Piperidine compound, method for its preparing, pharmaceutical composition and method for inhibition of sodium channels and potassium channels

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

 

The present invention relates to a new piperidinium compound, its salt or hydrate; the method thereof; pharmaceutical compositions containing these compounds, and the like, and to its manufacture. Atrial fibrillation, which is a type of arrhythmia is a condition in which the Atria is not regular excitation and contraction in accordance with the stimulation coming from the sinus-atrial node, and this excitation is often repeated arbitrarily classified in paroxysmal atrial fibrillation and chronic atrial fibrillation. It was also reported that in many cases, the crisis comes as a result of complications of organic heart disease such as lesions of the mitral valve, coronary heart disease, arterial hypertension, thyrotoxicosis (representing the four major diseases) and discrete atrial fibrillation that causes atrial fibrillation. In addition, the state of heart failure often manifests in the form of sarcopenia and discomfort in the chest, and the blood clot formed in the left atrium, often provokes embolization of thrombi in various organs systems of the body. Although the methods of treatment (cessation of attacks, prevention of relapses and the like) of the atrial predse the Dios in cases of paroxysmal fibrillation, and chronic atrial fibrillation differ, however, the effectiveness of drug therapy is insufficient in both cases, and the introduction of antiarrhythmic drugs is currently the choice of drugs 1 class. Known antiarrhythmic agent are divided into groups, such as group I classification Vaughn Williams (Vaughan Williams) (class I: the drug, the vast conductivity of the muscles of the Atria by means of selective blocking of Na+channel and inhibiting circulation of excitation), drugs class II according to this classification (class II: siege β-adrenergic receptors) and drugs class III according to this classification (class III: drug selectively blocking To+channel and extending the duration of the action potential), drugs class IV according to this classification (class IV: blocker of CA+channel), etc. However, drug, inhibiting circulation (circular wave) excitation potential of the muscles of the Atria, is effective for termination of atrial fibrillation, and it is assumed that the antiarrhythmic drug of class I and anti-arrhythmic drug class III are effective. As for antiarrhythmic drugs in this class, their description is found in many works; so, for example the EP, the invention related to piperidinium compounds used as antiarrhythmic drugs, described in the patent application of Japan No. 62-281858, JP-A 6-501242, JP-A 6-502273, JP-A 6-511014, etc. and, in addition, the invention related to piperidinium compounds used as antiarrhythmic drugs, described in JP-A 9-505597, JP-A 8-511014, WO 96/13479 etc.

However, as an antiarrhythmic agent of class I has a negative inotropic effect (reduces the pumping function of the heart), based on the inhibition of Na+channels, its use is associated with problems, which consists in the fact that it causes an exacerbation or progression of heart failure. In contrast, an antiarrhythmic agent of class III has no such effect and gives excellent results only in increasing refractory period, however, the standard antiarrhythmic agent of class III are not always effective in controlling the frequency of atrial fibrillation, it also lengthens the refractory period of the muscle of the Atria and often much more lengthens the refractory period of the muscle fibrillation in the normal state, and not with tachycardia (inverse dependence on frequency), and therefore at a dose that provides therapeutic effect, there are problems associated the with induced ventricular arrhythmia.

On the other hand, it is also known that the connection with the action, aimed at the inhibition of Na+channels, has a beneficial effect on various neuralgias (e.g., post herpetic neuralgia, diabetic neuralgia, HIV-associated neuralgia etc). For example, for the treatment of various neuralgia used LIDODERM applied post-herpetic neuralgia, carbamazepine, used for trigeminal neuralgia, an inhibitor of Na+channels, used as an antiarrhythmic agent (for example, meksiletin), inhibitors of Na+channels used as antidepressant and anti-convulsants (e.g., amitriptyline, carbamazepine), etc. in Addition, there are several works (Pain. 83 (1999) 389-400: European Journal of Pain 2 (1998) 3-14; Pain. 73 (1997) 123-139), which pointed to the fact that anti-arrhythmic drug (meksiletin, lidocaine) is an effective analgesic.

However, since the standard inhibitors of Na+channels have similar effects on the heart and nervous system, while the conventional treatment of disease, the dose of a compound that inhibits Na+-channels cannot be increased, and its analgesic effect is clearly apparent.

There are no drugs that would have p is abashedly action aimed at the inhibition of Na+channels, and would satisfy the requirements of its pharmacological activity, dose, reliability, etc. as to pharmaceutical means, and which, moreover, would be effective in clinical application. Therefore, the aim of the present invention is to research and obtain connection, which would have an excellent action, aimed at the inhibition of Na+channels and which would allow to solve all the above problems.

Description of the invention

The authors of the present invention have conducted intensive studies in which they were able to synthesize the compound representing a completely new piperidine compound of formula (I)

(where the ring a represents ring represented by the formula

or

(where R1means (1) a hydrogen atom, (2) halogen atom, (3) cyano, (4) optionally substituted C1-6alkyl group, (5) optionally substituted C2-6alkenylphenol group, (6) optionally substituted C2-6alkylamino group, (7) optionally substituted C3-8cycloalkyl group, (8) optional Thames is NUU 3-8cycloalkenyl group, (9) optionally substituted C1-6alkoxygroup, (10) optionally substituted C1-6allylthiourea, (11) optionally substituted C1-6alkylsulfonyl group, (12) optionally substituted C1-6alkylsulfonyl group, (13) optionally substituted C6-14aromatic hydrocarbon cyclic group or (14) optionally substituted 5 to 14-membered aromatic heterocyclic group;

R2represents (1) hydrogen atom, (2) optionally substituted C1-6alkyl group, (3) optionally substituted C2-6alkenylphenol group, (4) optionally substituted C2-6alkylamino group, (5) optionally substituted C3-8cycloalkyl group, (6) optionally substituted C3-8cycloalkenyl group, (7) optionally substituted by an amino group, (8) optionally substituted C6-14aromatic hydrocarbon cyclic group or (9) optionally substituted 5 to 14-membered aromatic heterocyclic group;

R3represents (1) optionally substituted C1-6alkoxygroup, (2) optionally substituted C2-6alkenylacyl, (3) optionally substituted C3-7cycloalkylation or (4) optionally substituted C3-7cycloalkanones;

W represents (1) a simple link, (2) it is certainly substituted C 1-6alkylenes group, (3) optionally substituted C2-6alkynylamino group, (4) optionally substituted C2-6alkynylamino group or (5) a group represented by the formula-U-V- (where U means (i) a simple link, (ii) an oxygen atom, (iii) a sulfur atom, (iv) a group represented by the formula-NH-, (v) optionally substituted C1-6alkylenes group, (vi) optionally substituted C2-6alkenylamine group or (vii) optionally substituted C2-6alkynylamino group; V means (i) a simple link, (ii) optionally substituted C1-6alkylenes group, (iii) optionally substituted C2-6alkynylamino group, (iv) optionally substituted C2-6alkynylamino group, (v) an oxygen atom, (vi) a sulfur atom or (vii) a group represented by the formula-CO-, (viii) -SO - or (ix) -SO2-, provided that excluded the case where U and V represent the same group in the above definition and one of U and V represents a simple bond, optionally substituted C1-6alkylenes group, optionally substituted C2-6alkenylamine group or optionally substituted C2-6alkynylamino group) ;

Z represents (1) optionally substituted C2-14aromatic hydrocarbon cyclic group, (2) optionally substituted 5 to 14-membered aromatic heterocyclic group or (3) group, p is redstavlennye formula-N(R 4R5(where R4and R5may be the same or different and each represents (i) hydrogen atom, (ii) optionally substituted C1-6alkyl group, (iii) optionally substituted C2-6alkenylphenol group, (iv) optionally substituted C2-6alkylamino group, (v) optionally substituted C3-8cycloalkyl group, (vi) optionally substituted C3-8cycloalkenyl group, (vii) optionally substituted C6-14aromatic hydrocarbon cyclic group, (viii) optionally substituted 5 to 14-membered aromatic heterocyclic group or (ix) C1-6aliphatic acyl group, or (x) R4and R5can be linked together with the formation of a 3-8-membered nitrogen-containing cyclic group);

l is an integer from 0 to 6,

and, in addition, the authors found that these compounds, etc. have excellent action, aimed at the inhibition of Na+channels, and therefore they can be used against diseases, for the treatment or prevention of which can be effective inhibition of Na+channels, for example against arrhythmia (also relieve patient stress caused by atrial fibrillation, for example, palpitations, discomfort in the chest, heart failure, blood clots in the evom atrium, embolism of thrombus, attacks), neuralgia of various types (for example, diabetic neuralgia, HIV neuralgia, herpetic neuralgia, and the like) and the like). Thus, all of these compounds are included in the scope of the present invention.

Thus, the present invention includes 1) a compound represented by the above formula (I), its salt or hydrate;

2) in the above connection 1) W may denote a group represented by the formula-CH2-, -CH2-CH2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH -,- ≡ -,- CO-, -O-, -O-CH2-, -CH2-O-, -CH2-CO-, -(CH2)2-CO-, -CH2-CH(CN)-, -CH2-CH(OH)-, -SO2-, -CH2-SO2, -NH-CO-, -CH2-NH-CO-, -NH-SO2- or-CH2-NH-SO2-;

3) in the above connection 1) W can mean a group represented by the formula-CH2-CH2-, -CH=CH-, -CH≡CH - or CH2-O-,

4) in the above item 1) Z may represent optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group, 5) in the above item 1) Z may represent optionally substituted phenyl group, pyridyloxy group or thienyl group, 6) in the above item 1) Z may present With6-14Aro is aricescu hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group, and the ring can be, respectively, substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) ceanography, (4) optionally substituted C1-6alkyl group, (5) optionally substituted C3-8cycloalkyl group, (6) optionally substituted C1-6alkoxygroup, (7) optionally substituted C3-8cycloalkylcarbonyl, (8) optionally substituted C1-6allylthiourea, (9) optionally substituted C6-14alloctype, (10) optionally substituted 5 to 14-membered heterokaryosis, (11) optionally substituted amino group, (12) optionally substituted 5 to 14-membered aromatic heterocyclic group, (13) optionally substituted 5 to 14-membered non-aromatic heterocyclic group, (14) C1-6alkylsulfonyl group and (15)1-4alkylenedioxy, 7) in the above item 1) Z can mean a group represented by formula-N(R4R5(where R4and R5have the meanings defined above, respectively), 8) in the above item 7) R4and R5may be the same or different and each represents a hydrogen atom, optionally substituted C1-6alkyl group, optionally substituted C2-6alkylamino group, optionally substituted C6-14arils1-6Ala is the function group or optionally substituted heteroaryl 1-6alkyl group, 9) in the above item 7) R4and R5can be linked together with education optionally substituted 3-8-membered nitrogen-containing cyclic group, 10) in the aforementioned item 9) Z can represent piperidino group which may be optionally substituted piperidine group, optionally substituted piperazine group or optionally substituted morpholinyl group, 11) in the above paragraph (1) l can represent an integer of 1 to 12) in the above item 1) ring And can be represented by the formula

(where R1and R2have the meanings defined above, respectively), 13) in the above item 12) R1can represent a hydrogen atom, halogen atom or C1-6alkyl group, 14) in the above item 12) R1can represent a hydrogen atom, 15) in the above item 12) R2can represent a hydrogen atom or optionally substituted C1-6alkyl group, 16) in the above item 1) ring And can be represented by the formula

where R1and R3has the values defined above, respectively, 17) in the above item 16) R3can represent a hydroxyl group or a C1-6alkoxygroup, 18) in the above PU is regarding subsection (1) position of joining the group-W-Z can be 2 - or 4-position piperidino rings. In addition, the present invention includes 19) the compound represented by the formula

(where R1, R2, W, Z and l have the same values that were defined in the above item 1), its salt or hydrate, 20), the compound represented by the formula

(where R1, W and Z have the meanings given in the above paragraph 1, respectively, and la denotes an integer of 1 or 2), its salt or hydrate, 21) 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(forfinal]ethyl]piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine, 1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl) methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine, 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(benzyloxy)phenyl]-1-ethynyl]piperidine, 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine, 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(Z)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine, 1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperid is h, 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,4-(divergence)methyl]piperidine or 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,5(divergence)methyl]piperidine, salt or hydrate, 22) the method of obtaining the compounds described in the above item 1), its salt or hydrate, including the stage of interaction of the compounds represented by the formula

(where ring a and l have the meanings defined above in claim 1, respectively; L represents a leaving group), its salt or reactive derivative with the compound represented by the formula

(where W and Z have the meanings defined above in claim 1, respectively), 23) the pharmaceutical composition comprising the compound represented by the formula

(in this formula the symbols have the meanings defined above in claim 1)), its salt or hydrate, 24) the composition in the above paragraph 23), which may be an inhibitor of sodium channels or inhibitor of potassium channels, 25) the composition in the above paragraph 23), which may be a means for the prevention or treatment of arrhythmia, 26) the composition in the above paragraph 23), which may be drug n is otiv arrhythmia class III classification Vaughn Williams 27) the composition in the above paragraph 23), which can be analgesic, 28) the composition in the above paragraph 23), which may be a means for the treatment or prevention of disease, and where 29) neuralgia in the above paragraph 28) may be diabetic neuralgia, HIV-associated neuralgia, posttherapeutic neuralgia, trigeminal neuralgia, pain in the amputated limb, pain in the spinal cord injury, thalamic pain or the after-shocks of pain.

The present invention relates to the use of compounds represented by the above formula (I), its salt or hydrate to obtain an inhibitor of sodium channels or inhibitor of potassium channels, means for treating or preventing arrhythmia drugs against arrhythmia class III classification Vaughn Williams, analgesic and means for the treatment or prevention of pain.

In addition, the present invention relates to a method for prevention or treatment of a disease, an effective remedy which is the inhibition of sodium channels or inhibition of potassium channels, where the method involves the administration to a patient a pharmacologically effective amount of the compounds represented by the above formula (I)or its salt or hydrate.

