CN101084215A

CN101084215A - Piperidine and azetidine derivatives as GLYT1 inhibitors

Info

Publication number: CN101084215A
Application number: CN200580044155.4A
Authority: CN
Inventors: W·P·布莱卡比; S·R·弗莱彻尔; A·詹宁斯; R·T·路易斯; E·M·奈洛尔; L·J·斯特里特; J·汤森
Original assignee: Merck Sharp and Dohme LLC
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2004-12-21
Filing date: 2005-12-21
Publication date: 2007-12-05
Anticipated expiration: 2025-12-21
Also published as: CN101084215B; GB0427987D0

Abstract

The present invention provides compounds of formula (I), wherein both p's are one or two, R<1> is generally heteroaryl or cycloalkyl, R<2> is C3-6cycloalkyl or phenyl and R<3> is heteroaryl, and pharmaceutically acceptable salts thereof, as GlyT1 inhibitors for treating schizophrenia, pharmaceutical compositions comprising the same and methods for their preparation.

Description

Piperidines and azetidine derivatives as the GLYT1 inhibitor

The present invention relates to heterocycle sulfonyl azetidine and piperidines, particularly the purposes in treatment schizophrenia as the GlyT1 inhibitor.

Background of invention

Schizophrenia is with negative symptoms (blunting of affect, avoidance, anhedonia) and positive symptom (bigoted, illusion, vain hope) and the significant cognitive weakness mental disorder that is combined as feature that lacks.Though schizoid nosetiology is still unknown now, this disease is seemingly interacted by the complexity of biological factor, environmental factors and inherited genetic factors and produces.Before more than 40 years, it is found that phencyclidine (PCP) induces the people to produce psychotic state, this state is very similar to observed state in the schizophreniac.The discovery of effect of noncompetitive antaganist that for the main mode of action of PCP is N-methyl-D-aspartate (NMDA) hypotype of ionotropic glutamate receptor has stimulated a series of research, it makes schizoid nmda receptor hypofunction model developed (Jentsch JD and Roth RH, 1999Neuropsychopharmacoogy, 20:201).

The quick L-glutamic acid of mammalian central nervous system can (glutamatergic) transmit mainly by acting on the excitatory amino acid L-glutamic acid mediation of ionotropic glutamate receptor (iGluRs).IGluRs comprises three main subclass, comprises the alpha-amino group-different  azoles of 3-hydroxy-5-methyl base-4-propionic acid (AMPA), and kainate and nmda receptor hypotype (HollmannM and Heinemann S, 1994, Annu.Rev.Neurosci.17:31).These three subclass are poly build part-gate cationic channel, and it responds L-glutamic acid combination and opens, thereby induce the depolarize excitement behind the cynapse electric current.Molecular cloning shows that nmda receptor family comprises two main subunits, NR1 and NR2.The new inhibition subunit of explorative ground called after NR3 has been described in addition, recently.The molecular diversity that in every group of subunit, has height.Up to now, have only a kind of NR1 subunit gene to be cloned; Yet the alternative splicing of NR1 gene can produce eight kinds of different subunits.By contrast, cloned 4 genes (NR2A, NR2B, NR2C and NR2D) of NR2 subunit, some of them show alternative splicing (Hollmann M and Heinemann S, 1994, Annu.Rev.Neurosci.17:31).These multifarious subunits form heteromers type (heteromeric) L-glutamic acid-gated ion channel.Though the accurate subunit stoichiometry of naturally occurring acceptor is still unknown, NR1 and NR2 subunit all are that the active acceptor of expressive function-the passage mixture is needed in the mammalian expression system.The activation of nmda receptor needs the combination (Johnson JW and Ascher P, 1987, Nature 325:529) of L-glutamic acid and glycine.What is interesting is, measure by site-directed mutagenesis research, the combining site that is used for these two kinds of co-agonists (co-agonists) is present in independent subunit (Laube B, Hirai H, Sturgess M, Betz H and Kuhse J, 1997, Neuron 18:493).In NR2A and NR2B subunit, the binding pocket of L-glutamic acid (binding pocket) interaction terminal by the N-of acceptor and extracellular loop forms.Similarly experiment places the glycine combining site in the homology zone (Kuryatov A, Laube B, Betz H and Kuhse J, 1994, Neuron 12:1291) of NR1 subunit.Depend on that actual subunit forms, L-glutamic acid and glycine are with the EC50 value activation nmda receptor of higher nanomolar concentration to lower micro-molar concentration scope.In addition, the hole of nmda receptor porous magnesium not.Under normal dormant state, extracellular magnesium can be incorporated into the site in the hole and produce the magnesium retardance of passage.This magnesium retardance is given passage with strong voltage-dependent, and it allows nmda receptor to serve as the coincidence detection device, and this detector requires the combination and the unpolarized generation of postsynaptic before conduction current of L-glutamic acid, glycine.Interested especially discovery is that psychotomimetic drugs MK-801, PCP and ketamine all serve as nmda receptor-channel opener channel blocker by being incorporated into magnesium binding site eclipsed position.Obviously, the rich diversity of nmda receptor subunit and regulatory site provides the complexity classification of the physiology heteromers receptor different with pharmacology, makes nmda receptor become the desirable target of the new treatment compound of design.

Nmda receptor plays a key effect in many neurophysiology phenomenons, includes but not limited to synaptic plasticity, cognition, attention and memory (Bliss T and Collingridge W, 1993, Nature361:31; People such as Morris RGM, 1986, Nature 319:774).Psychotomimetic drugs constitutes a big class medicine, comprises psychomotor stimulant (Cocaine, amphetamine), halluoinogen (LSD) and nmda receptor antagonist (PCP, ketamine).As if this wherein have only nmda receptor antagonist to cause inducing by force of the schizoid positive, feminine gender and cognitive symptom.Psychotic comparative study of ketamine-inductive and compellent the enumerating (Jentsch JD and the Roth RH that abuse have been produced similarity between nmda receptor antagonist inductive psychosis and schizophrenia as the patient's of the PCP of amusement medicine observation of symptoms in human subjects, 1999Neuropsychopharmacology, 20:201).The NMDA-receptor antagonist verily imitates the symptoms of schizophrenia, to such an extent as to be difficult in clinical the two be distinguished.In addition, nmda receptor antagonist can make schizoid severity of symptoms, and can cause reaccessing of the symptom stablized among the patient.At last, nmda receptor co-agonists such as glycine, D-seromycin and D-Serine produce benefit in the schizophreniac discovery has hinted nmda receptor hypofunction in these illnesss, and show that improving nmda receptor activation can provide therapeutics benefit (people such as Leiderman E, 1996, Biol.Psychiatry 39:213, people such as Javitt DC, 1994, Am.J.Psychiatry 151:1234, Heresco-Levy U, 2000, Int.J.Neuropsychopharmacol.3:243, people such as Tsai G, 1998, Biol.Psychiatry44:1081).Big quantity research in animal model has been supported schizoid NMDA hypofunction hypothesis.The generation of only expressing 5% mutant mice of NMDA NR1 subunit normal level has recently shown that the minimizing of this functional nmda receptor induces the observed state in schizoid other animal model that is very similar to (people such as Mohn AR, 1999, Cell98:427).Except that schizophrenia, the dysfunction of L-glutamic acid energy passage has involved the numerous disease state of people's central nervous system (CNS), includes but not limited to cognitive shortage, dementia, Parkinson's disease, alzheimer's disease and bipolar disorder.

The adjusting of nmda receptor function can be undertaken by the availability that changes the co-agonists glycine.This method has the decisive advantage of activity dependent enzymes activatory of keeping nmda receptor because the increase of glycine cynapse concentration not can not have L-glutamic acid in the presence of produce nmda receptor activation.Because cynapse L-glutamic acid level closely is maintained by the high affinity transporting mechanism, the activation of the glycine site of increase only can improve the NMDA component of activated cynapse.Wherein high dosage glycine oral administration shows schizophreniac's symptom improve people such as (, Int.J.Neuropsychopharmacol. (2001) 4:385-391) Javitt as the clinical trial of the addition method of the neuroleptic therapy of standard.A kind of method that need not to give exogenous glycine and increase cynapse glycine level is to suppress its elimination from cynapse.This method can be used for treating schizoid evidence from the double blinding placebo-controlled study that wherein schizophreniac of antipsychotic drug Low Response is given sarkosine.Observe beneficial effect, show that suppressing glycine reuptake is the schizoid rational method of treatment positive, negative and cognitive symptom.

Discern two specific specificity glycine transporter GlyT1 and GlyT2, and shown the Na that belongs to the neurotransmitter translocator that comprises taurine, γ-An Jidingsuan (GABA), proline(Pro), monoamine and orphan's translocator ⁺/ Cl ^-Dependency family (people such as Smith KE, 1992, Neuron 8:927; People such as Borowsky B, 1993, Neuron 10:851; People such as Liu QR, 1993, J.Biol.Chem.268:22802; People such as Kim KM, 1994, MoI.Pharmacol.45:608; People such as Morrow JA, 1998, FEBS Lett.439:334; NelsonN, 1998, J.Neurochem.71:1785).From different species, isolated GlyT1 and GlyT2, and it only shows 50% identity at amino acid levels.They also have different expression patterns in mammalian central nervous system, GlyT2 expresses in spinal cord, brain stem and cerebellum, GlyT1 be present in these zones and forebrain zone as cortex, hippocampus, barrier film and thalamus (people such as Smith KE, 1992, Neuron 8:927; People such as Borowsky B, 1993, Neuron 10:851; People such as Liu QR, 1993, J.Biol.Chem.268:22802).At cell levels, reported that GlyT2 can nerve ending be expressed by the glycine in the rat spinal cord, and GlyT1 as if preferentially by spongiocyte express (people such as Zafra F, 1995, J.Neurosci.15:3952).These expression studies are reached a conclusion, that is, GlyT2 mainly is responsible for the glycine uptake of glycinergic synapse, and GlyT1 involves near the glycine concentration of cynapse that nmda receptor is expressed in monitoring.Functional study in rat recently shows, usefulness potent inhibitor in rat (N-[3-(4 '-fluorophenyl)-3-(4 '-the phenyl phenoxy group) propyl group]) sarkosine (NFPS) blocking-up GlyT1, strengthened the active and nmda receptor dependency long-range reinforcing effect of nmda receptor (people such as Bergeron R, 1998, PNAS USA 95:15730; People such as Kinney G, 2003, J.Neurosci.23:7586).In addition, reported NFPS in mouse, strengthen metric prepulse as the known sensory gating that in the schizophreniac, lacks suppress (people such as Kinney G, 2003, J.Neurosci.23:7586).GlyT1 is at these physiological roles in forebrain zone and show that GlyT1 inhibitor sarkosine shows that in the clinical report (Tsai and Coyle WO99/52519) of improving the beneficial effect aspect schizophreniac's the symptom selectivity GlyT1 uptake inhibitor has been represented the new antipsychotic drug of a class.

WO-A-05094514 (Merck﹠amp; Co., Inc. and Merck Sharp﹠amp; DohmeLtd.) open piperidine derivative as the GlyT1 inhibitor.Yet, be not disclosed in R ³The place is the heterocyclic examples of compounds.

WO-A-05110983 (Merck﹠amp; Co., Inc. and Merck Sharp﹠amp; DohmeLtd.) open azetidine derivatives as the GlyT1 inhibitor.Yet, not open wherein R ³Be the heterocyclic compound.

Abstract of invention

The present invention relates to suppress glycine transporter GlyT1 and can be used for treating with L-glutamic acid can neurotransmission relevant sacred disease and the mental disorder of dysfunction and wherein relate to the compound of the disease of glycine transporter GlyT1.

Detailed Description Of The Invention

The present invention relates to the compound of formula I:

Wherein:

Two p are 1 or 2;

R ¹For-(CH ₂) _n-R ^1a, wherein n is 0-6 independently, and R ^1aBe selected from:

(1) (a) C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen atom or hydroxyl,

(b) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace, or

(c) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) C _3-6Cycloalkyl, it is unsubstituted or by C _1-6Alkyl, a 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace,

(3) piperidyl, it is unsubstituted or by C _1-6Alkyl, a 1-6 halogen, hydroxyl ,-O-C _1-6Alkyl or-NR ¹⁰R ¹¹Replace,

(4) pyranyl, it is unsubstituted or by C _1-6Alkyl, a 1-6 halogen, hydroxyl ,-O-C _1-6Alkyl or-NR ¹⁰R ¹¹Replace,

(5)-O-C _1-6Alkyl, its be unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace,

(6)-CO ₂R ⁹，

R wherein ⁹Be independently selected from:

(a) hydrogen,

(b)-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 fluorine,

(c) benzyl and

(d) phenyl,

(7)-NR ¹⁰R ¹¹，

R wherein ¹⁰And R ¹¹Be independently selected from:

(a) hydrogen,

(b)-C _1-6Alkyl, its be unsubstituted or by hydroxyl, a 1-6 fluorine or-NR ¹²R ¹³Replace, wherein R ¹²And R ¹³Be independently selected from hydrogen and-C _1-6Alkyl,

(c)-C _3-6Cycloalkyl, its be unsubstituted or by hydroxyl, a 1-6 fluorine or-NR ¹²R ¹³Replace,

(d) benzyl,

(e) phenyl and

(8)-CONR ¹⁰R ¹¹；

R ²Be selected from:

(1) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

(3) C _1-8Alkyl, its be unsubstituted or by 1-6 halogen, hydroxyl ,-NR ¹⁰R ¹¹, phenyl or heterocyclic substituted, wherein phenyl or heterocycle are by R ^2a, R ^2bAnd R ^2cReplace,

(4) C _3-6Cycloalkyl, its be unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace and

(5)-C _1-6Alkyl-(C _3-6Cycloalkyl), its be unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace;

R ^2a, R ^2bAnd R ^2cBe independently selected from:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl, it is unsubstituted or is replaced by following group:

(a) 1-6 halogen,

(b) phenyl,

(c) C _3-6Cycloalkyl, or

(d)-NR ¹⁰R ¹¹，

(4)-O-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen,

(5) hydroxyl,

(6)-SCF ₃，

(7)-SCHF ₂，

(8)-SCH ₃，

(9)-CO ₂R ⁹，

(10)-CN，

(11)-SO ₂R ⁹，

(12)-SO ₂-NR ¹⁰R ¹¹，

(13)-NR ¹⁰R ¹¹，

(14)-CONR ¹⁰R ¹¹And

(15)-NO ₂；

R ³Be heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace;

R ⁴And R ⁵Be independently selected from:

(1) hydrogen and

(2) C _1-6Alkyl, it is unsubstituted or is replaced by halogen or hydroxyl, or R ⁴And R ⁵Be combined to form C _3-6Cycloalkyl ring;

A is selected from:

(1)-O-and

(2)-NR ¹⁰-；

M is 0 or 1, thus when m is 0 R ²Directly be connected with carbonyl; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

R ¹Preferred C _3-6Cycloalkyl or heterocycle, wherein heterocycle is to comprise 1,2,3 or 4 heteroatoms that is selected from O, N or S, maximum heteroatomss are 5 yuan of unsaturated rings of O or S, or comprise 6 yuan of unsaturated rings of 1,2 or 3 nitrogen-atoms, R ¹Optional by halogen or hydroxyl replacement.Especially, R ¹Be C _3-6Cycloalkyl or nitrogen heterocyclic ring are as pyridine.So R ¹Can be cyclopropyl or pyridine such as pyridin-3-yl or 3-fluorine pyridine-2-base.

N preferred 0 or 1.

R ²Preferred phenyl or C _3-6Cycloalkyl, it is optional by hydroxyl, halogen, C _1-6Alkyl such as methyl, halo C _1-6Alkyl, C _1-6Alkoxyl group or amino the replacement.R ²Particularly phenyl or cyclohexyl, it is optional to be replaced by halogen such as chlorine or fluorine.R ²Embodiment be cyclohexyl, 2,4 dichloro benzene base, 2-chloro-6-fluorophenyl, 5-fluoro-2,4 dichloro benzene base and 6-chloro-2, the 5-difluorophenyl.

R ³Be generally 5 yuan of unsaturated rings, it contains 1,2,3 or 4 heteroatoms that is selected from O, N or S, and maximum heteroatomss are O or S, or 6 yuan of unsaturated rings, and it contains 1,2 or 3 nitrogen-atoms, and is optional by halogen, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halo C _1-6Alkoxyl group, nitro or amino the replacement.R ³5 yuan of rings preferably.R ³Preferably unsubstituted or by C _1-4Alkyl such as methyl or ethyl or halogen such as chlorine replace.R ³Can be replace or unsubstituted triazole, pyrazoles, indazole, pyridine or thiophene.R ³Specific embodiments be 1-methyl-pyrazol-4-yl, 1-methylindazole-4-base, 1,2,3-triazole-4-base, 1-methyl isophthalic acid, 2,3-triazole-4-base, 1-methyl isophthalic acid, 3,4-triazole-2-base, pyridin-3-yl, 1-methyl isophthalic acid, 2,3-triazole-3-base, 1-methyl isophthalic acid, 2,4-triazole-3-base, thiophene-2-base, 1,2-dimethyl indazole-5-base, 2-thiotolene-5-base, 2-chlorothiophene-5-base, 1-methyl isophthalic acid, 2,4-triazole-3-base, 2-methyl isophthalic acid, 2,3-triazole-4-base, 1-ethyl-1,2,3-triazole-4-base and 2-ethyl-1,2,3-triazoles-4-base.

R ⁴And R ⁵Be generally hydrogen.

M is generally 0.

In one embodiment, the present invention relates to formula I ' compound:

Wherein:

(1) C _1-6Alkyl, it is unsubstituted or by 1-6 halogen, hydroxyl, by R ^2a, R ^2bAnd R ^2cThe phenyl that replaces or by R ^2a, R ^2bAnd R ^2cThe heterocyclic substituted that replaces,

(6)-CO ₂R ⁹，

R wherein ⁹Be independently selected from:

(a) hydrogen,

(b)-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 fluorine,

(c) benzyl and

(d) phenyl,

(7)-NR ¹⁰R ¹¹，

R wherein ¹⁰And R ¹¹Be independently selected from:

(a) hydrogen,

(d) benzyl,

(e) phenyl and

(8)-CONR ¹⁰R ¹¹；

R ²Be selected from:

(1) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

(5)-C _1-6Alkyl-(C _3-6Cycloalkyl), it is unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace;

R ^2a, R ^2bAnd R ^2cBe independently selected from:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl, it is unsubstituted or is replaced by following group:

(a) 1-6 halogen,

(b) phenyl,

(c) C _3-6Cycloalkyl, or

(d)-NR ¹⁰R ¹¹，

(4)-O-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen,

(5) hydroxyl,

(6)-SCF ₃，

(7)-SCHF ₂，

(8)-SCH ₃，

(9)-CO ₂R ⁹，

(10)-CN，

(11)-SO ₂R ⁹，

(12)-SO ₂-NR ¹⁰R ¹¹，

(13)-NR ¹⁰R ¹¹，

(14)-CONR ¹⁰R ¹¹And

(15)-NO ₂；

R ³Be heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace;

R ⁴And R ⁵Be independently selected from:

(1) hydrogen and

(2) C _1-6Alkyl, it is unsubstituted or is replaced by halogen or hydroxyl,

Or R ⁴And R ⁵Be combined to form C _3-6Cycloalkyl ring;

A is selected from:

(1)-O-and

(2)-NR ¹⁰-；

In one embodiment, the present invention comprises formula I ' compound, wherein R ¹Be selected from CH ₂R ^1a, R wherein ^1aBe C _3-6Cycloalkyl, described C _3-6Cycloalkyl is unsubstituted or by C _1-6Alkyl, a 1-6 halogen, hydroxyl or NR ¹⁰R ¹¹Or by R ^2a, R ^2bAnd R ^2cThe heterocyclic substituted that replaces, or R ¹For by R ^2a, R ^2bAnd R ^2cThe heterocycle that replaces, or its pharmacologically acceptable salt or its each isomer or diastereomer.

In addition, in described embodiment, the present invention includes wherein R ¹Be selected from CH ₂R ^1aCompound, R wherein ^1aBe C _3-6Cycloalkyl such as cyclopropyl, or heterocycle, suitable unsaturated heterocycle such as pyridine.

In addition, in described embodiment, the present invention includes wherein R ¹Be the heterocyclic compound.Suitable described heterocycle is unsaturated heterocycle such as pyridine.This heterocycle is suitably by the defined R of preamble ^2a, R ^2bAnd R ^2cReplace.Suitably, R ^2a, R ^2bAnd R ^2cIn at least two be that hydrogen and the 3rd are hydrogen, methyl or fluorine.

One embodiment of the invention comprise formula I ' a compound:

Wherein:

R ^2dBe selected from:

(1) hydrogen,

(2) C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen atom, hydroxyl or phenyl,

(3) hydroxyl,

(4)-O-C _1-6Alkyl,

(5) halogen, particularly fluorine

(6)-NR ¹⁰R ¹¹；

And R ², R ³, R ⁴, R ⁵, R ¹⁰, R ¹¹, A and m as defined herein;

Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

One embodiment of the invention comprise formula I ' a ' compound:

Wherein:

R ^1bBe selected from:

(1) hydrogen,

(2) C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen, hydroxyl or phenyl,

(3) hydroxyl,

(4)-O-C _1-6Alkyl,

(5) halogen, particularly fluorine and

(6)-NR ¹⁰R ¹¹；

And R ², R ³, R ⁴, R ⁵, R ¹⁰, R ¹¹, A and m as defined herein; Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

In formula I ' a and I ' a ', R ^1aAnd R ^2dPreferably hydrogen or fluorine.

One embodiment of the invention comprise formula I ' a " compound:

R wherein ², R ³, R ⁴, R ⁵, A and m as defined herein; Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

One embodiment of the invention comprise formula Ib compound:

R wherein ⁴Be C _1-6Alkyl, and R ¹, R ², R ³, p, A and m as defined herein; Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

One embodiment of the invention comprise wherein R ⁴Be C _1-3Alkyl and R ⁵Be hydrogen or C _1-3The compound of alkyl.

In described embodiment, the present invention includes wherein R ⁴C for (S) configuration _1-3Alkyl and R ⁵Compound for hydrogen.

Also in described embodiment, the present invention includes wherein R ⁴Be methyl and R ⁵Compound for hydrogen.

Also in described embodiment, the present invention includes wherein R ⁴Be methyl and R ⁵Compound for methyl.

Also in described embodiment, the present invention includes wherein R ⁴Be hydrogen and R ⁵Compound for hydrogen.

One embodiment of the invention comprise that m wherein is 0 compound.

In described embodiment, the present invention includes the compound of formula Ic:

Wherein p, R ¹, R ², R ³, R ⁴And R ⁵As defined herein; Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

In addition, in described embodiment, the present invention includes wherein R ²Be selected from the compound of following group:

(1) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) thienyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(3) C _1-8Alkyl, it is unsubstituted or by 1-6 halogen, phenyl or-NR ¹⁰R ¹¹Replace, wherein phenyl is by R ^2a, R ^2bAnd R ^2cReplace,

R ^2a, R ^2bAnd R ^2cBe independently selected from:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl,

(4)-O-C _1-6Alkyl,

(5)-CF ₃，

(6)-OCF ₃，

(7)-OCHF ₂，

(8)-SCF ₃，

(9)-SCHF ₂And

(10)-NH ₂。

In addition, also in described embodiment, the present invention includes wherein R ²Be phenyl or thienyl and R ^2a, R ^2bAnd R ^2cBe independently selected from the compound of following radicals:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl,

(4)-O-C _1-6Alkyl,

(5)-CF ₃，

(6)-OCF ₃，

(7)-OCHF ₂，

(8)-SCF ₃，

(9)-SCHF ₂And

(10)-NH ₂。

In addition, also in described embodiment, the present invention includes wherein R ²Be phenyl and R ^2a, R ^2bAnd R ^2cBe independently selected from the compound of following radicals:

(1) hydrogen,

(2) fluorine,

(3) chlorine,

(4) bromine,

(5)-OCH ₃，

(6)-CF ₃And

(7)-NH ₂。

In addition, also in described embodiment, the present invention relates to wherein R of compound ²Be phenyl and R ^2a, R ^2bAnd R ^2cBe independently selected from the compound of following radicals:

(1) hydrogen,

(2) fluorine,

(3) chlorine and

(4) bromine.

In described embodiment, the present invention includes formula Id compound:

Wherein p, R ¹, R ^2a, R ^2b, R ², R ³, R ⁴And R ⁵As defined herein; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

In described embodiment, the present invention includes formula Id ' compound:

Wherein p, R ¹, R ^2a, R ^2b, R ^2cAnd R ³As defined herein; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

Also in described embodiment, the present invention includes formula Id " compound:

Wherein p, R ¹, R ^2a, R ^2b, R ^2c, R ³And R ⁴As defined herein; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

Suitably, R ³For by R ^2a, R ^2bAnd R ^2cThe unsaturated heterocycle that contains 1,2 or 3 nitrogen-atoms that is replaced, wherein R ^2a, R ^2bAnd R ^2cBe preferably selected from hydrogen, fluorine and C _1-6Alkyl, most preferably hydrogen or methyl.

The most suitably, R ³For containing 5 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms, it links to each other with alkylsulfonyl by a heterocyclic carbon atom.

Preferred R ³Be following radicals

Wherein among X, Y and the Z at least one be in nitrogen and other group one for nitrogen, the 3rd position is carbon; And R ^3aBe hydrogen or C _1-6Alkyl, preferable methyl or R ³Be pyridine.

R most preferably ³Be following radicals:

Or

And R ^3aBe hydrogen or methyl.

One group of preferred formula I ' compound is following formula I ' e:

R wherein ^1cBe CH ₂R ^1bOr by R ^2a, R ^2bOr R ^2cThe heterocyclic group that replaces, and R ^1b, R ², R ^2a, R ^2b, R ^2c, R ³, R ⁴, R ⁵, A and m such as preamble define; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

One group of formula (I ' e) compound is those formulas I ' f compound:

R wherein ^1b, R ², R ³, R ⁴, R ⁵, A and m such as preamble define; And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

Preferred R ^1bBe cyclopropyl or unsaturated heterocycle such as pyridine.

Another group formula (I ' e) compound is those formulas I ' g compound:

Wherein heterocycle, R ², R ³, R ⁴, R ⁵, A and m such as preamble define, and pharmacologically acceptable salt and its each enantiomorph and diastereomer.

Preferred this heterocycle is by R ^2a, R ^2bAnd R ^2cThe unsaturated heterocycle that replaces.

Suitably, this heterocycle comprises at least one nitrogen-atoms and R ^2a, R ^2bAnd R ^2cIn at least two be hydrogen, and the 3rd is hydrogen, methyl or fluorine.Preferred this heterocycle is a pyridine.

In another embodiment, formula I " compound:

Wherein:

(6)-CO ₂R ⁹，

R wherein ⁹Be independently selected from:

(a) hydrogen,

(b)-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 fluorine,

(c) benzyl and

(d) phenyl,

(7)-NR ¹⁰R ¹¹，

R wherein ¹⁰And R ¹¹Be independently selected from:

(a) hydrogen,

(d) benzyl,

(e) phenyl and

(8)-CONR ¹⁰R ¹¹；

R ²Be selected from:

(1) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

R ^2a, R ^2bAnd R ^2cBe independently selected from:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl, it is unsubstituted or is replaced by following group:

(a) 1-6 halogen,

(b) phenyl,

(c) C _3-6Cycloalkyl, or

(d)-NR ¹⁰R ¹¹，

(4)-O-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen,

(5) hydroxyl,

(6)-SCF ₃，

(7)-SCHF ₂，

(8)-SCH ₃，

(9)-CO ₂R ⁹，

(10)-CN，

(11)-SO ₂R ⁹，

(12)-SO ₂-NR ¹⁰R ¹¹，

(13)-NR ¹⁰R ¹¹，

(14)-CONR ¹⁰R ¹¹And

(15)-NO ₂；

R ³Be selected from:

(1) C _1-6Alkyl, its be unsubstituted or by 1-6 halogen, hydroxyl ,-NR ¹⁰R ¹¹Or by R ^2a, R ^2bAnd R ^2cThe heterocyclic substituted that replaces,

(2) C _3-6Cycloalkyl, its be unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace,

(3)-C _1-6Alkyl-(C _3-6Cycloalkyl), it is unsubstituted or by 1-6 halogen, hydroxyl or-NR ¹⁰R ¹¹Replace and

(4)-NR ¹⁰R ¹¹And

(5) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace;

R ⁴And R ⁵Be independently selected from:

(1) hydrogen and

A is selected from:

(1)-O-and

(2)-NR ¹⁰-；

In one embodiment, the present invention comprises formula I " compound, wherein R ¹Be selected from (CH ₂) _nR ^1a, R wherein ^1aBe C _3-6Cycloalkyl, described C _3-6Cycloalkyl is unsubstituted or by R ^2a, R ^2bAnd R ^2cReplace.Suitably n is 1 and R ^1aBe unsubstituted C _3-6Cycloalkyl, preferred cyclopropyl.

In addition, in described embodiment, the present invention includes formula I " compound, wherein R ¹For by R ^2a, R ^2bAnd R ^2cThe heterocycle that replaces.The preferred unsaturated heterocycle part of described heterocycle, for example nitrogenous unsaturated heterocycle such as pyridyl, and R ^2aAnd R ^2bBe hydrogen and R ^2cBe hydrogen or fluorine, or the saturated heterocyclic part, for example nitrogenous saturated heterocyclic such as piperidyl, optional by C _1-6Alkyl replaces.

One embodiment of the invention comprise formula I " a compound:

Wherein:

R is selected from:

(1) hydrogen and

(2) C _1-6Alkyl; Preferable methyl.

R ^1bBe selected from:

(1) hydrogen,

(3) hydroxyl,

(4)-O-C _1-6Alkyl,

(5) halogen and

(6)-NR ¹⁰R ¹¹；

And R ², R ³, R ⁴, R ⁵, A and m as defined herein; Or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.

R ^1bPreferred hydrogen.

One embodiment of the invention comprise formula I " a ' compound:

Wherein:

R ^1bBe halogen, preferred fluorine;

R ^1bPreferred hydrogen or fluorine.

One embodiment of the invention comprise formula I " a " compound:

R wherein ^1cBe C _3-6Cycloalkyl, it is unsubstituted or by R ^2a, R ^2bAnd R ^2cReplace and R ², R ^2a, R ^2b, R ^2c, R ³, R ⁴, R ⁵, A and m as defined herein or its pharmacologically acceptable salt or its each enantiomorph or diastereomer.Suitably, n is 1 and R ^1cBe unsubstituted C _3-6Cycloalkyl, preferred cyclopropyl.

One group of preferred formula (I) compound is formula I " the e compound:

R wherein ^1cAnd R ^2a, R ^2bAnd R ^2cDefine as preamble, and R ^3aFor choosing wantonly by halogen or C _1-6Alkyl or C _1-6The unsaturated heterocycle that the alkylhalide group group replaces.

Preferred R ^1cImplication such as preamble define.

R ^2a, R ^2b, R ^2cPreferably hydrogen or halogen suitably is chlorine or fluorine.Preferred R ^2a, R ^2b, R ^2cIn have only one for hydrogen.

R ^3aBe preferably the 6 yuan of heterocycles such as the pyridine that contain one or more nitrogen-atoms, or contain 5 yuan of heterocycles of a sulphur atom or 1-3 nitrogen-atoms and preferred 2-3 nitrogen-atoms, wherein heterocycle is chosen wantonly by one or two halogen atom or C _1-6Alkyl or C _1-6The alkylhalide group group replaces as methyl or ethyl.

Heterocycle preferably links to each other with alkylsulfonyl by ring carbon atom.

Preferred heterocycle comprises thienyl, triazolyl, pyrazolyl and imidazolyl.

Substituting group on the heterocycle can with ring carbon atom with or theheterocyclic nitrogen atom (under the nitrogen heterocyclic ring situation) link to each other.

Specific embodiment of the present invention comprises the motif compound and the compound of its pharmacologically acceptable salt with its each enantiomorph and diastereomer that is selected among this paper embodiment.

Therefore compound of the present invention can comprise one or more chiral centres, can be used as racemoid and racemic mixture, independent enantiomorph, non-enantiomer mixture and each diastereomer exists.According to the character of different substituents on the molecule, can there be other asymmetric center.Each this asymmetric center produces two optical isomers and all possible optical isomer and diastereomer (it is for form of mixtures with as pure or partial-purified compound form) independently and all comprises within the scope of the invention.The present invention is intended to comprise all described isomeric forms of these compounds.Formula I represents not have preferred other structure of stereochemical compounds.

Synthetic or their chromatographic separation of the independence of these diastereomers can pass through as known in the art to herein openly method carry out suitable improvement and realize.Their absolute stereo chemistry can be measured by the x-radiocrystallography of crystallized product or crystallization of intermediate, and described product or intermediate if necessary can use the reagent of the asymmetric center that contains known absolute configuration to carry out derivatize.

If expectation can separate the racemic mixture of compound so that separate each enantiomorph.Separation can be undertaken by method as known in the art, as the compound coupling that the racemic mixture of compound and mapping is pure to form non-enantiomer mixture, to separate each diastereomer by standard method such as fractional crystallization or chromatography subsequently.Linked reaction is generally uses pure acid of mapping or alkali to form salt.Then can be by falling to make non-enantiomer derivative to be converted into pure enantiomorph the chirality residue cracking of adding.The racemic mixture of compound also can directly separate by the chromatography of utilizing chiral stationary phase, and it is a method well known in the art.

Perhaps, can carry out the three-dimensional synthetic any enantiomorph that obtains compound of selecting by the reagent that uses optically pure starting raw material or have a configuration known by means commonly known in the art.

As understood by a person skilled in the art, halogen used herein or halogen are intended to comprise fluorine, chlorine, bromine and iodine.Similarly, as C _1-6C in the alkyl _1-6Be defined as and be meant group with 1,2,3,4,5 or 6 carbon with straight or branched configuration, so C _1-8Alkyl specifically comprises: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl and octyl group.Being designated as the group that is substituted the base replacement independently can be replaced by a plurality of this substituting groups independently.As used in this article, term " heterocycle " comprises unsaturated heterocycle part and saturated heterocyclic part, wherein unsaturated heterocycle part (i.e. " heteroaryl ") comprises benzimidazolyl-, the benzoglyoxaline ketone group, benzofuryl, benzo furazan base, the benzopyrazoles base, the benzotriazole base, benzothienyl, the benzoxazol base, carbazyl, carbolinyl, 1, the 2-phthalazinyl, furyl, isoindolyl, isoquinolyl, isothiazolyl, different  azoles base, naphthyridinyl (naphthpyridinyl), the  di azoly,  azoles base,  azoles quinoline, different  azoles quinoline, the oxa-cyclobutyl, pyrazinyl, pyrazolyl, pyridazinyl, the pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrazyl, the tetrazolo pyridyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, and N-oxide compound, and wherein saturated heterocyclic partly comprises azetidinyl, 1, the 4-dioxacyclohexyl, six hydrogen azatropylidene bases, piperazinyl, piperidyl, the pyridin-2-ones base, pyrrolidyl, morpholinyl, tetrahydrofuran base, thio-morpholinyl and tetrahydro-thienyl, and N-oxide compound.

Term " pharmacologically acceptable salt " is meant from the pharmaceutically useful nontoxic alkali or the salt of acid (comprising mineral alkali or organic bases, mineral acid or organic acid) preparation.The salt that comprises aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganic, bivalent manganese, potassium, sodium, zinc etc. derived from the salt of mineral alkali.The salt of preferred especially ammonium, calcium, magnesium, potassium and sodium.The salt of solid form can surpass a kind of crystalline structure form and exist, and can be the form of hydrate.Derived from pharmaceutically useful, organically, the salt of nontoxic alkali comprises primary amine, secondary amine and tertiary amine, the replacement amine that comprises naturally occurring replacement amine, cyclammonium, salt with deacidite, as arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine amine, Histidine, breathe out amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane or the like.When compound of the present invention is alkalescence, can prepare salt from comprising the pharmaceutically useful non-toxic acid of mineral acid and organic acid.This acid comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Particularly preferably be citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartrate.Should be appreciated that, as used in this article, also be intended to comprise pharmacologically acceptable salt when relating to compound of the present invention.

Use embodiment and compound disclosed herein that the present invention is carried out exemplary explanation.Particular compound among the present invention comprises the compound that is selected from disclosed compound in following examples and pharmacologically acceptable salt and its each diastereomer.

Motif compound is used in to be needed to suppress to suppress in the active method of glycine transporter GlyT1 in active patient of glycine transporter GlyT1 such as the Mammals, and this method comprises the described compound that gives significant quantity.The present invention relates to the purposes of compound disclosed herein as the active inhibitor of glycine transporter GlyT1.Except primate particularly the people, can multiple other Mammals of the method according to this invention treatment.

The invention further relates to the method be used for suppressing at humans and animals the active medicine of glycine transporter GlyT1 of producing, this method comprises compound of the present invention is combined with pharmaceutically acceptable carrier or thinner.

Main body with method treatment of the present invention is generally the active Mammals of needs inhibition glycine transporter GlyT1, preferably is the people, for male or female.Term " treatment significant quantity " is meant and causes tissue, system, animal or human, the amount of the motif compound that biological response of looking for for researcher, animal doctor, doctor or other clinician or medical science are replied.Should be realized that those skilled in the art can be by suffering from the patient of sacred disease and mental disorder or patient that prophylactic treatment suffers from this illness affect the nerves disease and mental disorder with the compounds for treating of the present invention of significant quantity.As used in this article, term " treatment (treatment) " and " treatment (treating) " are meant wherein all methods that may delay, interrupt, stop, control or stop the progress of described sacred disease and mental disorder herein, but needn't show and eliminate all illnesss fully, and prophylactic treatment is with the progress that postpones described situation or reduce its risk, particularly is easy to suffer among the patient of this disease or disease tendency having.

As used in this article, term " composition " is intended to comprise the product of the concrete component that contains concrete amount, and merges any product that obtains directly or indirectly by the concrete component that will specifically measure.This term is intended to comprise the product that contains activeconstituents and constitute the inert fraction of carrier when relating to pharmaceutical composition; And the component by any two or more compositions, compound or set, or the disassociation by one or more compositions, or the reaction of other type by one or more compositions or any product that interacts and obtain directly or indirectly.Therefore, pharmaceutical composition of the present invention comprise by with compound of the present invention and pharmaceutically acceptable carrier mixed any composition." pharmaceutically acceptable " be meant carrier, thinner or vehicle must with other component compatibility in the preparation and harmless to its recipient.

Term " give " and or " giving " compound be construed as the prodrug that the individuality that is meant needs treatments provides compound of the present invention or compound of the present invention.

The compound inhibition glycine transporter activity of the present invention particularly active application of GlyT1 can prove by method as known in the art.People's placenta choriocarcinoma cell (jar cell (ATCC No.HTB-144)) of endogenous expression GlyT1 is cultivated in RPMI 1640 substratum that comprising 10% foetal calf serum in the presence of penicillin (100 mcg/ml) and the Streptomycin sulphate (100 mcg/ml) in 96 hole Cytostar flicker microtest plates (Amersham Biosciences).Cell is at 5%CO ₂Moistening atmosphere in 37 ℃ of down growths 40-48 hour, be used for test then.Remove substratum from the Cytostar plate, with jar cell be with or without The compounds of this invention in the presence of with TB1A damping fluid (120mM NaCl, 2mM KCl, the 1mM CaCl of 30 microlitres ₂, 1mM MgCl ₂, 10mM HEPES, 5mM L-L-Ala, to be adjusted to pH with Tris alkali be 7.5) cultivated 1 minute.Then with 30 microlitres with TB1A dilution [ ¹⁴C]-it is 10 micromoles that glycine joins in each hole to ultimate density.After at room temperature cultivating 3 hours, with glimmer microtest plate sealing and go up counting of Cytostar at Top Count scintillometer (Packard).In the presence of the unlabelled glycine of 10mM, measure [ ¹⁴C]-non-specific uptake of glycine.According to same rules carry out [ ¹⁴C] taurine picked-up experiment, difference is to measure non-specific uptake with the unlabelled taurine of 10mM.In order to measure effectiveness, in cell, add the compound of the present invention of finite concentration scope, add subsequently fixed concentration [ ¹⁴C]-glycine.By non-linear curve fitting from testing data measure to suppress half [ ¹⁴C]-concentration (IC of the The compounds of this invention of the specificity of glycine picked-up ₅₀Value).

Particularly, the compound of following examples in above-mentioned test, have inhibition [ ¹⁴C]-activity of glycine specificity picked-up, the IC that has usually ₅₀Value is less than about 10 micromoles.Among the present invention preferred compound in above-mentioned test, have inhibition [ ¹⁴C]-activity of the specificity of glycine picked-up, the IC that has ₅₀Value is less than about 1 micromole.With to [ ¹⁴C] picked-up (by the taurine transporter TauT in the jar cell) of taurine compares, these compounds to [ ¹⁴C]-picked-up of glycine (by the picked-up of the GlyT1 in the jar cell) is selectively.This result shows that compound is used as the intrinsic activity of the active inhibitor of GlyT1 translocator.

Nmda receptor is important for the various CNS process, and works in the various disease states of people or other species.The function influence of GlyT1 translocator the partial concn of glycine around the nmda receptor.Selectivity GlyT1 inhibitor delays the removing of glycine from cynapse, causes that cynapse glycine level raises.This has increased again the capturing of the glycine binding site point on the nmda receptor, and this has increased the activation of nmda receptor after terminal release glutamate of presynaptic.Because nmda receptor performance useful effect needs a certain amount of glycine, can influence the neurotransmission of NMDA-mediation to any change of partial concn.The change of the neurotransmission of NMDA-mediation is own through involving some neuropsychiatric disease, as dementia, dysthymia disorders and psychosis such as schizophrenia and learning and memory obstacle, as attention-deficient disease and autism.

Compound of the present invention can be used for treating multiple and L-glutamic acid can relevant sacred disease and the mental disorder of neurotransmission dysfunction, it comprises symptom or disease that one or more are following: schizophrenia or psychosis, comprise schizophrenia (intolerance style, the entanglement type, catatonic type or undifferentiated type), schizophreniform diseases, the dissociation of sensibility disease, delusional disorders, brief psychotic disorder, shared psychotic disorder, because psychosis and material inductive or medicine (phencyclidine that the general medicine illness causes, ketamine and other dissociation anesthesia agent, amphetamine and other psychostimulant and Cocaine) inductive psychotic disease mental disorder (psychosispsychoticdisorder), the psychosis relevant with affective disorder, reactive psychosis in short-term, the dissociation of sensibility psychosis, " schizophrenia spectrum (schizophrenia-spectrum) " disease such as schizophrenia sample or schizotypal personality disorder, or with the psychosis diseases associated (as major depression, manic depression (two-phase) illness, irritability syndrome after Alzheimer and the wound), comprise schizophrenia and other psychotic positive and negative symptoms; Cognitive disorder comprises dementia (relevant with Alzheimer, ischemic, multi-infarct dementia, wound, vascular problem or apoplexy, HIV disease, Parkinson's disease, Huntington Chorea, Pick's disease, Creutzfeldt-Jakob disease, term anoxic, other general medicine illness or substance abuse); Delirium, amnesia or age related are cognitive to descend; Anxiety disorder comprises stress disorders after acute stress disorder, agoraphobia, generalized anxiety disorder, obsession, panic attack, panic disorder, the wound, separation anxiety disorder, social phobia, specific phobia disease, material inductive anxiety disorder and because the anxiety disorder that the general medicine illness causes; Material associated conditions and habit-forming behavior (comprise material inductive delirium, persistence dementia, persistence amnesia, psychosis or anxiety disorder; Comprise tolerance, the dependency of the material of alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, nicotine, opioid, phencyclidine, tranquilizer, soporific or anxiolytic or give up); Obesity, bulimia nervosa and force the feed disease; Bipolar disorder, emotional handicap comprise depressive illness; Dysthymia disorders comprises unipolar depression, seasonal depression disease and childbirth retarded depression disease, premenstrual tension syndrome (PMS) and through preceding dysphoria disease (PDD), because emotional handicap and the material inductive emotional handicap that the general medicine illness causes; Learning disorder, pervasive developmental disorders (pervasive develop mental disorder) comprise that autism, attention disorders comprise that attention lacks hyperkinetic syndrome (ADHD) and behavior disorder; Nmda receptor associated conditions such as autism, dysthymia disorders, optimumly forget, young learning disorder and closed injury of brain; Dyskinesia, comprise motion can not with motion can not-stiff syndrome (comprises Parkinson's disease, drug-induced Parkinson, postencephalitic parkinsonism, stein-leventhal syndrome, multiple system atrophy, corticobasal degeneration, dull-witted complex body of Parkinson-ALS and basal ganglion calcification), drug-induced Parkinson is (as psychosis inductive Parkinson, neuroleptic malignant syndrome, psychosis inductive acute dystonia, the psychosis inductive is acute cathisophobias, psychosis inductive tardive dyskinesia, drug-induced postural tremor), appropriate Reye syndrome (Gilles de la Tourette ' s syndrome), epilepsy, muscle spasm is trembled with comprising with muscle spasm state or weak relevant illness; Dyskinesia [comprises and trembling (static tremor for example, postural tremor and intetion tremor), tarantism is (as sydenham chorea, Huntington Chorea, optimum Huntington's chorea, Neuroacanthocytosis, symptomatic chorea, drug-induced tarantism and hemiballism), myoclonus (comprising general myoclonus and focal myoclonus), twitch and (comprise the simplicity tic, complexity is twitched and symptomatic tic) and myodystonia (comprise general myodystonia such as congenital myodystonia (iodiopathic dystonia), drug-induced myodystonia, symptomatic myodystonia and paroxysmal myodystonia, with focal myodystonia such as winking spasm, mouth chin portion's dystonia (oromandibular dystonia), spastic speech disorder, spasmodic torticollis, axle property myodystonia, dystonia dactylospasm and hemiplegia myodystonia)]; The urinary incontinence; Neuronal damage comprises macular degeneration, tinnitus, hearing loss and forfeiture and the cerebral edema of ocular damage, retinopathy or eyes; Vomiting; And somnopathy, comprise insomnia and narcolepsy.

In above-mentioned illness, schizophrenia, bipolar disorder, dysthymia disorders comprises unipolar depression, seasonal depression disease and childbirth retarded depression disease, premenstrual tension syndrome (PMS) and through preceding dysphoria disease (PDD), learning disorder, pervasive developmental disorders comprises autism, attention disorders comprises notes lacking hyperkinetic syndrome, autism, the tic illness comprises appropriate Rui Shi illness, anxiety disorder comprises stress disorders after phobia and the wound, the cognitive disorder relevant with dementia, the AIDS dementia, Alzheimer, Parkinson's disease, Huntington Chorea, spasticity, myoclonus, muscle spasm, the treatment of tinnitus and hearing loss and forfeiture has special importance.

In specific embodiment, the invention provides the method for treatment cognitive disorder, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.Concrete cognitive disorder is the cognitive decline of dementia, delirium, amnesia and age related.At present, the 4th edition text revision (DSM-IV-TR) (2000 of Diagnostic andStatistical Manual of Mental Disorders, American Psychiatric Association, Washington DC) cognitive disorder that comprises of the diagnostic tool that provides comprises that dementia, delirium, amnesia and age related are cognitive and descends.As used in this article, term " cognitive disorder " comprises the treatment to those mental illness described in DSM-IV-TR.One skilled in the art would recognize that mental illness has alternate nomenclature, nosotaxy and categorizing system, and these systems are along with medical treatment and advancement of science and developing.Therefore, term " cognitive disorder " is intended to comprise the similar conditions described in other diagnosis source.

In other specific embodiments, the invention provides the method for treatment anxiety disorder, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.Concrete anxiety disorder is generalized anxiety disorder, obsession and panic attack.At present, the 4th edition text revision (DSM-IV-TR) (2000 of Diagnostic and StatisticalManual of Mental Disorders, American Psychiatric Association, Washington DC) anxiety disorder that comprises of the diagnostic tool that provides is generalized anxiety disorder, obsession and panic attack.As used in this article, term " anxiety disorder " comprises the treatment to those mental illness described in DSM-IV-TR.One skilled in the art would recognize that mental illness has alternate nomenclature, nosotaxy and categorizing system, and these systems are along with medical treatment and advancement of science and developing.Therefore, term " anxiety disorder " is intended to comprise the similar conditions described in other diagnosis source.

In other specific embodiments, the invention provides treatment schizophrenia or psychotic method, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.Concrete schizophrenia or psychiatric pathology are intolerance style, entanglement type, catatonic type or undifferentiated schizophrenia and material inductive mental disorder.At present, the 4th edition text revision (DSM-IV-TR) (2000 of Diagnostic and StatisticalManual of Mental Disorders, American Psychiatric Association, Washington DC) diagnostic tool that provides comprises intolerance style, entanglement type, catatonic type or undifferentiated schizophrenia and material inductive mental disorder.As used in this article, term " schizophrenia or psychosis " comprises the treatment to those mental disorderes described in DSM-IV-TR.One skilled in the art would recognize that mental illness has alternate nomenclature, nosotaxy and categorizing system, and these systems are along with medical treatment and advancement of science and developing.Therefore, term " schizophrenia or psychosis " is intended to comprise the similar conditions described in other diagnosis source.

In other specific embodiments, the invention provides the method for the diseases related and habit-forming behavior of therapeutant, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.Diseases related and the habit-forming behavior of concrete material is by substance abuse inductive persistence dementia, persistence amnesia, mental disorder or anxiety disorder; With tolerance, the dependency of substance abuse or give up.At present, the 4th edition text revision (DSM-IV-TR) (2000 of Diagnostic and Statistical Manual of Mental Disorders, American PsychiatricAssociation, Washington DC) diagnostic tool that provides comprises substance abuse inductive persistence dementia, persistence amnesia, mental disorder or anxiety disorder; With tolerance, the dependency of substance abuse or give up.As used in this article, term " the diseases related and habit-forming behavior of material " comprises the treatment to those mental illness described in DSM-IV-TR.One skilled in the art would recognize that mental illness has alternate nomenclature, nosotaxy and categorizing system, and these systems are along with medical treatment and advancement of science and developing.Therefore, term " the diseases related and habit-forming behavior of material " is intended to comprise the similar conditions described in other diagnosis source.

In other specific embodiments, the invention provides the method for treatment pain, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.Concrete pain is presented as bone and arthralgia (osteoarthritis), repeatability motion pain, toothache, pain caused by cancer, muscular fascia pain (muscle injury, fibromyalgia), peri-operation period pain (general surgery, gynecology), chronic pain and neuropathic pain.

In other specific embodiments, the invention provides treatment of obesity or the eating disorder relevant and the method for relevant complication therewith with excessive food intake, it comprises: the compound of the present invention that the patient that needs are arranged is given significant quantity.At present, obesity is included among the tenth edition (ICD-10) (1992 World Health Organization) of International Classification of Diseases and Related Health Problems as general medical conditions.The 4th edition text revision (DSM-IV-TR) (2000 of Diagnostic and Statistical Manual of Mental Disorders, American PsychiatricAssociation, Washington DC) diagnostic tool that provides is included in the obesity under the existence of the psychological factor that influences medical conditions.As used in this article, term " obesity or the eating disorder relevant with excessive food intake " is included in those medical conditions and the treatment of diseases described in ICD-10 and the DSM-IV-TR.One skilled in the art would recognize that general medical conditions has alternate nomenclature, nosotaxy and categorizing system, and these systems are along with medical treatment and advancement of science and developing.Therefore, term " obesity or the eating disorder relevant with excessive food intake " is intended to be included in similar state and the illness described in other diagnosis source.

The method that described motif compound is further used for preventing, treat, control, improve described disease, illness and symptom herein or reduces its risk.

Described motif compound further makes up with other reagent (comprising the active inhibitor of glycine transporter GlyT1), the method that is used to prevent, treat, control, improve above-mentioned disease, illness and symptom or reduces its risk.

Compound of the present invention can with one or more drug regimens, be used for the treatment of, prevent, control, improve applicable disease of compound of the present invention or other medicines or symptom or reduce its risk, the combination together of its Chinese traditional medicine is more safer or more effective than any independent medicine.Described other medicines can be by its normally used approach and amount and compound of the present invention while or administration continuously.When compound of the present invention and one or more other medicines use simultaneously, preferably in unit dosage form, comprise the pharmaceutical composition of described other medicines and compound of the present invention.Yet combination therapy also can comprise the treatment of wherein compound of the present invention and one or more other medicines being carried out administration in different dosage regimens overlapping time.Considered also that when being used for being used in combination compound of the present invention and other activeconstituents can use by the lower dosage of dosage when using separately separately with one or more other activeconstituentss.Therefore, pharmaceutical composition of the present invention comprises that those also comprise the pharmaceutical composition of one or more other activeconstituentss except compound of the present invention.

Aforesaid combination not only comprises the combination of compound of the present invention and a kind of other active compound, and comprises the combination with two or more other active compounds.Similarly, compound of the present invention can be used for and the other drug combination that is used to prevent, treat, control, improve spendable disease of compound of the present invention or symptom or reduce its risk.Described other medicines can be by its normally used approach and amount and compound of the present invention while or administration continuously.When compound of the present invention and one or more other medicines use simultaneously, preferably except The compounds of this invention, also comprise the pharmaceutical composition of described other medicines.Therefore, pharmaceutical composition of the present invention comprises that those also comprise the pharmaceutical composition of one or more other activeconstituentss except The compounds of this invention.

The weight ratio of the compound of the present invention and second activeconstituents can change, and changes according to the effective dose of each composition.Usually, use effective dose separately.Therefore, for example, when compound of the present invention and another kind of agent combination, the weight ratio of compound of the present invention and other reagent is generally about 1000: 1～and about 1: 1000, be preferably about 200: 1～about 1: 200.The combination of compound of the present invention and other activeconstituents usually also in above-mentioned scope, but in all cases, should use the effective dose of each activeconstituents.

In this combination, compound of the present invention and other active agent are discriminably or administration jointly.In addition, a kind of composition give can be before other reagent gives, simultaneously or carry out afterwards.

Therefore, described motif compound can use separately or use with known other agent combination that is of value to described ideal adaptation disease or with the effectiveness, security, the accessibility that increase The compounds of this invention or reduce unwanted side effect or the toxic other medicines that influence acceptor or enzyme are used in combination.Motif compound can with other reagent co-administered in following treatment or in fixed combination.

In one embodiment, motif compound can be used in combination with medicine, beta-secretase inhibitor, inhibitors of gamma-secretase, HMG-CoA reductase inhibitor, NSAID (comprising Ibuprofen BP/EP), vitamin-E and the anti-amyloid antibody (anti-amyloidantibodies) of Kang Aercihaimoshi disease.

In another embodiment, motif compound can with tranquilizer, soporific, anxiolytic, antipsychotic drug, antianxiety agent, cyclopyrrole ketone (cyclopyrrolones), imidazopyridine, Pyrazolopyrimidines type, minor tranquilizer, melatonin agonist and antagonist, melatonin energy medicine (melatonergic agents), benzodiazepines, barbiturates, drug regimens such as 5HT-2 antagonist use, for example: adinazolam, Allobarbitone, alonimid, alprazolam, amisulpride, amitriptyline, Amobarbital, amoxapine, Aripiprazole, bentazepam, benzoctamine, brotizolam, amfebutamone, buspirone (busprione), neo-barb, butalbital, capuride, carbocloral, Cloral Betaine, Chloral Hydrate, clomipramine, clonazepam, the tall and erect oxazolone of chlorine piperazine nitrogen, chlordiazepoxide, zeisin, Cloretate, chlorpromazine, leoponex, cyprazepam, Desipramine, Dexclamol, diazepam, Dichloralphenazone, Sodium hydrogen divalproate, diphenhydramine, doxepin, estazolam, ethyl .beta.-chlorovinyl ethynyl carbinol, etomidate, fenobam, flunitrazepam, flupentixol, Fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, Mephogarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, 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, thioridazine, tiotixene, tracazolate, Tranylcypromine (tranylcypromaine), trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, Trimipramine, Uldazepam, Venlafaxine, Zaleplone, Ziprasidone, zolazepam, zolpidem, and salt, and combination etc., perhaps the administration of motif compound can with physical method such as actinotherapy or electrostimulation combination.

In another embodiment, motif compound can use with following drug regimen: levodopa (being with or without the outer decarboxylase inhibitor of selective brain such as carbidopa or benserazide); Anticholinergic such as biperiden (optional is its hydrochloride or lactic acid salt form) and Benzhexol HCL (artane); COMT inhibitor such as Entacapone; The MOA-B inhibitor; Antioxidant; The A2a 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.Should be appreciated that dopamine agonist can be the form of pharmacologically acceptable salt, as alentemol hydrobromide, bromocriptine methanesulfonate, Fenoldopam Mesylate, naxagolide hydrochloride and pergolide mesylate.Methylergol carbamide and pramipexole use with salt-independent shape usually.

In another embodiment, motif compound can be used for the compound combination with thiodiphenylamine, thioxanthene, heterocycle dibenzo azatropylidene, butyrophenone, diphenylbutylpiperidand and the indole ketone of psychosis.The suitable examples of phenothiazines comprises chlorpromazine, mesoridazine, thioridazine, Acetophenazine, Fluphenazine, trilafon and trifluoperazine.The suitable examples of thioxanthene class comprises chlorprothixene and tiotixene.The example of dibenzo azatropylidene class is a leoponex.The example of butyrophenones is a haloperidol.The example of diphenylbutylpiperidand class is a pimozide.The example of indole ketone is molindolone.Other psychosis comprises loxapine, Sulpiride and risperidone.Should be appreciated that, when being used in combination with motif compound, psychosis can be pharmaceutical acceptable salt, example hydrochloric acid chlorpromazine, mesoridazine besilate, Thioridazine Hydrochloride, Acetophenazine Dimaleate, fluphenazine hydrochloride, fluphenazine enanthate, Dapotum D, triphthasine, hydrochloric acid tiotixene, haloperidol decanoate, loxapine succinate and molindone hcl.Trilafon, chlorprothixene, leoponex, haloperidol, pimozide and risperidone use with salt-independent shape usually.Therefore, motif compound can be used for and Acetophenazine, alentemol, Aripiprazole, amisulpride, artane, bromocriptine, biperiden, chlorpromazine, chlorprothixene, leoponex, diazepam, Fenoldopam, Fluphenazine, haloperidol, levodopa, levodopa+benserazide, levodopa+carbidopa, methylergol carbamide, loxapine, mesoridazine, molindolone, Nazagolide, olanzapine, Pei Gaolite, trilafon, pimozide, pramipexole, Quetiapine, risperidone, Sulpiride; tetrabenazine; Trihexyphenidyl; thioridazine; tiotixene; trifluoperazine or Ziprasidone combination.

In another embodiment, motif compound can be used in combination with antidepressive or anxiolytic, comprises NRI (comprising tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants), selective serotonin reuptake inhibitor (SSRIs), oxidase inhibitor (MAOIs), the reversible inhibitor of monoamine oxidase (RIMAs), serotonin and NRI (SNRIs), corticotropin releasing factor(CRF) (CRF) antagonist, alpha-2-adrenoceptor antagonists, antagonists of neurokinine-1 receptor, atypical antidepressive, benzene diaza table class, 5-HT _1AAgonist or antagonist, particularly 5-HT _1APartial agonist, and corticotropin releasing factor(CRF) (CRF) antagonist.Concrete medicine comprises: amitriptyline, clomipramine, doxepin, imipramine and Trimipramine; Amoxapine, Desipramine, maprotiline, nortriptyline and protriptyline; Fluoxetine, fluvoxamine, paroxetine and Sertraline; Isocarboxazid, Phenelzine, Tranylcypromine and selegiline; Moclobemide; Venlafaxine; Duloxetine; A Rui smooth (aprepitant); Amfebutamone, lithium, nefazodone, trazodone and viloxazine; Alprazolam, zeisin, clonazepam, chlorazepate (chlorazepate), diazepam, Harrar wash dissolve, Laura wash dissolve, oxazepam and prazepam; Buspirone, flesinoxan, gepirone and ipsapirone, and pharmacologically acceptable salt.

Compound of the present invention can pass through oral administration, parenterai administration (as, intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), by sucking spraying, intranasal, vagina, rectum, hypogloeeis or topical administration, and can be separately or be formulated in together in the suitable dosage unit formulation that comprises carrier routine, nontoxic, pharmaceutically useful, auxiliary agent and the vehicle that are suitable for each route of administration.Except treating warm-blooded animal such as mouse, rat, horse, ox, sheep, dog, cat, monkey etc., compound of the present invention can be effective to the mankind.

As used in this article, term " composition " is intended to comprise the product of the concrete component that contains concrete amount or ratio, and merges any product that obtains directly or indirectly by the concrete combination that will specifically measure.This term is intended to comprise the product that contains one or more activeconstituentss and comprise the inessential carrier of inert fraction when relating to pharmaceutical composition; And the combination by any two or more compositions, compound or set or the disassociation by one or more described compositions or the reaction of other type by one or more described compositions or any product that interacts and obtain directly or indirectly.Usually, by activeconstituents and liquid vehicle or subdivided solids carrier or both are combined equably and nearly, then, if necessary, be required formulation preparation pharmaceutical composition with product shaping.In pharmaceutical composition, enough the process of disease or the amount of situation generation desired effects are comprised active target compound.Therefore, pharmaceutical composition of the present invention comprise by with compound of the present invention and pharmaceutically acceptable carrier mixed any composition.

The pharmaceutical composition that is designed for oral application can be according to any method preparation that is used to produce pharmaceutical composition as known in the art, and this composition can comprise one or more reagent that is selected from sweeting agent, seasonings, tinting material and sanitas, so that exquisite and agreeable to the taste preparation to be provided pharmaceutically.Tablet comprises and is suitable for producing the activeconstituents of the nontoxic pharmaceutically acceptable mixed with excipients of tablet.Tablet can be no dressing, and perhaps they can pass through the known technology dressing, with disintegration and the absorption of delay in gi tract, thereby is provided at the interior continuous action of long duration.The composition that is used for oral application also can be used as wherein activeconstituents and inert solid diluent such as lime carbonate, calcium phosphate or the existence of kaolin blended hard gelatin capsule, perhaps as the wherein soft gelatin capsule existence of activeconstituents and water or oil medium such as peanut oil, whiteruss or mixed with olive oil.Aqeous suspension, oil suspension, dispersible powder or particle, oil-in-water emulsion and sterile water for injection suspension or oil suspension can be by standard method preparations as known in the art.

When treatment wherein needed to suppress the active symptom of glycine transporter GlyT1, suitable dosage level was generally every kg of patient body weight about 0.01～500mg every day, and it can be used as single dose or multiple dose administration.Preferably, dosage level is about 0.1～about 250mg/kg/ days; More preferably about 0.5～about 100mg/kg/ days.Suitable dosage level can be about 0.01～250mg/kg/ days, about 0.05～100mg/kg/ days or about 0.1～50mg/kg/ days.In this scope, dosage can be 0.05～0.5,0.5～5 or 5～50mg/kg/ days.For oral administration, composition preferably provides with the tablet form that comprises 1.0～1000 milligrams of activeconstituentss, particularly comprise 1.0,5.0,10,15,20,25,50,75,100,150,200,250,300,400,500,600,750,800,900 and 1000 milligrams of activeconstituentss, be used for adjusting dosage according to the patient's who is treated symptom.Compound can 1～4 time/day the scheme administration, preferred every day one or twice.Can adjust this dosage regimen, so that best therapeutic response to be provided.Yet, should be appreciated that, the concrete dosage level and the frequency that are used for any concrete patient can change, and decide according to multiple factor, comprise the activity of the particular compound of use, metabolic stability and effect time-histories, patient's age, body weight, general health situation, sex, diet, administering mode and time, discharge rate, drug regimen, the tight degree of concrete situation and the patient who is treated of this compound.

The abbreviation that is used for following chemical descriptor and embodiment is as follows:

CH ₂Cl ₂Methylene dichloride

The DIEA diisopropyl ethyl amine

PS-DIEA polystyrene diisopropyl ethyl amine

PS-DMAP polystyrene 4-N, the N-dimethyl aminopyridine

DCC polystyrene dicyclohexylcarbodiimide

The Ra-Ni Raney nickel

The HOBt hydroxybenzotriazole

The THF tetrahydrofuran (THF)

The TFA trifluoroacetic acid

MeOH methyl alcohol

The several method that is used for preparing compound of the present invention illustrates in following scheme and embodiment.Starting raw material and necessary intermediate are commercially available in some cases, perhaps can be according to the method for document or preparation as described herein.

Except other standard operation of known or experimental procedure illustrated in the literature, can be by carrying out the prepared in reaction compound of the present invention shown in following scheme.Substituting group shown in scheme numbering not necessarily with claims in use relevant, and for clear, often demonstration is connected in single replacement wherein and is allowing to have under the condition defined above on a plurality of substituent compounds.Except known or the cracking of other standard operation of experimental procedure illustrated such as ester hydrolysis, protecting group etc. in the literature, the reaction that is used to produce compound of the present invention is undertaken by adopting the reaction shown in scheme and embodiment herein.

In some cases, the finished product can further be modified by for example substituent conversion.These conversion can include but not limited to the common known reduction of those skilled in the art, oxidation, alkylation, acidylate and hydrolysis reaction.In some cases, can change the carrying out order of above-mentioned reaction scheme, to promote reaction or to avoid unwanted reaction product.Provide following examples to be used for understanding more completely the present invention.These embodiment are illustrative, should not be seen as and limit the present invention by any way.

The present invention also provides the method for a kind of preparation formula (I) compound, and this method comprises the formula (II) or (III) acylation of compound:

Respectively with acylating agent X SO ₂R ³Or Y CO (A _m) R ²Effect, wherein p, R ¹～R ⁵, A and m such as preamble define, and X and Y be substituting group, and the method for knowing by those skilled in the art thereafter is optional with R ¹～R ⁵In a groups converted be R ¹～R ⁵In another group.

Therefore the formula III compound can be at alkali such as Et ₃N and solvent such as DCM exist down and R ²N=C=O reaction, wherein R ²Definition as mentioned, or at HOBt, DCM and alkali such as Et ₃N exists down and R ²CO ₂H reaction, wherein R ²Also as mentioned the definition, or in the presence of catalyzer such as CDI with R ²OH or R ²NH ₂Reaction, wherein R ²Definition as mentioned.

X and Y are suitable halogen atom such as chlorine.Acylation reaction is carried out in non-polar solvent in the presence of alkali usually, for example carries out in halon such as the methylene dichloride.

Can pass through method preparation formula (II) compound of scheme I:

Work as R ⁴And R ⁵Be hydrogen, can pass through method preparation formula (IIa) compound of scheme II:

Work as R ⁴Be C _1-4Alkyl and R ⁵Be hydrogen or C _1-6Alkyl, method preparation formula (IIa) compound that can be by scheme III:

Can pass through method preparation formula (III) compound of scheme IV or V:

Reaction scheme IV

L is a leavings group, as halogenide.

As described in the reaction scheme IV, this scheme is used for wherein R ⁴Be hydrogen and R ⁵Be the compound of the present invention of hydrogen, make the 4-cyano group piperidines deprotonation of suitable replacement, for example carry out nucleophilic substitution reaction then, obtain I-2 with 2-fluorine pyridine with alkali such as KHMDS.This material is exposed to removes the Boc protecting group under the HCl, obtain unhindered amina, unhindered amina is handled with SULPHURYL CHLORIDE under the standard reaction condition, obtains corresponding sulphonamide.Use Ra-Ni to carry out hydrogenation under nitrogen atmosphere, obtain corresponding amine, corresponding amine by acidylate, obtains final material under the standard reaction condition.In this case, all SULPHURYL CHLORIDE of use, acyl chlorides (acid chlorides) and carboxylic acid all are commercially available maybe can preparing by literature method, and initial 4-cyano group piperidines also is commercially available maybe can preparing by literature method.

Reaction scheme V

As described in the reaction scheme V, this scheme is used for wherein R ⁴Be C _1-6Alkyl and R ⁵Be hydrogen or C _1-6The compound of the present invention of alkyl, suitably the 4-cyano group piperidines that replaces reacts with SULPHURYL CHLORIDE under the standard reaction condition, obtains corresponding sulphonamide.Use Grignard reagent that nitrile is carried out nucleophilic addition(Adn) or use alkyl cerium reagent that nitrile is carried out parents and examine addition and obtain corresponding amine.Behind the chromatographic separation racemoid, this material carries out acidylate under standard conditions, obtain final material.In this case, all SULPHURYL CHLORIDE, acyl chlorides, Grignard reagent and alkyl lithium reagents, acyl chlorides and the carboxylic acid of use all are commercially available.Initial 4-cyano group piperidines is commercially available.

Embodiment 1

2,4-two chloro-N-{[4-(cyclopropyl methyl)-1-[(1-methyl isophthalic acid H-pyrazoles-4-yl) alkylsulfonyl] piperidin-4-yl] methyl } benzamide:

4-cyano group-4-(cyclopropyl methyl) piperidines-1-carboxylic acid tert-butyl ester:

At-70 ℃ of lithium diisopropylamine (2M solution in THF to stirring; 60ml; 0.12mol) THF (60ml) solution in, be added in 4-cyano group piperidines-1-carboxylic acid tert-butyl ester (21g among the THF (150ml) with 1 hour time; 0.1mol).Mixture stirred 1 hour at-70 ℃, was added in (brooethyl) cyclopropane (17.53g among the THF (20ml) then; 0.13mol).Solution stirred 1 hour at-70 ℃, the chien shih envrionment temperature of rising again during then with 2 hours.Reaction is poured in the salt solution (150ml), and (3 * 200ml) extract with EtOAc.The organic extract liquid that merges washs with salt solution (200ml), MgSO ₄Drying is filtered and evaporation obtains brown oil.The crude product product with 5%EtOAc-isohexane wash-out, obtains title product by the silica gel chromatography purifying, is colorless oil (24.8g).

¹H?NMRδ(ppm)(CDCl ₃)：4.15-4.09(2H，m)，3.05(2H，s)，2.02(2H，m)，1.49(13H，m)，1.00-0.84(1H，m)，0.61-0.55(2H，m)，0.19(2H，m).

4-aminomethyl-4-(cyclopropyl methyl) piperidines-1-carboxylic acid tert-butyl ester:

Product (19g forward; 71.86mmol) ethanol (300ml) and ammoniacal liquor (25%; 25ml) add Raney nickel (about 10ml, 50% water soup compound) in the solution, mixture stirred 18 hours with a Parr device at hydrogen (40psi) atmosphere.LC/MS shows no starting raw material, obtains expecting product quality ion (m/e=268).Mixture filters by catalyst filter, and (5 * 50ml) wash catalyzer widely with ethanol.Evaporating solvent obtains title compound, is colorless oil (19g) that it is directly used in next step.

4-cyclopropyl methyl-4-[(2,4-two chloro-benzoyl-amidos)-methyl]-piperidines-1-carboxylic acid tert-butyl ester:

(5g 18.6mmol) is dissolved in the methylene dichloride (50ml) with preceding product.Add N, the N-diisopropylethylamine (3.9ml, 22.3mmol), mixture in ice bath, cool off the while dropwise add 2,4 dichlorobenzyl chloride (2.9ml, 20.5mmol).Mixture is risen again to room temperature, stir 1 hour concentrating under reduced pressure then, directly by quick silica gel chromatography, use 20% ethyl acetate: 80% dichloromethane mixture wash-out obtains required product (8.1g).

¹H?NMRδ(ppm)(CDCl ₃)：7.66(1H，d，J＝8.3Hz)，7.43(1H，d，J＝1.9Hz)，7.33(1H，dd，J＝1.8，8.3Hz)，6.30(1H，m)，3.59(2H，br?s)，3.51-3.41(4H，m)，1.53(4H，m)，1.45(9H，s)，1.34(2H，d，J＝6.6Hz)，0.72-0.65(1H，m)，0.52(2H，m)，0.06(2H，m).

2,4-two chloro-N-{[4-(cyclopropyl methyl) piperidin-4-yl] methyl } benzamide:

Be dissolved in preceding product (8.1g) in the methylene dichloride (50ml) and in ice bath, cool off.Dropwise add trifluoroacetic acid (10ml), rise again room temperature and stirring 2 hours of mixture.Remove under vacuum and desolvate and excessive trifluoroacetic acid, resistates is with the sodium bicarbonate aqueous solution neutralization and with ethyl acetate extraction (4 * 100ml).Organic layer water (200ml) washing that merges, sal epsom (anhydrous) drying is filtered and evaporation obtains required product (5.2g).m/z(ES ⁺)341(M+H)。

(200mg 0.59mmol) is dissolved in the methylene dichloride (5ml) with preceding product.Add N, the N-diisopropylethylamine (0.15ml, 0.88mmol), add subsequently 1-methyl isophthalic acid H-pyrazoles-4-SULPHURYL CHLORIDE (116mg, 0.64mmol).Stirred 2 hours under the mixture room temperature, directly by quick silica gel chromatography, use 20% ethyl acetate then: 80% dichloromethane mixture wash-out obtains title compound (160mg).

¹HNMRδ(ppm)(CDCl ₃)：7.75(1H，s)，7.73(1H，s)，7.61(1H，d，J＝8.3Hz)，7.43(1H，d，J＝1.8Hz)，7.33(1H，dd，J＝1.9，8.3Hz)，6.26(1H，m)，3.98(3H，s)，3.48(2H，d，J＝6.4Hz)，3.22-3.18(2H，m)，3.02-2.96(2H，m)，1.74-1.67(4H，m)，1.27-1.25(2H，m)，0.67-0.61(1H，m)，0.52(2H，m)，0.05(2H，m).m/z(ES+)485(M+H).

Prepare following compounds by embodiment 1 described method.

Embodiment 2

2,4-two chloro-N-[4-(cyclopropyl methyl)-1-(1-methyl isophthalic acid H-[1,2,3]-triazole-4-alkylsulfonyl) the piperidin-4-yl methyl]-benzamide:

With 2, and 4-two chloro-N-[4-(cyclopropyl methyl)-1-(1H-[1,2,3] triazole-4-alkylsulfonyl) the piperidin-4-yl methyl] (472mg 1.0mmol) is dissolved in N to benzamide, in the dinethylformamide (5ml).Add salt of wormwood (276mg, 2mmol) and methyl iodide (81 μ l, 1.3mmol), stirring is spent the night under the mixture room temperature.

Mixture distributes between ethyl acetate (20ml) and water (20ml).Water layer is further used ethyl acetate, and (2 * 20ml) extractions, the organic phase of merging salt solution (20ml) washing, sal epsom (anhydrous) drying is filtered and evaporation obtains oily matter.Oily matter is used 15% ethyl acetate by quick silica gel chromatography: 85% dichloromethane mixture wash-out, by the preparative thin layer chromatography purifying, use 20% ethyl acetate: 80% dichloromethane mixture wash-out obtains title compound (60mg) then.

¹HNMRδ(ppm)(CDCl ₃)：7.96(1H，s)，7.61(1H，d，J＝8.3Hz)，7.43(1H，d，J＝1.8Hz)，7.32(1H，dd，J＝1.8，8.3Hz)，6.28(1H，m)，4.18(3H，s)，3.51(2H，d，J＝6.4Hz)，3.44-3.38(2H，m)，3.34-3.28(2H，m)，1.71(4H，m)，1.28(2H，d，J＝6.6Hz)，0.67-0.61(1H，m)，0.53-0.50(2H，m)0.05-0.02(2H，m).m/z(ES+)486(M+H).

Embodiment 3

2,4-two chloro-N-[1-(1-methyl isophthalic acid H-pyrazoles-4-alkylsulfonyl)-4-pyridine-2-ylmethyl-piperidin-4-yl methyl]-benzamide:

4-cyano group-4-(pyridine-2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester:

4-cyano group piperidines-1-carboxylic acid tert-butyl ester (500mg to the stirring of refrigerative in ice bath; 2.38mmol) and 2-(chloromethyl) pyridine (334mg; 2.62mmol) toluene (3.6ml) suspension in, (0.5M is in toluene to add two (trimethyl silicane) acid amides potassium with 10 fens clock times; 5.7ml; 2.86mmol) solution.The reaction mixture envrionment temperature of rising again was stirred 1.5 hours simultaneously.Reaction is poured in the salt solution (25ml), with EtOAc (3 * 30ml) extractions.The organic extract liquid that merges washs with salt solution (30ml), MgSO ₄Drying is filtered and evaporation obtains orange.The crude product product with 50%EtOAc-isohexane wash-out, obtains required product by the silica gel chromatography purifying, is colorless oil (375mg).

¹H?NMRδ(ppm)(CDCl ₃)：8.57-8.55(1H，m)，7.71-7.65(1H，m)，7.35(1H，t，J＝4.3Hz)，7.22-7.20(1H，m)，4.11(2H，m)，3.01(4H，t，J＝12.9Hz)，1.89(2H，d，J＝13.4Hz)，1.65-1.57(2H，m)，1.44(9H，s)；m/e＝202(m-Boc)

4-(aminomethyl)-4-(pyridine-2-ylmethyl) piperidines-1-carboxylic acid tert-butyl ester:

Compound (363mg forward; 1.20mmol) methyl alcohol (5ml) solution of 2.0M ammoniacal liquor in add Raney nickel (about 0.5ml, 50% water soup compound), mixture stirred 15.5 hours with a Parr device under hydrogen (45psi) atmosphere.Mixture filters by catalyst filter, and (5 * 25ml) wash catalyzer widely with methyl alcohol.Evaporating solvent obtains required compound, is green oily matter (351mg) that it is directly used in next step.m/e＝306。

4-[(2,4-two chloro-benzoyl-amidos)-methyl]-4-pyridine-2-ylmethyl-piperidines-1-carboxylic acid tert-butyl ester:

At 0 ℃ of preceding compound (349mg to stirring; 1.14mmol) and positive ethyl diisopropylamine (0.22g; 0.30ml; 1.71mmol) DCM (3.5ml) solution in dropwise add 2,4 dichlorobenzyl chloride (0.314g; 0.21ml; 1.49mmol), 3 hours envrionment temperatures of rising again of solution stirring.Add entry (5ml) and DCM (5ml), reaction was stirred 5 minutes, then by one 5 μ PTFE frit.Collect organic phase and evaporation.Crude product with 35%EtOAc-isohexane wash-out, obtains required compound by the silica gel chromatography purifying, is white foam shape solid (360mg).

¹H?NMRδ(ppm)(CDCl ₃)：8.42-8.38(2H，m)，7.65-7.59(2H，m)，7.46(1H，d，J＝2.0Hz)，7.33(1H，dd，J＝2.0，8.2Hz)，7.17-7.13(1H，m)，7.10(1H，d，J＝7.7Hz)，3.67-2.77(8H，m)，1.52-1.44(13H，m)；m/e＝478/480(3∶2).

2,4-two chloro-N-{[4-(pyridine-2-ylmethyl) piperidin-4-yl] methyl } benzamide:

(356mg adds trifluoroacetic acid (0.57ml in DCM 0.744mmol) (4ml) solution to the preceding compound that stirs; 7.44mmol), solution stirred 1.5 hours at ambient temperature.Evaporating solvent, resistates distribute between DCM (20ml) and saturated sodium bicarbonate solution (20ml).With the pH value to 10 that the 2M sodium hydroxide solution is regulated water, use DCM (20ml) aqueous phase extracted then.The organic phase MgSO that merges ₄Drying is filtered and drying, obtains spumescence white solid (150mg), and it need not be further purified and use m/e=378/380 (3: 2).

At 0 ℃ of preceding compound (148mg to stirring; 0.391mmol) DCM (2ml) solution in add positive ethyl diisopropylamine (0.0742g; 0.10ml; 0.587mmol), add 1-methyl isophthalic acid H-pyrazoles-4-SULPHURYL CHLORIDE (92mg subsequently; 0.508mmol), solution stirred 3.5 hours at ambient temperature.Add DCM (5ml) and water (5ml), mixture vigorous stirring 5 minutes is poured into one 5 μ PTFE separation of glasses material then.Evaporation DCM layer obtains oily matter, and it with 0.5%-5% methyl alcohol-DCM wash-out, obtains the product into oily matter by the silica gel chromatography purifying.This oily matter grinds with isohexane, obtains greenish orange look solid (39mg).

¹H?NMRδ(ppm)(CDCl ₃)：8.41(1H，d，J＝4.1Hz)，8.35(1H，t，J＝6.8Hz)，7.76(1H，s)，7.72(1H，s)，7.66-7.62(1H，m)，7.55(1H，d，J＝8.2Hz)，7.46(1H，d，J＝1.9?Hz)，7.32(1?H，dd，J＝1.9，8.3?Hz)，7.18-7.14(1H，m)，7.10(1H，d，J＝7.7?Hz)，3.97(3H，s)，3.51(2H，d，J＝12.9Hz)，3.16(2H，d，J＝6.5Hz)，2.80(4H，d，J＝-0.0Hz)，1.74-1.64(4H，m).m/e＝522/524(3∶2).

Embodiment 4

2,4-two chloro-N-{[4-(3-fluorine pyridine-2-yl)-1-[(1H-1,2,3-triazole-4-yl) alkylsulfonyl] piperidin-4-yl] methyl } benzamide:

4-cyano group-4-(3-fluorine pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester:

The 4-cyanogen piperidines-1-carboxylic acid tert-butyl ester (7g that under nitrogen atmosphere, stirs to refrigerative in acetone/ice bath with 30 fens clock times; 33.29mmol) and 2-chloro-3-fluorine pyridine (4.82g; 36.62mmol) toluene (40ml) suspension in, add two (trimethyl silicane) acid amides potassium (0.5M, in toluene, 79.9ml, 39.95mmol) solution keeps internal temperature to be lower than-10 ℃.The reaction mixture envrionment temperature of rising again was stirred 2 hours simultaneously.Reaction is poured in the salt solution (150ml), with EtOAc (3 * 100ml) extractions.The organic extract liquid that merges washs with salt solution (100ml), MgSO ₄Drying is filtered and evaporation, obtains brown oil.Crude product separates by silica gel chromatography, uses the 10%EtOAc-DCM wash-out, obtains required product, is colorless oil (4.8g).

¹H?NMR?δ(ppm)(CDCl ₃)：8.41(1H，dd，J＝1.3，3.2Hz)，7.51-7.45(1H，m)，7.37-7.33(1H，m)，4.16(2H，m)，3.28(2H，m)，2.28(2?H，d，J＝13.3Hz)，2.17(2H，t，J＝11.1Hz)，1.47(9H，d，J＝5.4Hz).；m/e206(m-Boc).

4-aminomethyl-4-(3-fluorine pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester:

Product (4g forward; 13.0997mmol) in methyl alcohol (15ml) solution of 2.0M ammoniacal liquor, adding Raney nickel (about 1ml, 50% water soup compound), mixture stirred 18 hours with a Parr device under hydrogen (50psi) atmosphere.LC/MS shows starting raw material consumption, obtains expecting product quality ion (m/e=309).Remove by filter catalyzer, (5 * 10ml) washings widely, evaporated filtrate obtains required compound, is jelly (3.9g) that it is directly used in next step with methyl alcohol.

4-{2,4-dichloro-benzoyl base } aminomethyl-4-(3-fluorine pyridine-2-yl) piperidines-1-carboxylic acid tert-butyl ester:

At 0 ℃ of compound (1g that stirs forward; 3.23mmol) and N-ethyl diisopropylamine (0.46g; 0.615ml; 3.56mmol) DCM (10ml) solution in dropwise add 2,4 dichlorobenzyl chloride (0.677g, 0.45ml; 3.23mmol), solution stirring made the envrionment temperature of rising again in 48 hours.Add entry (4ml), will react and stir 10 minutes, then by one 5 μ PTFE frit.Collect and the evaporation organic phase.Crude product is used the 10%EtOAc-DCM wash-out by the silica gel chromatography purifying, obtains product, is colorless oil (1.23g).

¹H?NMRδ(ppm)(CDCl ₃)：8.36(1H，d，J＝2.2Hz)，7.56(1H，d，J＝8.4Hz)，7.41-7.35(2H，m)，7.23(2H，m)，6.82(1H，s)，3.94(2H，s)，3.63(2H，m)，3.45-3.41(2H，m)，2.52(2H，m)，1.70(2H，m)，1.46(9H，s).；m/e＝482∶484(3∶2).

2,4-two chloro-N-{[4-(3-fluorine pyridine-2-yl) piperidin-4-yl] methyl } benzamide:

At 0 ℃ of preceding compound (1.2g to stirring; 2.5mmol) DCM (10ml) solution in add trifluoroacetic acid (2ml; 26mmol), solution stirred 3 hours at ambient temperature.Evaporating solvent, resistates distribute between EtOAc (50ml) and saturated sodium bicarbonate aqueous solution (50ml).Water extracts with EtOAc (50ml), the organic phase MgSO of merging ₄Drying is filtered and evaporation, obtains spumescence white solid (0.94g), and it need not be further purified and use.m/e＝382/384(3∶2)。

At 0 ℃ of preceding compound (0.3g to stirring; 0.78mmol) DCM (10ml) solution in add N-ethyl diisopropylamine (0.406g; 0.543ml; 3.13mmol), add 1,2,3-triazoles-4-SULPHURYL CHLORIDE (0.32g subsequently; 0.252ml; 1.56mmol), solution stirred 2.5 hours at ambient temperature.Add DCM (5ml) and water (5ml), mixture vigorous stirring 5 minutes is poured into one 5 μ PTFE separation of glasses material then.Evaporation DCM layer obtains oily matter, and it with 5% methyl alcohol-DCM wash-out, obtains title compound by the silica gel chromatography purifying, is white foam shape solid (105mg).

¹H?NMR(ppm)(DMSO)：8.53(1H，s)，8.40(1H，t，J＝6.4Hz)，8.32(1H，d，J＝4.5Hz)，7.62-7.56(2H，m)，7.43(1H，dd，J＝2.0，8.2Hz)，7.35-7.31(1H，m)，7.15(1H，d，J＝8.2Hz)，3.56(2H，d，J＝6.4Hz)，3.48(2H，d，J＝12.9Hz)，2.68(2H，t，J＝10.2Hz)，2.56(2H，s)，1.87(2H，t，J＝10.5Hz)；m/e＝513∶515(3∶2).

Prepare following compounds by embodiment 4 described methods with suitable SULPHURYL CHLORIDE and acyl chlorides.

Embodiment 5

2,4-two chloro-N-{[4-(3-fluorine pyridine-2-yl)-1-[(1-methyl isophthalic acid H-1,2,3-triazole-4-yl) alkylsulfonyl] piperidin-4-yl] methyl } benzamide:

To 2,4-two chloro-N-{[4-(3-fluorine pyridine-2-yl)-1-[(1H-1,2,3-triazole-4-yl) alkylsulfonyl] piperidin-4-yl] methyl } benzamide (0.15g; 0.29mmol) toluene (5ml) suspension in add N, dinethylformamide dimethylacetal (0.35g; 0.4ml; 2.92mmol), mixture heating up refluxed 1 hour.Under vacuum, remove and desolvate twice of resistates and methylbenzene azeotropic.Crude product with 3% methyl alcohol-DCM wash-out, obtains title compound by preparation silica gel tlc purifying, is polar isomer (30mg).

¹H?NMR(ppm)(CDCl ₃)：8.32(1H，d，J＝4.5Hz)，7.95(1H，s)，7.49(1H，d，J＝8.3Hz)，7.40-7.33(2H，m)，7.25(2H，dd，J＝0.0，7.9Hz)，6.74(1H，s)，4.17(3H，s)，3.87(2H，d，J＝6.2Hz)，3.52(2H，t，J＝8.7Hz)，3.36(2H，dd，J＝3.5，7.6Hz)，2.70-2.64(2H，m)，1.90-1.86(2H，m)；m/e＝527∶529.

Method by embodiment 5 is got the row compound ready by the alkylation to prepare of NH heterocycle (as embodiment 4 preparations).

Embodiment 6

2,4-two chloro-N-{[3-(3-fluorine pyridine-2-yl)-1-(2-thienyl sulphonyl base) azetidine-3-yl] methyl } benzamide:

3-cyano group-3-(3-fluorine pyridine-2-yl) azetidine-1-carboxylic acid tert-butyl ester:

Under N2 atmosphere to the 3-of the stirring in acetone/ice bath cyano group azetidine-1-carboxylic acid tert-butyl ester (5g; 27.43mmol) and 2-chloro-3-fluorine pyridine (5.05g; 38.41mmol) toluene (100ml) suspension in, add two (trimethyl silicane) acid amides potassium (0.5M, toluene solutions with 30 fens clock times; 71.34ml; 35.67mmol) solution, keep internal temperature to be lower than-10 ℃.Make the reaction mixture envrionment temperature of rising again, stirred in addition then 2 hours.Reaction is poured in the salt solution (150ml), with EtOAc (3 * 100ml) extractions.The organic phase that merges is washed with salt solution (100ml), dry (MgSO ₄), filter and evaporation, obtain brown oil.Crude product is used the 5%EtOAc-DCM wash-out by the silica gel chromatography purifying, obtains required product, is colorless oil (2.67g).

¹H?NMR(ppm)(CDCl ₃)：8.45(1H，dd，J＝1.1，4.6Hz)，7.55-7.49(1H，m)，7.43-7.39(1H，m)，4.66(2H，d，J＝8.9Hz)，4.57(2H，d，J＝8.8Hz)，1.45(9H，s).

3-aminomethyl-3-(3-fluorine pyridine-2-yl) azetidine-1-carboxylic acid tert-butyl ester:

Product (2.5g forward; 9.0157mmol) methyl alcohol (30ml) solution of 2.0M ammoniacal liquor in add Raney nickel (about 1ml, 50% water soup compound), mixture stirred 12 hours with a Parr device under hydrogen (50psi) atmosphere.LC/MS shows starting raw material consumption, obtains expecting product quality ion (m/e=282).Remove by filter catalyzer, with methyl alcohol (5 * 10ml) extensively washings.Evaporated filtrate obtains required compound, is jelly, and it is directly used in next step (2.5g).

3-{2,4-dichlorobenzene acyl group } aminomethyl-3-(3-fluorine pyridine-2-yl) azetidine-1-carboxylic acid tert-butyl ester:

At 0 ℃ of preceding product (2.2g to stirring; 7.8201mmol) and N-ethyl di-isopropyl (1.21g, 1.62ml; 9.38mmol) DCM (30ml) solution in dropwise add 2,4 dichlorobenzyl chloride (1.802g 1.20ml; 8.60mmol), 4 hours envrionment temperatures of rising again of solution stirring are by adding entry (1ml) quencher reaction, the volatile matter evaporation.Resistates distributes between EtOAc (100ml) and water (50ml).Water extracts with EtOAc (50ml), the organic phase MgSO of merging ₄Drying is filtered and evaporation obtains orange.Crude product is used the 20%EtOAc-DCM wash-out by the silica gel chromatography purifying, obtains product, is colorless oil (3.2g).

¹H?NMR(ppm)(CDCl ₃)：8.36(1H，d，J＝4.5Hz)，7.55(1H，d，J＝8.4Hz)，7.42(2H，dd，J＝9.2，20.7Hz)，7.29(2H，s)，6.72(1H，s)，4.40(2H，d，J＝8.9Hz)，4.10(4H，m)，1.44(9H，s).；m/e＝454∶456.

