receptor competition bonded part.The associativity incubation is to carry out in 25 ℃ in the TE damping fluid of 0.5ml at final volume, stops after 30 minutes.Use Thioperamide (30mM) to determine non-specific binding.By filtration under diminished pressure on Unifilters of pre-soaking polymine (0.3%) (Perkin Elmer Life Sciences) or Whatman GF/B filter, wash momently 3 times with the ice-cold TE damping fluid of 2ml then, stop all association reactions.Utilize liquid scintillation counting to determine the bonded radioactively labelled substance.For all radioligand competition combination tests, IC ₅₀Value and Hill slope are all measured with Hill data-switching method, and the pK1 value is determined with the Cheng-Prusoff equation.

Usually, The compounds of this invention demonstrates the binding affinity of about 0.1nM to about 500nM in above test.Preferred The compounds of this invention is with binding affinity and histamine-3 receptors bind of about 0.01nM to about 10nM.Preferred The compounds of this invention is with associativity and histamine-3 receptors bind of about 0.01nM to about 0.9nM.

The compounds of this invention is histamine-3 receptors ligand, and it regulates the function of histamine-3 acceptor by the activity that changes acceptor.These compounds can be the basic active inverse agonists that suppresses acceptor, perhaps can be the antagonists of effect of blocking the agonist of activated receptor fully.These compounds also can be the partial agonists that part blocking-up or part activate histamine-3 acceptor, perhaps can be the agonists of activation this receptor.

Certainly, above detailed description and appended embodiment are example explanation, not will be understood that it is restriction to scope of the present invention, and scope of the present invention is only limited by appended claim and Equivalent thereof.For those skilled in the art, the variations and modifications of disclosed embodiment are conspicuous.Under situation without departing from the spirit and scope of the present invention, can make these variations and modification, include but not limited to, with chemical structure, substituting group, derivative, intermediate, synthetic, preparation or method, or change and relevant variation or the modification of revising of any combination with using of the present invention these.

Claims

1. a formula (I) compound:

M is 0 or 1;

R _3aAnd R _3bBe selected from hydrogen independently of one another, cyano group, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxyl group, alkoxyalkyl, fluoroalkyl, alkylthio ,-SO ₂N (R _14a) (R _14b) and-N (R ₁₄) SO ₂(R ₁₄);

R ₆Be selected from aryl, heterocyclic radical and Heterocyclylalkyl;

R _6aBe selected from aryl and heterocyclic radical;

R _6bBe selected from aryl and heterocyclic radical;

L is a key or alkylidene group;

L ₂Be selected from a key ,-O-, alkylidene group ,-C (=O)-,-S-,-SO ₂N (R _14a)-,-N (R _14a) SO ₂-,-C (O) N (R _14a)-,-N (R _14a) C (O)-and-N (R ₁₅)-;

R ₁₀Be selected from hydrogen, cyano group, fluorine, hydroxyl and alkyl;

2. the compound of claim 1, wherein R ₁Be-L ₂-R ₆, L wherein ₂Be a key, R ₆Identical with the definition in the claim 1.

3. the compound of claim 2, wherein R ₆Be a heterocycle, it can be unsubstituted, and one or more substituting groups that perhaps can be selected from following group replace: acyl group, acyloxy, alkenyl, alkoxyl group; alkoxyalkoxy group, alkoxyalkyl, carbalkoxy, alkoxyimino, alcoxyl alkylsulfonyl; alkyl, alkyl-carbonyl, alkane alkylsulfonyl, alkynyl, amido; carboxyl, cyano group, cycloalkyl, fluoroalkyl, formyl radical; halogenated alkoxy, alkylhalide group, halogen, hydroxyl, hydroxyalkyl; sulfydryl, nitro, oxygen base, alkylthio ,-NR _AR _B, (NR _AR _B) carbonyl ,-SO ₂N (R _14a) (R _14b) and-N (R _14a) SO ₂(R _14b).

4. the compound of claim 3, wherein R _bBe selected from following radicals: furyl, imidazolyl ， isoxazolyl, isothiazolyl oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiadiazoles ketone group, thiadiazine ketone group, oxadiazole base; oxadiazole ketone group, oxadiazine ketone group, thiazolyl, thienyl, triazinyl, triazolyl, the pyridazine ketone group, pyriconyl, pyrimidine ketone group, indyl, benzothienyl, benzofuryl, indazolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, benzisothiazole base, benzoisoxazole base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, pteridyl, purine radicals, naphthyridinyl, cinnolines base, thieno-[2,3-d] imidazolyl, pyrrolo-pyrimidine radicals, the nitrogen heterocyclic heptyl, azelidinyl, nitrogen heterocyclic propyl group, the nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl, dihydro-thiazolyl, dihydropyridine base, parathiazan base alkyl dioxin, dithiane base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl and [1,3] dioxolane base.

5. the compound of claim 4, wherein R ₆Be selected from the benzonitrile base, pyrazolyl, pyrimidyl, the pyrimidine ketone group, pyridyl, pyridazine ketone group and quinolyl, wherein each ring is selected from 0,1 or 2 substituting group replacement of methoxyl group and methyl.

6. the compound of claim 1, wherein R _3aAnd R _3bAll be hydrogen.

7. the compound of claim 1, wherein R ₄And R ₅The nitrogen-atoms that all connects with them forms a non-aromatic ring, and this non-aromatic ring is one 4 to 9 yuan a non-aromatic ring.