In addition,the present invention relates to a method for prevention or treatment of arrhythmia, a drug against arrhythmia class III classification Vaughn Williams, and to a method of treating or preventing pain and neuralgia, involving the administration to a patient a pharmacologically effective amount of the compounds represented by the above formula (I), its salt or hydrate.

The meanings of symbols, terms, etc. described in this application are listed below and more fully illustrate the present invention.

In addition, in the description of this application the structural formula of the compound present as a specific isomer, thus, the present invention encompasses all geometric isomers, which have the structure of this compound, optical isomers based on asymmetric carbons, stereoisomers are isomers of the tautomers and the like, and mixtures of these isomers. The present invention is not limited to the description of these formulas are given for convenience of description, and may include one of these isomers and their mixtures. In accordance with this, in the compounds of the present invention may be an optical activator and racemic structure, which has in the molecule asymmetric carbon atom, but they do not limit the scope of the present invention and both of them are included in the scope of the invention. The invention also includes a polymorphic f is rmy of compound I, but, as mentioned above, the invention is not limited, and any of the crystalline forms may be present separately or in the form of a mixture of crystalline forms and addition of the anhydride may be a hydrate. The so-called metabolite, which is formed by decomposition of compounds of the present invention in vivo, is also in the scope claimed in the present patent application.

The term "arrhythmia" in the description of the present invention is a generic name of the States in which the violated regulation function heartbeat (violation Genesis stimulator and a violation of stimulating conductivity), and includes, for example, sinus arrhythmia, early beats, coarse atrial fibrillation, paroxysmal supraventricular tachycardia, sinoatrial blockade, includes, for example, sinus arrhythmia, early beats, atrial fibrillation, paroxysmal supraventricular tachycardia, sinoatrial blockade, atrioventricular blockade, etc. From all specified arrhythmias compounds of the present invention is particularly effective for the treatment of atrial fibrillation.

The term "neuralgia" in the description of the present invention is calorifically symptom (true or secondary)that occur in the nervous system, and means pain that occurs during ner is a or in the field of localization. For example, the term includes such conditions as diabetic neuralgia, HIV-associated neuralgia, pain in the amputated limb pain after spinal cord injury, thalamic pain, the after-shocks of pain, etc. the Term "analgesic" means a drug that reduces or relieves pain by altering perception of stimuli, without causing anestesiologi or unconsciousness.

The term "halogen atom"used in the description of this application, means atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom.

The term "C1-6alkyl group"used in the description of this application, means alkiline group having from 1 to 6 carbon atoms, and examples of such groups are linear or branched alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropyl group, 2-ethylpropyl group, n-exilda group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-ethylpropyl group, 1,1,2-trimethylpropyl group, 1-popypropylene group, 1-methylbutyl group, 2-methylbutyl the th group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group and 3-methylpentyl group.

The term "C2-6Alchemilla group"used in the description of this application, means alkenylphenol group having from 2 to 6 carbon atoms, and examples of such groups are linear or branched alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 2-methyl-1-protanilla group, 3-methyl-1-protanilla group, 2-methyl-2-protanilla group, 3-methyl-2-protanilla group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group, 1,3-hexadienyl group and 1.6-hexadienyl group.

The term "C2-6Alchemilla group"used in the description of this application, means alkylamino group having from 2 to 6 carbon atoms, and examples of such groups are linear or branched alkyline groups, such as etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 3-methyl-1-proponila group, 1-ethinyl-2-proponila group, 2-methyl-3-proponila group, 1-pentenyl the Naya group, 1-hexylamine group, 1,3-hexadienyl group and 1.6-hexadienyl group.

The term "C1-6alkoxygroup"used in the description of this application, means "C1-6alkyloxy", in which the oxygen atom is associated with a group that has the same values that were defined above for C1-6alkyl group, and examples of such groups are methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine, second-pentyloxy, n-hexachrome, isohexadecane, 1,1-dimethylpropyleneurea, 1,2-DIMETHYLPROPANE, 2,2-dimethylpropylene, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyramide, 1,2-dimethylbutylamino, 2,2-dimethylbutyramide, 2,3-dimethylbutylamino, 1,3-dimethylbutylamino, 2-itivuttaka, 1,3-dimethylbutyramide, 2-methylphenoxy, 3-methylphenoxy etc.

The term "C1-6alkenylacyl"'used in the description of the present application means a group in which an oxygen atom is associated with a group that has the same values that were defined above for C1-6alkenylphenol group, and preferred examples and such groups are vinyloxy, alliancegroup, 1-propionyloksypo, 2-propionyloksypo, isopropenylacetate, 2-methyl-1-propionyloksypo, 3-methyl-1-propionyloksypo, 2-methyl-2-propionyloksypo, 3-methyl-2-propionyloksypo, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 1-hexaniacinate, 1,3-hexanediamine, 1,6-hexanediamine etc.

Examples "C1-6ancilliary"'used in the description of the present application are, for example, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, second-butylthiourea, tert-butylthiourea, n-intelligroup, 1,1-dimethylpropyleneurea, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1-ethylpropylamine, 2-ethylpropylamine, n-vexillographer, 1-methyl-2-ethylpropylamine, 1-ethyl-2-ethylpropylamine, 1,1,2-trimethylpropyl, 1-profileproperties, 1-methylbutyrate, 2-methylbutyrate, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 2,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutadiene, 2-ethylbutyrate, 2-methylpentylamino, 3-methylpentylamino.

The term "C3-8cycloalkyl group"used in the description of this application, means cycloalkyl group in which the ring is formed of 3-8 atoms in which laroda, and examples of such groups are cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, etc. in Addition, "3-8cycloalkane group"used in the description of this application, means a ring corresponding to the above With3-8cycloalkyl group.

The term "C3-8cycloalkenyl group"used in the description of this application, means cycloalkenyl group in which the ring is formed of 3-8 carbon atoms, and examples of such groups include groups represented by the formula

or

Examples "C6-14aromatic hydrocarbon cyclic group"used in the description of the present invention are monocyclic, bicyclic or tricyclic6-14aromatic hydrocarbon cyclic group, such cachanilla group, angenlina group, 1-naftalina group, 2-naftalina group, atulananda group, heptylaniline group, biphenylene group, Indianola group, acenaphthylene group, fluoroaniline group, phenylaniline group, phenanthroline group, antarctilyne group, Cyclopentasiloxane group and benzocyclobutene group.

The term "5 to 14-membered aromatic heterocyclic group"used in the description of this application, means a monocyclic, bicyclic or tricyclic 5 to 14-membered aromatic heterocyclic group containing one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and examples of such groups are: (i) nitrogen-containing aromatic heterocyclic groups such as pyrrolidine group, Peregrina group, pyridazinyl group, pyrimidinyl group, piratininga group, thiazolidine group, tetrataenia group, benzotriazolyl group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, kinolinna group, izochinolina group, hyalinella group, talasila group, naphthylidine group, khinoksalinona group, chinadaily group, indolenine GRU is PA, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, carbazolyl group, pyrimidinyl group, phenanthroline group, ventimilia group, imidazopyridine group, imidazolidinyl group, pyrazolopyrimidine group; (ii) sulfur-containing aromatic heterocyclic groups such as thienyl group and benzothiazoline group; (iii) oxygen-containing aromatic heterocyclic groups such as furilla group, Pernilla group, cyclopentadienyl group, benzofuranyl group and isobenzofuranyl group; (iv) an aromatic heterocyclic group containing 2 or more different heteroatoms selected from a nitrogen atom, atom sulfur and oxygen atom, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, oxazoline group, benzoxazolyl group, oxadiazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group and pyridoxamine group.

The term "5 to 14-membered non-aromatic heterocyclic ring"used in the description of this C the turnout, means a monocyclic, bicyclic or tricyclic 5 to 14-membered non-aromatic heterocyclic ring containing any one or more heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and examples of such rings are pyrolidine, pyrrolinone, piperidino, pieperazinove, imidazoline, pyrazolidine, imidazolidine, morpholine, tertrahydrofuran ring, tetrahydropyrrole, aziridine, oxirane, oxathiolane and Spiridonova ring, and condensed rings, such as phthalimide ring and operations ring.

The term "hydrocarbon group"used in the description of this application, in particular, means C1-6alkyl group, a C2-6alkenylphenol group2-6alkylamino group3-8cycloalkyl or3-8cycloalkenyl group, and the corresponding values of these groups are the same as defined above.

In the compound of the present invention represented by the above formula (I), particularly preferred aspect for each group are described below.

In the group represented by the formula

or

(where R1, R2and R3are what I like, as they were defined above in paragraph (1), and As shown in the above formula (I)preferably "halogen atom"defined R1is a fluorine atom, a chlorine atom and a bromine atom, and more preferred are fluorine atoms and chlorine.

"C1-6alkyl group" in the "C1-6alkyl group which may be substituted"represented by the above R1and R2preferably is a methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group, etc. in Addition, "2-6alkenylphenol group" in the "C2-6alkenylphenol group which may be substituted"represented by R1or R2preferably is a vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group, etc. in Addition, "C2-6alkenylphenol group" in the "C2-6alkenylphenol group which may be substituted"represented by the above R1or R2preferably is etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, Butyrina group, 1-penicilina group, 1-hexylamine group, etc.

"C3-8cycloalkyl group" in the "C3-8cycloalkyl group which may be substituted"represented by the above R1or R2preferably is cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, etc. in Addition, "3-8cycloalkenyl group" in the "C3-8cycloalkenyl group which may be substituted"represented by R1or R2preferably is cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc.

"C1-6alkoxygroup" "C1-6alkoxygroup, which may be substituted"represented by the above R1or R3, is preferably a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine, second-pentyloxy, n-hexachrome, isohexadecane, etc. in Addition, "C1-6alkenylacyl C2-6alkenylacyl, which may be substituted"represented by the above R3preferably is vinyloxy, alliancegroup, 1-propionyloksypo, 2-propionyloksypo, isopropenylacetate, 2-methyl-1-p is openaxiom, 3-methyl-1-propionyloksypo, 2-methyl-2-propionyloksypo, 3-methyl-2-propionyloksypo, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 1-hexaniacinate, 1,3-hexanediamine, 1,6-hexanediamine etc.

"C1-6alkylthiophene" "C1-6allylthiourea, which may be substituted"represented by the above R1preferably is methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, second-butylthiourea, tert-butylthiourea, n-intelligroup, n-vexillographer etc.

"C1-6alkylsulfonyl group" in the "C1-6alkylsulfonyl group which may be substituted"represented by the above R1preferably is methylmethanesulfonamide group, ethylsulfinyl group, n-propylsulfonyl group, isopropylaniline group, n-butylsulfonyl group, isobutylphenyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylaniline group, n-hexylaniline group, etc.

"C1-6alkylsulfonyl group" in the "C1-6alkylsulfonyl group which may be substituted"represented by the above R1preferably is methylmethanesulfonamide g is the SCP, ethylsulfonyl group, n-propylsulfonyl group, isopropylaniline group, n-butylsulfonyl group, isobutylphenyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylaniline group, n-hexylaniline group, etc.

"C6-14aromatic hydrocarbon cyclic group" in "C6-14aromatic hydrocarbon cyclic group which may be substituted"represented by the above R1or R2preferably is a phenyl group, naftalina group, etc. in Addition, the "5 to 14-membered aromatic heterocyclic group" in the "5 to 14-membered aromatic heterocyclic group which may be substituted"represented by the above R1or R2preferably is Peregrina group, perazella group, pyridinoline group, pyridazinyl group, thienyl group, thiazolidine group, imidazolidinyl group, furilla group, etc.

As a preferred substituent of the amino group in the "amino group which may be substituted"represented by the above R2can be mentioned, for example, (1) C1-6alkyl group which may be substituted (for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-butyln the group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group, which may be respectively substituted),

(2) C2-6Alchemilla group which may be substituted (for example, vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group and the like, which may be respectively substituted),

(3) (C2-6Alchemilla group which may be substituted (for example, etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 1-penicilina group, 1-hexylamine group and the like, which may be respectively substituted),

(4)3-8cycloalkyl group which may be substituted (for example, cyclopropylamino group, cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group and the like, which may be respectively substituted),

(5)3-8cycloalkenyl group which may be substituted (for example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and the like, which may be respectively substituted), (6) acyl group, (7) the carbs the ilen group, which may be substituted, etc. Corresponding amino group may have as substituents one or two groups selected from these groups, and more preferred examples of such amino group is unsubstituted amino group, methylaminopropyl, dimethylaminopropyl, atramentaria, diethylaminopropyl, n-propylamino, di(n-propyl)amino group, isopropylamino, di(isopropyl)amino group, etc.

"C3-7cycloalkylcarbonyl C3-7cycloalkylation, which may be substituted"represented by the above R3preferably is cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexyloxy, etc. in Addition, "3-7cycloalkylcarbonyl C3-7cycloalkylation, which may be substituted"represented by the above R3preferably is cyclobutylamine, Cyclopentasiloxane, cyclohexasiloxane etc.

Preferred examples of the "substituent" C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group3-8cycloalkenyl group, C1-6alkoxygroup, C1-6allylthiourea, C1-6alkylsulfonyl group, C1-6alkylsulfonyl group6-14aromatizes the th cyclic hydrocarbon group, 5-14-membered aromatic heterocyclic group2-6alkenylacyl,3-7cycloalkylcarbonyl,3-7cycloalkanones presented above R1, R2or R3and optionally substituted, respectively, are (1) hydroxyl group, (2) halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), (3) cyano, (4) the nitro-group, (5) C1-6alkyl group (e.g. methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group and the like), (6) With2-6Alchemilla group (for example, vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group and the like),

(7)2-6Alchemilla group (for example, etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 1-penicilina group, 1-hexylamine group and the like),

(8)3-8cycloalkyl group (for example, cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group and the like),

(9) C1-6alcox the group (for example, the methoxy group, ethoxypropan, n-propoxylate, isopropoxide etc.),

(10) C1-6allylthiourea (for example, methylthiourea, ethylthiourea etc., (11) 5-14-membered non-aromatic heterocyclic group (for example, piperideine group, piperacilline group, morpholinyl group and the like), (12)6-14aromatic heterocyclic group (for example, phenyl group, naftalina group and the like), (13) 5 to 14-membered aromatic hydrocarbon group (for example, Peregrina group, thienyl group, furilla group, thiazolidine group and the like), (14) an amino group which may be substituted (for example, amino group which may be substituted by one or two groups selected from C1-6alkyl group, a C1-6alkenylphenol group, C1-6alkenylphenol group3-8cycloalkyl group3-8cycloalkenyl group, acyl group, karbonilnoj group which may be substituted With1-6alkylsulfonyl group and the like (for example, unsubstituted amino group, methylaminopropyl, dimethylaminopropyl, atramentaria, diethylaminopropyl, n-propylamino, di(n-propyl)amino group, isopropylamino, di(isopropyl)amino group and the like), or the specified substituents, taken together, form a nitrogen-containing cyclic group which contains a nitrogen atom with which they are associated) as Deputy they may have one or more groups, selected from the above groups.

Examples of more preferred group of the above R1are a hydrogen atom or halogen atom (e.g. fluorine atom, chlorine atom, bromine atom and the like). In addition, examples of preferred groups represented by R2are a hydrogen atom, a C1-6alkyl group, halogenated C1-6alkyl group, a C1-6alkoxyl1-6alkyl group, a C3-8cycloalkyl1-6alkyl group, kalkilya group (e.g. benzyl group, penicilina group and the like), mono(C1-6alkyl)amino1-6alkyl group, and di(C1-6alkyl)aminoalkyl group, and most preferred is a hydrogen atom. In addition, examples of preferred groups represented by R3is C1-6alkoxygroup, which may be optionally substituted, and most preferred is a methoxy group.

In a preferred aspect of the present invention, in the compound represented by the above formula (I), ring a is represented by the formula

or

where R1, R2and R3have the same values that were defined in the above item 1. In particular, it is preferable number of the TSO, represented by the formula

or

Examples of "C1-6alkalinous group which may be substituted", "C1-6alkenylamine group which may be substituted" or "C2-6alkynylamino group which may be substituted"represented by W in the above formula (I)is a group which can be optionally substituted and which is represented by the formula-CH2-, -CH2-CH2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2-CH2-CH=CH, -CH2-CH=CH-CH2-,orIn addition, examples of the "substituent" C1-6alkalinous group2-6alkynylamino group and2-6alkynylamino group include hydroxyl group, halogen atom, cyano, C6-14aromatic hydrocarbon cyclic group (for example, phenyl group and the like), a 5 to 14-membered aromatic heterocyclic group (for example, perederina, thienyl, furilla group and the like) and the like, and preferred are a hydroxyl group and cyano.

Examples of preference is sustained fashion group represented by W in the above formula (I)is a group, which may be optionally substituted and which is represented by the formula: -CH2-, -CH2-CH2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2-CH2-CH=CH-, -CH2-CH=CH-CH2,oror a group represented by the formula-CH2-CO-, -CH2-CH2-CO, (CH2)3-CO-, -CH=CH-CO-, -CH=CH-CH2-CO-,-CH2-O-, -O-CH2-, -CH2-CH2-O-, (CH2)3-O-, -CH-CH-O-, -CH=CH-CH2-O,-CH2-SO2-, -CH2-CH2-SO2-, -(CH2)3-SO2-, -CH=CH-SO2-, -CH=CH-CH2-SO2-,, -CH2-NH-CO-, -CH2-CH2-NH-CO-, (CH2)3-NH-CO-, -CH=CH-NH-CO-, -CH=CH-CH2-NH-CO-,-CH2-NH-SO2-, -CH2-CH2-NH-SO2-, -(CH2)3-NH-SO2-, -CH=CH-NH-SO2-, -CH=CH-CH2-NH-SO2orand more preferred is a group represented by the formula-CH2-CH2-, -CH=CH -,- ≡C-, -CH2-O and the fact is such.

Preferred examples of "C6-14aromatic hydrocarbon cyclic group" in "C6-14aromatic hydrocarbon cyclic group which may be substituted"represented by Z in the above formula (I)is a phenyl group, naftalina group (for example, 1-naftalina group, 2-naftalina group and the like), atulananda group, heptylaniline group, etc.

Examples of preferred groups called "5 to 14-membered aromatic heterocyclic group which may be substituted"represented by Z in the above formula (I)is pyrrolidine, Peregrina group, thienyl group, pyridazine group, piramidalnaya group, perazella group, imidazolidinyl group, pyrazolidine group, indayla group, kinolinna group, chinadaily group, thiazolidine group, benzothiazoline group, etc.

If Z in the above formula (I) is "C6-14aromatic hydrocarbon cyclic group which may be substituted", or "5 to 14-membered aromatic heterocyclic group which may be substituted", the "Deputy" is one or more groups selected from (1) hydroxyl group, (2) halogen atom (e.g. fluorine atom, chlorine atom and bromine atom), (3) nitrile group, (4) hydrocarbon group which may replace the Jena one or more groups, selected from (i) halogen atom, (ii)6-14aromatic hydrocarbon cyclic group (phenyl group, naftilos group), which may be substituted by halogen atom (such as fluorine atom and chlorine atom), (iii) a 5 to 14-membered aromatic heterocyclic group (for example, peredelnoj group, thienyl group, shriley group, thiazole group, and the like), which may be substituted by halogen atom (such as fluorine atom and chlorine atom), (iv) C1-6alkylsulfonyl group, etc. such as C1-6alkyl group, a C2-6Alchemilla group2-6Alchemilla group3-8cycloalkyl group or3-8cycloalkenyl group, (5) C1-6alkoxygroup (metoxygroup, ethoxypropan, n-propoxylate, isopropoxy), which may be substituted by one or more groups selected from (i) hydroxyl group, (ii) halogen atom (e.g. fluorine atom, chlorine atom and the like), (iii) C1-6alkoxygroup, (iv) sulfonyloxy group, substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (5) amino groups, substituted hydrocarbon group, (C1-6alkyl group, a C1-6alkenylphenol group2-6alkenylphenol groups is th, With3-8cycloalkyl group or3-8cycloalkenyl group), (6) With3-7cycloalkylcarbonyl, which may be substituted by (i) hydroxyl group, (ii) a halogen atom (e.g. fluorine atom, chlorine atom and the like), (iii) C1-6alkoxygroup, (iv) sulfonyloxy group, substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (v) amino group, substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (7)6-14alloctype (for example, fenoxaprop), which may be substituted by halogen atom (e.g. fluorine atom, chlorine atom and the like), (8) heterokaryosis (for example, pyridyloxy, taylortype, ferrochrome and the like), which may be substituted by halogen atom (for example, fluorine atom, chlorine atom and the like), (9) uglevodorodnogo (for example, methylthiourea, ethylthiourea, n-PropertyGroup, isopropylthio and the like), which may be substituted by a group selected from (i) hydroxyl group, (ii) halogen atom (for example, fluorine atom, chlorine atom and the like), (iii) C1-6alkoxygroup, (iv) Sul is Honiley group, substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group) and (v) an amino group which may be substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), (10) acyl group represented by the formula-CO-N(R6R7(where R6and R7are the same or different and each represents (i) hydrogen atom or (ii) hydrocarbon group (C1-6alkyl group, a C2-6alkenylphenol group2-6alkylamino group3-8cycloalkyl group or3-8cycloalkenyl group), which may be substituted by halogen atom (e.g. fluorine atom, chlorine atom and the like), or R6and R7taken together, may form a 3-7-membered nitrogen-containing non-aromatic heterocyclic ring (for example, piperidino, pieperazinove, morpholine ring and the like), which contains one or two atoms selected from nitrogen atom, sulfur atom and oxygen atom), (11) 5-14-membered aromatic heterocyclic group (for example, phenyl group, naftilos group, peredelnoj group, thienyl g is uppy, shriley group, thiazole group, and the like), which may be substituted by a group selected from (i) hydroxyl group, (ii) halogen atom (e.g. fluorine atom, chlorine atom and the like), (iii) hydrocarbon group (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), which may be substituted by halogen atom (e.g. fluorine atom, chlorine atom and the like), (iv) C1-6alkoxygroup (metoxygroup, ethoxypropan, n-propoxylate, isopropoxy etc.) and (v) C1-6alkoxygroup (metoxygroup, ethoxypropan, n-propoxylate, isopropoxy and the like), a substituted hydrocarbon group, (C1-6alkyl group, a C1-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group), which may be substituted by halogen atom (e.g. fluorine atom, chlorine atom and the like), (12) 3-8-membered non-aromatic heterocyclic group (piperidino group, piperazine group, morpholinyl group and the like), which contains one or two atoms selected from nitrogen atom, sulfur atom and oxygen atom), (13) sulfonyloxy group, substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol what Ruppel, With3-8cycloalkyl group or3-8cycloalkenyl group), (14) sulfonamidnuyu group which may be substituted hydrocarbon group, (C1-6alkyl group, a C2-6alkenylphenol group2-6alkenylphenol group3-8cycloalkyl group or3-8cycloalkenyl group) and (15)1-4alkylenedioxy (for example, methylenedioxy, Ethylenedioxy and propyleneoxide). As example can serve as a hydroxyl group, a nitrile group, a halogen atom (fluorine atom, chlorine atom, bromine atom), a methyl group, ethyl group, n-bucilina group, triptorelin group, methoxy group, ethoxypropan, cyclopropylmethoxy, 2,2,2-triftoratsetata, 2-methoxyethoxy, 2-hydroxyethoxy, 2-(N,N-dimethylamino)ethoxypropan, fenoxaprop, phenyl group, imidazolidinyl group, pyrazolidine group, thiazolidine group, metoksifenilny group, piperideine group, piperacilline group, morpholinyl group, N-acetylpiperidine group, methylsulfonyl group, amino group, triptoreline, methylsulfonyl group, ethylsulfonyl group, alkylenedioxy, etc. In the present description, "C1-6alkyl group", "C2-6Alchemilla group", "C2-6Alchemilla group", "C3-8cycloalkene the group a" and "C 3-8cycloalkenyl group"represented as the "hydrocarbon group" have the meanings defined above, respectively.

In the group represented by formula-N(R4R5(where R4and R5have the meanings given above), denoted by Z in the above formula (I), "C1-6alkyl group" in the "C1-6alkyl group which may be substituted"represented by R4or R5preferably is a methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, n-exilda group, etc., "C2-6alkenylphenol group" in the "C2-6alkenylphenol group which may be substituted", is preferably vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 1-penttila group, 1-examilia group, etc. and "C2-6alkenylphenol group" in the "C2-6-alkenylphenol group which may be substituted", is preferably etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 1-penicilina group, 1-hexylamine group, etc. in Addition " 3-8cycloalkyl group" in the "C3-8-cycloalkyl group which may be substituted"represented by R4or R5preferably is cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, etc. and "C3-8cycloalkenyl group" in the "C3-8-cycloalkenyl group which may be substituted", is preferably cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc. in Addition, "6-14aromatic hydrocarbon cyclic group" in "C6-14aromatic hydrocarbon cyclic group which may be substituted"represented by R4or R5preferably is a phenyl group, naftalina group, etc. "5 to 14-membered aromatic heterocyclic group" in the "5 to 14-membered aromatic heterocyclic group which may be substituted", is preferably Peregrina group, perazella group, piramidalnaya group, pyridazinyl group, thienyl group, thiazolidine group, imidazolidinyl group, furilla group, etc.

If the above R4or R5are the same or different, and each represents a C1-6alkyl group which may be substituted With2-6alkenylphenol group, which can be the t to be substituted, With2-6alkylamino group which may be substituted With3-8cycloalkyl group which may be substituted or3-8cycloalkenyl group which may be substituted, preferred examples of the "substituent" are (1) hydroxyl group, (2) halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), (3) C1-6alkoxygroup, which may be substituted (for example, methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, tert-butoxypropan, etc. which may be substituted by halogen atoms, respectively), (4)6-14aromatic hydrocarbon cyclic group which may be substituted (for example, 5 to 14-membered aromatic group which may be substituted by one or more groups selected from hydroxyl group, halogen atom, hydrocarbon group which may be substituted by a halogen atom, a C1-6alkoxygroup, which may be substituted by a halogen atom, and a 5-14-membered aromatic group), (5) 5-14-membered aromatic heterocyclic group which may be substituted (for example, 5 to 14-membered aromatic group which may be substituted by any one or more groups selected from hydroxyl group, halogen atom, hydrocarbon group, which can the be replaced by halogen atom, C1-6alkoxygroup, which may be substituted by a halogen atom, and a 5-14-membered aromatic group and the like) and the like, Specific examples of such groups are one or two groups selected from an ethyl group, 2-methylpropyloxy group, isopropyl group, n-Pintilei group, n-aktiline group, tert-butilkoi group, hydroxy-tert-butilkoi group, tsiklogeksilnogo group, cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2,2,2-triptorelin group, moralisation group, hydroxyethylene group, hydroxypropyl group, 5-phenylpentane group, 2-propyne-1-ilen group, 1,2-dimethylpropylene group, 2-ethyl-n-butilkoi group, benzyl group, fenetylline group, halogenated benzyl group, hydroxybenzene group, vinylbenzyl group, methylsulfonylamino group, methylsulfonylmethyl group, pyridylmethyl group, furylmethyl group, N-methylpyrrolidine group, diphenylmethylene group, methylenedioxyphenylacetone group, methoxypolyethylene group and dimethylaminomethylene group.

If the above R4and R5are the same or different, and each of them optionally substituted C6-14aromatic hydrocarbon cyclic group, a 5-14-membered aromatic hetero Klionsky group, the preferred examples of the "substituent" are (1) a hydroxy-group, (2) halogen atom, (3) nitrile group, (4) hydrocarbon group which may be substituted by the Deputy, such as a halogen atom, a 5 to 14-membered aromatic group which may be substituted by a halogen atom, and C1-6alkylsulfonyl group, (5) C1-6alkoxygroup, which can be substituted by the Deputy, such as a hydroxyl group, a halogen atom, a C1-6alkoxygroup, sulfonylurea group, substituted, hydrocarbon group, and amino group which may be substituted hydrocarbon group, (6) With3-7cycloalkylation, which can be substituted by the Deputy, such as a hydroxyl group, a halogen atom, a C1-6alkoxygroup, sulfonylurea group, substituted hydrocarbon group, and amino group which may be substituted hydrocarbon group, (7) (C6-10aryl)oxygraph, which may be substituted by a halogen atom and the like, (8) (5-14-membered heteroaryl)oxygraph, which may be substituted by a halogen atom and the like, (9) uglevodorodnogo, which may be substituted by a group selected from hydroxyl group, halogen atom, a C1-6alkoxygroup, sulfonyloxy group, substituted hydrocarbon group, and an amino group which may be substituted hydrocarbon group, (0) acyl group, represented by the formula-CO-N(R12R13(where R12and R13are the same or different, and each represents a hydrogen atom or a hydrocarbon group which may be substituted by a halogen atom, and, in addition, in the formula-CO-N(R12R13, R12and R13taken together, may form a 3-7-membered nitrogen-containing non-aromatic heterocyclic ring containing one or two atoms selected from nitrogen atom, oxygen atom and sulfur atom), (11) 5-14-membered aromatic group which may be substituted by a group selected from hydroxyl group, halogen atom, hydrocarbon group which may be substituted by a halogen atom, and a hydrocarbon, C1-6alkoxygroup, which may be substituted by a halogen atom, (12) 3-7-membered non-aromatic heterocyclic group which contains one or two atoms selected from nitrogen atom, oxygen atom and sulfur atom), (13) sulfonylurea group, substituted hydrocarbon group, (14) sulfonamidnuyu group which may be substituted hydrocarbon group, (15) C1-2alkylenedioxy etc.

"C1-6aliphatic acyl group"represented by the above R4or R5means a carbonyl group which was substituted groups, such as C1-6alkyl group, a C2-6alkenyl the Naya group, With2-6Alchemilla group1-6alkoxyl1-6alkyl group, a C1-6alkoxygroup,6-14aryl group, a 5-14-membered aromatic heterocyclic group and the like, and preferred examples are acetyl group, acylcarnitine group, etc.

In the above formula (I) Z can mean a 3-8-membered nitrogen-containing cyclic group formed by R4and R5in the formula-N(R4R5connected together, and the preferred examples of this group are piperideine group, piperacilline group, morpholinyl group, etc.

In the above formula (I), the symbol l indicates an integer 0, 1, 2, 3, 4, 5 or 6, while preferred is an integer from 1 to 3, more preferred is an integer 1 or 2, and still more preferred is an integer of 1.

The preferred compound of formula (I) of the present invention is a compound represented by the formula

(where R1, R2, W, Z and l have the meanings defined above, respectively), its salt or hydrate, and as a particularly preferred aspect of the proposed compound represented by the formula

(where R1, W and Z have the meanings defined above, respectively), its salt or hydrate.

Ter is in the "salt" in the description of the present invention has no specific limitation, if only she can be formed by the connection of the present invention and is pharmacologically acceptable. The preferred salt is the salt halogenation acid (for example, hydroptere, hydrochloride, hydrobromide, hydroiodide, and the like), a salt of an inorganic acid (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), salts of organic acids (e.g. acetate, triptorelin, oxalate, maleate, tartrate, fumarate, citrate and the like), salt selforganizes acid (for example, methanesulfonate, triftorbyenzola, aconsultant, bansilalpet, toluensulfonate, camphorsulfonate and the like), salt, amino acids (e.g., aspartate, glutamate and the like), Quaternary ammonium salt the alkali metal salt (e.g. sodium salt, potassium salt and the like), a salt of alkaline earth metal (e.g. magnesium salt, calcium salt and the like). More preferred are the hydrochloride, oxalate, triptorelin etc.

A typical method of producing the compounds represented by the above formula (I) of the present invention, is described below.

The method of obtaining 1

In the above formula, R1, W, Z and l have the meanings given above, a L1means a leaving group (e.g. halogen atom, tosylate etc) or aldehyde group. The compound (I)-1 is altoadige of the invention can be obtained by condensation piperidino derivative (II) with pyridine derivative (III) in a solvent by the method of reductive amination or by condensation of in the presence of a base. The method of reductive amination solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1-organic, acetonitrile and the like as a reducing agent can be used metal hydrides, such as borohydride sodium, triacetoxyborohydride sodium, etc. can also be carried out catalytic reduction method that is commonly used in these cases. The amount of reducing agent is 1 to 5 equivalents relative to the original material. The reaction temperature is usually from -50°C to the boiling point of the solvent, and preferably from approximately 0°to 25°C. In the case of condensation in the presence of a base can be used all organic solvents which are inert to this reaction, and these solvents can be, for example, benzene, dichloromethane, acetonitrile, THF, dioxane, Dima is informed, dimethyl sulfoxide, 1-organic, etc. the Bases do not have specific restrictions, but preferred are sodium hydride, tert-piperonyl potassium, diisopropylamide lithium, potassium carbonate, sodium hydroxide, etc. the Amount of base is 1 to 10 equivalents relative to the original material. The reaction temperature is usually from -50°C to the boiling point of the solvent, and preferably from 20°C to 80°C.

Below describes how to obtain when in the above formula (I), W represents a hydrocarbon chain which may be substituted"

The method of obtaining 2

In the above formula, R1and l have the meanings given above, a Z1means 5-14-membered aromatic group which may be substituted, and g denotes 0, 1 and 2. Paradiseparadise derivative (I)-1-1 of the present invention can be obtained by the implementation of the Wittig reaction or a similar reaction, which is subjected to piperidinylidene derivative (IV) in an organic solvent. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF, dioxane and dimethyl ether of diethylene glycol, ethyl acetate, dimethylformamide, dimethylsulfoxide, toluene, benzene, etc. Wittig Reagent, which is commercially available buy, and a reagent that is not commercially available, can be easily obtained by a standard method. The number of Wittig reagent is 1 to 2 equivalents relative to the original material. The examples of the base are preferably sodium hydride, tert-piperonyl potassium methoxide, potassium ethoxide sodium, diisopropylamide lithium, databaseconnect, n-utility, sodium hydroxide, etc. the Amount of base is 1 to 2 equivalents relative to the original material. The reaction temperature is usually from -70°C to the boiling point of the solvent, and preferably from about -40°C to 60°C.

The method of obtaining 3

In the above formula, R1and l have the meanings defined above; Z2means 5-14-membered aromatic group which may be substituted, a L2means a leaving group (e.g. halogen atom, triplet etc). The compound (I)-1-1 of the present invention can be obtained by reaction of compound (VI) (for example, arylalkenes, aristigueta etc) with alkylpiperidines of proizvodi the m (V) in a solvent in the presence of a catalyst. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethylsulfoxide, toluene, benzene, 1-organic, etc. This reaction can be carried out in the presence of any reagent selected from tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine) palladium (II)taken in a catalytic amount of copper iodide and a tertiary amine. As the tertiary amine is preferable to use, for example, triethylamine, diisopropylethylamine, dimethylaniline, databaseconnect etc. the Amount of catalyst is about 0,001-0,1 mol.% in relation to the original material. The reaction is carried out in a stream of nitrogen, and the reaction temperature is usually from -20°C to the boiling point of the solvent, and preferably from about 80°to 140°C.

The method of obtaining 4

In the above formula, R1, l, g, and Z1have the meanings defined above, a h is any integer from to 3. The compound (I)-(1-3 of the present invention can be obtained by implementing catalytic hydrogenation paradiseparadise derivative (I)-1-1 obtained in the reaction of 2". Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethylsulfoxide, ethanol, methanol, etc. In this reaction, a good result can be achieved by adding to the reaction solution of the appropriate amount of acid. As catalyst, preferably palladium on coal (Pd-C), the Nickel catalyst of the Raney, platinum oxide (PtO2and the like, the reaction Temperature is usually from 0°to 120°and preferably about 25°C. the hydrogen Pressure during the hydrogenation is 1-140 kg/cm2and preferably 1-3 kg/cm2.

The method of obtaining 5

In the above formula, R1l and Z2have the meanings given above. The compound (I)-(1-4 of the present invention can be obtained put the m implementation catalytic hydrogenation of compound (I)-1-2, obtained in the reaction of 3". This reaction can be conducted under conditions described in reaction 4".

The method of obtaining 6

In the above formula, R1, l, g, h and Z1have the meanings given above. The compound (I)-(1-3 of the present invention can be obtained by the reaction of Wittig reagent with piperidinylidene derivative (IV) in the presence of a base and implementation catalytic reduction obtained paradiseparadise derivative (I)-1-1 without selection. The Wittig reaction can be carried out by the method described in "reaction 2", and the catalytic reduction can be carried out by the method described in "response 4".

The method of obtaining 7

In the above formula, R1, l, i, and Z1have the meanings defined above; L3means a leaving group (e.g. halogen atom, triflate and the like), a Q1and Z3mean 5-14-membered aromatic group which may be substituted. The compound (I)-(1-5 of the present invention can be obtained in the presence of a palladium catalyst of the compound (I)-1-1-i, where Z1presents Z3-L3in compound (I)-1-1 obtained in the reaction of 2". As compounds Arimathea used for this reaction are, for example, artribute is the term, kilborne acid and other commonly used compounds such as arielcoceres, arylalkylamine etc. the Amount of catalyst is about 1-5 equivalents, preferably about 2 equivalents relative to the original material. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium (II), etc. the Amount used of the catalyst is approximately 0.05 mol.% in relation to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are tetrahydrofuran (THF), dioxane, dimethyl ether of diethylene glycol, toluene, benzene, etc. If the connection Arimathea used kilborne acid, the preferred solvents are aqueous sodium carbonate, methanol and a mixture of organic solvents. The reaction temperature is usually in the range from room temperature to 150°s, and preferably from 80°to 130°C. the Compound (I)-1-5, obtained in this way can be used as a starting compound in the reaction of 4".

The way to obtain 8

In the above formula, R 1and l have the meanings defined above; j is any whole integer from 1 to 3; L4means a leaving group (e.g. halogen atom, tosylate, triflate and the like), a Q2means a substituent (for example, C1-6alkoxygroup, alkylamino etc). The compound (I)-(1-8 of the present invention can also be obtained by the subsequent interaction of the pyridine derivative (I)-1-7, which has useplease group L4in the 2-position of the aromatic groups represented by Z and Z1the compound obtained in the above reactions 1 or 4, with the nucleophile. As the nucleophile, the preferred alkoxides are obtained through the interaction of bases, such as sodium hydride, tert-piperonyl potassium, sodium metal, lithium metal and diisopropylamide sodium, with alcohols, such as methanol, ethanol and dimethylaminoethanol, and, in addition, primary and secondary amines such as piperidine and morpholine. If as a nucleophile amine is used, a good result can be achieved even if there is a base having a weak nucleophilic properties, such as potassium carbonate, diisopropylethylamine and triethylamine. The amount of the nucleophile is in the range of 1 equivalent to a large excess relative to Ref demo material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, dimethylformamide, dimethyl sulfoxide, 1-organic, etc. If as a nucleophile alkoxide is used, the solvent may be used alcohol. The reaction temperature is usually from 0°to 200°s, and preferably from 100°170°C.

The method of obtaining 9

In the above formula, R1, l and g have the meanings defined above, and Z4means 5-14-membered aromatic group which may be substituted. The compound (I)-(1-9 of the present invention can also be obtained through the interaction of Arimathea or halide Arimathea with the aldehyde derivative (IV) by 1,2-addition with formation of an intermediate compound and its oxidation. Used allmetal or halide Arimathea in the reaction of 1,2-addition can be purchased, if it is commercially available, or it can be obtained article is hartym method if it is not commercially available. The number of Arimathea or halide armetale is 1-5 equivalents relative to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, toluene, benzene and the like, the reaction Temperature is usually from -78°0°C. as the oxidant used for the oxidation reaction, preferred are, for example, the oxidant Swarna, which is corrected by a complex of sulfur trioxide-pyridine", (chlorproma acid)pyridine, manganese dioxide, di(chromic acid)pyridine, oxalicacid-sulfoxide. Used in the oxidation of the solvent has no particular restrictions, provided that it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, acetonitrile, ethyl acetate, dimethylformamide, Dima is insulted, 1-the organic and the like, the reaction Temperature is usually from 0°C to the boiling point of the solvent.

The method of obtaining 10

In the above formula, R1l and Z4have the meanings defined above, a k is any integer from 0 to 2. The compound (I)-(1-9 of the present invention can also be obtained through the interaction of Arimathea or halide armetale with amide derivative (VII). Used allmetal or halide armetale can be purchased, if it is commercially available, or it can be obtained with the standard method, if it is not commercially available. The number of Arimathea or halide armetale is about 1 to 2 equivalents relative to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, toluene, benzene and the like, the reaction Temperature is usually from -78°0°C.

The method of obtaining 11

In the above formula, R1, R4, R5and l have knowledge is to be placed, defined above, a is any integer m means an integer of 0, 1 and 2. The compound (I)-(1-10 of the present invention can be also obtained by the reaction of condensation of the carboxylic acid derivative (VIII) and an amine represented by the formula NH(R4R5in an organic solvent. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, dimethylformamide, dimethylsulfoxide, ethanol, methanol, etc. as the condensation reaction can be used in the standard reaction. So, for example, can be used DCC method, the DCC-HOBt method, DCC-HOSu method and an advanced method based on these methods (for example, WSC-HOBt method), etc. the Amount of the condensing agent is 1 to 5 equivalents relative to the original material (VIII). In addition, after receiving carbonbearing derivative of piperidine as a commonly used reactive derivative of this reaction can be carried out by means of this interaction is derived from an amine. As the reactive derivative is used, for example, acid chloride, obtained by treatment with thionyl chloride and the like, acid anhydride, introduced through the interaction of isobutylacetophenone (IBCF), 1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), atilglukuronida etc. with a carboxylic acid derivative (VIII), it is preferable reactive derivative, obtained by the transformation of the carboxylic acid (VIII) in the acid azide using diphenylphosphinite (DPPA), etc. in Addition, they can be put into active esters such as p-nitrophenyloctyl ester (ONp) and N-hydroxysuccinimide (ONSu). The compound (I)-(1-10 of the present invention can be obtained by reaction of a reactive derivative with an amine NH(R4R5in an organic solvent.

The method of obtaining 12

In the above formula, R1, W, Z and l have the meanings given above. Pyridopyrimidines derivative (I)-2, which is the compound of the present invention can be obtained by hydrolysis paradiseparadise derivative (I)-1. This reaction can be carried out by reaction of 2 equivalents or significant excess of the appropriate acid in water or in a mixed solvent of water and org the organic solvent, such as methanol, ethanol, dioxane and tetrahydrofuran. The acid is preferably used, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, triperoxonane acid and the like, and this acid can be obtained in the reaction system by adding thionyl chloride in an alcohol solvent. The reaction temperature is usually in the range from room temperature to the boiling temperature of the solvent. In addition, this reaction can be carried out by reaction of 2 equivalents or significant excess of trimethylsilane iodide or a mixture of chloride of trimethylsilyl - sodium iodide in an organic solvent, such as dichloromethane, chloroform, dichloroethane and acetonitrile. The reaction temperature is usually from -78°C to the boiling point of the solvent, preferably from -20°C to room temperature.

The method of obtaining 13

In the above formula, R1, W, Z and l have the meanings given above, a L5means a leaving group (e.g. halogen atom and the like). Pyridopyrimidines derivative (I)-2, which is the compound of the present invention can be obtained by hydrolysis of a derivative of 2-substituted pyridine derivative (X). Used solvent has no particular Ogre is the restrictions provided if it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are tert-butanol and the like, the Base used for hydrolysis, has no particular restrictions, but preferred is tert-piperonyl potassium. The reaction temperature is usually in the range from room temperature to the boiling point of the solvent, and preferably from 100°to 140°C.

The method of obtaining 14

In the above formula, R1, W, Z and l have the meanings given above. In addition, in this formula TBSO means tert-butyldimethylsilyloxy ether. The compound (I)-2 of the present invention can be obtained by condensation piperidino derivative (II) and pyridine derivative (X) in a solvent by the method of reductive amination. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, dimethylformamide, dimethylsulfoxide, etc. In ka is este reducing agent is preferably used, for example, metal hydrides such as borohydride sodium and triacetoxyborohydride sodium. In addition, can be made catalytic reduction method that is commonly used in these cases. The amount of the halide of the metal is 1-5 equivalents relative to the original material. In this reaction of tert-butyldimethylsilyloxy group is usually removed by acidification of the silica gel used in the stage of purification of the product. The reaction temperature is usually from -50°C to the boiling point of the solvent, and preferably from approximately 0°to 25°C.

The method of obtaining 15

In the above formula, R1, W, Z and l have the meanings given above, a L2means a leaving group (e.g. halogen atom, tosylate, mesilate, etc.). N-Substituted pyridopyrimidines derivative (I)-3, which is the compound of the present invention can be obtained by reaction of compounds R2L2with pyridopyrimidines derivative (I)-3, together with an appropriate base in an organic solvent. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are the camping dimethylformamide, dimethyl sulfoxide, 1-organic, ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, ethanol, methanol, etc. as a reason it is preferable to use, for example, sodium hydride, tert-piperonyl potassium methoxide, potassium diisopropylamide lithium, potassium carbonate, sodium hydroxide, etc. the Amount of base is 1 to 10 equivalents relative to the original material. The number of used connections R2L2is from 1 equivalent to much of the excess in relation to the original material. The reaction temperature is usually in the range from room temperature to the boiling temperature of the solvent.

The method of obtaining 16

In the above formula, R1, l and g have the meanings given above. Piperidinylidene derivative (IV), which is ishtim material in the above-mentioned reactions 2, 4, and 1" (I)1-9 can be obtained by oxidation of the alcohol compound (XI). Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are the two who are dimethylformamide, dimethyl sulfoxide, 1-organic, ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, acetonitrile, toluene and the like, the Preferred methods of oxidation used for the oxidation reaction, are, for example, a method using (chlorproma acid)pyridinium, manganese dioxide and di(chlorproma acid)pyridinium as oxidant, such methods of oxidation, as oxidation Swarna, oxidation, Jones oxidation, Corey-Kim (Corey-Khim) and the like, the reaction Temperature is usually from -50°C to the boiling point of the solvent.

The method of obtaining 17

In the above formula, R1, l and g have the meanings defined above, a L7means a leaving group (e.g. halogen atom, tosylate etc) or aldehyde group. Paradiseparadise derivative (XI), which is a starting material for the above-mentioned "reaction 17", can be obtained by condensation piperidino derivative (XIII) and pyridine derivative (XII) or by reductive amination or by condensation in the presence of a base. This reaction can be carried out under the conditions described in the above-the-Uta "reaction 1". Commercially available product pyridine derivative (XII) can be purchased, and the product that is not commercially available, can be easily obtained by a standard method.

The method of obtaining 18

In the above formula, R1and l have the meanings defined above, and each of Hal1and Hal2which may be identical or different, denote a halogen atom. Alkylpiperidines derivative (V), which is a starting material for the above-mentioned "reaction 3 can be obtained by performing the reaction dehalogenase olefin derivative (XIV). Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, toluene, etc. as a reason it is preferable to use, for example, n-utility, second-utility, tert-utility etc. the Amount of base is 1 to 10 equivalents relative to the original material. The reaction temperature is usually from -100°-50°C.

The method of obtaining 19

In the above formula, R1/sup> , l, Hal1and Hal2have the meanings given above. Olefin derivative (XVI), which is a starting material for the above-mentioned "reaction 19", can be obtained through the interaction piperidinylidene derivative (IV)-1 and tetrachlorophenol in the presence of triphenylphosphine. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are 1-organic, ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, acetonitrile, toluene, etc. as a reason it is preferable to use, for example, tertiary amines such as triethylamine and diisopropylethylamine. The amount of base ranges from 2 equivalents to a large excess relative to the original material. The reaction temperature is usually from -50°C to 80°and preferably approximately 0°C.

The method of obtaining 20

In the above formula, R1and l have the meanings defined above; L8means a leaving group (e.g. halogen atom, tosylate, trifl the t and the like); Q3means a substituent (for example, C1-6alkoxygroup, alkylamino and the like), and n means an integer from 1 to 3. In pyridopyrimidines derivative (I)-2 obtained in each of the above-mentioned "reaction 13, 14 and 15, the compound (I)-2-1, in which Z represents pyridyloxy group having a leaving group in the 2-position can be converted into compound (I)-2-2 of the present invention through the reaction of interaction with the corresponding with the nucleophile. This reaction can be carried out in conditions similar to the above-mentioned conditions of the reaction 9".

The method of obtaining 21

In the above formula, R1, l, W and L5have the meanings defined above, and L7means a leaving group (e.g. halogen atom, tosylate etc) or aldehyde group. Paradiseparadise derivative (XI), which is a starting material for the above-mentioned "reaction 13", can be obtained by condensation piperidino derivative (II) and pyridine derivative (XV) in a solvent, carried out by reductive amination or by condensation in the presence of a base. This reaction can be carried out in conditions similar to the conditions in the above-mentioned "reaction 1". Commercially available pyridine derivative (XV) mo is et to be purchased, and derivatives that are not commercially available, can be easily obtained from the known starting material standard method.

The method of obtaining 22

In the above formula, W and Z have the meanings defined above, and Q4means a group that is typically used to protect the amino group. Piperidino derivative (II) can be obtained by removing the protection from piperidino derivative (XVI), which has a protective group. Removing the protection can be carried out in conditions which are usually used to remove the protection. For example, if Q4is benzyloxycarbonyloxy group, it may be carried out by the method of catalytic reduction using palladium-on-coal as a catalyst in an organic solvent, and if Q4represents tert-butyloxycarbonyl group, it may be carried out through the interaction of the appropriate acid, such as hydrochloric acid, sulfuric acid and triperoxonane acid, in an organic solvent or a mixture of water and an organic solvent. Moreover, if Q4represents a benzyl group, then removing the protection can be accomplished through consistent communication 1-chloroethylphosphonic and methanol in organic the immediate vicinity of the solvent (for example, in halogenated solvents such as dichloromethane).

The method of obtaining 23

In the above formula, Z and Q4have the meanings defined above, and p is either 0 or 1. Piperidinylidene derivative (XVIII), which is a starting compound in the above-mentioned "reaction 22", can be obtained by catalytic reduction of olefinic derivative obtained through a reaction of the Wittig reagent with piperidinylidene derivative (XVII) in the presence of a base. This Wittig reaction can be carried out under the conditions described in the above-mentioned "reaction 2". Commercially available Wittig reagent can be purchased, and a reagent that is not commercially available, can be easily obtained by a standard method. Catalytic hydrogenation in the reaction can be carried out under the conditions described in the above "response 4".

The method of obtaining 24

In the above formula, R4, R5and Q4have the meanings defined above, and q is any integer integer 1 or 2. Amide derivative (XX), which is the starting compound for obtaining the compounds of the present invention can be obtained by standard implementation the condensation reaction of proizvodi the th carboxylic acid (XXI) and Amin, represented by the formula NH(R4R5in organic solvents. This reaction can be carried out under the conditions described in the above-mentioned "reaction 11".

The method of obtaining 25

In the above formula, Q4and q have the meanings defined above. Carboxylic acid derivative (XIX), used as starting compound in the above-mentioned "reaction 24", can be obtained by protecting group of the nitrogen atom piperidino derivative (XXI) of the corresponding group. This reaction can be carried out in appropriate conditions, usually used to protect the amino group. For example, if Q4represents tert-butoxycarbonyl group (Boc), the preferred reagent for attaching Boc is di-tert-BUTYLCARBAMATE. The amount of reagent used is 1-5 equivalents relative to the original connection. Response join Signal can be carried out in a mixed solvent consisting of water and organic solvents, such as tert-butanol, in the presence of a base, and the reaction temperature is usually from 0°C to 80°s, and preferably from 0°to 25°C.

The method of obtaining 26

In the above formula, R1, l, g, h and Z4have the meanings defined above, and Z4means 5-14-membered aromatic group which may be substituted. The compound (XXII) of the present invention can be obtained by 1,2-addition of Arimathea to the aldehyde derivative (IV) with the formation of the alcohol intermediate compound and its dehydration. Commercially available allmetal used for 1,2-addition can be purchased, and allmetal that are not commercially available, can be obtained by a standard method. The number of Arimathea is 1-5 equivalents relative to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane, ether and dimethyl ether of diethylene glycol, and, in addition, toluene, benzene and the like, the reaction Temperature is usually from -78°0°C. as the dehydrating agent used for the reaction of dehydration, preferred are acids such as p-toluensulfonate acid, camphorsulfonic acid, methanesulfonate acid, triperoxonane acid, phosphoric acid, polyphosphoric acid, hydrochloric acid, Hydrobromic acid, AZ the percentage acid and sulfuric acid, and the acid chlorides, such as phosphorus oxychloride and thionyl chloride. If the dehydrating agent is used, the acid chloride, a good result can be achieved if in the reaction system are bases, such as pyridine, triethylamine and diisopropylethylamine. This reaction can be carried out in an appropriate solvent or without solvent. Used in the oxidation of the solvent has no particular restrictions, provided that it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, toluene, benzene and the like, the reaction Temperature is usually from -20°C to the boiling point of the solvent, and preferably from 0°to 120°C.

The method of obtaining 27

In the above formula, R1, R2, W, Z and l have the meanings given above. The compound (1)-2 of the present invention can be obtained by condensation piperidino derivative (II) and pyridine derivative (YYYY) in the solvent by reductive amination. Solvent used has no particular limitation, provided it is not inhibited this reacts the Yu and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane and dimethyl ether of diethylene glycol, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and, in addition, ethyl acetate, dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1-organic, acetonitrile and the like as a reducing agent can be used, for example, metal hydrides such as borohydride sodium and triacetoxyborohydride sodium. In addition, can be made catalytic reduction method that is commonly used in these cases. The amount of reducing agent is 1 to 5 equivalents relative to the original material. The reaction temperature is usually from -50°C to the boiling point of the solvent, and preferably from approximately 0°to 25°C.

The method of obtaining 28

In the above formula, R1and l have the meanings defined above; X is a leaving group (e.g. halogen atom, triflate and the like), and R1and L mean the connection of Arimathea or connection alkalimetal. Examples of compounds of Arimathea or compounds of alkalimetal used in this reaction are, for example, commonly used kilborne acid, arilcarboksilova, alkylborane acid, alkylthio illovo, derivatives of alkoxysilane, derivatives of alkylborane etc. the Number of used connections armetale or connection alkalimetal is generally 1-5 equivalents, preferably about 2 equivalents relative to the original material. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium (II), etc. the Amount used of the catalyst is approximately 0.05 mol.% in the calculation of the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are tetrahydrofuran (THF), dioxane, dimethyl ether of diethylene glycol, toluene, benzene, dimethylformamide (DMF), 1-organic, etc. If the connection armetale or alkalimetal used kilborne acid or alkylborane acid, preferably present base such as potassium carbonate, cesium carbonate and sodium carbonate or aqueous solutions. The reaction temperature is usually in the range from room temperature to the boiling point of the solvent, and preferably from 80°to 130°C.

The method of obtaining 29

In the above formula, R1 and l have the meanings defined above, and X denotes a leaving group (e.g. halogen atom, triplet etc). The compound (XXVI) can be obtained from the aldehyde derivative (XXV) under the conditions normally used for acetalization. For example, it can be obtained through the interaction of triethylorthoformate, dimethoxypropane, etc. in an organic solvent in the presence of a catalyst (e.g. p-toluensulfonate acid) or montmorillonite K-10.

The method of obtaining 30

In the above formula, R1and l have the meanings given above and X denotes a leaving group (e.g. halogen atom, triplet etc). The compound (XXVII) can be obtained through the interaction of cyanide compounds with acetaline derivative (XXVI) in the presence of copper iodide and a catalyst, followed by hydrolysis of the specified acetal. Used cyanide compound is, for example, sodium cyanide, potassium cyanide, hydrogen cyanide zinc, etc. the Number of cyanide compounds is generally 1-5 equivalents, preferably about 2 equivalents relative to the original material. As the catalyst used, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium (II), etc. the Amount of catalyst is about 0,001-0,1 mol.%in relation to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are tetrahydrofuran (THF), dioxane, dimethyl ether of diethylene glycol, toluene, benzene, dimethylformamide (DMF), 1-organic, acetonitrile, propionitrile and the like, the reaction Temperature is usually in the range from room temperature to the boiling point of the solvent, and preferably from 80°to 140°C.

The hydrolysis reaction can be carried out under the conditions normally used for hydrolysis. For example, it can be done by interacting the appropriate acid, such as hydrochloric acid, sulfuric acid, acetic acid and triperoxonane acid, in an organic solvent or in a mixed solvent consisting of water and an organic solvent.

The method of obtaining 31

In the above formula l have the values defined above. The compound (XXIX) of the present invention may be obtained through the interaction acatalog derivative (XXVIII) with an ORGANOMETALLIC reagent to metallation of this derivative and its interaction with the fluorinating agent, followed by hydrolysis of the specified acetal. Reacts what I metallation can be carried out under conditions usually used for metallation. As the ORGANOMETALLIC reagent for metallation used, for example, n-utility, second-utility, tert-utility, peneliti etc. as the fluorinating agent is used, for example, N-foremily, such as N-forbindelseshastighed or N-ftorpirimidinu derivatives, such as N-fluoro-4-methylpyridine-2-sulfonate. The amount of fluorinating agent is usually 1-2 equivalents, relative to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as tetrahydrofuran (THF), dioxane, ether and dimethyl ether of diethylene glycol. The reaction temperature is usually from -78°0°and preferably from -78°-40°C.

The hydrolysis reaction can be carried out under the conditions normally used for hydrolysis. For example, it may be carried out by reaction with an appropriate acid, such as hydrochloric acid, sulfuric acid, acetic acid and triperoxonane acid, in an organic solvent or in a mixed solvent consisting of water and an organic solvent.

The method of obtaining 32/p>

In the above formula l has the meanings given above, a R means aracelio group. Compound (XXX) of the present invention may be obtained through the interaction acatalog derivative (XXVIII) with an ORGANOMETALLIC reagent to metallation, the interaction of the compounds with organic sulfur compound, oxidation arkitip with subsequent hydrolysis of the acetal. The metallation reaction can be carried out in conditions that are typically used for metallation. As the ORGANOMETALLIC reagent used for the metallation can be proposed, for example, n-utility, second-utility, tert-utility, finality, etc. as organic sulfur reagent used for alkylsilane can be proposed, for example, disulfides such as dimethyl disulfide and diphenyldisulfide, sulphonylchloride, such as phenylsulfinyl etc. the Amount of organic sulfur compounds is usually 1-2 equivalents, relative to the original material. Solvent used has no particular limitation, provided it does not inhibit the reaction and dissolves the starting material to some extent. For example, preferred are ethers, such as t trihydrogen (THF), dioxane, ether and dimethyl ether of diethylene glycol and the like, the reaction Temperature is usually from -78°0°and preferably from -78°-40°C.

The oxidation reaction of arkitip in Arakishvili group can be carried out in commonly used oxidizing conditions. For example, it can be done through the interaction of inorganic peroxide such as hydrogen peroxide or an organic peroxide such as m-chloroperbenzoic acid in a halogenated hydrocarbon solvent such as dichloromethane. Preferably, this reaction was attended by bases, such as sodium bicarbonate, sodium carbonate and potassium carbonate.

Subsequent hydrolysis reaction can be carried out under the conditions normally used for hydrolysis. For example, it can be done by interacting the appropriate acid, such as hydrochloric acid, sulfuric acid, acetic acid and triperoxonane acid, in an organic solvent or in a mixed solvent consisting of water and an organic solvent.

The method of obtaining the compound (I) of the present invention has been described above, however, the source connection is used to obtain the compounds of the present invention may form a salt, hydrate, which does not have the t specific restrictions except in those cases when they inhibited the reaction. In addition, if the compound (I) of the present invention obtained as a free form, the above compound (I) can be converted into the salt form. In addition, various kinds of isomers that may be present in the compound (I) of the present invention (for example, geometric isomers, optical isomers based on asymmetric carbon atom, stereoisomer, tautomer and the like) can be cleared and the selected standard partitioning methods (for example, by recrystallization, method of obtaining diastereomeric salt by the method of enzymatic fractionation, various kinds of chromatography).

The connection represented by the above formula (I), its salt or hydrate can be used for the manufacture of preparations for the standard method, and preferred examples of such medicines are pills, powders, fine granules, Urania granules, coated tablets, capsules, syrups, lozenges, aerosols, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices, lotions, etc. To obtain drugs commonly used excipients, binders, disintegrators, sizing, coloring and flavoring agents, and if necessary it can be used stabilizers, emulsifiers, absorption accelerators,surfactants, pH regulators, antiseptics, antioxidants and other Ingredients that are commonly used as raw materials for pharmaceutical preparations can be prepared by a standard method. As such ingredients can be, for example, oils of animal and vegetable origin, such as soybean oil, glycerides of animal fat and synthetic glycerides; hydrocarbons such as liquid paraffin oil, squalane and solid paraffin; essential oils, such as octyldodecanol and isopropylmyristate; higher alcohols, such as cetosteatil alcohol and beganby alcohol; silicone resins; silicone oils; surfactants such as esters of polyoxyethylene and fatty acids, ester sorbitan and fatty acids, esters of glycerin and fatty acids, esters of polyoxyethylenesorbitan and fatty acids, utverjdenie a polyoxyethylene castor oil and a block copolymer of polyoxyethylene-polyoxypropylene; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; a lower alcohol, such as ethanol and isopropanol; polyvalent alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and dextrose; inorganic powders, that is their as silicic acid anhydride, silicate of aluminum-magnesium and aluminum silicate; purified water, etc. In particular, as fillers are used, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like; as binders are used, for example, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragacanth gum, gelatin, shellac, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, block-copolymer polypropylenglycol-polyoxyethylene, meglumine, calcium citrate, dextrin, pectin and the like; as disintegrators are used for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium carboxymethylcellulose and the like; as oil is used, for example, magnesium stearate, talc, polyethylene glycol, silicon dioxide, utverjdenie vegetable oil and the like; as dyes used any dyes that are allowed to be added to pharmaceutical preparations; perfumes are used cocoa powder, menthol, powder flavor, peppermint oil, borneol and powdered cinnamon, etc. and as oxidants, which permitted to add to farmacevticheskie drugs used, for example, ascorbic acid and α-tocopherol, respectively.

So, for example, (1) oral drugs are made in the form of powders, fine granules, large granules, tablets, coated tablets, capsules, etc. in accordance with standard method after adding fillers and, in addition, if necessary, a binder, disintegrant, oiling agents, dyes, perfumes and the like to the compound of the present invention, its salt or hydrate. (2) In the case of manufacturing tablets and granules may be coated in a sugar coating and a gelatin coating, if necessary, other suitable coating. (3) In the case of the manufacture of syrups, injectables, eye drops, etc. add regulators, pH, additives that improve the allocation; the agents, giving isotonicity, etc. and, if necessary, solubilizer, stabilizer, buffers, suspendresume agents, antioxidants, etc. and is made of a composition in accordance with the standard method. In the manufacture of these drugs can also be obtained liofilizovannye product, and preparations for injection can be administered intravenously, subcutaneously or intramuscularly. Preferred examples of the suspending agent include methylcellulose, Polysorbate 80, hydroxyethylcellulose, Arabian gum, powder traakan the OIC gum, sodium carboxymethylcellulose, polyoxyethylenesorbitan and the like; preferable examples of solubilization are utverjdenie a polyoxyethylene castor oil, Polysorbate 80, nicotinamide, polyoxyethylenesorbitan and the like; preferable examples of the stabilizer include sodium sulfide, metasulfite sodium, ether and the like; preferable examples of preservatives are methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol etc. (4) in Addition, in the case of the manufacture of preparations for external use of the retrieval method has no specific limitation, and such a drug can be obtained by a standard method. As the source material for the base of this drug can be used in a variety of source materials that are typically used for pharmaceuticals, quatercentennial tools, cosmetics, etc. So, for example, can be used such source materials, such as oils of animal and vegetable origin, mineral oil, essential oil, waxes, higher alcohols, fatty acids, silicone oil, a surfactant, phosphatides, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, purified water, etc. If you want, you can of batobalani a pH regulator, antioxidant, chelate forming agent, an antiseptic and fungicide, a dye, perfumes, etc. in Addition, if necessary, the composition can be introduced ingredients that have a differential modifying effect, the accelerator of blood flow, antibacterial agents, anti-inflammatory, cell activators, vitamins, amino acids, humidifier, drug against keratolysis etc. Dose of the pharmaceutical agents of the present invention to some extent varies depending on the symptom, age, sex, body mass, forms of administration, the type of the salts, susceptibility to medicinal drug, the specific effect of the drug, however, an adult individual basically, a dose comprising about 30 μg to 1000 mg per day for oral administration, preferably 100 μg to 500 mg, and more preferably 100 μg to 100 mg, from one to several times a day. For administration in the form of injection of this dose is approximately 3000 μg/kg, and preferably 3-1000 mg/kg, once or several times a day.

The connection represented by the above formula (I)or its salt, or hydrate has action, aimed at the inhibition of Na+channels, and can be used as an inhibitor of Na+-channels. In accordance with this connection, presents the second of the above formula (I), or its salt, or a hydrate or pharmaceutical composition containing this compound, can provide excellent therapeutic or prophylactic effect on the disease, treatment and prevention which is aimed at the inhibition of Na+channels, and are effective as a means for treating or preventing, for example, arrhythmia (and, in addition, to relieve stress in a patient caused by the disease such as atrial fibrillation, such as palpitations, discomfort in the chest, heart failure, blood clots in the left atrium, pulmonary embolism, stroke), neuralgia of various types (for example, diabetic neuralgia, HIV-associated neuralgia, herpetic neuralgia, trigeminal neuralgia, pain in the amputated extremities, pain associated with damage to bone marrow, thalamic pain, the after-shocks of pain and etc) and as analgesics.

Examples

Below are examples of the best choices compounds of the present invention (in addition, its pharmacologically acceptable salt or hydrate containing pharmaceutical preparations), however, in any case, the following comparative examples, examples and sample tests are illustrative, and compounds of the present invention is not limited to the shown and examples. Each specialist can be made different modifications not only in the examples below, but also in the scope of the claims of this application is limited. In addition, such options are included in the scope of the claims presented in this application.

Comparative example 1

1-[(2-Methoxy-3-pyridyl)methyl]-4-piperidinemethanol

10 g of 4-piperidinemethanol, 13 g of 3-(chloromethyl)-2-methoxypyridine and 24 g of potassium carbonate are suspended in 80 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 12 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, and then this layer is dried over anhydrous magnesium sulfate. The solvent is evaporated, resulting in a gain of 16.1 g specified in the title compound as light brown oil.

1H-NMR (400 MHz, CDCl3) δ 1,26-to 1.38 (2H, m), of 1.52 (1H, m), by 1.68 to 1.76 (2H, m), 2,01-of 2.09 (2H, m), 2,90-2,96 (2H, m), 3,49 (2H, s), 3,50 (2H, d, J=7.5 Hz), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), the 7.65 (1H, DD, J=7,2, 1,9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Comparative example 2

1-[(2-Methoxy-3-pyridyl)methyl]-4-piperidinecarboxylic

16,1 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinemethanol and 38 ml of triethylamine are suspended in 60 ml of dimethylsulfoxide, and then added dropwise a mixed solution of 21.7 g of the complex of the sulfur trioxide - pyridine and 100 ml of dimethylsulfoxide and the mixture was stirred at room temperature for one hour. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate) to obtain 10,9 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.66 to 1.76 (2H, m), 1,87-of 1.94 (2H, m), 2,15-of 2.30 (3H, m), 2,82-is 2.88 (2H, m), 3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7,63 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5.0 and 2.0 Hz), to 9.66 (1H, d, J=1.1 Hz).

Comparative example 3

1-Benzyl-4-(2,3-methylenedioxyphenethyl)piperidine

of 20.3 g of 4-(1-benzyl)piperidinecarboxylate and 48.0 g of the bromide (2,3-methylenedioxybenzyl)triphenylphosphine and 12.0 g of tert-butoxide potassium suspended in 200 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:4). Received the product and 2.03 g of 10% is poroshkoobraznogo palladium on coal (product, containing water) are suspended in 200 ml of ethanol. After replacing the atmosphere in the vessel to the hydrogen, the mixture is stirred at room temperature in a normal atmosphere for two hours. The reaction solution is filtered and the filtrate is evaporated to obtain a 20.3 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.36 (3H, m), 1,52-to 1.59 (2H, m), 1,68 is 1.75 (2H, m), 1,88 is 1.96 (2H, m), 2,84-only 2.91 (2H, m), of 3.48 (2H, s), 5,91 (2H, s), 6,63-6,69 (2H, m), 6,74 (1H, DD, J=7,8, and 7.8 Hz), 7,24 (1H, m), 7,29-7,33 (4H, m).

Comparative example 4

4-(2,3-Methylenedioxyphenethyl)piperidine

of 20.3 g of 1-benzyl-4-(2,3-methylenedioxyphenethyl)of piperidine are dissolved in 100 ml of 1,2-dichloroethane, and then while cooling with ice, add 7 ml of 1-chloroethylphosphonic and the mixture is refluxed for 30 minutes. The solvent is evaporated, the obtained residue is dissolved in 100 ml of methanol and the mixture refluxed for one hour. The solvent is removed and the resulting residue is alkalinized by adding 5 N. aqueous sodium hydroxide solution, and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on NH form silica gel (ethyl acetate), resulting in a gain of 13.1 g indicated in the title the connection information in the form of a light yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,08 is 1.20 (2H, m)of 1.39 (1H, m), 1,52-to 1.59 (2H, m), 1.70 to of 1.78 (2H, m), 2,53-2,62 (4H, m), 3,03-3,10 (2H, m), to 5.93 (2H, s), 6,64-6,70 (2H, m), 6,76 (1H, DD, J=7,8, 7,8 Hz).

Comparative example 5

3-Methylthio-2-thiophenecarboxaldehyde

4.44 g of 3-bromo-2-thiophenecarboxaldehyde and 1.63 g of timelocked sodium dissolved in 20 ml of N,N-dimethylformamide and the mixture is stirred under ice cooling for 3 hours. To the reaction solution was added ethyl acetate. The mixture is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:9), resulting in a gain on 3.36 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ at 2.59 (3H, s), 7,10 (1H, d, J=5,1 Hz), 7,73 (1H, DD, J=5,1, 0.9 Hz), and 10.0 (1H, d, J=0.9 Hz).

Comparative example 6

3-Methylthio-2-thiophenemethyl

3,36 g of 3-methylthio-2-thiophenecarboxaldehyde and 802 mg of sodium borohydride are suspended in 20 ml of methanol and the mixture is stirred at room temperature for one hour. The solvent is evaporated, to the residue water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, and then the layer is dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting product is distilled, colonos the second chromatography on silica gel (ethyl acetate:hexane=1:5) to obtain 3,16 g specified in the title compounds as colorless oils.

1H-NMR(400 MHz, CDCl3) δ 2,05 (1H, t, J=4,8 Hz), 2, 42 (3H, s), to 4.87 (1H, d, J=4,8 Hz), 7,03 (1H, d, J=5.3 Hz), 7, 27 (1H, d, J=5, 3 Hz).

Comparative example 7

Chloride [(3-methylthio-2-thienyl)methyl]triphenylphosphane

of 6.26 g of 3-methylthio-2-thiophenemethyl dissolved in 40 ml of dichloromethane, are added dropwise to 2.85 ml of thionyl chloride under ice cooling and the mixture is stirred for 30 minutes under ice cooling. The reaction solution was washed with aqueous saturated solution of NaHCO3and then dried over anhydrous magnesium sulfate.

The solvent is evaporated and the crude product and 15.4 g of triphenylphosphine are dissolved in 120 ml of toluene, and the mixture is then refluxed for 20 hours. The resulting crystals are collected by filtration, washed with ethyl acetate and air-dried to obtain 14.3 g specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 2,07 (3H, s), to 5.85 (2H, d, J=13,2 Hz), 6,92 (1H, d, J=5.3 Hz), 7,24 (1H, DD, J=5,3, 2.4 Hz), 7,63-7,70 (6N, m), 7,72-7,83 (N, m).

Comparative example 8

1-tert-Butoxycarbonyl-4-[2-(3-methylsulphonyl-2-thienyl)ethyl]piperidine

14.4 g of the chloride [(3-methylthio-2-thienyl)methyl]triphenylphosphine and 3.67 g of tert-butoxide potassium dissolved in 120 ml of N,N-dimethylformamide. While cooling with ice add the mixed solution 6,97 g of 1-tert-butoxycarbonyl-4-piperidinecarboxylate and 30 ml of N,N-d is methylformamide and the resulting mixture was stirred at room temperature for one hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:10). The obtained product is dissolved in 40 ml of chloroform, then with cooling with ice add 3,59 g of 3-chloroperbenzoic acid and the mixture is stirred at room temperature for one hour. To the reaction mixture is added aqueous saturated sodium thiosulfate solution to separate the organic layer. The organic layer was washed with 1 N. aqueous sodium hydroxide solution and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:3). The resulting product, and 3.0 g of 10% palladium on powdered coal (product containing water) are suspended in 150 ml of ethanol. After replacing the atmosphere of the container with hydrogen, the mixture is stirred at room temperature and under normal pressure for 4 hours. The reaction solution is filtered and then the solvent of the filtrate is evaporated to obtain 11.1 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,10-1,22 (2H, m), 1,46 (N, C), 1,58-of 1.64 (2H, m), of 1.66-1.77 in (3H, m), 2,63 is 2.75 (2H, m), 3,06 (3H, s), 3,18-3,24 (2H, m), 4,10 (2H, Sirs), 7,19 (1H, DD, J=5,5, 0,4 Hz), 7,31 (1H, d, J=5,5 Hz).

Comparative example 9

Hydrochloride 4-[2-(3-methylsulphonyl-2-thienyl)ethyl]piperidine

11.1 g of 1-tert-butoxycarbonyl-4-[2-(3-methylsulphonyl-2-thienyl)ethyl]piperidine are dissolved in 100 ml of ethyl acetate, was added 100 ml of an ethyl acetate solution of 4 G. hydrochloric acid and the mixture is stirred at room temperature for 2 hours. The resulting crystals are collected by filtration, washed with ethyl acetate, air-dried and receive a 7.92 g specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-of 1.42 (2H, m), 1,48-of 1.65 (3H, m), 1,82-of 1.88 (2H, m), was 2.76-is 2.88 (2H, m), 3,12-3,18 (2H, m), 3,20 (3H, s), 3,20 of 3.28 (2H, m), 7,31 (1H, d, J=5.5 Hz), EUR 7.57 (1H, d, J=5,5 Hz).

Comparative example 10

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2,2-dibromovinyl)piperidine

3.0 g of acetaldehyde 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidine, to 5.4 ml of triethylamine, 20,1 g of triphenylphosphine and 12.9 g of tetrabromomethane are dissolved in 77 ml of dichloroethane at 0°and the mixture is stirred for one hour. To the reaction solution was added dichloromethane and the mixture is washed with saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on NH-form specification of the gel (hexane:ethyl acetate=20:1), resulting in a gain of 2.9 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,44 is 1.60 (2H, m), 1,67-of 1.78 (2H, m), 2,07-of 2.20 (2H, m), 2,31 (1H, m), 2,84-to 2.94 (2H, m), 3,52 (2H, s), of 3.95 (3H, s), 6,27 (1H, d, J=9.1 Hz), to 6.88 (1H, DD, J=7,0, 5.0 Hz), the 7.65 (1H, DD, J=7,0, 1.5 Hz), 8,07 (1H, DD, J=5.0 and 1.5 Hz).

Comparative example 11

1-[(2-Methoxy-3-pyridyl)methyl]-4-(1-ethinyl)piperidine

2.9 g of 1-[(2-methoxy-Z-pyridyl)methyl]-4-(2,2-dibromovinyl)of piperidine are dissolved in 25 ml of tetrahydrofuran and added dropwise to 12.3 ml of a 1.50 M solution of n-utility in hexane at -78°C. After completion of adding dropwise, the mixture was stirred at -78°C for one hour. To the reaction solution was added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and get listed in the title compound as a yellow oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ of 1.66-1.77 in (2H, m), 1,83-of 1.92 (2H, m)2,07 (1H, d, J=4.0 Hz), 2,17-to 2.29 (2H, m), is 2.41 (1H, m), 2,71 is 2.80 (2H, m), of 3.48 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,4, 5.0 Hz), to 7.64 (1H, DD, J=7,4, 1.8 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Comparative example 12

1-[(Ethoxyethoxy)methyl]-3,4-methylenedioxybenzene

4,56 g piperonyl alcohol and 1.20 g of 60% sodium hydride are suspended in 30 ml of N,N-dimethylformamide. the donkey stirring for 30 minutes under cooling with ice add 2,28 ml chloromethylation ether and the mixture is stirred at room temperature for one hour. To the reaction solution was added ethyl acetate. The mixture is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:20), resulting in a gain to 4.98 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ to 1.24 (3H, t, J=7,1 Hz)to 3.64 (2H, q, J=7,1 Hz), 4,50 (2H, s), to 4.73 (2H, s), 5,95 (2H, s), is 6.78 (1H, d, J=7.9 Hz), for 6.81 (1H, DD, J=7,9, and 1.6 Hz), 6,86 (1H, DD, J=1.6 Hz).

Comparative example 13

1-[(Ethoxyethoxy)methyl]-2-(methylthio)-3,4-methylenedioxybenzene

of 1.05 g of 1-[(ethoxyethoxy)methyl]-3,4-methylenedioxybenzene dissolved in 10 ml of diethyl ether, add 2 ml of 2.52 M solution of n-utility in hexane at 0°and the mixture is stirred for 2 hours and then added dropwise 471 mg metilsulfate at -70°C. After completion of adding dropwise, the mixture is stirred at room temperature for 12 hours. To the reaction solution was added 1 N. aqueous sodium hydroxide solution and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:20) to obtain 561 mg specified in the header is VCE connection in the form of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ 1,25 (3H, t, J=7,1 Hz), 2,44 (3H, s), 3,66 (2H, q, J=7,1 Hz), and 4.68 (2H, s), was 4.76 (2H, s), 6,03 (2H, s), of 6.73 (1H, d, J=7.9 Hz), 6,92 (1H, d, J=7.9 Hz).

Comparative example 14

1-[(Ethoxyethoxy)methyl]-2-(methylsulphonyl)-3,4-methylenedioxybenzene

1.73 g of 1-[(ethoxyethoxy)methyl]-2-(methylthio)-3,4-methylenedioxybenzene dissolved in 70 ml of chloroform. Then, while cooling with ice add 3.33 g of 3-chloroperbenzoic acid and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated and the residue purified column chromatography on NH form silica gel (ethyl acetate:hexane=1:3), resulting in a gain of 1.87 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,25 (3H, t, J=7,1 Hz), 3,24 (3H, s)to 3.64 (2H, q, J=7,1 Hz), of 4.77 (2H, s), 4,94 (2H, s), x 6.15 (2H, s), 6,97 (1H, d, J=8.1 Hz), 7,05 (1H, d, J=8,1 Hz).

Comparative example 15

[2-(Methylsulphonyl)-3,4-methylenedioxyphenyl]methanol

571 mg of 1-[(ethoxyethoxy)methyl]-2-(methylsulphonyl)-3,4-methylenedioxybenzene dissolved in 2 ml of dichloromethane, add 2 ml triperoxonane acid and the mixture is stirred at room temperature for 30 minutes. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate:hexane=1:2), resulting in a gain of 308 mg specified in the title compounds as colorless oils.

H-NMR (400 MHz, CDCl3) δ or 3.28 (3H, s), 4,82 (2H, s), 6,18 (2H, s)6,94 (1H, d, J=7.9 Hz), 6,98 (1H, d, J=7.9 Hz).

Comparative example 16

[1-(methyl bromide)-2-(methylsulphonyl)]-3,4-methylenedioxybenzene

907 mg of [2-(methylsulphonyl)-3,4-methylenedioxyphenyl]methanol, 1,31 g of tetrabromomethane and 1.03 g of triphenylphosphine dissolved in 5 ml dichloromethane and the resulting mixture was stirred at room temperature for 30 minutes. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate:hexane=1:3), resulting in a gain of 1.10 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ and 3.31 (3H, s), 5,04 (2H, s), to 6.19 (2H, s), of 6.96 (1H, d, J=8.1 Hz), of 6.99 (1H, d, J=8,1 Hz).

Comparative example 17

Bromide [2-(methylsulphonyl)-3,4-methylenedioxybenzyl]triphosgene

1.10 g of 1-(methyl bromide)-2-(methylsulphonyl)-3,4-methylenedioxybenzene and 1.48 g of triphenylphosphine dissolved in 20 ml of toluene and the mixture is refluxed for 12 hours. The resulting crystals are collected by filtration, washed with ether and air-dried, resulting in a gain 1,90 g specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ to 3.02 (3H, s), 5,90 (2H, d, J=14,5 Hz), x 6.15 (2H, s), of 6.96 (1H, DD, J=8,1, 0.9 Hz), 7,30 (1H, DD, J=8,1, 3,3 Hz), 7,62-7,70 (N, m), 7,75-7,83 (3H, m).

Comparative example 18

1-[(2-Methoxy-3-pyrid the l)methyl]-4-[2-[[[(trifluoromethyl)sulfonyl]oxy]-3-pyridyl]ethyl]piperidine

110 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine, 382 mg of N-phenyl(triptorelin)sulfonamide, 311 mg of triethylamine and 13 mg of dimethylaminopyridine dissolved in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 20 hours. The solvent is evaporated and the residue purified column chromatography on NH form silica gel (ethyl acetate:hexane=1:9), resulting in a gain of 151 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.40 (3H, m), 1,50-of 1.62 (2H, m), 1,67 to 1.76 (2H, m), 1,98-of 2.08 (2H, m), 2,65-of 2.72 (2H, m), 2,87-to 2.94 (2H, m), of 3.48 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,6, 5,2 Hz), 7,29 (1H, DD, J=7,6, 4,8 Hz), to 7.64 (1H, DD, J=7,6, 2.0 Hz), of 7.70 (1H, DD, J=7,6, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz), 8,21 (1H, DD, J=4,8, 2.0 Hz).

Comparative example 19

1-[(6-Bromo-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

636 mg specified in the title compound as a pale yellow oil is obtained from 457 mg of 4-(2,3-methylenedioxyphenethyl)piperidine, obtained as described in comparative example 4, and 409 mg 6-bromo-2-pyridinecarboxamide the method described below in example 29.