2,4-two chloro-N-[(1-(3-fluorine pyridine-2-yl) azetidine) methyl] benzamide:

At 0 ℃ of preceding product (2.8g to stirring; 6.163mmol) DCM (30ml) solution in add trifluoroacetic acid (2.37ml; 30.8mmol), solution stirred 3 hours at ambient temperature then.Evaporating solvent, resistates distribute between EtOAc (50ml) and saturated sodium bicarbonate aqueous solution (50ml).Water extracts with EtOAc (50ml), the organic phase MgSO of merging ₄Drying is filtered and evaporation obtains spumescence white solid (2.05g), and it need not be further purified and can use.m/e＝354/356。

At 0 ℃ of preceding product (0.1g to stirring; 0.28mmol) and positive ethyl diisopropylamine (0.091g0.12ml; 0.70mmol) DCM (5ml) solution in add thiophene-2-SULPHURYL CHLORIDE (0.056g; 0.31mmol), solution stirred 18 hours at ambient temperature.LC/MS shows single product m/e=500: 502 (3: 2).Reaction is diluted vigorous stirring 10 minutes with DCM (5ml) and water (2ml).Topple over mixture by 5 μ PTFE separation of glasses material, collect the DCM layer, the vaporising under vacuum solvent obtains oily matter.Crude product is used the 20%EtOAc-DCM wash-out by the silica gel chromatography purifying, obtains title compound, is spumescence white solid (69mg).

¹H?NMR(ppm)(DMSO)：8.77(1H，t，J＝5.9Hz)，8.26(1H，d，J＝4.5?Hz)，7.95(1H，d，J＝4.8Hz)，7.69(1H，d，J＝2.9Hz)，7.62(2H，dd，J＝0.0，1.8Hz)，7.48(1H，dd，J＝1.8，8.2Hz)，7.35-7.31(1H，m)，7.24(1H，d，J＝8.2Hz)，7.17(1H，t，J＝4.3Hz)，4.21(2H，d，J＝8.9Hz)，4.05(2H，dd，J＝0.0，8.8Hz)，3.71(2H，d，J＝6.3Hz)；m/e＝500∶502(3∶2)

Adopt suitable SULPHURYL CHLORIDE to prepare following compounds by embodiment 6 described methods.

Embodiment 7

2,4-two chloro-N-{[3-(cyclopropyl methyl)-1-(1H-1,2,3-triazole-4-base alkylsulfonyl) azetidine-3-yl] methyl } benzamide:

3-cyano group-3-(cyclopropyl methyl) azetidine-1-carboxylic acid tert-butyl ester:

At 0 ℃ to Diisopropylamine (3.33g 4.64ml; 32.92mmol) THF (60ml) solution in add n-Butyl Lithium (2.5M be in hexane; 13.17ml; 32.92mmol).Solution stirring 30 minutes is cooled to-78 ℃ then.Add 3-cyano group azetidine-1-carboxylic acid tert-butyl ester (5g; 27.43mmol) THF (40ml) solution, solution stirring 1 hour.Dropwise add (brooethyl) cyclopropane (4.81g then; 3.42ml; 35.67mmol) stir simultaneously, solution stirred 30 minutes at-78 ℃, made the envrionment temperature of rising again then, stirred 3 hours.Be reflected in the ice bath and cool off, use the saturated aqueous ammonium chloride quencher.Evaporating solvent, resistates distribute between EtOAc (300ml) and water (100ml).Separate organic phase, use MgSO ₄Drying is filtered and evaporation obtains orange.Crude product is used the 15%EtOAc-DCM wash-out by silica gel plug, obtains product, is faint yellow oily thing (5.25g).

¹H?NMR(ppm)(CDCl ₃)：4.27(2H，d，J＝8.7Hz)，3.90(2H，d，J＝8.7Hz)，1.82(2H，d，J＝6.8Hz)，1.45(9H，s)，0.88-0.78(1H，m)，0.63-0.57(2H，m)，0.26(2H，m).

3-(aminomethyl)-3-(cyclopropyl methyl) azetidine-1-carboxylic acid tert-butyl ester:

Product (2.2g forward; 9.31mmol) ammoniacal liquor methyl alcohol (2.0M; 20ml) add Raney nickel (about 1ml, 50% aqueous slurries) in the solution, mixture stirred 12 hours with a Parr device under hydrogen (50psi) atmosphere.LC/MS shows starting raw material consumption, obtains new product expection peak mass ion (m/e=240).Catalyzer removes by filter under nitrogen, with methyl alcohol (6 * 20ml) washings.Evaporated filtrate obtains colorless oil, and it need not be further purified and can use in next step.

3-{2,4-dichloro-benzoyl base } aminomethyl-3-(cyclopropyl methyl)-3-fluorine pyridine-2-yl) azetidine-1-carboxylic acid tert-butyl ester:

At 0 ℃ of product (2.12g forward; 8.82mmol) and N-ethyl diisopropylamine (1.71g; 2.3ml; 13.23mmol) DCM (30ml) solution in dropwise add 2,4 dichlorobenzyl chloride (2.21g; 1.48ml; 10.58mmol), solution stirring 4 hours, the envrionment temperature of rising again.By adding entry (5ml) quencher reaction, the volatile matter evaporation.Resistates distributes between EtOAc (100ml) and water (50ml).Water extracts with EtOAc (50ml), the organic phase MgSO of merging ₄Drying is filtered and evaporation obtains orange.Crude product is used the 20%EtOAc-DCM wash-out by the silica gel chromatography purifying, obtains product, is colorless oil (2.58g).

¹H?NMR(ppm)(CDCl ₃)：7.64(1H，d，J＝8.3Hz)，7.43(1H，d，J＝1.9Hz)，7.33-7.31(1H，m)，6.51(1H，s)，3.80-3.72(6H，m)，1.61(2H，d，J＝6.5Hz)，1.42(9H，s)，0.72-0.64(1H，m)，0.57-0.51(2H，m)，0.12(2H，q，J＝5.0Hz)；m/e＝413∶415

2,4-two chloro-N-{[3-(cyclopropyl methyl) azetidine-3-yl] methyl } benzamide:

At 0 ℃ of preceding product (2.58g to stirring; 6.24mmol) DCM (30ml) solution in add trifluoroacetic acid (3.51g; 2.37ml; 30.81mmol), solution stirred 3 hours at ambient temperature.LC/MS shows starting raw material consumption, obtains expecting product quality ion (m/e=313: 315[3: 2]).Evaporating solvent, resistates distribute between EtOAc (50ml) and saturated sodium bicarbonate aqueous solution (50ml).(2 * 50ml) extract the organic phase MgSO of merging to water with EtOAc ₄Drying is filtered and evaporation obtains the spumescence white solid, and it need not be further purified and can use (1.95g).

(0.5g adds N-ethyl diisopropylamine (0.52g in DCM 1.59mmol) (8ml) solution to the preceding product that stirs at 0 ℃; 0.69ml; 3.99mmol), add 1,2,3-triazoles-4-SULPHURYL CHLORIDE (0.45g subsequently; 2.23mmol), solution was stirred 18 hours at ambient temperature.LC/MS shows single product m/e=444: 446 (3: 2).Reaction usefulness DCM (10ml) and water (2ml) dilution and vigorous stirring 10 minutes.The mixture impouring is collected the DCM layer by one 5 μ PTFE separation of glasses material, and the vaporising under vacuum solvent obtains oily matter.Crude product obtains title compound by the silica gel chromatography purifying with 5% methyl alcohol-DCM wash-out, is the spumescence white solid, and it obtains white solid (350mg) with recrystallizing methanol.

¹H?NMR(ppm)(CD ₃OD)：8.41(1H，s)，7.54(1H，s)，7.42(2H，s)，3.82(4H，q，J＝8.4Hz)，3.56(2H，s)，1.33(2H，d，J＝6.3Hz)，0.50(1H，s)，0.49(1H，m)，0.39(2H，m)，0.00(2H，m).

Use the suitable following compound of SULPHURYL CHLORIDE preparation by embodiment 7 described methods.

Embodiment 8

2,4-two chloro-N-(3-(cyclopropyl methyl)-1-[(1-methyl isophthalic acid H-1,2,3-triazole-4-yl) and alkylsulfonyl] azetidine-3-yl } methyl) benzamide:

0 ℃ to stir 2,4-two chloro-N-{[3-(cyclopropyl methyl)-1-(1H-1,2,3-triazole-4-base alkylsulfonyl) azetidine-3-yl] methyl benzamide (0.1g; 0.23mmol) DMF (5ml) solution in add salt of wormwood (0.062g; 0.45mmol), add methyl iodide (0.048g subsequently; 0.021ml; 0.34mmol), solution stirred 18 hours at ambient temperature.Three new product m/e=458 of LC/MS display quality ion unanimity: 460 (3: 2).Add water (1ml), removal of solvent under reduced pressure, twice of resistates and methylbenzene azeotropic.Crude product with 4% methyl alcohol-DCM wash-out, obtains title compound by preparation silica gel tlc purifying, is polar isomer (24mg).

¹H?NMR(ppm)(DMSO)：8.85(1H，s)，8.62(1H，t，J＝6.1Hz)，7.69(1H，d，J＝2.0Hz)，7.50(1H，dd，J＝2.0，8.2Hz)，7.43(1H，d，J＝8.2Hz)，4.14(3H，s)，3.75(2H，d，J＝8.4Hz)，3.67(2H，d，J＝8.4Hz)，3.40(2H，d，J＝6.2Hz)，1.24(2H，d，J＝6.7Hz)，0.43(1H，m)，0.33-0.29(2H，m)，-0.05(2H，m)；m/e＝458∶460(3∶2).

Prepare compound the following table by embodiment 8 described methods from suitable NH heterocycle (as embodiment 6 or 7 preparations) and suitable alkiodide.

Claims

1. formula I compound:

Wherein:

Two p are 1 or 2;

(b) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace, or

(c) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

(6)-CO ₂R ⁹，

R wherein ⁹Be independently selected from:

(a) hydrogen,

(b)-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 fluorine,

(c) benzyl and

(d) phenyl,

(7)-NR ¹⁰R ¹¹，

R wherein ¹⁰And R ¹¹Be independently selected from:

(a) hydrogen,

(d) benzyl,

(e) phenyl and

(8)-CONR ¹⁰R ¹¹；

R ²Be selected from:

(1) phenyl, it is by R ^2a, R ^2bAnd R ^2cReplace,

(2) heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace,

R ^2a, R ^2bAnd R ^2cBe independently selected from:

(1) hydrogen,

(2) halogen,

(3)-C _1-6Alkyl, it is unsubstituted or is replaced by following group:

(a) 1-6 halogen,

(b) phenyl,

(c) C _3-6Cycloalkyl, or

(d)-NR ¹⁰R ¹¹，

(4)-O-C _1-6Alkyl, it is unsubstituted or is replaced by 1-6 halogen,

(5) hydroxyl,

(6)-SCF ₃，

(7)-SCHF ₂，

(8)-SCH ₃，

(9)-CO ₂R ⁹，

(10)-CN，

(11)-SO ₂R ⁹，

(12)-SO ₂-NR ¹⁰R ¹¹，

(13)-NR ¹⁰R ¹¹，

(14)-CONR ¹⁰R ¹¹And

(15)-NO ₂；

R ³Be heterocycle, it is by R ^2a, R ^2bAnd R ^2cReplace;

R ⁴And R ⁵Be independently selected from:

(1) hydrogen and

(2) C _1-6Alkyl, it is unsubstituted or is replaced by halogen or hydroxyl,

Or R ⁴And R ⁵Be combined to form C _3-6Cycloalkyl ring;

A is selected from:

(1)-O-and

(2)-NR ¹⁰-；

M is 0 or 1, thus when m is 0 R ²Directly be connected with carbonyl;

And pharmacologically acceptable salt and its each enantiomorph and diastereomer.

2. the compound of claim 1, wherein R ¹Be C _3-6Cycloalkyl or heterocycle, this heterocycle are to comprise 1,2,3 or 4 heteroatoms that is selected from O, N or S, and maximum heteroatomss are 5 yuan of unsaturated rings of O or S, or for comprising 6 yuan of unsaturated rings of 1,2 or 3 nitrogen-atoms, R ¹Optional by halogen or hydroxyl replacement.

3. claim 1 or 2 compound, wherein R ²Be phenyl or C _3-6Cycloalkyl, it is optional by hydroxyl, halogen, C _1-6Alkyl, halo C _1-6Alkyl, C _1-6Alkoxyl group or amino the replacement.

4. claim 1,2 or 3 compound, wherein R ³For comprising 1,2,3 or 4 heteroatoms that is selected from O, N or S, maximum heteroatomss are 5 yuan of unsaturated rings of O or S, or comprise 6 yuan of unsaturated rings of 1,2 or 3 nitrogen-atoms, and it is optional by halogen, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halo C _1-6Alkoxyl group, nitro or amino the replacement.

5. pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of any aforementioned claim.

6. the compound or pharmaceutically acceptable salt thereof of arbitrary claim in the claim 1～4 is by the purposes in the method for therapy for treating human body.

7. the purposes of the compound or pharmaceutically acceptable salt thereof of arbitrary claim in the claim 1～4, it is used for the treatment of purposes in the schizoid medicament in preparation.

8. a treatment suffers from the method for schizophrenia main body, and it comprises the compound or pharmaceutically acceptable salt thereof of the claim 1 that gives described main body treatment significant quantity.