8. the compound of claim 7, wherein this non-aromatic ring ring that is following structure:

Q ₁Be O, S ,-N (R ₂₀)-or C;

Q ₂Be-N (R ₂₀)-or C;

Q ₃Be N or C;

R ₂₀Be selected from hydrogen, alkyl and alkyl-carbonyl;

p ¹And p ²Be 1,2 or 3 independently of one another;

q ¹, q ², q ³, q ⁴And q ⁵Be 0,1 or 2 independently of one another; With

r ¹, r ²And r ³Be 1 or 2 independently of one another;

Wherein, each carbon atom of intra-annular all replaces by hydrogen or by 0,1 or 2 substituting group, and these substituting groups all are independently selected from following group at every turn when occurring: hydrogen, hydroxyl, fluorine, alkyl, hydroxyalkyl, fluoroalkyl, cycloalkyl, cyano group, fluoroalkyl, alkoxyalkyl, alkoxyl group, alkylhalide group and N (R _21a) (R _21b), R wherein _21aAnd R _21bBe selected from hydrogen, alkyl and alkyl-carbonyl independently of one another.

9. the compound of claim 1, wherein R ₄And R ₅The nitrogen-atoms that all connects with them forms nitrogen heterocyclic heptyl, azelidinyl, nitrogen heterocyclic propyl group, nitrogen heterocyclic octyl group, morpholinyl, piperazinyl, piperidyl, pyrrolidyl, pyrrolinyl and hexahydropyrrolo also [3,4-b] pyrryl, wherein each group is selected from 0,1 or 2 substituting group replacement of alkyl, hydroxyalkyl and fluorine.

10. the compound of claim 1, wherein m is 0, L is a key, R ₆It is heterocycle.

11. the compound of claim 1, wherein this compound has chemical formula (II):

R wherein ₁, R ₂, R _3a, R _3b, R ₄And R ₅Identical with the definition in the claim 1.

12. the compound of claim 1, wherein this compound has chemical formula (III):

R wherein ₁, R ₂, R _3a, R _3b, R ₄And R ₅Definition and claim 1 in identical.

13. the compound of claim 1, wherein R ₁And R ₂In one of be L ₂R ₆, L ₂Be a key, R ₆Have the following formula structure:

R wherein ₁₆And R ₁₇Be selected from hydrogen, alkyl, alkylhalide group, cycloalkyl, alkoxyalkyl, aryl and heteroaryl independently of one another; Perhaps R ₁₆And R ₁₇The carbon atom that all connects with them forms 3 to 7 yuan of rings; V is 1,2,3,4,5 or 6.

14. the compound of claim 1 is selected from:

Instead-and 6-(2,4-dimethyl pyrimidine-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl] cyclobutyl }-1, the 3-benzothiazole;

Suitable-N-sec.-propyl-N-methyl-N-[3-(6-pyrimidine-5-base-1,3-benzothiazole-2-yl) cyclobutyl] amine;

Suitable-6-bromo-2-) 3-piperidines-1-basic ring butyl]-1, the 3-benzothiazole;

Suitable-2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Instead-and 2-(3-azetidin-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Instead-and 2-(3-azepan-1-basic ring butyl)-6-bromo-1, the 3-benzothiazole;

Instead-and 6-bromo-2-(3-morpholine-4-basic ring butyl)-1, the 3-benzothiazole;

Instead-and 6-bromo-2-[3-(pipecoline-1-yl) cyclobutyl]-1, the 3-benzothiazole;

Instead-and 6-bromo-2-[3-(4-fluorine piperidines-1-yl) cyclobutyl]-1, the 3-benzothiazole;

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] diethylamine;

Anti--[3-(6-bromo benzothiazole-2-yl) cyclobutyl] methyl-propyl amine;

6-bromo-2-(3-tetramethyleneimine-1-ylmethyl cyclobutyl) benzothiazole; With

Instead-5-chloro-2-[3-(2-methylpyrrolidin-1-yl) cyclobutyl benzothiazole.

15. the compound of claim 1 is selected from:

16. a pharmaceutical composition, wherein contain claim 1 compound for the treatment of the amount of having and with a kind of pharmaceutically acceptable carrier of its combination.

17. a selectivity is regulated the method for the effect of histamine-3 acceptor in the Mammals, comprises the compound of the claim 1 of using effective quantity.

18. treat and be subjected to the illness that histamine-3 acceptor regulates or the method for obstacle in the Mammals for one kind, comprise claim 1 compound of using effective quantity.

19. the method for claim 18, wherein this illness or obstacle are selected from: acute myocardial infarction, alzheimer's disease, asthma, the attention deficit hyperinetic disorder, the bipolarity obstacle, cognitive function is bad, the cognitive defect in the psychosis, memory impairment, study defective, dementia, skin cancer, drug abuse, diabetes, type ii diabetes, dysthymia disorders, epilepsy, gastrointestinal disorders, inflammation, insulin resistance syndrome, trouble with jet lag, Tiroidina encephaloid, melanoma, Meniere, metabolic syndrome, the mild cognitive damage, migraine, mental state and attention change, motion sickness, narcolepsy, neurogenic inflammation, obesity, obsession, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, the cognitive defect of schizophrenia, epileptic seizures, septic shock, the X syndromes, Tourette syndrome, dizzy and somnopathy.

20. the radio-labeling form of the compound of claim 1 is as the application of radioligand.

21. the application of compound of claim 20, this compound is selected from: