CN101479243A

CN101479243A - Glycine transporter-1 inhibitors

Info

Publication number: CN101479243A
Application number: CNA200780024216XA
Authority: CN
Inventors: S·希奇库克; A·阿马加兹; 钱文远; 夏晓阳; S·S·哈里德
Original assignee: Amgen Inc
Current assignee: Amgen Inc
Priority date: 2006-06-28
Filing date: 2007-06-26
Publication date: 2009-07-08
Anticipated expiration: 2027-06-26
Also published as: UA94615C2; CN101479243B; ZA200810599B

Abstract

The present invention provides compounds of formula (I) that are glycine transporter 1 (hereinafter referred to as GlyT-1) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of GlyT1 such as cognitive disorders associated with Schizophrenia, ADHD (attention deficit hyperactivity disorder), MCI (mild cognitive impairment), and the like. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

Glycine transporter-1 inhibitors

Cross reference

The application requires the U.S. provisional application Nos.60/816 that submitted on June 28th, 2006,60/850,027 the right of priority of submitting on October 8th, 936 and 2006, and its disclosure is incorporated the present invention into as a reference at this.

Technical field

The invention provides is glycine transporter 1 (below be called GIyT-I) inhibitor with therefore can be used for treating can be by suppressing disease that GIyTl treats as the cognitive illness relevant with schizophrenia, ADHD (attention shortcoming superfunction illness), the compound of MCI (mild cognitive impairment) and similar disease.Pharmaceutical composition that comprises these compounds and the method that is used to prepare these compounds also are provided.

Background technology

Glycine is a kind of main inhibitory nerve transporter among the Mammals CNS, and forces co-agonists and glutaminate to be used to activate N-methyl D-aspartate (NMDA) acceptor as interior originality.The cynapse effect of glycine stops by the sub activity of high affinity transhipment that is arranged in neurone and neuroglia membrane.1 type glycine transporter (GIyTl) relates to the glycine reuptake process on excited cynapse level.The blocking-up of GIyTl is increased in the glycine concentration in the excited cynapse, therefore strengthens the neural transhipment of NMDA.Because the dysfunction of the nmda receptor in the brain region of schizophrenia and prefrontal cortex and hippocampus and so on is relevant, the inhibitor of GIyTl can restore normal NMDA transhipment and reduce the symptoms of schizophrenia like this.Except schizophrenia, the GIyTl inhibitor can be used for it is characterized in that impaired NMDA transhipment, as other patient's condition of general cognitive shortcoming (comprising MCI) and alzheimer's disease.

Existing schizophrenia therapy is being virtuous aspect the positive symptom of this disease of treatment only.The existing medicine of main target corpus callosum Dopamine HCL system can not improve adverse symptoms, comprises smooth emotion, unsocial and cognitive shortcoming.Therefore, be used for schizoid novel therapeutic needs and improve adverse symptoms relevant and cognitive shortcoming particularly with this disease.The present invention satisfies this requirement and related request.

Summary of the present invention

On the one hand, the present invention relates to the to have structural formula compound of (I):

Wherein:

N is an integer 1 to 3;

R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or R ¹And R ²Can form oxo group jointly in the time of on being connected to same carbon; Or

R ¹And R ², in the time of on being connected to same carbon, can form cycloalkyl or monocycle saturated heterocyclyl jointly, obtain volution, wherein cycloalkyl or monocycle saturated heterocyclyl can optionally be independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^e, or R ^fReplace; Or

R ¹And R ², in the time of on the carbon atom 2 that is connected to piperazine ring and 5 or 3 and 6, can form jointly-C ₁-C ₃-alkylidene chain, wherein a carbon atom in the alkylidene chain optionally is replaced by-NR-,-O-,-S (O) n-(wherein R is that hydrogen or alkyl and n are 0-2) and further wherein one or two hydrogen atom in the alkylidene chain can optionally replace with one or two alkyl;

R ³, R ⁴And R ⁵Be hydrogen independently, alkyl, fluorine, or fluoroalkyl; With

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hOr R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Or

Its drug acceptable salt, prerequisite is:

Compound with structural formula (I) is not 2-(4-benzhydryl piperazidine-1-yl) acetate, 2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) acetate, 2-((2R, 5S)-4-((R)-(4-(1H-tetrazolium-5-yl) phenyl) (3-hydroxy phenyl) methyl)-2,5-lupetazin-1-yl) acetate, or 2-((2R, 5S)-4-((R)-(4-cyano-phenyl) (3-hydroxy phenyl) methyl)-2,5-lupetazin-1-yl) acetate.

In some embodiments, the compound with structural formula (I) has the following formula structure:

Wherein:

R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy.Aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or R ¹And R ²Can form oxo group jointly in the time of on being connected to same carbon; Or

R ³, R ⁴And R ⁵Be hydrogen independently, alkyl, fluorine, or fluoroalkyl; And Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein Rg is an alkyl, halo, haloalkyl; halogenated alkoxy, alkylthio, cyano group, alkoxyl group; amino, single substituted-amino, disubstituted amido, alkylsulfonyl; acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group; aminoalkoxy, amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein aromatics or alicyclic ring are at R ^g, R ^hAnd R ⁱOptionally be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Or

Its drug acceptable salt, prerequisite is:

In some embodiments, in compound with structural formula (I), R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace.

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Prerequisite is, if (i) R ¹And R ²Be methyl, R ³, R ⁴And R ⁵Be hydrogen, and Ar ¹Be 3-hydroxy phenyl, Ar so ²Not 4-cyano-phenyl or 4-1H-tetrazolium-5-base phenyl and (ii) R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen and Ar ¹Be phenyl, Ar so ²Not phenyl or 4-chloro-phenyl-.

Second aspect the present invention relates to pharmaceutical composition, comprises the have structural formula compound of (I), its drug acceptable salt or have the compound of structural formula (I) and the mixture of its drug acceptable salt; Can accept vehicle with medicine.In one embodiment, n is 1.

The third aspect the present invention relates to the method for the disease that a kind of treatment can treat by the GIyTl acceptor that suppresses patient, and this method comprises and will comprise the have structural formula pharmaceutical composition of compound of (I) to patient's administration:

Wherein: n is 1 to 3 integer;

R ³, R ⁴And R ⁵Be hydrogen independently, alkyl, fluorine, or fluoroalkyl; And Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Or

Its drug acceptable salt, or mixture and medicine with the compound of structural formula (I) and its drug acceptable salt can be accepted vehicle.

In some embodiments, in above method, the compound with structural formula (I) is R wherein ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be with being independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace;

Or R ¹And R ², in the time of on being connected to same carbon, can form jointly cycloalkyl or-the monocycle saturated heterocyclyl, obtain volution, wherein cycloalkyl or monocycle saturated heterocyclyl can optionally be independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^c, or R ^fReplace; Or

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace.

In some embodiments, in above method, the compound with structural formula (I) is that wherein n is 1.In one embodiment, disease is ADHD (an attention shortcoming superfunction illness), MCI (mild cognitive impairment), or the cognitive illness relevant with schizophrenia.

Fourth aspect the present invention relates to the method that a kind of manufacturing has the compound of structural formula (I):

Wherein:

N is an integer 1 to 3;

R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Comprise:

(a) ester group in the hydrolysis following formula: compound under acidity or basic hydrolysis condition:

Wherein R is alkyl and R ¹, R ², R ³, R ⁴, R ⁵, Ar ¹And Ar ²Group definition as above;

(b) optionally change any R ¹, R ², R ³, R ⁴, R ⁵, Ar ¹And Ar ²Group is to provide the have structural formula compound of (I);

(c) optionally form derives from the acid salt of above step (a) and/or the compound with structural formula (I) (b);

(d) optionally separation derives from above step (a), (b), and/or the steric isomer of the compound with structural formula (I) (c);

Prerequisite is, if (i) R ¹And R ²Be methyl, R ³, R ⁴And R ⁵Be hydrogen, and Ar ¹Be 3-hydroxy phenyl, Ar so ²Not 4-cyano-phenyl or 4-1H-tetrazolium-5-base phenyl and (ii) R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen and Ar ¹Be phenyl, Ar so ²Not phenyl or 4-chloro-phenyl-;

In some embodiments of above method, the compound with structural formula (I) is wherein:

R ¹And R ²Be hydrogen or alkyl independently;

R ³, R ⁴, and R ⁵Be hydrogen; With

Ar ¹And Ar ²Be phenyl independently, each is looked around and need use R ^gOr R ^hReplace, wherein R ^gAnd R ^hBe alkyl independently, halo, haloalkyl, halogenated alkoxy, alkylthio, alkoxyl group, alkyl-carbonyl, or alkoxy carbonyl.

In some embodiments of above method, the compound with structural formula (I) is such, wherein:

R ¹And R ²Be hydrogen or alkyl independently;

R ³, R ⁴, and R ⁵Be hydrogen; With

Ar ¹And Ar ²Be phenyl independently, each is looked around and need use R ^gOr R ^hReplace, wherein R ^gAnd R ^hBe alkyl independently, halo, haloalkyl, halogenated alkoxy, alkylthio, alkoxyl group, alkyl-carbonyl, or alkoxy carbonyl and carry R ³, Ar ¹And Ar ²Stereochemistry on the carbon of group is (R).

Describe in detail

Definition:

Unless have describedly in addition, the following term that is used for specification sheets and claim defines for the application and has a following implication:

＂ alkyl ＂ is meant the linear saturated unit price hydrocarbyl group with 1 to 6 carbon atom or has the saturated unit price hydrocarbyl group of side chain of 3 to 6 carbon atoms, as, methyl, ethyl, propyl group, 2-propyl group, butyl (comprising all isomeric forms), amyl group (comprising all isomeric forms), and analogue.

The alicyclic ＂ of ＂ be meant non-aromatic ring as, cycloalkyl or heterocyclic ring.

＂ alkylidene group ＂ is meant the linear saturated divalent hydrocarbyl mission with 1 to 6 carbon atom or has the saturated divalent hydrocarbyl mission of side chain of 3 to 6 carbon atoms, unless have in addition described, as, methylene radical, ethylidene, propylidene, 1-methyl propylidene, 2-methyl propylidene, butylidene, pentylidene, and analogue.

＂ alkylthio ＂ is meant-the SR group that wherein R defines alkyl as above, as, methyl sulfo-, ethylenebis dithiocarbamate, and analogue.

＂ alkyl sulphonyl ＂ is meant-SO ₂The R group, wherein R defines alkyl as above, as, methyl sulphonyl, ethylsulfonyl, and analogue.

The amino ＂ of ＂ is meant-NH ₂

＂ alkylamino ＂ is meant-the NHR group that wherein R defines alkyl as above, as, methylamino, ethylamino, propyl group amino, or 2-propyl group amino, and analogue.

＂ alkoxyl group ＂ is meant-the OR group that wherein R defines alkyl as above, as, methoxyl group, oxyethyl group, propoxy-, or 2-propoxy-, n-, different, or tert.-butoxy, and analogue.

＂ alkoxy carbonyl ＂ is meant-C (O) OR group that wherein R defines alkyl as above, as, methoxycarbonyl, ethoxy carbonyl, and analogue.

＂ alkoxyalkyl ＂ is meant with at least one definition alkoxy base as above, linear monovalent hydrocarbon group that preferred 1 or 2 alkoxy base replaces or side chain monovalent hydrocarbon group with 3 to 6 carbon with 1 to 6 carbon atom, as, the 2-methoxy ethyl, 1-, 2-, or 3-methoxy-propyl, 2-ethoxyethyl group, and analogue.

＂ alkoxyalkyl oxygen base ＂ or ＂ alkoxyl group alkoxyl group ＂ are meant-the OR group that wherein R defines alkoxyalkyl as above, as, methoxy ethoxy, 2-ethoxy ethoxy, and analogue.

＂ aminoalkyl group ＂ is meant and uses at least one, preferably one or two-linear monovalent hydrocarbon group that NRR ' replaces or have the side chain monovalent hydrocarbon group of 3 to 6 carbon with 1 to 6 carbon atom, wherein R is a hydrogen, alkyl, or-COR ^a, R wherein ^aBe alkyl, each defines as above, and R ' is selected from hydrogen, alkyl; hydroxyalkyl, alkoxyalkyl, aryl, aralkyl; heteroaryl, heteroaralkyl, or haloalkyl, respectively as defined herein; as, amino methyl, methylamino ethyl, 2-ethylamino-2-methylethyl; 1,3-diamino propyl group, dimethylaminomethyl; the diethylamino ethyl, acetylamino propyl group, and analogue.

＂ aminoalkoxy ＂ is meant-the OR group that wherein R defines aminoalkyl group as above, as, 2-amino ethoxy, 2-dimethylamino propoxy, and analogue.

＂ aminocarboxyl ＂ is meant-CONRR ' group, and wherein R is a hydrogen independently, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl group, respectively as defined herein, and R ' is a hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, the heterocyclic radical alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl group, respectively as defined herein, as ,-CONH ₂, methylamino carbonyl, 2-dimethylamino carbonyl, and analogue.

＂ amino-sulfonyl ＂ is meant-SO ₂NRR ' group, wherein R is a hydrogen independently, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl group, respectively as defined herein, and R ' is a hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, the heterocyclic radical alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl group, respectively as defined herein, as ,-SO ₂NH ₂, methylamino alkylsulfonyl, 2-dimethylamino alkylsulfonyl, and analogue.

＂ acyl group ＂ is meant-the COR group that wherein R is an alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl; aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, or heterocyclic radical alkyl, respectively as defined herein; as, ethanoyl, propionyl, benzoyl, pyridyl carbonyl, and analogue.If R is an alkyl, this group is also referred to as alkyl-carbonyl in this article.

＂ acyl amino ＂ is meant-the NHCOR group that wherein R is an alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl; aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, or heterocyclic radical alkyl; respectively as defined herein, as, acetylamino, propionyl amino, and analogue.

＂ aryl ＂ is meant that unit price monocycle with 6 to 10 annular atomses or bicyclic aromatic hydrocarbyl group are as, phenyl or naphthyl.

＂ aralkyl ＂ is meant-(alkylidene group)-R group that wherein R is that aryl defines as above.

＂ cycloalkyl ＂ is meant the saturated unit price hydrocarbyl group of the ring-type with 3 to 10 carbon atoms, and one of them or two carbon atoms can be replaced by oxo group, as, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and analogue.

Cycloalkylalkyl ＂ is meant-(alkylidene group)-R group that wherein R defines cycloalkyl as above; As, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl ethyl, or cyclohexyl methyl, and analogue.

＂ carboxyl ＂ is meant-COOH.

＂ center piperazinyl ring ＂ is meant in the structural formula (I)

Encircle and shown in above, number.

＂ disubstituted amido ＂ is meant-NRR ' group that wherein R and R ' are alkyl independently, cycloalkyl, cycloalkylalkyl; acyl group, alkylsulfonyl, aryl, aralkyl; heteroaryl, heteroaralkyl, heterocyclic radical; the heterocyclic radical alkyl, hydroxyalkyl, alkoxyalkyl; or aminoalkyl group, respectively as defined herein, as; dimethylamino, phenyl methyl amino, and analogue.

＂ halo ＂ is meant fluorine, chlorine, bromine, or iodine, preferred fluorine or chlorine.

＂ haloalkyl ＂ is meant and uses one or more halogen atoms, preferred one to five halogen atom, and the definition alkyl group as above that preferred fluorine or chlorine replaces comprises those that replace with different halogens, as ,-CH ₂Cl ,-CF ₃,-CHF ₂,-CH ₂CF ₃,-CF ₂CF ₃,-CF (CH ₃) ₃, and analogue.If alkyl only replaces with fluorine, it is called fluoroalkyl in this application.

＂ halogenated alkoxy ＂ is meant-the OR group, and wherein R definition haloalkyl as above is as ,-OCF ₃,-OCHF ₂, and analogue.If R is that wherein alkyl is only with the haloalkyl of fluorine replacement, it is called Fluoroalkyloxy in this application.

＂ hydroxyalkyl ＂ is meant with the linear monovalent hydrocarbon group with 1 to 6 carbon atom of one or two oh group or has the branching monovalent hydrocarbon group of 3 to 6 carbon that prerequisite is that if there are two oh groups, they are not all on identical carbon atoms.Representative example includes, but not limited to hydroxymethyl, the 2-hydroxyethyl, the 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methyl-propyl, 2-hydroxybutyl, the 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxyl butyl, 3,4-dihydroxyl butyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferred 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

＂ hydroxy alkoxy base ＂ or ＂ hydroxyalkyl oxygen base ＂ are meant-the OR group that wherein R defines hydroxyalkyl as above.

＂ heterocyclic radical ＂ is meant the saturated or unsaturated unit price monocyclic groups with 5 to 8 annular atomses, and one of them or two annular atomses are to be selected from N, O, or the heteroatoms of S (O) n, and wherein n is an integer 0 to 2, the residue ring atom is C.Heterocyclic ring optionally is fused on (one) aryl or heteroaryl ring defined herein, and prerequisite is that aryl and heteroaryl ring are monocycles.The heterocyclic ring that is fused on monocyclic aryl or the heteroaryl ring is also referred to as ＂ bicyclic heterocyclic radical ＂ ring in this application.In addition, one or two available ring carbon atom in the heterocyclic ring optionally is replaced by-the CO-group.More specifically the term heterocyclic radical includes, but not limited to pyridyl, piperidyl, homopiperidinyl, 2-oxo-pyrrolidine base, 2-oxo-piperidine base, morpholino, piperazinyl, THP trtrahydropyranyl, thiomorpholine generation, and analogue.If heterocyclic ring is undersaturated, it can comprise the two keys of one or two ring, and prerequisite is that this ring is not an aromatics.If the heterocyclic radical group comprises at least one nitrogen-atoms, it is also referred to as heterocyclic amino group in this article and is the child group of heterocyclic radical group.If the heterocyclic radical group be saturated rings and uncondensed to aforesaid aryl or heteroaryl ring, it is also referred to as saturated monocycle heterocyclic radical in this article.

＂ heterocyclic radical alkyl ＂ is meant-(alkylidene group)-R group, wherein R definition heterocyclic ring as above as, tetrahydrofuran (THF) ylmethyl, piperazinyl methyl, morpholinyl ethyl, and analogue.

＂ heteroaryl ＂ is meant unit price monocycle or the bicyclic aromatic group with 5 to 10 annular atomses, wherein one or more, preferred one, two, or three, annular atoms is to be selected from N, O, or the heteroatoms of S, and the residue ring atom is a carbon.Representative example includes, but not limited to pyrryl, thienyl, thiazolyl, imidazolyl, furyl, indyl, pseudoindoyl ， oxazolyl ， isoxazolyl, benzothiazolyl benzoxazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazyl, and analogue.

＂ heteroaralkyl ＂ is meant-(alkylidene group)-R group that wherein R defines heteroaryl as above.

The single substituted-amino ＂ of ＂ is meant-the NHR group that wherein R is an alkyl, cycloalkyl, cycloalkylalkyl; acyl group, alkylsulfonyl, aryl, aralkyl; heteroaryl, heteroaralkyl, heterocyclic radical, heterocyclic radical alkyl; hydroxyalkyl, alkoxyalkyl, or aminoalkyl group; respectively as defined herein, as, methylamino; the 2-phenyl amino, hydroxyethyl amino, and analogue.

＂ spiral shell ＂ compound is the dicyclic compound with the ring that connects by atom only, and described connection atom is also referred to as spiro atom, the most common quaternary carbon (＂ spiral shell carbon ＂).Representative example includes, but not limited to

And analogue.

The present invention also comprises the prodrug of the compound with structural formula (I).The term prodrug means the carrier of expression covalency keyed jointing, when this prodrug during to the mammalian subject administration, and the activeconstituents that it can releasing structure formula (I).Take place in the releasing body of activeconstituents.Prodrug can be by the known technology preparation of those skilled in the art.The general suitable functional group that changes in the given compound of these technology.But in the sense group of these modifications or pass through the routine operation original functional group of regenerating.Prodrug with compound of structural formula (I) comprises wherein hydroxyl, amino, carboxylic acid, or the compound that is modified of similar group.The example of prodrug includes, but are not limited to ester (as, acetic ester; manthanoate; and benzoate derivatives), carbamate (as, the hydroxyl in the compound of structural formula (I) or the N of amido functional group had; N-dimethylamino carbonyl)); acid amides (as, trifluoroacetyl group amino, acetylamino; and analogue and analogue).Have structural formula (I) compound prodrug also within the scope of the invention.

The present invention also comprises the shielded derivative of the compound with structural formula (I).For example, comprise group such as hydroxyl if having the compound of structural formula (I), carboxyl, mercaptan or comprise any group of nitrogen-atoms, these groups can be with suitable blocking group protection.Exhaustive list to suitable blocking group can be at T.W.Greene, the blocking group in the organic synthesis, John Wiley; Sons, Inc. finds in (1999), and its disclosure is incorporated the present invention into as a reference at this.Protected derivative with compound of structural formula (I) can prepare by method well known in the art.

The ＂ drug acceptable salt ＂ of compound is meant pharmaceutically acceptable and has the salt of the required pharmaceutical active of parent compound.These salt comprise:

Acid salt, and at organic acid such as spirit of salt, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid and analogue form; Or with organic acid such as form acid, acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, Succinic Acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methanesulfonic, ethane sulfonic acid, 1,2-ethane disulfonic acid, 2-hydroxyethanesulfonic acid, Phenylsulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthene sulfonic acid, 4-toluenesulphonic acids, camphorsulfonic acid, glucoheptonic acid, 4,4 '-methylene radical two-(3-hydroxyl-2-base-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, gluconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid and analogue form; Or

Acid proton in being present in parent compound is replaced by metal ion, as, alkalimetal ion, alkaline earth ion, or aluminum ion; Or with organic bases such as thanomin, diethanolamine, trolamine, Trometamol, formed salt when N-methylglucosamine and analogue coordination.Be appreciated that drug acceptable salt is atoxic.Other information about suitable drug acceptable salt can be at Remington ' s DrugScience, 17th., and Mack Publishing Company, Easton finds among the PA 1985, incorporates the present invention as a reference at this.

The compounds of this invention can have center of asymmetry.The The compounds of this invention that comprises the atom of asymmetric replacement can be separated into optical activity or racemic form.The well known optical activity form that how to prepare is as the fractionation by material.All chiralitys, diastereomer, racemic form within the scope of the present invention, unless specifically noted specific stereochemistry or isomeric forms.

Some compound with structural formula (I) can be used as tautomer and/or geometrical isomer and exists.As the institute of each form and its mixture might tautomer and cis and trans-isomer(ide) within the scope of the present invention.In addition, term alkyl used herein comprises all possible isomeric forms of described alkyl group, even only provided a few.In addition, if cyclic group such as aryl, heteroaryl, heterocyclic radical replaces, and they comprise all positional isomerss, even only provided a few.In addition, have all polymorph forms of compound of structural formula (I) and hydrate within the scope of the present invention.

＂ oxo ＂ or ＂ carbonyl ＂ be meant=(O) group.

Dispensable ＂ of ＂ or ＂ optionally ＂ be meant, subsequently incident of Miao Shuing or situation can but needn't take place and describe to comprise situation that this incident wherein occurs and the situation that this incident does not wherein take place.For example, the heterocyclic radical group ＂ that optionally replaces of ＂ with alkyl group be meant alkyl can but needn't exist and this description comprise situation that heterocyclic radical group wherein replaces with alkyl group and wherein the heterocyclic radical group without the situation of alkyl replacement.

＂ drug acceptable carrier or vehicle ＂ are meant Generally Recognized as safe, non-toxicity and can be not biologically or otherwise unwelcomely can be used for the carrier or the vehicle of pharmaceutical compositions and comprise and to accept that the animal doctor uses and the carrier or the vehicle of people's drug use.The ＂ A drug acceptable carrier/vehicle ＂ that is used for specification sheets and claim comprises a kind of and more than one these vehicle.

＂ alkylsulfonyl ＂ is meant-SO ₂The R group, wherein R is an alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, the heterocyclic radical alkyl, respectively as defined herein, as, methyl sulphonyl, phenyl sulfonyl, benzyl alkylsulfonyl, pyridyl sulfonyl, and analogue.

In the application's claim and the specification sheets to radicals R ¹And R ²Definition in word ＂ ..., wherein aforementioned looking around need be with being independently selected from ... R ^a, R ^b, or R ^cReplace ＂ and be used for other groups [as, Ar at structural formula (I) and compound (IA)-(IF) in claim with in specification sheets ¹And Ar ²Group] similar word be meant, this ring can be single-, two, or trisubstituted, unless refer else.

The ＂ treatment ＂ or the ＂ therapeutic action ＂ of disease comprise:

(1) wards off disease, promptly be exposed to or easily be exposed to this disease but do not experience as yet or show that the clinical symptom of disease can not take place the Mammals of the symptom of this disease;

(2) suppress disease, that is, stop or reduce the development of disease or its clinical symptom; Or

(3) palliate a disease, that is, cause going down of disease or its clinical symptom.

＂ treatment significant quantity ＂ is meant the amount that is enough to when treating disease to influence to the compound with structural formula (I) of this treatment of disease when being administered for to Mammals.＂ is according to this compound for ＂ treatment significant quantity, and disease and its seriousness and the mammiferous age of being treated, weight waits and changes.

Representative The compounds of this invention provides in following table 1-8:

Table 1 has provided the compound that representativeness has structural formula (I), wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²Be phenyl, Ar wherein ²As follows by R ^gAnd R ^hReplace.

Table 1

Cpd#	R ^g	R ^h	^*Stereochemistry on the C
Cpd#	R ^g	R ^h	^*Stereochemistry on the C		1	3-CF ₃	H	R
2	3-Br	H	RS		1	3-CF ₃	H	R
2	3-Br	H	RS		3	3-CF ₃	H	RS
4	3-Cl	5-Cl	RS		3	3-CF ₃	H	RS
4	3-Cl	5-Cl	RS		5	3-CF ₃	H	S
6	4-Br	H	RS		5	3-CF ₃	H	S
6	4-Br	H	RS		7	H	H	-
8	4-Cl	H	RS	2HCl	7	H	H	-
8	4-Cl	H	RS	2HCl	9	4-CF ₃	H	RS	2HCl
10	2-Br	H	RS	2HCl	9	4-CF ₃	H	RS	2HCl
10	2-Br	H	RS	2HCl	11	The 3-phenyl	H	RS	2HCl
12	4-Br	H	S	2HCl	11	The 3-phenyl	H	RS	2HCl
12	4-Br	H	S	2HCl	13	4-Br	H	R	2HCl
14	3-Br	H	S	2HCl	13	4-Br	H	R	2HCl
14	3-Br	H	S	2HCl	15	3-Br	H	R	2HCl

Be named as:

(R)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((3, the 5-dichlorophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(S)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-benzhydryl piperazidine-1-yl) acetate;

2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

2-(4-(phenyl (4-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

2-(4-((2-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

2-(4-((3-biphenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

(S)-and 2-(4-((4-bromophenyl) phenyl) methyl) piperazine-1-yl) the acetate dihydrochloride;

(R)-2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

(S)-2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride; With

(R)-2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride.

Table 2 has provided representational compound with structural formula (I), wherein R ¹Be (R)-methyl, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²Be phenyl, Ar wherein ²The following R that uses ^gAnd R ^hReplace.

Table 2

Cpd.#	R ^g	R ^h	^*Stereochemistry on the C
Cpd.#	R ^g	R ^h	^*Stereochemistry on the C		16	3-CF ₃	H	RS
17	3-Br	H	RS		16	3-CF ₃	H	RS
17	3-Br	H	RS		18	H	H	(nothing)	2HCl
19	3-I	H	R	2HCl	18	H	H	(nothing)	2HCl
19	3-I	H	R	2HCl	20	3-Br	H	R	2HCl
21	3-Br	H	S	2HCl	20	3-Br	H	R	2HCl
21	3-Br	H	S	2HCl	22	The 3-phenyl	H	RS	2HCl
23	3-CF ₃	H	S	2HCl	22	The 3-phenyl	H	RS	2HCl
23	3-CF ₃	H	S	2HCl	24	3-CF ₃	H	R	2HCl
25	4-Cl	H	RS	2HCl	24	3-CF ₃	H	R	2HCl
25	4-Cl	H	RS	2HCl	26	The 4-phenyl	H	RS	2HCl
27	4-Br	H	RS	2HCl	26	The 4-phenyl	H	RS	2HCl
27	4-Br	H	RS	2HCl	28	4-CN	H	RS
29	3-Cl	H	RS	2HCl	28	4-CN	H	RS
29	3-Cl	H	RS	2HCl	30	The 3-phenyl	H	R

Cpd.#	R ^g	R ^h	^*Stereochemistry on the C
Cpd.#	R ^g	R ^h	^*Stereochemistry on the C	31	3-SCH ₃	H	RS
32	2-Br	H	S	31	3-SCH ₃	H	RS
32	2-Br	H	S	33	2-Br	H	R
34	3-CH ₃	H	R	33	2-Br	H	R
34	3-CH ₃	H	R	35	3-CH(CH ₃) ₂	H	R
36	4-F	H	RS	35	3-CH(CH ₃) ₂	H	R
36	4-F	H	RS	37	3-F	H	RS
38	3-thiophene-2 base	H	R	37	3-F	H	RS
38	3-thiophene-2 base	H	R	39	3-SCH ₃	H	R
40	3-SCH ₃	H	S	39	3-SCH ₃	H	R
40	3-SCH ₃	H	S	41	4-SCH ₃	H	R
42	2-F	H	S	41	4-SCH ₃	H	R
42	2-F	H	S	43	2-F	H	R
44	3-OCF ₃	H	S	43	2-F	H	R
44	3-OCF ₃	H	S	45	3-OCF ₃	H	R
46	The 4-phenyl	H	R	45	3-OCF ₃	H	R
46	The 4-phenyl	H	R	47	4-(2-CH ₃Phenyl)	H	R
48	4-(3-CH ₃Phenyl)	H	R	47	4-(2-CH ₃Phenyl)	H	R
48	4-(3-CH ₃Phenyl)	H	R	49	4-(4-CH ₃Phenyl)	H	R
50	2-F	4-F	S	49	4-(4-CH ₃Phenyl)	H	R
50	2-F	4-F	S	51	2-F	4-F	R
52	4-F	H	S	51	2-F	4-F	R
52	4-F	H	S	53	4-F	H	R
54	3-F	H	S	53	4-F	H	R
54	3-F	H	S	55	3-F	H	R
55A	4-(2-phenylacetylene base)	H	R	55	3-F	H	R
55A	4-(2-phenylacetylene base)	H	R	55B	4-(2-pyridine-3-ethynyl)	H	R
55C	4-(2-pyridin-4-yl ethynyl)	H	R	55B	4-(2-pyridine-3-ethynyl)	H	R

Be named as:

2-((R)-2-methyl-4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((R)-(3-iodophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((R)-(3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((S)-(3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-2-methyl-4-(biphenyl-3-base-phenyl-methyl)-piperazine-1-yl)-acetate dihydrochloride;

2-((R)-2-methyl-4-((S)-phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

2-((R)-2-methyl-4-((R)-phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((4-chloro-phenyl-) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((JR)-2-methyl-4-(biphenyl-4-base-phenyl-methyl)-piperazine-1-yl)-acetate dihydrochloride;

2-((R)-4-((4-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((4-cyano-phenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((3-chloro-phenyl-) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

[(R)-4-((R)-biphenyl-3-base-phenyl-methyl)-2-methyl-piperazine-1-yl]-acetate;

2-((R)-2-methyl-4-((3-(methyl sulfo-) phenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((S)-(2-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(2-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (m-tolyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((R)-(3-isopropyl phenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((4-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((3-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(thiophene-2-yl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-(3-(methyl sulfo-) phenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((S)-(3-(methyl sulfo-) phenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-(4-(methyl sulfo-) phenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((S)-(2-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(2-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-((S)-phenyl (3-(trifluoromethoxy) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(trifluoromethoxy) phenyl) methyl) piperazine-1-yl) acetate;

[(R)-4-((R)-biphenyl-4-base-phenyl-methyl)-2-methyl-piperazine-1-yl]-acetate;

(R)-and the 2-methyl-4-[(R)-(2 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

(R)-and the 2-methyl-4-[(R)-(3 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

(R)-and the 2-methyl-4-[(R)-(4 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

2-((R)-4-((S)-(2,4 difluorobenzene base) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(2,4 difluorobenzene base) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((S)-(4-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(4-fluorophenyl) (phenyl) methyl)-2-is at ethyl piperazidine-1-yl) acetate;

2-((R)-4-((S)-(3-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(3-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (4-(2-phenylacetylene base) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(2-pyridin-3-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate; With

2-((R)-2-methyl-4-((R)-phenyl (3-(2-pyridin-4-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate.

Table 3 has provided representational compound with structural formula (I), wherein R ¹Be R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²Be phenyl, Ar wherein ²The following R that uses ^gAnd R ^hReplace.

Table 3

Cpd#	R ^g	R ^h	^*Stereochemistry on the C
Cpd#	R ^g	R ^h	^*Stereochemistry on the C		56	H	H	(nothing)	2HCl
57	3-CF ₃	H	RS	2HCl	56	H	H	(nothing)	2HCl

Be named as:

(S)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride; And 2-((S)-2-methyl-4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride.

Table 4 has provided representational compound with structural formula (I), wherein R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²Be phenyl, Ar wherein ²Use R ^gReplace and R ^hAs follows and R ^bAnd R ¹And R ²As follows.

Table 4

Cpd#	R ¹	R ²	R ^g	R ^h	^*Stereochemistry on the C
Cpd#	R ¹	R ²	R ^g	R ^h	^*Stereochemistry on the C		58	H	3S-CH ₃	H	H	(nothing)	2HCl
59	H	3R-CH ₃	H	H	(nothing)	2HCl	58	H	3S-CH ₃	H	H	(nothing)	2HCl
59	H	3R-CH ₃	H	H	(nothing)	2HCl	60 and 62, as two mappings	2R-CH ₃	5S-CH ₃	H	H	(nothing)	2HCl
The mixture of body (all being trans dimethyl)							60 and 62, as two mappings	2R-CH ₃	5S-CH ₃	H	H	(nothing)	2HCl
The mixture of body (all being trans dimethyl)							62	2S-CH ₃	5R-CH ₃	H	H	(nothing)	2HCl
63	H	3R-CH ₃	The 4-phenyl	H	RS		62	2S-CH ₃	5R-CH ₃	H	H	(nothing)	2HCl

Be named as:

(S)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate dihydrochloride;

(R)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate dihydrochloride;

2-((2,5-is trans)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate dihydrochloride;

2-((2, the 5-cis)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate dihydrochloride; With

2-((R)-3-methyl-4-(phenyl (4-phenylbenzene) methyl) piperazine-1-yl) acetate.

Table 5 has provided representational compound with structural formula (I), wherein R ¹As follows, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²Be phenyl, Ar wherein ¹Use R ^gReplace and Ar ²Use R ^hReplace, as follows.

Table 5

Cpd#	R ^g	R ^h	R ^l	^*Stereochemistry on the C
Cpd#	R ^g	R ^h	R ^l	^*Stereochemistry on the C		64	3-Cl	3-Cl	2R-CH ₃	(nothing)
65	3-F	3-F	2R-CH ₃	(nothing)		64	3-Cl	3-Cl	2R-CH ₃	(nothing)
65	3-F	3-F	2R-CH ₃	(nothing)		66	4-CF ₃	3-CF ₃	H	RS
67	4-F	The 3-phenyl	2R-CH ₃	RS	2HCl	66	4-CF ₃	3-CF ₃	H	RS
67	4-F	The 3-phenyl	2R-CH ₃	RS	2HCl	68	4-Cl	4-Cl	2R-CH ₃	(nothing)	2HCl
69	4-F	3-Br	2R-CH ₃	RS	2HCl	68	4-Cl	4-Cl	2R-CH ₃	(nothing)	2HCl
69	4-F	3-Br	2R-CH ₃	RS	2HCl	70	4-F	4-F	3R-CH ₃	(nothing)	2HCl
71	4-F	4-F	2-R-CH ₃	(nothing)		70	4-F	4-F	3R-CH ₃	(nothing)	2HCl
71	4-F	4-F	2-R-CH ₃	(nothing)		72	3-CF ₃	3-CF ₃	2-R-CH ₃	(nothing)
73	3-CF ₃	3-CF ₃	H	(nothing)		72	3-CF ₃	3-CF ₃	2-R-CH ₃	(nothing)

Be named as:

(R)-2-(4-(two (3-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (3-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-(4-((3-(trifluoromethyl) phenyl) (4-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((4-fluorophenyl) (3-(phenylbenzene) methyl))-(/ 2)-2-methylpiperazine-1-yl) acetate dihydrochloride;

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-4-((3-bromophenyl) (4-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride;

(R)-2-(4-(two (4-fluorophenyl) methyl)-3-methylpiperazine-1-yl) acetate dihydrochloride;

(R)-2-(4-(two (4-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate; With

2-(4-(two (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate.

Table 6 has provided representational compound with structural formula (I), wherein R ¹Be (R)-methyl, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹And Ar ²

Cpd.#	Ar ¹	Ar ²	^*Stereochemistry on the C
Cpd.#	Ar ¹	Ar ²	^*Stereochemistry on the C		74	Thiophene-2-yl	3-CF ₃Phenyl	RS
75	Thiophene-2-yl	3-CF ₃Phenyl	R		74	Thiophene-2-yl	3-CF ₃Phenyl	RS
75	Thiophene-2-yl	3-CF ₃Phenyl	R		76	Thiophene-2-yl	3-CF ₃Phenyl	S
77	Chloropropyl	3-CF ₃Phenyl	RS	2HCl	76	Thiophene-2-yl	3-CF ₃Phenyl	S

Be named as:

2-((R)-2-methyl-4-(thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-thiophene-2-base (3-(three fluoridize methyl) phenyl) methyl) piperazine-1-yl) acetate; With

2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride.

Table 7 has provided representational compound with structural formula (I), wherein R ⁵And R ³Be hydrogen, Ar ¹And Ar ²Be respectively 4-Cl phenyl and R ¹, R ², and R ⁴

Cpd#	R ⁴	R ¹	R ²	R ¹+R ²
Cpd#	R ⁴	R ¹	R ²	R ¹+R ²		78	H	H	2(R)-CH ₃
79	(S)-CH ₃	H	3(R)-CH ₃			78	H	H	2(R)-CH ₃
79	(S)-CH ₃	H	3(R)-CH ₃			80	H			3-＝(O)
81	(S)-CH ₃	H	2(R)-CH ₃			80	H			3-＝(O)
81	(S)-CH ₃	H	2(R)-CH ₃			82	(R)-CH ₃	H	2(R)-CH ₃
83	H	H		2-＝(O)		82	(R)-CH ₃	H	2(R)-CH ₃
83	H	H		2-＝(O)		84	H	6(S)-CH ₃	2(R)-CH ₃		2HCl
85	H	2-CH ₃	2-CH ₃		2HCl	84	H	6(S)-CH ₃	2(R)-CH ₃		2HCl
85	H	2-CH ₃	2-CH ₃		2HCl	86	-CH ₃	H	H		2HCl
87	H	H	2(R)-CH(CH ₃) ₂		2HCl	86	-CH ₃	H	H		2HCl
87	H	H	2(R)-CH(CH ₃) ₂		2HCl	88	H	H	H		2HCl

Be named as:

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate;

(S)-2-((R)-4-(two (4-chloro-phenyl-s) are at ethyl)-3-methylpiperazine-1-yl) propionic acid;

2-(4-(two (4-chloro-phenyl-) methyl)-3-oxo piperazine-1-yl) acetate;

(S)-2-((R)-4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) propionic acid;

(R)-2-((R)-4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) propionic acid;

2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetate;

2-((2R, 6S)-4-(two (4-chloro-phenyl-) methyl)-2,6-lupetazin-1-yl) the acetate dihydrochloride;

2-(4-(two (4-chloro-phenyl-) methyl)-2,2-lupetazin-1-yl) acetate dihydrochloride;

2-(4-(two (4-chloro-phenyl-) methyl) piperazine-1-yl) propionic acid dihydrochloride;

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-sec.-propyl piperazine-1-yl) acetate dihydrochloride; With

2-(4-(two (4-chloro-phenyl-) methyl) piperazine-1-yl) acetate dihydrochloride.

Table 8

Be named as 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl)-1,4-diazene-1-yl)-acetate.

Embodiment

(A) in one embodiment, the structural table with compound of structural formula (I) is shown structural formula (IA):

Wherein:

R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace;

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl group ^j, R ^kOr R ^lReplace; With

The definition in the present invention's summary of other groups.

In this group (A), one group of compound is such, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, or halogenated alkoxy, prerequisite is R ¹And R ²In at least one be not hydrogen.

In this group (A), another group compound is such, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, or halogenated alkoxy.

In this group (A), another group compound is such, wherein R ¹And R ²Be independently selected from hydrogen, methyl, ethyl, propyl group, trifluoromethyl, 2,2, the 2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2, the 2-trifluoro ethoxy.

In this group (A), another group compound is such, wherein R ¹With R be hydrogen.

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²It is alkyl.

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²It is methyl.

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²Be methyl, ethyl, propyl group, trifluoromethyl, 2,2, the 2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2, on the ortho position carbon atom of 2-trifluoro ethoxy and the piperazine nitrogen-atoms that is positioned at the replacement of usefulness carboxyl methyl group.

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²Be methyl, ethyl, propyl group, trifluoromethyl, 2,2,2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2,2-trifluoro ethoxy and be positioned on the ortho position carbon atom of the piperazine nitrogen-atoms that replaces with the carboxyl methyl group and carry R ²Stereochemistry on the carbon atom of group is (R).

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²Be on methyl and the ortho position carbon atom that is positioned at the piperazine nitrogen-atoms that replaces with the carboxyl methyl group with carry R ²Stereochemistry on the carbon atom of group is (R).

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²Be methyl, ethyl, propyl group, trifluoromethyl, 2,2,2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2,2-trifluoro ethoxy and be positioned on the ortho position carbon atom of the piperazine nitrogen-atoms that replaces with the carboxyl methyl group and carry R ²Stereochemistry on the carbon atom of group is (S).

In this group (A), another group compound is such, wherein R ¹And R ²Be independently selected from methyl, ethyl, propyl group, trifluoromethyl, 2,2, the 2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2, the 2-trifluoro ethoxy.

In this group (A), another group compound is such, wherein R ¹And R ²Be independently selected from methyl, ethyl, propyl group, trifluoromethyl, 2,2, the 2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2, the 2-trifluoro ethoxy is R wherein ¹Be positioned on the ortho position carbon atom of the piperazine nitrogen-atoms that replaces with the carboxyl methyl group and R ²Be positioned at and carry R ¹On the para-position carbon of the carbon atom of group.

In this group (A), another group compound is such, wherein R ¹And R ²Be independently selected from methyl, ethyl, propyl group, trifluoromethyl, 2,2, the 2-trifluoroethyl, methoxyl group, oxyethyl group, propoxy-, trifluoromethoxy, difluoro-methoxy, or 2,2, the 2-trifluoro ethoxy is R wherein ¹Be positioned on the ortho position carbon atom of the piperazine nitrogen-atoms that replaces with the carboxyl methyl group and R ²Be positioned at and carry R ¹On the para-position carbon of the carbon atom of group and carry R ¹And R ²Stereochemistry on the carbon atom of group be (R, S), (R, R), (S, R) or (S, S).

In this group (A), another group compound is such, wherein R ¹Be hydrogen and R ²Be aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace.

(B) in another embodiment, the structural table with compound of structural formula (I) is shown structural formula (IB):

Wherein:

R ¹And R ²The common oxo group that forms;

The definition in the present invention's summary of other groups.

At this group (B), one group of compound is such, and wherein oxo group is positioned on the ortho position carbon atom of the piperazine nitrogen-atoms that is replaced by the carboxyl methyl group.

(C) in another embodiment, the structural table with compound of structural formula (I) is shown structural formula (IC):

Wherein:

R ¹And R ²Be connected on the identical carbon atoms and be combined to form cycloalkyl optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fReplace;

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl group ^j, R ^kOr R ^lReplace; With the definition in the present invention's summary of other groups.

In this group (C), one group of compound is such, wherein R ¹And R ²Be combined to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring are optionally with being independently selected from alkyl, hydroxyl, or the R of fluorine ^dOr R ^eReplace.

(D) in another embodiment, the structural table with compound of structural formula (I) is shown structural formula (ID):

Wherein:

R ¹And R ²Be connected on the identical carbon atoms and be combined to form the monocycle saturated heterocyclyl, optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fReplace;

The definition in the present invention's summary of other groups.

In this group (D), one group of compound is such, wherein R ¹And R ²Be combined to form tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, or pyrrolidyl, wherein each is looked around and need be independently selected from one or two alkyl, hydroxyl, or the R of fluorine ^dOr R ^eReplace.

(E) in another embodiment, the structural table with compound of structural formula (I) is shown structural formula (IE):

Wherein:

R ¹And R ²When being connected to the carbon atom 2 of piperazine ring and 5 or 3 and 6 and going up and be combined to form-C ₁-C ₂-alkylidene chain, wherein one or two hydrogen atom in the alkylidene chain can optionally replace with one or two alkyl;

The definition in the present invention's summary of other groups.

(F) in another embodiment, the structural table with compound of structural formula (I) is shown structural formula (IF):

Wherein:

R ¹And R ²When being connected to the carbon atom 2 of piperazine ring and 5 or 3 and 6 and going up and be combined to form-C ₁-C ₃-alkylidene chain, wherein a carbon atom in the alkylidene chain is replaced by-NR-,-O-,-S (O) n-(wherein R is that hydrogen or alkyl and n are 0-2) and further wherein one or two hydrogen atom in the alkylidene chain can optionally replace with one or two alkyl;

The definition in the present invention's summary of other groups.

In this group (F), one group of compound is such, wherein R ¹And R ²When being connected to the carbon atom 2 of piperazine ring and 5 or 3 and 6 and going up and be combined to form-C ₁-C ₂-alkylidene group, one of them carbon are replaced by-NR-(wherein R is a hydrogen or alkyl).

(a) in above embodiment (A)-(F) and the group that wherein comprised, one group of compound is such, wherein R ³Be hydrogen.In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (S).In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (R).

(b) in above embodiment (A)-(F) and the group that wherein comprised, another group compound is such, wherein R ³Be alkyl, preferable methyl or ethyl.In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (S).In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (R).

(c) in above embodiment (A)-(F) and the group that wherein comprised, another group compound is such, wherein R ³It is fluorine.In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (S).In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (R).

(d) in above embodiment (A)-(F) and the group that wherein comprised, another group compound is such, wherein R ³Be fluoroalkyl, preferred difluoromethyl or trifluoromethyl.In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (S).In this group, one group of compound is such, wherein carries R ³Stereochemistry on the carbon atom of group is (R).

(i) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised and will organize in the group of (A)-(F) formation with (a)-(d) combination, one group of compound is such, wherein Ar ¹And Ar ²Be phenyl, each phenyl optionally as above defines and is substituted.

In this embodiment (i), one group of compound is such, wherein Ar ¹And Ar ²It is phenyl.In this embodiment, another group compound is such, wherein Ar ¹Be phenyl and Ar ²Be with being selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gThe phenyl that replaces.

In this embodiment (i), another group compound is such, wherein Ar ¹Be phenyl and Ar ²Be with being selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gThe phenyl and the R that replace ⁸Be positioned on the 3-position of benzyl ring, be connected to-CR ³Ar ¹Carbon atom on the group is in the 1-position.

In this embodiment (i), another group compound is such, wherein Ar ¹With being selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gThe phenyl that replaces, preferred R ^gBe positioned at the 3-position and the Ar of benzyl ring ²Be selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^hThe phenyl that replaces, preferred R ^hBe positioned at 3-position benzyl ring.

(ii) at embodiment (A)-(F), (a)-(d) and in the group that is wherein comprised and will organize in the group that (A)-(F) form with (a)-(d) combination, another organizes compound is such, wherein Ar ¹Be phenyl and Ar ²Be heteroaryl, each is looked around as above to define and is substituted.

This embodiment (ii) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, or thienyl, each Ar ¹And Ar ²Optionally as above definition is substituted.

This embodiment (ii) in, another group compound is such, Ar wherein ¹Be phenyl and Ar ²Be optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hThe pyridyl that replaces, pyrimidyl, pyridazinyl, pyrazinyl, or thienyl.

This embodiment (ii) in, another group compound is such, Ar wherein ¹Be optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hThe phenyl and the Ar that replace ²Be pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, or thienyl, preferred thienyl.

(iii) at above embodiment (A)-(F), (a)-(d) and in the group that is wherein comprised and will organize in the group that (A)-(F) form with (a)-(d) combination, another organizes compound is such, wherein Ar ¹Be phenyl and Ar ²Be heterocyclic radical, each Ar ¹And Ar ²Optionally as above definition is substituted, and prerequisite is Ar ²Not to be fused to pyrimidine-4 (the 3H)-ketone on the quinary heteroaryl ring and optionally as above to define to be substituted.

This embodiment (iii) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be THP trtrahydropyranyl, piperidyl, or tetrahydrofuran base, each Ar ¹And Ar ²Optionally as above definition is substituted.

This embodiment (iii) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hThe THP trtrahydropyranyl that replaces, piperidyl, or tetrahydrofuran base.

In this group, another group compound is such, wherein Ar ¹Be optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hThe phenyl and the Ar that replace ²Be THP trtrahydropyranyl, piperidyl, or furyl.

(iv) at embodiment (A)-(F), (a)-(d) and in the group that is wherein comprised and will organize in the group that (A)-(F) form with (a)-(d) combination, another organizes compound is such, wherein Ar ¹Be phenyl and Ar ²Be cycloalkyl, each Ar ¹And Ar ²Optionally as above definition is substituted.

This embodiment (iv) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be cyclopentyl or cyclohexyl, each Ar ¹And Ar ²Optionally as above definition is substituted.

This embodiment (iv) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be cyclopentyl or cyclohexyl, each Ar ¹And Ar ²Optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hReplace.

This embodiment (iv) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be cyclopropyl, Ar ¹Optionally as above definition is substituted.

This embodiment (iv) in, one group of compound is such, wherein Ar ¹Be phenyl and Ar ²Be cyclopropyl, Ar ¹Optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hReplace.

(v) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised and will organize in the group that (A)-(F) form with (a)-(d) combination, another organizes compound is such, wherein Ar ¹And Ar ²Be heteroaryl optionally as above the definition be substituted.

(v), one group of compound is such, wherein Ar in this embodiment ¹And Ar ²Be respectively optionally with being independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, preferable methyl, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or 2,2, the R of 2-trifluoro ethoxy ^gOr R ^hThe heteroaryl that replaces.

(vi) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised and will organize in the group that (A)-(F) form with (a)-(d) combination, another organizes compound is such, wherein Ar ¹Be heteroaryl and Ar ²Be each Ar of cycloalkyl ¹And Ar ²Optionally as above definition is substituted.

(vii) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised, one group of compound is such, wherein Ar ¹Be heterocyclic radical and Ar ²Be each Ar of heteroaryl ¹And Ar ²Optionally as above definition is substituted.

(viii) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised, one group of compound is such, wherein Ar ¹Be cycloalkyl and Ar ²Be each Ar of heterocyclic radical ¹And Ar ²Optionally as above definition is substituted.

(ix) at embodiment (A)-(F), (a)-(d) and in the group that wherein comprised, one group of compound is such, wherein Ar ¹Be cycloalkyl and Ar ²Be each Ar of cycloalkyl ¹And Ar ²Optionally as above definition is substituted.

Above embodiment, comprise be included in wherein each group and son group as, each is included in group in the group (A) to (F) and all combinations of son group, can be independently be included in group (a)-(d) and (i)-(ix) in each group and son group and by organizing (a)-(d) and (i)-(ix) making up each group that forms and make up.

(G) in another embodiment, the present invention relates to the to have structural formula compound of (I), wherein Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl; hydroxyalkyl, alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base; the alkoxyl group alkoxyl group, aminoalkoxy, amino-sulfonyl, aminocarboxyl; acyl amino, aryl, or cycloalkyl, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace.

(H) in another embodiment, the present invention relates to the to have structural formula compound of (I), wherein Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; hydroxyalkyl, alkoxyalkyl, aminoalkyl group; the hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace, prerequisite is R ^hAnd R ⁱNot that replace or unsubstituted tetrazolium.

(I) in another embodiment, the present invention relates to the to have structural formula compound of (I), wherein Ar ¹Be phenyl and Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe heteroaryl or the heterocyclic radical that replace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; hydroxyalkyl, alkoxyalkyl, aminoalkyl group; the hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; hydroxyalkyl, alkoxyalkyl, aminoalkyl group; the hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace, prerequisite is R ^hAnd R ⁱNot that replace or unsubstituted tetrazolium.

(J) in another embodiment, the present invention relates to the to have structural formula compound of (I), Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Prerequisite is:

(i) if the phenyl that Ar is replaced by one or more hydroxyls or alkoxyl group, Ar is not phenyl or the bicyclic heteroaryl that the phenyl moiety by the dicyclo ring connects so, wherein phenyl or bicyclic heteroaryl ring are that replace or unsubstituted tetrazyl;

If (ii) Ar ¹By the phenyl of one or more hydroxyls or alkoxyl group replacement, Ar so ²Be not with heterocycle or the cyclosubstituted phenyl of heteroaryl, wherein heterocycle or heteroaryl ring are by carboxyl, and alkoxy carbonyl replaces, or that replace or unsubstituted tetrazole ring;

If (iii) Ar ¹Be to use alkyl, the quinary heteroaryl ring that heteroaryl replacement or unsubstituted or heterocyclic radical replace, Ar so ²Be not 5 or 6 yuan of replacements or unsubstituted heteroaryl or heterocyclic ring, wherein heteroaryl or heterocyclic ring comprise at least one azo-cycle atom; With

If (iv) Ar ¹Be replace or unsubstituted phenyl and Ar ²Be pyrimidine-4 that on N-3 nitrogen, replaced or unsubstituted (3H)-ketone and be connected to-CR by C-2 ring carbon by Rh ³On-the carbon, its uncondensed is to the quinary heteroaryl ring so.

In above embodiment (G)-(J), other groups with compound of structural formula (I) are such, wherein R ¹, R ², R ³, Ar ¹And Ar ²Definition as be included in (A) to (F), (a)-(d) and (i)-(ix) and group in the combination and son group.

(J) in another embodiment, the present invention relates to the to have structural formula compound of (I):

Wherein:

R ¹And R ²Be hydrogen or alkyl independently; With

Ar ¹And Ar ²Be phenyl independently, each is looked around and need use R ^gOr R ^hReplace, wherein R ^gAnd R ^hBe alkyl independently, halo, haloalkyl, halogenated alkoxy, alkylthio, alkoxyl group, alkyl-carbonyl, or alkoxy carbonyl.In the embodiment in this group, R ¹And R ²Be hydrogen.In another embodiment in this group, R ¹And R ²In at least one be not hydrogen.

In the embodiment in this group, the compound with structural formula (I) has one of following structure:

Or

R wherein ¹Be hydrogen or methyl and R ^gAnd R ^hBe hydrogen independently, alkyl, halo, haloalkyl, or halogenated alkoxy, prerequisite is, in compound (a), R ^gNot hydrogen.In another embodiment in this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup is connected on the 3-position of benzyl ring and R ^gAnd R ^hBe methyl independently, chlorine, trifluoromethyl, or trifluoromethoxy.In another embodiment in this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup is connected on the 3-position of benzyl ring and R ^gAnd R ^hBe methyl independently, chlorine, trifluoromethyl, or trifluoromethoxy and ^*Stereochemistry on the C is (R).In another embodiment of this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup is connected on the 3-position of benzyl ring.In another embodiment in this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup be connected on the 3-position of benzyl ring and ^*Stereochemistry on the C is (R).

(K) in another embodiment, the present invention relates to the to have structural formula compound of (I):

Wherein:

R ¹And R ²Be hydrogen or alkyl independently;

R ³Be hydrogen, alkyl, fluorine, or fluoroalkyl; With

Ar ¹And Ar ²Be phenyl independently, each is looked around and need use R ^g, R ^hOr R ^lReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace, prerequisite is, if R ¹, R ², R ³And R ⁴Be hydrogen, R ^g, R ^hOr R ⁱDependently be selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio, alkoxyl group, alkyl-carbonyl, or alkoxy carbonyl.

In the embodiment in this group, R ³And R ¹Be hydrogen, R ^gBe hydrogen or halo, and R ^hBe cyano group, heteroaryl (just tetrazyl) or phenyl, each is looked around and need use R ^j, R ^kOr R ^lReplace.

In another embodiment in this group, R ³And R ¹Be hydrogen, R ^gBe hydrogen or halogen, and R ^hBe cyano group, heteroaryl (except tetrazyl) or phenyl, each is looked around and need replace with alkyl.

In another embodiment in this group, the compound with structural formula (I) has one of following structure:

Or

R wherein ^lBe hydrogen or methyl, R ^gBe cyano group, heteroaryl or phenyl, each is looked around and need be replaced and R by alkyl ^hBe alkyl, halo, haloalkyl, or halogenated alkoxy.In another embodiment in this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup is connected on the 3-position of benzyl ring and R ^hBe methyl, chlorine, trifluoromethyl, or trifluoromethoxy.In another embodiment in this group, the compound with structural formula (I) has one of structure (a)-(e), wherein R ^gGroup be connected on the 3-position of benzyl ring and ^*Stereochemistry on the C is (R).

(L) in another embodiment, the present invention relates to the to have structural formula compound of (I), wherein:

N is 1;

R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be with being independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or

R ¹And R ², in the time of on the carbon atom 2 that is connected to piperazine ring and 5 or 3 and 6, can form jointly-C ₁-C ₃-alkylidene chain, wherein a carbon atom in the alkylidene chain optionally is replaced by-NR-,-O-,-S (O) n-(wherein R is that hydrogen or alkyl and n are 0-2) and further wherein one or two carbon atom in the alkylidene chain can optionally replace with one or two alkyl; With

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace, prerequisite is:

In this embodiment, one group of compound is such, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace.In this embodiment, one group of compound is such, if Ar wherein ¹And Ar ²Be phenyl, carrying Ar ¹And Ar ²Stereochemistry on the carbon atom of group (promptly-CR ³Ar ¹Ar ²) be (R).

In this embodiment, another group compound is such, if Ar wherein ¹And Ar ²Be phenyl or cycloalkyl independently, prerequisite is Ar ¹And Ar ²At least a in the group is cycloalkyl, carries Ar ¹And Ar ²Stereochemistry on the carbon atom of group (promptly-CR ³Ar ¹Ar ²) be (R).In this embodiment, one group of compound is such, if Ar wherein ¹And Ar ²Be phenyl or heteroaryl independently, Ar is provided ¹And Ar ²At least a in the group is phenyl, carries Ar ¹And Ar ²Stereochemistry on the carbon atom of group (promptly-CR ³Ar ¹Ar ²) be (S).

In this embodiment, another group compound is such, wherein R ¹And R ²Be hydrogen.

In this embodiment, another group compound is such, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, or halogenated alkoxy, prerequisite is R ¹And R ²In at least one be not hydrogen.In this embodiment, another group compound is such, wherein R ¹Be hydrogen and R ²It is alkyl.In this embodiment, one group of compound is such, wherein R ²It is methyl.

In this embodiment, another group compound is such, wherein R ¹And R ²Be connected on the identical carbon atoms and be combined to form optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fThe cycloalkyl that replaces.

In this embodiment, another group compound is such, wherein R ¹And R ²Be connected on the identical carbon atoms and be combined to form optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fThe monocycle saturated heterocyclyl that replaces.

In this embodiment, another group compound is such, wherein R ¹And R ²When being connected to the carbon atom 2 of piperazine ring and 5 or 3 and 6 and going up and be combined to form-Cj-C ₂-alkylidene chain, wherein one or two carbon atom in the alkylidene chain can optionally replace with one or two alkyl.

In this embodiment, another group compound is such, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl independently, and Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces, prerequisite is R ¹, R ², and R ⁴In at least one be not hydrogen.

In this embodiment, another group compound is such, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl independently, Ar ¹Be optionally to use R ^g, R ^hOr R ⁱThe phenyl and the Ar that replace ²Be cycloalkyl, prerequisite is R ¹, R ², and R ⁴In at least one be not hydrogen.In this embodiment, another group compound is such, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl independently, Ar ¹Be phenyl and Ar ²Be heteroaryl, each is looked around and need use R ^g, R ^hOr R ⁱReplace, prerequisite is R ¹, R ², and R ⁴In at least one be not hydrogen.

General synthetic schemes

The compounds of this invention can be by the method manufacturing of being described in the following reaction scheme that provides.

The starting raw material and the reagent that are used to prepare these compounds can be available from commercial supplier such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St.Louis, Mo.) or by the procedure known to those skilled in the art according to reference paper such as Fieser and Fieser ' s Reagents for Organic Synthesis, Volumes 1-17 (JohnWiley and Sons, 1991); Rodd ' s Chemistry of Carbon Compounds, Volumes 1-5and Supplementals (Elsevier Science Publishers, 1989); OrganicReactions, Volumes 1-40 (John Wiley and Sons, 1991), March ' sAdvanced.OrganicChemistry, (JohnWiley and Sons, the 4th edition) and Larock ' sComprehensive Organic Transformations (VCH Publishers Inc., 1989) in the technology that provides and preparing.These schemes only are the explanations to the certain methods that can be used for synthetic The compounds of this invention, can expect various modification to these schemes with reference to the those skilled in the art of present disclosure.The starting raw material of reaction and intermediate and final product can use routine techniques as required, include but not limited to filter, and distillation, crystallization, chromatogram is separated and purifying with similar techniques.These materials can use usual manner, comprise that physical constant and spectroscopic data characterize.

Unless otherwise prescribed, reaction as herein described is under atmospheric pressure-78 degrees centigrade to about 150 degrees centigrade approximately of temperature ranges, more preferably from about 0 degree centigrade to about 125 degrees centigrade down with most preferably in about room temperature (or environment) temperature, as, carry out under about 20 degrees centigrade.

Ar wherein ¹, Ar ², R ¹, R ², R ³, R ⁴And R ⁵In the present invention summary the compound with structural formula (I) of definition can be according to following option A illustrated and being prepared of describing.

Option A

(wherein LG is suitable leavings group such as halo, tosylate, mesylate, fluoroform sulphonate, and analogue, and Ar will to have the compound of structural formula 1 ¹, Ar ², and R ³Definition in the present invention summary) with having structural formula 2 (R wherein ¹And R ²Definition in the present invention's summary) piperazine is handled, and obtains the compound of structural formula 3.Be reflected at appropriate organic solvent such as acetonitrile, toluene, and carry out in the analogue (being with or without alkali such as triethylamine or diisopropylethylamine) and carry out in 70 to 150 degrees centigrade of following heating of suitable temperature.

Compound with structural formula 1 is commercially available or can be easily by method preparation well known in the art.For example, the compound (wherein LG is a halo) with structural formula 1 can prepare like this: with structural formula Ar ¹COAr ²Ketone compound and appropriate reductant such as sodium borohydride, and analogue at suitable organic alcohol solvent such as methyl alcohol, reacts in ethanol and the analogue, and the corresponding structural formula Ar that has is provided ¹C (OH) Ar ²Alcohol, with halogen agent such as thionyl chloride, oxalyl chloride, triphenylphosphine/carbon tetrabromide and analogue are handled, and the compound with structural formula 1 is provided, wherein LG is a halo.In addition, Ar ¹C (OH) Ar ²Available methylsulfonyl chloride, toluene sulfonyl chloride, trifluoromethanesulfanhydride anhydride are handled under condition well known in the art so that the compound with structural formula 1 to be provided, and wherein LG is respectively a mesylate, tosylate, or fluoroform sulphonate.Structural formula Ar ¹COAr ²Compound be commercially available or they can be by method well known in the art preparation.For example, with Ar ¹(Ar wherein ¹Be aryl or heteroaryl ring) use Ar ²COCl is acidylate under Fridel-Crafts acylation reaction condition.

Structural formula Ar ¹C (OH) Ar ²Compound be commercially available or also can be by with structural formula Ar ¹The aldehyde of CHO structural formula Ar ²The Grignard reagent of MgX (wherein X is a halo) is handled under condition well known in the art and is prepared.Structural formula Ar ¹COAr ²And Ar ¹C (OH) Ar ²Compound as (2-bromophenyl) (phenyl) ketone, 4-bromine benzophenone, 2-fluorine benzophenone, 2,4-difluoro benzophenone, (4-fluorophenyl)-(phenyl) ketone, 2-(trifluoromethyl) benzophenone, 3-(trifluoromethyl)-benzophenone, 4-(trifluoromethyl)-benzophenone, 3,4-two chloro benzophenones, 4-chloro-benzophenone, the 2-hydroxy benzophenone, 2,4 dihydroxy benzophenone, the 3-hydroxy benzophenone, 5-chloro-2-hydroxy-4-methyl benzophenone, 4-hydroxy benzophenone, 2-hydroxy-5-methyl base-benzophenone, 3-benzoyl phenylformic acid, 4-benzoyl phenylformic acid, 4-benzoyl biphenyl, 4-morpholino-benzophenone, 4-amino-3-nitro benzophenone, 3-nitro-benzophenone, 2-chloro-5-nitro-benzophenone, 4-nitro-benzophenone, 2-amino-5-nitro-benzophenone, 2-amino-benzophenone, 3,4-diamino-benzophenone, 2-amino-5-chloro-benzophenone, 4-Uvinul A Plus, 4-(dimethylamino)-benzophenone, 2-hydroxyl-4-methoxyl group-benzophenone, 4-methoxyl group-benzophenone, 2-methyldiphenyl ketone, 3-methyl-benzophenone, (2,4-dimethyl-phenyl) (phenyl) ketone, 4-methyldiphenyl ketone, 3-chloro-benzophenone, 3,4-difluoro benzophenone, 4-cyano group benzophenone, (3-monophen base)-(phenyl) ketone, 3,4-dihydro-2H-1,5-benzo dioxepin-7-base (phenyl) ketone, 3,4-dihydroxy benzophenone, 4-fluorine benzophenone, 2-benzoyl phenylformic acid, 2-benzoyl-naphthalene, 4-chloro-3-nitro-benzophenone, 3,4-dimethyl benzophenone, 2,5-two fluoro-benzophenone, 1,4-dibenzoyl benzene, 4-ethyl benzophenone, 3,5-two (trifluoromethyl)-benzophenone, 3-amino-benzophenone, 2-methoxyl group benzophenone, 1-naphthyl phenyl ketone, 2,3-two fluoro-benzophenone, 3,5-difluoro benzophenone, 2-fluoro-5-(trifluoromethyl) benzophenone, 4-fluoro-3-(three fluoro-methyl) benzophenone, 4-benzoyl-4 '-bromo biphenyl, 6-benzoyl-beta naphthal, 2-amino-4-methyldiphenyl ketone, 5-chloro-2-(methylamino) benzophenone, 2,5-dimethyl-benzophenone, 2-benzoyl phenylformic acid methyl ester, 4-benzyl oxygen base benzophenone, 5-chloro-2-hydroxy benzophenone, 2-(3-benzoyl phenyl) propionitrile, 2-fluoro-3-(trifluoromethyl)-benzophenone, 4-(diethylamino)-benzophenone, 3-bromine benzophenone, 2-cyano group-benzophenone, 4-oxyethyl group-2-hydroxy benzophenone, the 2-chloro benzophenone, (4-chloro-phenyl-)-(phenyl) methyl alcohol, (3-chloro-phenyl-) (phenyl) methyl alcohol, (4-bromophenyl) (phenyl) methyl alcohol, (3-trifluoromethyl) (phenyl) methyl alcohol, (4-three fluoro-aminomethyl phenyls) (phenyl) methyl alcohol, 4,4 '-difluorodiphenyl base methyl alcohol, 4,4 '-two chloro-di-phenyl-methanols, 2-methyldiphenyl base methyl alcohol, 4-chloro-di-phenyl-methanol, 4-methyldiphenyl base methyl alcohol, 4,4 '-two (dimethylamino) diphenyl-carbinol, 4,4 '-dimethoxy-diphenyl-carbinol, 4,4 '-the dimethoxy diphenyl-carbinol, 2-(trifluoromethyl) diphenyl-carbinol, 3-(trifluoromethyl)-diphenyl-carbinol, 4-methoxyl group diphenyl-carbinol, 4-(trifluoromethyl) diphenyl-carbinol, 4,4 '-dimethyl diphenyl methyl alcohol, with two [3,5-two (trifluoromethyl) phenyl]-methyl alcohol, two (4-diethyl monophen base)-methyl alcohol can be available from Lancaster Synthesis Ltd.; Fluka Chemie GmbH; Aldrich ChemicalCompany, Inc.; Alfa Aesar, A Johnson Matthey Company; Acros OrganicsUSA; May bridge; Or VWR International.

Compound 3 usefulness bromacetates (wherein R is an alkyl, preferable methyl, ethyl, the tertiary butyl, and analogue) are handled, the compound of structural formula 4 is provided.Be reflected at alkali such as triethylamine, DIEA ₅With the existence of analogue down with at appropriate organic solvent such as acetonitrile, tetrahydrofuran (THF), DMF carries out in methylene dichloride and the analogue.The acidity of the ester group in 4 or alkaline hydrolysis obtain having the compound of structural formula (I) subsequently.

Compound with structural formula 4 can be by further modification before changing into the have structural formula compound of (I).For example, has structural formula 4 (Ar wherein ¹Or Ar ²Replace with the halo group) compound can with alkynyl, aryl, or heteroaryl boric acid reacts so that the compound of corresponding construction formula 4, wherein Ar to be provided under Suzuki linked reaction condition ¹Or Ar ²Use alkynyl respectively, aryl, or heteroaryl ring replaces.Reaction is usually at common palladium catalyst such as Pd (PPh ₃) ₄, Pd (PPH ₃) ₂Cl ₂, Pd ₂Dba ₃, Pd (dppf) Cl ₂, CH ₂Cl ₂With analogue and weak base such as Na ₂CO ₃Under the existence of analogue, at aqueous solvent and appropriate organic solvent such as acetonitrile, the p-diox, DMF carries out in the mixture of THF and analogue.Reaction is heated to 70-130 degree celsius temperature scope (oil bath or microwave irradiation) usually.The acidic hydrolysis of the ester group in 4 obtains having the compound of structural formula (I) subsequently.

In addition, more than transform and under the linked reaction condition, to carry out.Under the Stille reaction conditions, compound 4 (Ar wherein ¹Or Ar ²Replace with the halo group) use alkynyl, aryl, heteroaryl tributyl tin (or tin trimethyl) derivative is handled so that the compound with structural formula 4, wherein Ar to be provided ¹Or Ar ²Use alkynyl respectively, aryl, or heteroaryl ring replaces.Reaction is usually at common palladium catalyst such as Pd (PPh ₃) ₄, Pd (PPh ₃) ₂Cl ₂, Pd ₂Dba ₃, Pd (dppf) Cl ₂, CH ₂Cl ₂With under the existence of analogue and be with or without other part such as tBu ₃P, Ph ₃P, Ph ₃Under the situation of As and analogue, at appropriate organic solvent such as toluene, acetonitrile, the p-diox, DMF carries out in THF and the analogue.Range of reaction temperature is 20 to 150 degrees centigrade (room temperature, oil bath or microwave irradiations).The acidic hydrolysis of the ester group in 4 obtains having the compound of structural formula (I) subsequently.In addition, more than transforming can be at Negishi or Sonogashira (Ar wherein ¹Or Ar ²Replace with end alkane alkynes) carry out under the linked reaction condition.

Compound with structural formula (I) can be converted to the compound that other have structural formula (I).For example, the compound (Ar wherein that has structural formula (I) ¹Or Ar ²Replace with mono-substituted or disubstituted amido, as definition in the present invention's summary) can be by corresponding compound with structural formula (I) (Ar wherein ¹Or Ar ²Replace with nitryl group) by at first nitryl group being reduced into amino group and alkylation under condition well known in the art subsequently, arylation, this amino group of alkylsulfonylization or acylations and preparing.Single substituted-amino can be as required by single substituted-amino is carried out alkylation, arylation, alkylsulfonylization, or acylations and change into disubstituted amido.React usually at alkali such as potassium tert.-butoxide, and in suitable solvent such as tetrahydrofuran (THF) and analogue, carry out under the existence of analogue and catalyzer such as 18-hat-6.Compound (Ar wherein with structural formula (I) ¹Or Ar ²Use alkoxyl group, halogenated alkoxy, hydroxy alkoxy base, or aminoalkoxy replaces) can be by with corresponding compound with structural formula (I) (wherein Ar or Ar ²Replace with hydroxyl) to use and alkylogen, alkoxy halide, aminoalkyl group halogen or haloalkyl are handled in the presence of alkali and are prepared.Those skilled in the art can recognize, more than transform also and can carry out in the stage morning of synthesis technique according to the feasibility of this conversion.

In addition, has the compound of structural formula (I), wherein Ar ¹, Ar ², R ¹, R ², R ³, R ⁴And R ⁵Definition in the present invention's summary can be prepared with description according to following option b is illustrated.

Option b

In addition, the compound (Ar wherein that has structural formula (I) ¹, Ar ², R ¹, R ²And R ³Definition in the present invention's summary) can prepare like this: the compound that will have structural formula 1 reacts with the compound with structural formula 5, obtains having the compound of structural formula 4, is subsequently converted to have the compound of structural formula (I) as mentioned above.Be reflected at alkali such as triethylamine, in appropriate organic solvent, carry out under the existence of diisopropylethylamine and analogue.Compound with structural formula 5 can be prepared as mentioned above by commercially available piperazine.

Practicality

Nmda receptor is important to various CNS processes and plays a role under the various disease states of people or other species.The partial concn of the glycine around the function influence nmda receptor of GIyTl transhipment.The removal of glycine from the cynapse of slowing down of selectivity GIyTl inhibitor causes cynapse glycine level to rise.This is increased in the occupancy of the glycine binding site on the nmda receptor again, increases the activation of nmda receptor like this after terminal the release from pre-cynapse at glutaminate.Because need the glycine of certain tittle to be used for effective operation of nmda receptor, it is matchmaker's nerve transhipment that any variation of partial concn can influence with NMDA.NMDA-occurs in some neuropsychiatry illness such as dementia for the variation of matchmaker's nerve transhipment, depression and psychosis, for example schizophrenia and learning and Memory illness, for example attention shortcoming illness and autism.

Therefore, The compounds of this invention can be used for treating and relevant various neurologicals and the psychosis illness of the glutaminate neural transport function obstacle of energy, comprise one or more following patient's condition or diseases: schizophrenia or psychosis, comprise schizophrenia (Paranoia, amorphous, catatonia or not differentiation), the Schizophreniform illness, the schizoaffective psychosis illness, the vain hope illness, of short duration mental illness, share mental illness, because mental illness and the material inductive or the drug-induced (phencyclidine of the general medicine patient's condition, ketamine and other separable narcotic, amphetamine and other psychostimulants and Cocaine) mental illness, the psychosis relevant with the emotion illness, of short duration reactive psychosis, schizoaffective psychosis, ＂ schizophrenia scope ＂ illness such as schizophrenia or schizophrenia type individual character illness, or with the psychosis diseases associated (as major depression, the mad depression of making an uproar (bipolar) illness, alzheimer's disease and wound back compressing syndromes), comprise schizophrenia and other psychotic front and adverse symptoms; Cognitive illness, (with alzheimer's disease, local asphyxia, many infractions are dull-witted to comprise dementia, wound, vascular problem or apoplexy, parkinsons disease, Huntington, Pick ' s disease, the Creutzfeldt-Jacob disease, term hypoxia, other general medicine patient's condition or substance abuse are relevant); Delirium, forgetful illness or the cognition relevant with the age descend; The anxiety illness comprises acute compressing illness, agoraphobia, and pan focus is considered illness, mandatory-as to force illness, panic attack, panic disorder, wound back compressing illness, the separation anxiety illness, social phobia, specific phobia disease, material inductive anxiety illness and because the anxiety of the general medicine patient's condition; Illness relevant with material and Addictive Behaviors (comprise material inductive delirium, continue dementia, continue forgetful illness, mental illness or anxiety illness; Tolerance to material, comprises alcohol, amphetamine, hemp, Cocaine, fantasy, inhalation, Nicotine, OPIOIDS, phencyclidine, tranquilizer, the dependency of hypnotic or anxiolytic or withdrawal); Bipolar illness, the mood illness comprises depressed illness; Depression comprises the one pole depression, seasonal depression and postpartum depression, and premenstrual syndrome (PMS) and premenstrual dysphoric illness (PDD) are because the mood illness and the material inductive mood illness of the general medicine patient's condition; The study illness, the general development illness comprises the autism illness, the attention illness comprises attention-shortcoming superfunction illness (ADHD) and conduction illness; Illness that nmda receptor is relevant such as autism, depression, optimum ignorance, children learn illness and airtight head damage; The motion illness, comprise that motion can not can not syndromes (comprise parkinsons disease with the strictness campaign, drug-induced Parkinson's disease, Parkinson's disease after the encephalitis, paralysis on the gradual I nuclear, a plurality of system atrophies, the cortex base is degenerated, dull-witted complex body of Parkinson's disease-ALS and basic neuroganglion calcification), drug-induced Parkinson's disease (as neural Depressant inductive Parkinson's disease, the pernicious syndromes of neural Depressant, the acute dystonia of neural Depressant inductive, acute the cathisophobiaing of neural Depressant inductive, neural Depressant inductive lag motion obstacle and drug-induced position tremble), Gilles de Ia Tourette ' s syndromes, epilepsy, muscle spasm and with muscle spasm or weakness, comprise the relevant illness of trembling; Dyskinesia [comprise and trembling (as static tremor, position tremble and; Intention is trembled), tarantism is (as Sydenham ' s tarantism, Huntington, optimum hereditary tarantism, Neuroacanthocytosis, the symptom tarantism, drug-induced tarantism and hemiballism), myoclonus (comprising general myoclonus and focus myoclonus), spasm (comprises simple spasm, compound spasm and symptom spasm), and dystonia (comprises general dystonia such as cerebral infarction dystonia, drug-induced dystonia, symptom dystonia and ictal dystonia, with focus dystonia such as blepharospasm, occupational dystonia, dysphonia spastica, spasmodic torticollis, axle dystonia, Writer's spasm of dystonia and hemiplegia dystonia); The urinary incontinence; The neurone infringement comprises the glasses infringement, the macula degeneration of retinopathy or eye, tinnitus, hearing impairment and forfeiture, and cerebral edema; Vomiting; With the sleep illness, comprise insomnia and narcolepsy.

In above illness, to schizophrenia, bipolar illness, depression comprises the one pole depression, seasonal depression and postpartum depression, premenstrual syndrome (PMS) and premenstrual dysphoric illness (PDD), study illness, general development illness, comprise the autism illness, the attention illness comprises attention-shortcoming/superfunction illness, the autism illness comprises Tourette ' s illness, the anxiety illness, comprise phobia and wound back compressing illness, cognitive with dull-witted relevant illness, AIDS dementia, alzheimer's, Parkinson, Huntington, spastic, myoclonus, muscle spasm, tinnitus and hearing impairment and forfeiture are particularly importants.

In a particular, the invention provides a kind of method that is used for the treatment of cognitive illness, comprising: to patient's effective dosage The compounds of this invention of needs.Special cognitive illness is dull-witted, delirium, and forgetful illness descends with the cognition relevant with the age.At present, the diagnostic and statistical manual of mental illness (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) the 4th edition text revision version provides and comprises that cognitive illness (comprises dementia, delirium, forgetful illness and the cognition relevant with the age descend) diagnostic tool.The cognitive illness ＂ of term ＂ used herein comprises for example being described in those intelligence treatment of conditions of DSM-IV-TR.Those of skill in the art can recognize that the intelligence illness has selectable nomenclature, nosonomy and taxonomic hierarchies, and also these systems relate to medical science and scientific advance.Therefore the cognitive illness ＂ of term ＂ means and comprises the similar conditions that is described in other diagnostic source.

In another embodiment, the invention provides a kind of method that is used for the treatment of the anxiety illness, comprising: to patient's effective dosage The compounds of this invention of needs.Special anxiety illness is a generalized anxiety disorder, mandatory-pressure illness and panic attack.At present, the diagnostic and statistical manual of mental illness (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) the 4th edition text revision version provides and comprises anxiety illness such as generalized anxiety disorder, the diagnostic tool of mandatory pressure illness and panic attack.Term ＂ anxiety illness ＂ used herein comprises for example being described in those intelligence treatment of conditions of DSM-IV-TR.Those of skill in the art can recognize that the intelligence illness has selectable nomenclature, nosonomy and taxonomic hierarchies, and also these systems relate to medical science and scientific advance.Therefore term ＂ anxiety illness ＂ means and comprises the similar conditions that is described in other diagnostic source.In another embodiment, the invention provides a kind of schizophrenia or psychotic method of being used for the treatment of, comprising: to patient's effective dosage The compounds of this invention of needs.Special inspirit Split disease or psychiatric pathology are the Paranoia, and be amorphous, catatonia or undifferentiated schizophrenia and material inductive mental illness.At present, the diagnostic and statistical manual of mental illness (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) the 4th edition text revision version provides and comprises the Paranoia, amorphous, the diagnostic tool of catatonia or undifferentiated schizophrenia and material inductive mental illness.Term ＂ schizophrenia used herein or psychosis ＂ comprise for example being described in those intelligence treatment of conditions of DSM-IV-TR.Those of skill in the art can recognize that the intelligence illness has selectable nomenclature, nosonomy and taxonomic hierarchies, and also these systems relate to medical science and scientific advance.Therefore term ＂ schizophrenia or psychosis ＂ mean and comprise the similar conditions that is described in other diagnostic source.

In another embodiment, the invention provides a kind of illness relevant and method of Addictive Behaviors of being used for the treatment of, comprising: to patient's effective dosage The compounds of this invention of needs with material.Special illness relevant with material and Addictive Behaviors are the persistence dementias, continue forgetful illness, mental illness or by substance abuse, and tolerance, the anxiety illness that the tolerance of the dependence of abuse material or withdrawal is caused.At present, the 4th edition text revision version of the diagnostic and statistical manual of mental illness (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington DC) provides and comprises lasting dementia, continue forgetful illness, mental illness or by substance abuse; Analysis tool with the anxiety illness that the tolerance of abuse dependence of material or withdrawal is caused.Illness that term ＂ used herein is relevant with material and Addictive Behaviors ＂ comprise for example being described in those intelligence treatment of conditions of DSM-IV-TR.Those of skill in the art can recognize that the intelligence illness has selectable nomenclature, nosonomy and taxonomic hierarchies, and also these systems relate to medical science and scientific advance.Therefore term ＂ illness relevant with material and Addictive Behaviors ＂ mean and comprise the similar conditions that is described in other diagnostic source.

Test

The GIyTl inhibitory activity of The compounds of this invention can use and be described in the external of following work embodiment 1 and body inner analysis and test.

Administration and pharmaceutical composition

In general, any received mode of administration used by the reagent place that plays similar purposes with the treatment significant quantity of The compounds of this invention and administration.Treatment significant quantity with compound of structural formula (I) can be about 0.01 to about 500mg/kg weight in patients/sky, can single or multiple dose administration.Preferably, dosage level is about 0.1 to about 250mg/kg/ day; More preferably from about 0.5 to about 100mg/kg/ day.The proper dosage level can be about 0.01 to about 250mg/kg/ day, about 0.05 to about 100mg/kg/ day, or about 0.1 to about 50mg/kg/ day.In this scope, dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50mg/kg/ days.For oral administration, composition is preferably to comprise about 1.0 to about 1000 milligrams of activeconstituentss, especially about 1.0,5.0,10,15,20,25,50,75,100,150,200,250,300,400,500,600,750, the tablet form of 800,900 and 1000 milligrams of activeconstituentss provides.The compounds of this invention, that is, the actual amount of activeconstituents depends on the severity of disease of many factors as treating, patient's age and relative health, the effectiveness of used compound, administration path and form and other factors.

In general, The compounds of this invention is as pharmaceutical composition administration by any following path: oral, system (as, through skin, in the nose or pass through suppository), or without enteron aisle (as, intramuscular, intravenously or subcutaneous) administration.Preferred administering mode is to use suitable every day of the dosage regimen and oral that can regulate according to painful degree.Composition can be a tablet, pill, and capsule, semisolid, powder continues release formulation, solution, suspension, elixir, aerosol, or the form of any other suitable composition.

To being selected from of prescription depend on the various factors such as drug administration pattern (as, for oral administration, tablet, pill or capsular prescription are preferred) and the bioavailability of drug substance.Up-to-date, especially go out formula of medicine at drug development with bad bioavailability, its principle is by increasing surface-area promptly, reduces particle size and increases bioavailability.For example, U.S.Pat.No.4,107,288 have described a kind of particle size 10 to 1 that has, the formula of medicine of 000nm, wherein active material is carried on the macromolecular crosslinked matrix.U.S.Pat.No.5,145,684 have described the production of formula of medicine, and wherein drug substance is ground into nano particle (average particle size particle size 400nm) and is dispersed in subsequently in the liquid medium in the presence of surface-modifying agent, obtains having the formula of medicine of remarkable high bioavailability.

Composition generally can be accepted vehicle by compound with structural formula (I) and at least a medicine and form.It is atoxic can accepting vehicle, auxiliary administration and the treatment benefit of compound with structural formula (I) do not had disadvantageous effect.These vehicle can be any solids, liquid, semi-solid or, under the situation of aerosol composition, the general available gaseous state vehicle of those skilled in the art.

The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, glyceryl monostearate, sodium-chlor, skimmed milk powder and analogue.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and various oil comprise oil, animal, those of plant or synthetic source, as, peanut oil, soybean oil, mineral oil, sesame oil, comprise water Deng the preferred liquid vehicle that is particularly useful for Injectable solution, salt solution, dextrose hydrate, and glycol.

Pressurized gas can be used for The compounds of this invention is dispersed into aerosol form.The rare gas element that is applicable to this is a nitrogen, carbonic acid gas, etc.

Other suitable drug excipients and its prescription are described in Remington ' s Drug Science, edit (Mack Publishing Company, the 18th edition, 1990) by E.W.Martin.

The content of this compound in prescription can change in the gamut that those skilled in the art adopted.Usually, prescription comprises, and at % weight (wt%) base, based on the compound with structural formula (I) of the about 0.01-99.99wt% of total prescription, surplus is one or more suitable drug excipients.Preferably, the content of compound is about 1-80wt%.

The compounds of this invention can combine with one or more other drugs and be used for the treatment of The compounds of this invention or the applicable disease of other drug or the patient's condition, and it is safer or more effective that independent medicine is compared in the combination together of its Chinese traditional medicine.These other drugs can be by path and amount and the simultaneously or in a sequence administration of The compounds of this invention that is usually used in this.If The compounds of this invention and one or more other drugs use simultaneously, the pharmaceutical composition in unit dose form that comprises these other drugs and The compounds of this invention is preferred.But combined therapy also can comprise wherein The compounds of this invention and the treatment of one or more other drugs in the administration of different overlapping program.Expection in addition, if be used in combination with one or more other activeconstituentss, the dosage that The compounds of this invention and other activeconstituentss can be lower than when using separately respectively uses.

Therefore, pharmaceutical composition of the present invention also comprises except The compounds of this invention and also comprises those of one or more other activeconstituentss.

More than combination comprise The compounds of this invention not only with a kind of other active compounds, and with the combination of two or more other active compounds.Equally, The compounds of this invention can be used for prevention, treatment, control relaxes, or reduces and can use the disease of The compounds of this invention or the other drug of patient's condition danger is used in combination.These other drugs can be by path and amount and the simultaneously or in a sequence administration of The compounds of this invention that is usually used in this.If The compounds of this invention and one or more other drugs use simultaneously, the pharmaceutical composition that comprises these other drugs and The compounds of this invention is preferred.Therefore, pharmaceutical composition of the present invention also comprises except The compounds of this invention and also comprises those of one or more other activeconstituentss.The weight ratio of the The compounds of this invention and second activeconstituents can change and depend on the effective dose of each composition.The general effective dose of using each composition.

In one embodiment, The compounds of this invention can with anti-alzheimer's agent, beta-secretase inhibitor, inhibitors of gamma-secretase, the HMG-CoA reductase inhibitor, NSAID ' s comprises Ibuprofen BP/EP, vitamin-E and the administration of anti-starch antibodies.In another embodiment, The compounds of this invention can with tranquilizer, hypnotic, anxiolytic, anti-spiritual medicine, antianxiety agent, cyclopyrrole ketone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonists and antagonist, the agent of melatonin energy, the benzo diazepam, veronal, 5HT-2 antagonist, PDE10 antagonist, and analogue, as: adinazolam, Allobarbitone, alonimid, alprazolam, amisulpride, amitriptyline, Amobarbital, amoxapine, Aripiprazole, bentazepam, benzoctamine, brotizolam, Bupropion, buspirone, cloth tower veronal, butalbital, capuride, carbocloral, Cloral Betaine, Chloral Hydrate, clomipramine, clonazepam, Domperidone, Clorazepic acid, zeisin, Cloretate, chlorpromazine, leoponex, cyprazepam, Desipramine, ring Yu pyrrole quinoline alcohol, diazepam, Dichloralphenazone, two valproic acids, diphenhydramine, doxepin, estazolam, ethyl .beta.-chlorovinyl ethynyl carbinol, etomidate, fenobam, flunitrazepam, flupentixol, Fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam (lorazopam), lormetazepam, maprotiline, mecloqualone, melatonin, Mephogarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, surem, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, Sodital, perlapine, trilafon, Phenelzine, phenylethyl barbituric acid, prazepam, promethazine, Disoprofol, protriptyline, quazepam, Quetiapine, reclazepam, risperidone, roletamide, secobarbital, Sertraline, suproclone, temazepam (temazopam), sulfo-Soz 6457, tiotixene, tracazolate, card Neil ring third U.S. (kanylcypromaine), trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoro Perazine, trimetozine, Trimipramine, Uldazepam, Venlafaxine, Zaleplone, Ziprasidone, zolazepam, zolpidem, with its salt and its combination combination medicine-feeding.

In another embodiment, The compounds of this invention can with levodopa (being with or without the outer decarboxylase inhibitor of selective brain such as carbidopa or benserazide), anticholinergic such as biperiden (optionally as its hydrochloride or lactic acid salt) and Trihexyphenidyl (Trihexyphenidyl) hydrochloride, COMT inhibitor such as Entacapone, the MOA-B inhibitor, antioxidant, A ₂The a adenosine receptor antagonists, cholinergic agonist, nmda receptor antagonist, 5-hydroxytryptamine receptor antagonist and dopamine-receptor stimulant such as alentemol, bromocriptine, Fenoldopam, methylergol carbamide, Nazagolide, pergolide and pramipexole are in conjunction with administration.Be appreciated that dopamine agonist can be a drug acceptable salt, for example, alentemol hydrobromide, bromocriptine parlodel, fenoldopam mesylate, the form of Nazagolide hydrochloride and LY-127809.Methylergol carbamide and pramipexole use with salt-independent shape usually.

In another embodiment, The compounds of this invention can be selected from phenothiazine, sulfo-cluck ton, heterocycle hexichol azepan, butyrophenone, the neural compound of medicament that suppresses of diphenylbutylpiperidand and indole ketone is in conjunction with administration.The example of suitable phenothiazine comprises chlorpromazine, mesoridazine, sulfo-Soz 6457, Acetophenazine, Fluphenazine, trilafon and trifluoro Perazine.The example of suitable sulfo-cluck ton comprises chlorprothixene and tiotixene.An example of hexichol azepan is a leoponex.An example of butyrophenone is a haloperidol.An example of diphenylbutylpiperidand is a pimozide.An example of indolone is a molindone.Other neural medicaments that suppress comprise loxapine, Sulpiride and risperidone.Be appreciated that if be used in combination neural inhibition medicament can be a drug acceptable salt with this motif compound, for example, chlorpromazine hydrochloride, mesoridazine besilate, sulfo-Soz 6457 hydrochloride, Acetophenazine maleic acid ester, fluophenazine hydrochloride, fluphenazine, certain herbaceous plants with big flowers acid Fluphenazine, trifluoro Perazine hydrochloride, thiothixene hydrochloride, the haloperidol caprate, the form of Loxapine succinate and molindone hydrochloride.Trilafon, chlorprothixene, leoponex, haloperidol, pimozide and risperidone use with salt-independent shape usually.Therefore, The compounds of this invention can with Acetophenazine, alentemol, Aripiprazole, amisulpride, Trihexyphenidyl, bromocriptine, biperiden, chlorpromazine, chlorprothixene, leoponex, diazepam, Fenoldopam, Fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, methylergol carbamide, loxapine, mesoridazine, molindone, Nazagolide, olanzapine, pergolide, trilafon, pimozide, pramipexole, Quetiapine, risperidone, Sulpiride, tetrabenazine, Trihexyphenidyl, sulfo-Soz 6457, tiotixene, trifluoro Perazine or Ziprasidone combination medicine-feeding.

In another embodiment, The compounds of this invention can with antidepressive or antianxiety agent, comprise and reduce ephedrine reuptake inhibithors (comprising tertiary amine three ring things and secondary amine three ring things), selectivity serotonin reuptake inhibithors (SSRIs), oxidase inhibitor (MAOIs), the reversible inhibitor of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitor (SNRIs), corticotrophin releasing factor (CRF) antagonist, the adrenoceptor antagonist, antagonists of neurokinine-1 receptor, undesired antidepressive, benzo diazepam, 5-HTA agonist or antagonist, especially 5-HTA partial agonist, and corticotrophin releasing factor (CRF) antagonist combination medicine-feeding.Particular agent comprises: amitriptyline, clomipramine, doxepin, imipramine and tr imipramine; Amoxapine, Desipramine, maprotiline, nortriptyline and protriptyline; Fluoxetine, fluvoxamine, paroxetine and Sertraline; Isocarboxazid, Phenelzine, Tranylcypromine and selegiline; Moclobemide, Venlafaxine; Duloxetine; Aprepitant; Bupropion, lithium, nefazodone, trazodone and viloxazine; Alprazolam, zeisin, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; Buspirone, flesinoxan, gepirone and ipsapirone and medicine can be accepted its salt.

Embodiment

The preparation that below provides compound with structural formula (I) and intermediate (reference) is so that those skilled in the art more are expressly understood and implement the present invention.They should not be considered to limit scope of the present invention, and only are illustrative and representational.

Synthetic embodiment

With reference to A

Synthetic 1-(chlorine (phenyl) methyl)-3-(trifluoromethyl) benzene

At room temperature (5mL is 20mmol) at CH to 3-(trifluoromethyl) diphenyl-carbinol ₂Cl ₂Solution thionyl chloride (10mL) (3mL, 41mmol).Be reflected at 50 degrees centigrade and stir down 18h, under vacuum, concentrate,, obtain title compound (4.9g, 89% productive rate), in next step, need not to be further purified and use as oil with methylbenzene azeotropic and dry under vacuum.MS (ESI, pos. ion) m/z:235.0 (M-HCl).

Use aforesaid method, prepare 1-(chlorine (phenyl) methyl)-4-(trifluoromethyl)-benzene.

With reference to B

Synthetic (3-bromophenyl) (phenyl) methyl alcohol

At room temperature (1.00g, 4mmol) solution in MeOH (15mL) adds sodium borohydride in batches (0.3mL 8mmol) and with suspension at room temperature stirs 1-24h to 3-bromine benzophenone.The reaction water slowly dilutes and uses CH ₂Cl ₂Extract.Organic layer is water successively, and the salt water washing is at Na ₂SO ₄Last dry and concentrate, obtain title compound as oil (0.8g, 79%), in next reaction, need not to be further purified and use.MS (ESI, pos. ion) m/z:247.1 (M-OH).

Use aforesaid method, (2-bromophenyl) (phenyl) methyl alcohol is prepared (4-bromophenyl) (phenyl) methyl alcohol, and phenyl (3-(trifluoromethyl) phenyl) methyl alcohol.

Optionally synthetic

Under-78 degrees centigrade from dropping funnel to the 3-bromobenzaldehyde (15.6g, 84mmol) drips of solution in THF (60mL) be added in 3.0M phenyl-magnesium-bromide solution in the Anaesthetie Ether (18mL, 101mmol) and will be reflected under-78 degrees centigrade or the room temperature and stir.Under-78 degrees centigrade or room temperature, stir after the 4h the saturated NH of reaction mixture ₄Cl solution dilution and use CH ₂Cl ₂Extract.Organic layer is merged, with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product passes through ISC and purifying.

With reference to C

Synthetic 1-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine

At room temperature (10.0g is 39.6mmol) at CH for methyl alcohol to phenyl (3-(trifluoromethyl) phenyl) ₂Cl ₂Solution thionyl chloride (20mL) (5.78mL, 79.3mmol).After adding, reaction is warmed to 40 degrees centigrade of 18h.Solvent is evaporated and in a vacuum with resistates dry 1h under vacuum pump.Residue is dissolved in CH ₃(13.7g is 159mmol) at CH with adding piperazine among the CN ₃Solution among the CN and be heated to 100 degrees centigrade of 12h.Solvent is removed in a vacuum, and residue is dissolved in CH ₂Cl ₂(150mL) neutralization is washed with 1N NaOH (150mL).Organic layer uses K ₂CO ₃Or Na ₂SO ₄Drying is filtered and is concentrated.Crude product 1-(phenyl (3-(trifluoromethyl) phenyl)-methyl) piperazine (10.8g, 85.0% productive rate) oil need not to be further purified and uses maybe and can use 0-15% at CH by the ISCO flash chromatography ₂Cl ₂In 2N NH ₃Methanol solution and purifying.MS (ESI, pos. ion) m/z:321.1 (M+1).

Use is similar to method, 1-((2-bromophenyl) (phenyl) methyl) piperazine and 1-((3-bromophenyl) (phenyl)-methyl) piperazine of synthetic 1-(phenyl (3-(trifluoromethyl) phenyl)-methyl)-piperazine.

With reference to D

Synthetic (3R)-3-methyl isophthalic acid-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine

(2.2g is 22mmol) at CH to (R)-(-)-2-methylpiperazine ₃Solution among the CN (20mL) add 1-(chlorine (phenyl) methyl)-3-(trifluoromethyl) benzene (2.0g, 7.4mmol) and be heated to 100 degrees centigrade of 12h and vacuum concentration.Residue is dissolved in CH ₂Cl ₂(150mL) neutralization is washed with 1N NaOH (150mL).Organic layer uses K ₂CO ₃Or Na ₂SO ₄Drying is filtered and is concentrated.Crude product uses 0-20% at CH by ISCO ₂Cl ₂In 2N NH ₃/ MeOH solution and purifying obtain title compound (2.00g, 81% productive rate) as oil.MS (ESI, pos. ion) m/z:335.1 (M+1).

The method of use is similar to synthetic (3R)-3-methyl isophthalic acid-(phenyl (3-(three fluoro-methyl) phenyl) methyl) piperazine is prepared (R)-1-((3-bromophenyl) (phenyl) methyl)-3-methyl-piperazine and 1-(phenyl (4-(trifluoromethyl) phenyl) methyl) piperazine.

With reference to E

Synthetic 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) ra-butyl acetate

From syringe to-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine (10.0g, 31mmol) solution in acetonitrile (60mL) drip bromoacetic acid t-butyl ester (6.1mL, 31mmol).Reaction mixture at room temperature stirs 5min.With add triethylamine (11mL, 78mmol).Water adds after 18h, adds CH subsequently ₂Cl ₂Layer separates, water layer CH ₂Cl ₂Extract and with the organic layer salt water washing that merges, at Na ₂SO ₄Last dry and concentrated.Crude product by ISCO use 0-80% in hexane EtOAc and purifying obtains title compound (9.1g, 67% productive rate) as brown oil, leave standstill to solidify.MS (ESI, pos. ion) m/z:435.2 (M+1).

Optionally synthetic:

At room temperature to 1-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine (1.70g, 5.3mmol) solution in acetonitrile (20mL) drip 2-bromoacetic acid methyl ester (0.49mL, 5.3mmol).Reaction stir 30min and add triethylamine (2.2mL, 16mmol).After at room temperature stirring 18 hours, react dilute with water and use CH ₂Cl ₂Extract.Organic layer is merged, with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product uses at CH by ISCO ₂Cl ₂In 0-40% ethyl acetate or 0-2% ethyl acetate and purifying obtains title compound (1.0g, 48% productive rate).MS (ESI, pos. ion) m/z:393.2 (M+1).

Use is similar to the method for Synthetic 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) ra-butyl acetate, prepares following compound.

2-(4-((3, the 5-dichlorophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate;

2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate;

2-(4-((2-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate;

2-((R)-2-methyl-4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) ra-butyl acetate;

2-((R)-4-((3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) ra-butyl acetate;

2-(4-(phenyl (4-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) ra-butyl acetate; With

2-(4-benzhydryl piperazidine-1-yl) ra-butyl acetate.

With reference to F

Synthetic 2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate

Method 1

To (3-bromophenyl) (phenyl) methyl alcohol (0.64g, 2mmol) solution in ethylene dichloride (5mL) adds thionyl chloride (0.4mL, 5mmol) stir 18h with reaction, concentrate and be added in the piperazine-1-base-ra-butyl acetate dihydrochloride (0.7g in the acetonitrile (10mL), 2mmol) and DIEA (2mL, 12mmol) in.After 100 degrees centigrade are stirred 18 hours down, react dilute with water and use CH ₂Cl ₂Extract.Organic layer is merged, with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product uses the 0-50% EtOAc in hexane by ISCO and purifying obtains title product (0.3g, 28% productive rate).MS (ESI, pos. ion) m/z:447.2.2 (M+2).

Continue as mentioned above, prepare 2-(4-((4-bromophenyl) (phenyl) methyl)-piperazine-1-yl) ra-butyl acetate.

Method 2

Use 2-(4-(phenyl (3-(trifluoromethyl) phenyl)-methyl)-piperazine-1-yl) the described method of ra-butyl acetate, title compound uses 1-((3-bromophenyl) (phenyl)-methyl) piperazine (6.8g, 21mmol) (3.3mL 21mmol) synthesizes with the bromoacetic acid tertiary butyl ester.

With reference to G

Synthetic (R) and (S)-methyl 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl)-acetic ester

With

At room temperature to 1-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine (2.0g, 6mmol) solution in acetonitrile (20mL) drip the bromoacetic acid methyl ester (0.59mL, 6mmol).Reaction stir 30min and add triethylamine (3.6mL, 26mmol).After at room temperature stirring 18 hours, reaction mixture dilute with water and use CH ₂Cl ₂Extract.Organic layer is merged, with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product uses at CH by ISCO ₂Cl ₂In 0-40% ethyl acetate or 0-2% ethyl acetate and purifying, obtain the mixture (2.0g, 80%) of enantiomer.Enantiomer divides with two peaks by chiral chromatography as described below collects with～100%ee.

Be used to analyze instrumentation and the condition of SFC:

Analyze SFC and have FCM 1200 flow control assemblies, double pump control unit and TCM 2100 plume assemblies, the Berger SFC unit of post selector valve and solvent control valve.SFC is furnished with Agilent1100 photodiode array detector and high pressure chute.The self-actuated sampler unit is HTCPAL (Leap Technologies).Having on the Waters ZQ stool of atmospheric pressure chemical ionization (APCI) single quadrupole mass spectrometer is connected to and analyzes on the SFC system.The software that is used to analyze is BergerMass Ware v 4.01 and MassLynx v 4.0 SPl.Used analysis packed column is ChiralcelOJ-H (Chrial Technologies, 4.6mm x 150mm, 5 μ m).Mobile phase is made up of 95% carbonic acid gas and 5% methyl alcohol.Total flow rate is 4.0 milliliters/min, and furnace temperature is 40 degrees centigrade.

Be used to prepare the specimen preparation of SFC

The mixture of (R) that obtains more than the 600mg and (S)-methyl 2-(4-(phenyl (3-(trifluoromethyl) phenyl)-methyl) piperazine-1-yl)-acetic ester is absorbed in 5 ml methanol and the 5ml dimethoxy ethylene glycol (DME) and adds 40ml methyl alcohol subsequently, filters 0.45 μ m PTFE syringe filter before injection.

Be used to prepare instrument and the condition of SFC:

Preparation SFC is Berger Multigram II.Element is to separate or control unit (SCM)-2500, Electronic Control Unit (ECM)-2500, carbon dioxide solvent transmission assembly, direct expansion probe water cooler, UV variable-wavelenght detector and Cavro XL 3000 Modular digital pump (syringe).Equipment from Mettler-Toledo Autochem (Newark, DE).Software in the purifying is Berger SFCPronTo vl.5.305.15.Used preparation packed column uses linear two the Chiralcel OJH (Chiral Technologies, 21mm x 250mm, 5 μ m) that link together.Mobile phase is made up of Liquid carbon dioxide (A) and methyl alcohol (B).This method is the degree such as grade, the ratio 92:8 of A:B.Total flow rate is 60ml/min.Stove and column temperature are about 40 degrees centigrade.Above sample is injection in per 224 seconds in operational process such as degree of grade.First peak 0.8g is that (S) isomer and the second peak 0.9g are (R) isomer.MS (ESI, pos. ion) m/z:393.1 (M+1).

Embodiment 1

Synthetic (S)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride

Step 1

The chlorodiphenyl methylmethane (404mg, 1.993mmol) and (S)-(+)-mixture of 2-methyl-piperazine (599mg, 5980 μ mol) in 2.5mL MeCN heating 30min under 140 degrees centigrade under microwave irradiation.Solvent is evaporated and solid residue is carried out column chromatography handle (SiO ₂, the 2M NH of EtOAc to EtOAc/ in MeOH ₃=100:20), the mixture that obtains two kinds of position isomer (5)-1-diphenyl-methyl-3-methylpiperazine and (5)-1-diphenyl-methyl-2-methylpiperazine is as white solid.Two kinds of mixture of products are directly used in next step.

Step 2

To (S)-1-diphenyl-methyl-2-methylpiperazine and (S)-1-diphenyl-methyl-3-methylpiperazine (490mg, 1.839mmol) mixture in 25mL MeCN adds tert.-butyl bromide acetic ester (356 μ l, 2.207mmol), slowly add triethylamine (384 μ l, 2759 μ mol) subsequently.Reaction mixture at room temperature stirs and spends the night.Solution is evaporated to anhydrous and resistates is carried out flash chromatography handle (SiO ₂DCM to DCM/EtOAc=100:3 is to 100:5 to 100:10), obtain (S)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) ra-butyl acetate as water white oil and (S)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) ra-butyl acetate as water white oil.

Step 3

(S)-and 2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) ra-butyl acetate (340mg, 894 μ mol) is at 3mL 1, and the solution in the concentrated HCl solution (37%) of 4-diox and 1mL at room temperature stirs and spends the night.Solvent is evaporated to anhydrous and resistates is extracted (crash) from ether, obtains (S)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride as white solid.MS (ESI, pos. ion) m/z:325 (M+1).

Following compound prepares by the step that for example is described in above embodiment 1.

(S)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate dihydrochloride; MS (ESI, pos. ion) m/z:325 (M+1);

(R)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate dihydrochloride; MS (ESI, pos. ion) m/z:325 (M+1);

(R)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride; MS (ESI, pos. ion) m/z:325 (M+1);

(S)-2-((R)-4-(two (4-chloro-phenyl-) methyl)-3-methylpiperazine-1-yl) propionic acid;

2-((2R, 6S)-4-(two (4-chloro-phenyl-) methyl)-2,6-lupetazin-1-yl) acetate;

2-(4-(two (4-chloro-phenyl-) methyl)-2,2-lupetazin-1-yl) acetate; With

2-((2R, 5S)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate dihydrochloride and 2-(mixture M S (ESI, the pos. ion) m/z:339 (M+1) of (2S, 5R)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate dihydrochloride.

Embodiment 2

Synthetic 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate

Method A

(9.3g, 21mmol) (25mL, 337mmol) solution in stirs 6h down at 60 degrees centigrade to 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) ra-butyl acetate at TFA.Reaction mixture is concentrated and crude product is used 2N NH by the SCX post subsequently with MeOH ₃(in MeOH solution) wash-out and purifying obtains title compound as raceme (4.Sg, 59%).MS (ESI, pos. ion) m/z:379.1 (M+1).

Method B

(0.86g, 2mmol) (0.1mL, 4mmol) solution in MeOH (20mL) is heated to 70 degrees centigrade of 1h to acetic ester to methyl 2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) with 5N sodium hydroxide.Under reduced pressure remove after the solvent,, be acidified to pH 4, and use CH subsequently with 1N HCl with residue diluted with water ₂Cl ₂Extract.Organic layer salt water washing is at Na ₂SO ₄Last dry and concentrated.Purifying obtains title compound (0.7g, 84% productive rate) to crude product by be used in the 0-15% MeOH wash-out in the methylene dichloride by ISCO.MS (ESI, pos. ion) m/z:379.1 (M+1).

Use is similar to the synthetic method of Synthetic 2 in method A-(4-(phenyl (3 (trifluoromethyl) phenyl)-methyl) piperazine-1-yl) acetate, prepares

2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. ion) m/z:389.1 (M+); 2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. ion) m/z:389.1 (M+);

2-(4-((3, the 5-dichlorophenyl) (phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. ion) m/z:379.0 (M+1); With

2-(4-benzhydryl piperazidine-1-yl) acetate MS (ESI, pos. ion) m/z:311.1 (M+1).

Use is similar to the synthetic method of Synthetic 2 in method B-(4-(phenyl (3 (trifluoromethyl) phenyl)-methyl) piperazine-1-yl) acetate, prepare (R)-2-(4-(phenyl (3-(trifluoromethyl)-phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. m/z:379.1 (M+1 and (S)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. ion) m/z:379.1 (M+1) ion).

Embodiment 3

Synthetic 2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate

To tertiary butyl 2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetic ester (2.0g, 4mmol) the solution in the Zai diox (10mL) is added in 1, and the 4N HCl solution in the 4-diox (30mL, 823mmol), the concentrated HCl of adding subsequently (2.0mL, 55mmol).Be reflected at 50 degrees centigrade and stir 6h and concentrated under vacuum down.Crude product is used 2N NH by the SCX post subsequently with methyl alcohol ₃(in MeOH solution) wash-out and purifying obtains title compound as raceme (1.62g, 93%).MS (ESI, pos. ion) m/z:389.1 (M+).

Embodiment 4

Synthetic 2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride

To tertiary butyl 2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) acetic ester (1.0g, 2mmol) the solution in the Zai diox (10mL) is added in 1, and the 4N HCl solution in the 4-diox (20mL, 549mmol), the concentrated HCl of adding subsequently (1.0mL, 27mmol).Be reflected at 50 degrees centigrade and stir 6h and concentrated under vacuum down.Crude product grinds with EtOAc or Anaesthetie Ether, filters, and dry, obtain title compound (0.8g, 77% productive rate).MS (ESI, pos. ion) m/z:345.1 (M+1-2HC ₁).

Use is similar to the method for Synthetic 2-(4-((4-chloro-phenyl-) (phenyl) methyl)-piperazine-1-yl) acetate dihydrochloride, prepares following compound:

2-((R)-4-((3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride MS (ESI, pos. ion) m/z:403.1 (M+)-2HCl;

2-((R)-2-methyl-4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride MS (ESI, pos. ion) m/z:393.1 (M+1)-2HC ₁

2-(4-((2-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride MS (ESI, pos. ion) m/z:390.1 (M-H)-2HC ₁With

2-(4-(phenyl (4-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride MS (ESI, pos. ion) m/z:379.1 (M+1)-2HC ₁

Embodiment 5

Synthetic 2-(4-(two (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate dihydrochloride

Step 1

At room temperature to 3,3 '-two (trifluoromethyl) benzophenone (11.4g, 36mmol) solution in MeOH (50mL) add in batches sodium borohydride (1.9ml, 53mmol).Suspension at room temperature stirs 24h.The reaction water slowly dilutes and uses CH ₂Cl ₂Extract.Organic layer order water, the salt water washing is at Na ₂SO ₄Last dry and concentrated, obtain two (3-(trifluoromethyl) phenyl) methyl alcohol (10.8g, 94% productive rate).Crude oil is used for next reaction and is not further purified.

Step 2

At room temperature (1.1g is 3.4mmol) at CH for methyl alcohol to two (3-(trifluoromethyl) phenyl) ₂Cl ₂Solution thionyl chloride (10mL) (0.50ml, 6.9mmol).Be reflected at 50 degrees centigrade and stir 4h down, vacuum concentration, with methylbenzene azeotropic, and vacuum-drying, obtain thick chlorine two (3-(trifluoromethyl) phenyl) methane.Thick chlorine two (3-(trifluoromethyl)-phenyl) methane is added piperazine, and (0.81ml, the 10mmol) solution in acetonitrile (10mL) is heated to 100 degrees centigrade of 18h and vacuum concentration.Resistates is dissolved in CH ₂Cl ₂(150mL) neutralization is washed with 1N NaOH (150mL).Organic layer K ₂CO ₃Drying is filtered and is concentrated, and obtains 1-(two (3-(trifluoromethyl)-phenyl) methyl) piperazine.With thick 1-(two (3-(trifluoromethyl) phenyl)-methyl) piperazine dissolved acetonitrile (10mL) neutralization add the bromoacetic acid tertiary butyl ester (0.55mL, 3.4mmol) and triethylamine (0.96ml, 6.9mmol).Solution stirring 4h, dilute with water and use CH ₂Cl ₂Extract.Organic layer is with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product uses the 0-50% EtOAc in hexane by ISCO and purifying obtains tertiary butyl 2-(4-(two (3-(trifluoromethyl)-phenyl) methyl) piperazine-1-yl) acetic ester (0.86g, 50% productive rate).MS (ESl, pos. ion) m/z:503.1 (M+1) changes into title compound by as above embodiment 4 described steps subsequently.

Embodiment 6

Synthetic 2-(4-((3-biphenyl) (phenyl) methyl) piperazine-1-yl) acetate dihydrochloride

2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate (0.31g, 0.70mmol), phenyl-boron dihydroxide (0.085g, 0.70mmol), single sodium carbonate hydrate (0.077ml, 1.4mmol), and tetrakis triphenylphosphine palladium (O) (0.80g, 0.70mmol) the mixture in Zai diox (4mL) and the water (2mL) is heating 20min under 120 degrees centigrade under microwave irradiation.React dilute with water and use CH ₂Cl ₂Extract.Organic layer is with saturated NaCl solution washing, subsequently at Na ₂SO ₄Last dry and concentrated.Crude product uses the 0-50% EtOAc in hexane by ISCO and purifying obtains tertiary butyl 2-(4-((3-biphenyl) (phenyl) methyl)-piperazine-1-yl) acetic ester (0.28g, 91% productive rate).MS (ESI, pos. ion) m/z:443.2 (M+1) is subsequently by as above changing into title compound in the step described in the embodiment 4.

As above embodiment 6 is described, but 2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate is replaced with 2-((R)-2-methyl-4-((R)-(3-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate and phenyl-boron dihydroxide is replaced with thiophene-2-ylboronic acid, obtain ((R)-2-methyl-4-((R)-phenyl (3-(thiophene-2-yl) phenyl) methyl) piperazine-1-yl) acetate 2-tertiary butyl ester, as above embodiment 4 is described and change into 2-((R)-2-methyl-4-((R)-phenyl (3-(thiophene-2-yl) phenyl) methyl)-piperazine-1-yl) acetate.

As above embodiment 6 is described, but 2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) ra-butyl acetate is replaced with 2-((R)-2-methyl-4-((R)-(4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetic ester and uses phenyl-boron dihydroxide, 2-aminomethyl phenyl boric acid, 3-aminomethyl phenyl boric acid and 4-aminomethyl phenyl boric acid are handled, obtain ((R)-2-methyl-4-((R)-(4-biphenyl) (phenyl) methyl)-piperazine-1-yl) ra-butyl acetate respectively, ((R)-2-methyl-4-((R)-(4-(2-aminomethyl phenyl) phenyl) (phenyl) methyl)-piperazine-1-yl) ra-butyl acetate, ((R)-2-methyl-4-((R)-(4-(3-aminomethyl phenyl) phenyl)-(phenyl) methyl)-piperazine-1-yl) ra-butyl acetate, ((R)-2-methyl-4-((R)-(4-(4-aminomethyl phenyl) phenyl)-(phenyl) methyl)-piperazine-1-yl) ra-butyl acetate, as above embodiment 4 is described is changed into respectively [(R)-4-((R)-biphenyl-4-base-phenyl-methyl)-2-methyl-piperazine-1-yl]-acetate; (R)-and the 2-methyl-4-[(R)-(2 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl }-acetate; (R)-and the 2-methyl-4-[(R)-(3 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl }-acetate; (R)-and the 2-methyl-4-[(R)-(4 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl }-acetate.

Embodiment 7

Synthetic 2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate

Step 1

(3.48g, (0.5M in THF 24mmol) and with gained solution stirs 1h down at 0 degree centigrade 20mmol) to drip cyclopropyl bromination magnesium in (with benzene azeotropic) to 3-(trifluoromethyl) phenyl aldehyde under 0 degree centigrade.Reaction mixture aq.NH ₄The Cl cancellation is extracted with ether, washes with water, at Na ₂SO ₄Last dry, filter and be evaporated to anhydrous.Column chromatography is handled (SiO ₂, hexane is to DCM/ hexane=1:1 to pure DCM) and provide (3-bromophenyl) (cyclopropyl) methyl alcohol as yellow oil.

Step 2

At room temperature (3.00g, (1.52ml, 20.8mmol) relatively gained solution at room temperature stirs 1h slowly to add thionyl chloride in 13.9mmol) to clean cyclopropyl (3-(trifluoromethyl) phenyl) methyl alcohol.Excess reagent by remove with methylbenzene azeotropic and thick 1-(chloro-(cyclopropyl) methyl)-3-(trifluoromethyl) benzene further dry and be directly used in next step under high vacuum.

Step 3

1-(chlorine (cyclopropyl) methyl)-3-(trifluoromethyl) benzene (2.5g, 11mmol) and (R)-(3.2g, 32mmol) mixture in 30mL MeCN is 90 degrees centigrade of following heated overnight for the 2-methylpiperazine.Solvent is evaporated and solid residue is carried out column chromatography handle (SiO ₂, the 2M NH of EtOAc to EtOAc/ in MeOH ₃=100:20), obtain thick (2R)-1-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine (3.15g), be directly used in next step.

Step 4

To thick (2R)-1-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine (3.15g, 105.6mmol) solution in 25mL MeCN adds tert.-butyl bromide acetic ester (2.046ml, 12.67mmol), slowly add subsequently triethylamine (2.203ml, 15.837mmol).Reaction mixture at room temperature stirs and spends the night.Solution is evaporated to anhydrous and resistates is carried out flash chromatography handle (SiO ₂, hexane to hexane/EtOAc=100:5 to 100:10 to 100:30), obtain tertiary butyl 2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetic ester as water white oil.

Step 5

(350mg 0.849mmol) adds 3mL 37% HCl and gained solution stirred 3h down at 50 degrees centigrade to the 2-in the 150mL flask ((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) ra-butyl acetate.After HPLC-MS shows conversion fully, solvent is evaporated to anhydrous under high vacuum, obtain 2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride (290mg, 79.6% productive rate) as white solid.MS (ESI, pos. ion) m/z:357 (M+1).

Described according to above embodiment 7, but cyclopropyl bromination magnesium is replaced with thiophene-2-base magnesium bromide, obtain 2-((R)-2-methyl-4-(thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate MS (ESI, pos. ion) m/z:399 (M+1).

2-((R)-2-methyl-4-(thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate is separated into 2-((R)-2-methyl-4-((R)-thiophene-2-base-(3-(trifluoromethyl) phenyl)-methyl) piperazine-1-yl) acetate and 2-((R)-2-methyl-4-((S)-thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate diastereomer subsequently.

Embodiment 8

Synthetic 2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetate

Step 1

(407mg, 1.5mmol) (601mg, 6.0mmol), (the 626 μ l's adding of the solution in MeCN piperazine-2-ketone 4.5mmol) and with the backflow of gained mixture spend the night to add triethylamine subsequently to chlorine two (4-chloro-phenyl-) methane.After being cooled to room temperature, solvent is evaporated to anhydrous and resistates is carried out column chromatography handle (SiO ₂, DCM to DCM/MeOH=100:5), obtain 4-(two (4-chloro-phenyl-) methyl) piperazine-2-ketone (420mg) as white solid.

Step 2

To 4-(two (4-chloro-phenyl-) methyl) piperazine-2-ketone (180mg, 537 μ mol) solution of doing among the THF at 10mL adds methyl 2-bromacetate (60 μ l, 644 μ mol), adds sodium hydride subsequently, 60% dispersion in mineral oil (16 μ l, 644 μ mol).At room temperature stir and spend the night, solvent is evaporated to anhydrous and directly carries out column chromatography and handle (SiO ₂, hexane is to hexane/EtOAc=100:5 to 100:10 to 100:20 to 100:30), obtain methyl 2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetic ester (160mg) as white solid.

Step 3

To 2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetate methyl ester (160mg, 393 μ mol) at THF/MeOH/H ₂Solution among the O=5:5:1 (5.5mL) adds lithium hydroxide monohydrate, and (49.5mg 1.179mmol) and with the gained solution stirring spends the night.Solvent is evaporated, and dilute with water is adjusted to pH=5 with 10% HCl, extracts with DCM, at Na ₂SO ₄Last dry, filter and under high vacuum, be evaporated to anhydrous.Resistates is loaded into flash distillation post (SiO ₂, DCM to DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) on, obtain 2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetate (136mg) as white solid.

Embodiment 9

Synthetic 2-((R)-2-methyl-4-((R)-phenyl (4-(2-phenylacetylene base) phenyl) methyl) piperazine-1-yl) acetate

Step 1

2-((R)-4-((S)-(4-bromophenyl) (phenyl) methyl)-2-methyl-piperazine-1-yl) ra-butyl acetate (459mg, 0.1mmol, the general step with reference to G is followed in its preparation), 1-phenylacetylene (0.137ml, 1.249mmol), 4-butyl ammonium fluoride trihydrate (946mg, 2.997mmol) and dichloro two (triphenylphosphine) palladium (ii) (21.0mg, mixture 0.030mmol) under 80 degrees centigrade at N ₂Heat 1h under the atmosphere.Resistates is carried out flash chromatography handle (SiO ₂, hexane to hexane/EtOAc=100:10 to 100:15 to 100:20), obtain 2-((R)-2-methyl-4-((S)-phenyl (4-(2-phenylacetylene base) phenyl) methyl)-piperazine-1-yl) ra-butyl acetate (460mg) as yellow oil.

Step 2

(320mg is 0.666mmol) at THF/MeOH/H for ra-butyl acetate to 2-((R)-2-methyl-4-((S)-phenyl (4-(2-phenylacetylene base) phenyl)-methyl) piperazine-1-yl) ₂Solution among the O=5:5:1 (5.5mL) adds lithium hydroxide monohydrate, and (279mg 6.658mmol) and with the gained solution stirring spends the night.Solvent is evaporated to anhydrous under high vacuum and with residue diluted with water, regulates pH=5, extracts with DCM, at Na ₂SO ₄Last dry, filter and be evaporated to anhydrous.Resistates is loaded into flash distillation post (SiO ₂, DCM to DCMZMeOH=100:5 to 100:10 to 100:15 to 100:20) on, obtain 2-((R)-2-methyl-4-((S)-phenyl (4-(2-phenylacetylene base) phenyl) methyl) piperazine-1-yl) acetate (240mg) as white solid.

According to the above, synthetic following compound: 2-((R)-2-methyl-4-((R)-phenyl (3-(2-pyridin-3-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate; With

2-((R)-2-methyl-4-((R)-phenyl (3-(2-piperidin-4-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate.

Biological Examples

Embodiment 1

Glycine transporter 1 (GIyTl) absorption analysis

External:

This cell-Ji assay determination test compound suppresses the ability that glycine is absorbed by 1 type glycine transporter.People's placenta suede cancer (JAR) cell that interior originality is expressed 1 type people glycine transporter (GIy-Tl) is used for this analysis.For absorption analysis, jar cell is being comprised cultivation in the presence of penicillin (100pg/ml) and Streptomycin sulphate (100pg/ml) in RPMI 1640 media of 10% tire cattle serum in 96-well Cytostar T flicker microplate (Amersham Biosciences).Cell is at density 4X10 ⁴Cell/down-hole making sheet and under 37 degrees centigrade at 5% CO ₂Humid atmosphere under the 24h that grows.

Substratum is absorbed buffer reagent (120mM NaCl from the removal of Cytostar plate and with jar cell with 30 μ l ₅2mM KCl, 1mM CaCl ₂, 1mM MgCl ₂, 10mM Hepes, the 5mM L-Ala, pH 7.5) and cultivate 5min being with or without under the situation of compound.30 μ l[that will in absorbing buffer reagent, dilute subsequently ¹⁴C] glycine (101mCi/mmol derives from Perkin Elmer) adds each well, obtains ultimate density 5pM.At room temperature cultivate required time, 1-2h goes up counting with the 96-well Cytostar plate of sealing at TopCount (Packard) usually.[ ¹⁴C] glycine the nonspecific existence that is absorbed in 10pM cooling ALX-5407 (Sigma) measures down.

IC ₅₀Raw data from TopCount generates curve and four-parameter logical equation match of the data analysis tool (active alkali) of use itself by collecting.Specific compound of the present invention has and is lower than about 10 micromolar IC ₅₀Value.

Haply, the IC of compound in this analysis with structural formula (I) of representative number ₅₀Value provides in following table.

Cpd#	IC ₅₀(nM)	Cpd#	IC ₅₀(nM)	Cpd#	IC ₅₀(nM)
Cpd#	IC ₅₀(nM)	Cpd#	IC ₅₀(nM)	Cpd#	IC ₅₀(nM)	1	79.1	30	0.934	49	7.2
18	37.6	34	17.8	55A	1.5	1	79.1	30	0.934	49	7.2
18	37.6	34	17.8	55A	1.5	20	1.51	38	0.98	75	4.32
21	217	39	2.7	77	41.1	20	1.51	38	0.98	75	4.32
21	217	39	2.7	77	41.1	24	3.94	48	2.14	78	4.8
79	1190	82	2200	88	134	24	3.94	48	2.14	78	4.8

The body inner analysis:

Male Sprague-Dawley mouse (250-300 gram) is used the IyTl inhibitor in the table 1, and compound 3 is handled by oral tube feed under dosage 1 to 100mg/kg among 2% hydroxypropyl in water-methylcellulose gum and 1% tween 80.After acute compound administration two hours, collect CSF and use the HPLC that is connected on the fluorimetric detector (ESA inc, Chelmsford MA) to analyze glycine content subsequently.The basal level of glycine in mouse CSF is the CSF of 0.5ng/ microlitre or lower.

Formulation Example

Below be to comprise the have structural formula representative drugs prescription of compound of (I).

Tablet formulation

Following composition is closely mixed and is pressed into the tablet of single marking.

Composition	Amount/tablet, mg
Composition	Amount/tablet, mg	The compounds of this invention	400
Cereal starch	50	The compounds of this invention	400
Cereal starch	50	Cross-linked carboxymethyl cellulose sodium	25
Lactose	120	Cross-linked carboxymethyl cellulose sodium	25
Lactose	120	Magnesium Stearate	5

Capsule formula

Following composition closely mixed and load firmly-the shell gelatine capsule in.

Composition	Amount/capsule, mg
Composition	Amount/capsule, mg	The compounds of this invention	200
The lactose spraying drying	148	The compounds of this invention	200
The lactose spraying drying	148	Magnesium Stearate	2

Injectable formula

The compounds of this invention (as, compound 1) at 2% HPMC of DI water, among 1% Tween 80, pH2.2 uses MSA q.s. 20mg/mL extremely at least

Aforementioned invention is by explanation and embodiment and described in detail so that clarify and understand.Those skilled in the art obviously find out, can change within the scope of the appended claims and revise.Therefore, more than description will be exemplified to meaning illustrative and nonrestrictive.Therefore should not determine in the scope of the present invention, and should be with reference to following appended claims with reference to above description, and the four corner of the equivalent of these claims and determining.All patents of being quoted in this application, patent application and publication are incorporated the present invention into as a reference fully at this, and just as each single patent, patent application or publicization are by so individually expression is such.

Claims

1. the compound that has structural formula (I):

Wherein: n is an integer 1 to 3;

R ¹And R ², in the time of on being connected to same carbon, can form cycloalkyl or monocycle saturated heterocyclyl jointly, obtain volution, wherein cycloalkyl or monocycle saturated heterocyclyl can optionally be independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^c, or R ^fReplace; Or

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace; Or

Its drug acceptable salt, prerequisite is:

2. the compound of claim 1, wherein: n is 1; R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace; Or

R ¹And R ², in the time of on the carbon atom 2 that is connected to piperazine ring and 5 or 3 and 6, can form jointly-C ₁-C ₃-alkylidene chain, wherein a carbon atom in the alkylidene chain optionally is replaced by-NR-,-O-,-S (O) n-(wherein R is that hydrogen or alkyl and n are 0-2) and further wherein one or two hydrogen atom in the alkylidene chain can optionally replace with one or two alkyl; With

Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ¹Replace.

3. the compound of claim 2, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclic radical, wherein aforementioned looking around need be independently selected from alkyl, halo, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, cyano group, single substituted-amino, or the R of disubstituted amido ^a, R ^b, or R ^cReplace.

4. the compound of claim 2, wherein R ¹And R ²Be hydrogen.

5. the compound of claim 2, wherein R ¹And R ²Be independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, or the replacement of the substituting group of halogenated alkoxy, prerequisite is R ¹And R ²In at least one be not hydrogen.

6. the compound of claim 2, wherein R ¹Be hydrogen and R ²It is alkyl.

7. the compound of claim 2, wherein R ¹And R ²Be connected on the identical carbon atoms and be combined to form optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fThe cycloalkyl that replaces.

8. the compound of claim 2, wherein R ¹And R ²Be connected on the identical carbon atoms and be combined to form optionally with being independently selected from alkyl; Alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^eOr R ^fThe monocycle saturated heterocyclyl that replaces.

9. the compound of claim 2, wherein R ¹And R ²In the time of on the carbon atom 2 that is connected to piperazine ring and 5 or 3 and 6 and be combined to form-C ₁-C ₂-alkylidene chain, wherein one or two hydrogen atom in the alkylidene chain can optionally replace with one or two alkyl.

10. the compound of claim 2, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen and Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces.

11. the compound of claim 2, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl, and Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl of getting, prerequisite are R ¹, R ², and R ⁴In at least one be not hydrogen.

12. the compound of claim 2, wherein R ¹, R ³, R ⁴, and R ⁵Be hydrogen, R ²Be alkyl, and Ar ¹And Ar ²Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces.

13. the compound of claim 2, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹Be optionally to use R ^g, R ^hOr R ⁱThe phenyl that replaces, and Ar ²It is cycloalkyl.

14. the compound of claim 2, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl, Ar ¹Be optionally to use R ^g, R ^hOr R ⁱThe phenyl and the Ar that replace ²Be cycloalkyl, prerequisite is R ¹, R ², and R ⁴In at least one be not hydrogen.

15. the compound of claim 2, wherein R ¹, R ³, R ⁴, and R ⁵Be hydrogen, R ²Be alkyl, Ar ¹Be optionally to use R ^g, R ^hOr R ⁱThe phenyl and the Ar that replace ²It is cycloalkyl.

16. the compound of claim 2, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen, Ar ¹Be phenyl and Ar ²Be heteroaryl, each is looked around and need use R ^g, R ^hOr R ⁱReplace.

17. the compound of claim 2, wherein R ³And R ⁵Be hydrogen, R ¹, R ², and R ⁴Be hydrogen or alkyl, Ar ¹Be phenyl and Ar ²Be heteroaryl, each is looked around and need use R ^g, R ^hOr R ⁱReplace, prerequisite is R ¹, R ², and R ⁴In at least one be not hydrogen.

18. the compound of claim 2, wherein R ¹, R ³, R ⁴, and R ⁵Be hydrogen, R ²Be alkyl, Ar ¹Be phenyl and Ar ²Be heteroaryl, each is looked around and need use R ^g, R ^hOr R ⁱReplace.

19. the compound of claim 2, wherein compound has structure:

Wherein: R ¹And R ²Be hydrogen or alkyl independently; With

Ar ¹And Ar ²Be phenyl independently, each is looked around and need use R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio, alkoxyl group, alkyl-carbonyl, or alkoxy carbonyl.

20. the compound of claim 2, wherein compound has structure:

R ^gAnd R ^hBe alkyl independently, halo, haloalkyl, or halogenated alkoxy is connected on the 3-position of benzyl ring and ^*Stereochemistry on the C is (R).

21. the compound of claim 2, wherein compound has structure:

Or

R wherein ^gAnd R ^hBe hydrogen independently, alkyl, halo, haloalkyl, or halogenated alkoxy.

22. the compound of claim 2 wherein has in the compound of structural formula (I) and has following a kind of structure

Or

R wherein ¹Be hydrogen or methyl and R ^gBe cyano group, heteroaryl or phenyl optionally replace and R with alkyl respectively ^hBe alkyl, halo, haloalkyl, or halogenated alkoxy.

23. the compound of claim 22, wherein R ^gBe positioned on the 3-position of benzyl ring and the stereochemistry on * C is (R).

24. a compound is selected from:

(R)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((3, the 5-dichlorophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(R)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-benzhydryl piperazidine-1-yl) acetate;

2-(4-((4-chloro-phenyl-) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-(phenyl (4-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((2-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-(4-((3-biphenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(S)-2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(R)-2-(4-((4-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(S)-2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

(R)-2-(4-((3-bromophenyl) (phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(3-iodophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((R)-(3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((S)-(3-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-(biphenyl-3-base-phenyl-methyl)-piperazine-1-yl)-acetate;

2-((R)-2-methyl-4-((S)-phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((4-chloro-phenyl-) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-(biphenyl-4-base-phenyl-methyl)-piperazine-1-yl)-acetate;

2-((R)-4-((4-bromophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((4-cyano-phenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((3-chloro-phenyl-) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

[(R)-4-((R)-biphenyl-3-base-phenyl-methyl)-2-methyl-piperazine-1-yl]-acetate;

2-((R)-2-methyl-4-((R)-phenyl (m-tolyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-((4-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((3-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

[(R)-4-((R)-biphenyl-4-base-phenyl-methyl)-2-methyl-piperazine-1-yl]-acetate;

[(R)-the 2-methyl-4-[(R)-(2 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

[(R)-the 2-methyl-4-[(R)-(3 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

[(R)-the 2-methyl-4-[(R)-(4 '-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazine-1-yl]-acetate;

2-((R)-4-((R)-(4-fluorophenyl) (phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(2-pyridin-3-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((R)-phenyl (3-(2-pyridin-4-yl ethynyl) phenyl) methyl) piperazine-1-yl) acetate;

(R)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate;

2-((S)-2-methyl-4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

(S)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate;

(R)-2-(4-diphenyl-methyl-3-methylpiperazine-1-yl) acetate;

2-((2,5-is trans)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate;

2-((2, the 5-cis)-4-diphenyl-methyl-2,5-lupetazin-1-yl) acetate;

2-((R)-3-methyl-4-(phenyl (4-phenylbenzene) methyl) piperazine-1-yl) acetate;

(R)-2-(4-(two (3-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (3-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-(4-((4-fluorophenyl) (3-(phenylbenzene) methyl))-(R)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate;

2-((R)-4-((3-bromophenyl) (4-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (4-fluorophenyl) methyl)-3-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (4-fluorophenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

2-(4-(two (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-2-methyl-4-((S)-thiophene-2-base (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate;

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-methylpiperazine-1-yl) acetate;

(S)-2-((R)-4-(two (4-chloro-phenyl-) methyl)-3-is at ethyl piperazidine-1-yl) propionic acid;

2-(4-(two (4-chloro-phenyl-) methyl)-3-oxo piperazine-1-yl) acetate;

2-(4-(two (4-chloro-phenyl-) methyl)-2-oxo piperazine-1-yl) acetate;

2-((2R, 6S)-4-(two (4-chloro-phenyl-) methyl)-2,6-lupetazin-1-yl) acetate;

2-(4-(two (4-chloro-phenyl-) methyl)-2,2-lupetazin-1-yl) acetate;

2-(4-(two (4-chloro-phenyl-) methyl) piperazine-1-yl) propionic acid;

(R)-2-(4-(two (4-chloro-phenyl-) methyl)-2-sec.-propyl piperazine-1-yl) acetate; 2-(4-(two (4-chloro-phenyl-) methyl) piperazine-1-yl) acetate; With

2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl)-1,4-diazene-1-yl)-acetate;

Or its drug acceptable salt

25. a compound is selected from;

(R)-2-(4-(phenyl (3-(trifluoromethyl) phenyl) methyl) piperazine-1-yl) acetate;

(R)-2-(4-diphenyl-methyl-2-methylpiperazine-1-yl) acetate dihydrochloride;

2-((R)-2-methyl-4-((R)-phenyl (m-tolyl) methyl) piperazine-1-yl) acetate; With

26. a compound is selected from: 2-((R)-4-(cyclopropyl (3-(trifluoromethyl) phenyl) methyl)-2-methylpiperazine-1-yl) acetate dihydrochloride.

27. a pharmaceutical composition comprises the compound of arbitrary claim 1-26 or has the compound of structural formula (I) and the mixture of its drug acceptable salt; Can accept vehicle with medicine.

28. the method for the disease that a treatment can be treated by the GIyT1 acceptor that suppresses the patient, this method comprise pharmaceutical composition to patient's administration, described composition comprises the have structural formula compound of (I):

Wherein: n is an integer 1 to 3;

R ¹And R ², in the time of on being connected to same carbon, can form cycloalkyl or monocycle saturated heterocyclyl jointly, obtain volution, wherein cycloalkyl or monocycle saturated heterocyclyl can be optionally with being independently selected from alkyl, alkoxyl group, fluorine, fluoroalkyl, Fluoroalkyloxy, hydroxyl, single substituted-amino, or the R of disubstituted amido ^d, R ^e, or R ^fReplace; Or

R ¹And R ², in the time of on the carbon atom 2 that is connected to piperazine ring and 5 or 3 and 6, can form jointly-C ₁-C ₃-alkylidene chain, wherein a carbon atom in the alkylidene chain optionally is replaced by-NR-,-O-,-S (O) n-(wherein R is that hydrogen or alkyl and n are 0-2) and further wherein one or two hydrogen atom in the alkylidene chain can be optionally to replace with one or two alkyl;

R ³, R ⁴And R ⁵Be hydrogen independently, alkyl, fluorine, or fluoroalkyl; And Ar ¹And Ar ²Be aryl independently, heteroaryl, cycloalkyl, or heterocyclic radical, wherein each aforementioned looking around need be by R ^g, R ^hOr R ⁱReplace, wherein R ^gBe alkyl ,-C ≡ C-R ⁶(R wherein ⁶Be aryl or heteroaryl), halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or acyl amino and R ^hAnd R ⁱBe independently selected from alkyl, halo, haloalkyl, halogenated alkoxy, alkylthio; cyano group, alkoxyl group, amino, single substituted-amino, disubstituted amido; alkylsulfonyl, acyl group, carboxyl, alkoxy carbonyl, hydroxyalkyl; alkoxyalkyl, aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, acyl amino, aryl; heteroaryl, cycloalkyl, or heterocyclic radical, wherein R ^g, R ^hAnd R ⁱIn aromatics or alicyclic looking around need be independently selected from alkyl, halo, haloalkyl, halogenated alkoxy; alkylthio, cyano group, alkoxyl group, amino; single substituted-amino, disubstituted amido, alkylsulfonyl, acyl group; carboxyl, alkoxy carbonyl, hydroxyalkyl, alkoxyalkyl; aminoalkyl group, hydroxy alkoxy base, alkoxyl group alkoxyl group, aminoalkoxy; amino-sulfonyl, aminocarboxyl, or the R of acyl amino ^j, R ^kOr R ^lReplace;

Its drug acceptable salt or have the compound of structural formula (I) and the mixture of its drug acceptable salt and

Medicine can be accepted vehicle.

29. the method for the disease that a treatment can be treated by the GIyT1 acceptor that suppresses the patient, this method comprises can accept the pharmaceutical composition of vehicle to patient's administration with comprising the mixture of compound of the compound of arbitrary claim 2-26 or arbitrary claim 2-26 and its drug acceptable salt and medicine.

30. the method for claim 28 or 29, wherein disease is a schizophrenia.

31. the method for claim 30, wherein disease is the cognitive illness relevant with schizophrenia.