1H-NMR (400 MHz, CDCl3) δ 1,26-to 1.38 (3H, m), 1,52-of 1.62 (2H, m), 1.70 to of 1.78 (2H, m), 2,02 is 2.10 (2H, m), 2,56-2,62 (2H, m), 2,83-2,90 (2H, m), 3,62 (2H, s), of 5.92 (2H, s), of 6.65 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz)that's 6.75 (1H, DD, J=7,6, 7,6 Hz), 7,34 (1H, d, J=7,6 Hz), 7,44 (1H, d, J=7,6 Hz), 7,51 (1H, DD, J=7,6, 7,6 Hz).

Comparison is sustained fashion example 20

1-[(2-Chloro-3-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

673 mg specified in the title compound as a colourless oil is obtained from 505 mg of 4-(2,3-methylenedioxyphenethyl)piperidine, obtained as described in comparative example 4, and 464 mg of 2-chloro-3-pyridinecarboxamide the method described below in example 29.

1H-NMR (400 MHz, CDCl3) δ 1,26-to 1.38 (3H, m), 1,55-of 1.62 (2H, m), 1,70-1,80 (2H, m), 2.06 to of 2.16 (2H, m), 2,56-2,62 (2H, m), 2,84-only 2.91 (2H, m)and 3.59 (2H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,8, 1.0 Hz), of 6.68 (1H, DD, J=7,8, 1.0 Hz), 6,76 (1H, DD, J=7,8, and 7.8 Hz), 7.23 percent (1H, DD, J=7,2, 5.0 Hz), 7,87 (1H, DD, J=7,2, 2.0 Hz), of 8.27 (1H, DD, J=5.0 and 2.0 Hz).

Comparative example 21

1-[(2-Methoxy-Z-pyridyl)methyl]-4-piperidinemethanol

of 8.2 g of 4-piperidinemethanol, 10.0 g of 3-(chloromethyl)-2-methoxypyridine and 17.5 g of potassium carbonate are suspended in 65 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 12 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and get listed in the title compound as a yellow oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ 1,26-1,72 (7H, m), 2.00 in of 2.10 (2H, m), 2,86-to 2.94 (2H, m), 3,49 (2H, s), 3,70 (2H, t, J=6,7 Hz), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,0, 5.0 Hz), the 7.65 (1H, DD, J=7,0, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Comparative example 22

1-[(2-Methoxy-Z-pyridyl)methyl]-4-piperidinylidene

12.0 g specified in the title compound as a yellow oil is obtained from 17,4 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinemethanol the method described in comparative example 30.

1H-NMR (400 MHz, CDCl3) δ 1,30 was 1.43 (2H, m)of 1.65 to 1.76 (2H, m), 1,91 (1H, s), 2,02-2,17 (2H, m), 2,83-to 2.94 (2H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,63 (1H, DD, J=7,1, 1.9 Hz), with 8.05 (1H, DD, J=4,9, 1.9 Hz), 9,78 (1H, t, J=2.0 Hz).

Comparative example 23

1-[(2-Methoxy-3-pyridyl)methyl]-4-piperidone

4.0 g of the hydrochloride of 4-piperidone, 4.1 g of 3-(chloromethyl)-2-methoxypyridine and 12.6 g of potassium carbonate are suspended in 26 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 15 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate), resulting in a gain of 5.5 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 2,45-2,52 (4H, m), 2.77-to 2,85 (4H, m)to 3.64 (2H, s), of 3.96 (3H, s), make 6.90 (1H, DD, J=7,1, 4.9 Hz), of 7.70 (1H, DD, J=7,1, 2.0 Hz), of 8.09 (1H, DD, J=4,9, 2.0 Hz).

Comparative example 24

Ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]hexahydro-4-pyridinoline]acetate

When ohlord the Sri ice to a suspension of 0.40 g of 60% sodium hydride (oil suspension) and 18 ml of tetrahydrofuran are added dropwise a mixed solution of 2.2 ml of triethylphosphate and 18 ml of tetrahydrofuran. After stirring for 5 minutes, added dropwise a mixed solution of 2.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidone and 9 ml of tetrahydrofuran. After completion of adding dropwise, the mixture is stirred under ice cooling for 30 minutes. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:1), resulting in a gain of 2.6 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.28 (3H, t, J=6.9 Hz), 2,32-of 2.38 (2H, m), 2,54-2,62 (4H, m), 2,97 was 3.05 (2H, m), 3,53 (2H, s), of 3.95 (3H, s), 4,14 (2H, q, J=6, 9 Hz), 5,64 (1H, s), to 6.88 (1H, DD, J=7,2, 4.9 Hz), to 7.67 (1H, DD, J=to 7.2, 2.1 Hz), 8,07 (1H, DD, J=4,9, 2,1 Hz).

Comparative example 25

Ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]acetate

2.6 g of ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]hexahydro-4-pyridinoline]acetate and 380 mg of 10% palladium on powdered coal (product containing water) are suspended in 20 ml of ethyl acetate. After replacing the atmosphere of the container with hydrogen, the mixture is stirred at room temperature under normal pressure for one hour. The reaction solution is filtered and then the solvent of the filtrate is evaporated from the floor is the group specified in the title compound as a yellow oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ 1,25 (3H, t, J=7,1 Hz), 1,28-of 1.41 (2H, m), 1,65 is 1.86 (3H, m), 2,02-2,12 (2H, m), of 2.23 (2H, d, J=7,0 Hz), 2,84 of 2.92 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), of 4.12 (2H, q, J=7,1 Hz)6,86 (1H, DD, J=7,2, 5.0 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5.0 and 2.0 Hz).

Comparative example 26

N-(tert-Butoxycarbonyl)-4-[2-[2-(methylsulphonyl)phenyl]-2-oxoethyl]piperidine

2.0 g of N-(tert-butoxycarbonyl)-4-[2-hydroxy-2-[2-(methylthio)phenyl]atility]piperidine obtained from 2.2 g of 2-bromothioanisole, 6.9 ml of 1.53 M solution of n-utility in hexane and 2.0 g of N-(tert-butoxycarbonyl)-4-piperidinylidene the method described below in example 71. Then obtain 2.0 g of N-(tert-butoxycarbonyl)-4-[2-[2-(methylthio)phenyl]ethyl-2-oxoethyl]piperidine as a pale yellow oil by the method described in comparative example 30. Received the product and 2.7 g of 3-chloroperbenzoic acid dissolved in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added aqueous sodium thiosulfate solution and an aqueous solution of sodium hydroxide and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (ethyl acetate:hexane=1:1), resulting in a gain of 1.8 g specified in the connection header in the IDA yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,14-of 1.29 (2H, m), 1,46 (N, C), 1,78-of 1.88 (2H, m), 2,22 (1H, m), 2,73-of 2.86 (2H, m), 2,87 (2H, d, J=6,6 Hz)at 3.25 (3H, s), 3.96 points-4,24 (2H, s), 7,40 (1H, d, J=7.5 Hz), a 7.62 (1H, DD, J=7,8, 7.5 Hz), of 7.70 (1H, DD, J=7,5, 7.5 Hz), 8,07 (1H, d, J=7,8 Hz).

Comparative example 27

Methyl-3-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidine]propanoic

2.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, 1.6 ml of trimethylphosphate and 60% sodium hydride are suspended in 30 ml of tetrahydrofuran, and the mixture is stirred at room temperature for one hour. To the reaction solution was added ethyl acetate and the mixture washed with 1 N. aqueous sodium hydroxide and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product and 400 mg powder 10% palladium on coal (product containing water) are suspended in 100 ml of ethanol. After replacing the atmosphere of the container with hydrogen, the mixture is stirred at room temperature and under normal pressure for 20 hours. The reaction solution is filtered and the filtrate is evaporated to obtain 2.20 g specified in the title compound as light brown oil.

1H-NMR (400 MHz, CDCl3) δ of 1.20 and 1.35 (3H, m), 1,55-1,70 (4H, m), 1,96 e 2.06 (2H, m), of 2.33 (2H, t, J=7.8 Hz), 2,84-of 2.93 (2H, m), of 3.48 (2H, s)to 3.67 (3H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,2, 4,8 Hz), 7,63 (1 is, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Comparative example 28

3-[1-[(2-Methoxy-3-pyridyl)methyl]-4-piperidyl]propanal

2.20 g of 3-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidine]propanoate subjected to standard recovery using lithium aluminum hydride. The resulting product is treated by the method described in comparative example 30, resulting in a gain of 1.29 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ to 1.22 to 1.34 (3H, m), 1.56 to to 1.70 (4H, m), 1,97-to 2.06 (2H, m), of 2.45 (2H, TD, J=7,6, to 7.6, 1.8 Hz), 2,85-of 2.93 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,0, 5.0 Hz), 7,63 (1H, DD, J=7,0, 2.0 Hz), 8,05 (1H, DD, J=5.0 and 2.0 Hz), made up 9.77 (1H, t, J=1,8 Hz).

Comparative example 29

2-[1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidyl]-1-ethanol

15.6 g of 2-methoxynicotinate aldehyde, 14 g of 2-piperidinemethanol, 30 g triacetoxyborohydride sodium, and 6.6 ml of acetic acid and 200 ml of tetrahydrofuran was stirred at room temperature for one hour. Then add dilute sodium hydroxide solution, the mixture is extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Then, the drying agent is filtered off and the solvent is evaporated. The residue is purified column chromatography on silica gel (ethyl acetate, then ethyl acetate:methanol=2:1).

1H-NMR (400 MHz, CDCl3) δ 1,35-of 1.84 (8H, m), 1.93 and-2,04 (1H, m), 2.05 is-of 2.34 (1H, m), was 2.76-to 2.85 (1H, m), 2.95 and-to 3.02 (1H, m), 3,9 (1H, d, J=16.0 Hz), 3,65-to 3.73 (1H, m), 3,84-to 3.92 (1H, m), of 3.97 (3H, s), was 4.02 (1H, d, J=16.0 Hz), 6,85 (1H, DD, J=6,8 Hz, 6.8 Hz), 7,58 (1H, d, J=6.8 Hz), of 8.06 (1H, d, J=6,8 Hz).

Comparative example 30

2-[1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidyl]acetaldehyde

A solution of 4.2 g of the complex pyridine-sulfur trioxide", dissolved in dimethyl sulfoxide (DMSO), added dropwise to a solution of 3 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-1-ethanol and 7.3 ml of triethylamine, dissolved in 15 ml of DMSO, supporting the bulk temperature of 20°s or less. After completion of adding dropwise, the mixture is stirred at room temperature for one hour. Then add an aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. After drying with sodium sulfate the solvent is evaporated. The residue is purified column chromatography on silica gel (methanol) and obtain 2.5 g of red-brown oil.

1H-NMR (400 MHz, CDCl3) δ 1,36-1,83 (6N, m), 2,18-of 2.26 (1H, m), 2,59-2,69 (2H, m), 2,70-and 2.79 (1H, m), 2,98 was 3.05 (1H, m), 3,37 (1H, d, J=16.0 Hz), 3,76 (1H, d, J=16.0 Hz), of 3.95 (3H, s)6,86 (1H, DD, J=6,8 6,8 Hz), 7,63 (1H, d, J=6.8 Hz), with 8.05 (1H, d, J=6.8 Hz), 9,83 (1H, s).

Comparative example 31

1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidinecarboxylic

1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidinecarboxylic receive the same manner as described in comparative example 30, using a 2-piperidinemethanol instead of 2-piperidinemethanol.

1H-NMR (400 MHz, CDCl3) δ 1,29-to 1.38 (1H, m), 1,46 and 1.80 (5H, m), 2.05 is with 2.14 (1H, m), 2,86-of 2.97 (2H, m), 3,50 (1H, d, J=16.0 Hz), 3,62 (1H, d, J=16.0 Hz), of 3.94 (3H, s), to 6.88 (1H, DD, J=6,8, 6,8 Hz), to 7.64 (1H, DD, J=6,8, 2.0 Hz), 8,08 (1H, DD, J=6,8, 2.0 Hz), 9,60 (1H, s).

Comparative example 32

Ethyl-2-(2-piperidyl)acetate

50 ml of ethyl-2-(2-pyridyl)acetate, 18.7 ml of acetic acid, 5 g of Pd-C (water-containing product) and 200 ml of ethanol is loaded into the autoclave and the mixture is stirred at 70°C for 9 hours under hydrogen pressure of 56 kg/cm2. Pd-C is filtered off and the ethanol is evaporated from the receipt of 72.3 g of white crystals.

1H-NMR (400 MHz, CDCl3) δ of 1.12 (3H, t, J=7.2 Hz), 1,40-1,86 (6N, m)a 1.96 (3H, s)to 2.54 (1H, DD, J=16,4 7,2 Hz), 2,70-2,89 (2H, m), of 3.10-3.20 (1H, m), 3,12-3,30 (1H, m), of 4.13 (2H, q, J=7.2 Hz), 8,39 (2H, s).

Comparative example 33

Ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetate

25 g of ethyl-2-(2-piperidyl)acetate, 15.6 g of aldehyde 2-methoxynicotinic acid, 30 g triacetoxyborohydride sodium, and 6.6 ml of acetic acid and 200 ml of THF was stirred at room temperature overnight. Then add the sodium hydroxide and the mixture extracted with ethyl acetate. After drying over anhydrous magnesium sulfate the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=2:1), resulting in a gain of 2.8 g of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ of 1.12 (3H, t, J=7.2 Hz), of 1.40 and 1.80 (6N, m), 2,22 of-2.32 (1H, m),2,42 (1H, DD, J=16,4, 7,2 Hz), 2,62-by 2.73 (2H, m), 2,98 was 3.05 (1H, m)to 3.41 (1H, DD, J=15.6 Hz), 3,70 (1H, d, J=15.6 Hz), 2,95 (3H, s), of 4.12 (2H, q, J=7.2 Hz), 6,86 (1H, DD, J=7,6 4,8 Hz), 7,69 (1H, DD, J=7,6 2,0 Hz), 8,02 (1H, DD, J=4,8 2,0 Hz).

J=7,6, 2.0 Hz), 8,02 (1H, DD, J=4,8, 2.0 Hz).

Comparative example 34

2-[1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidyl]acetic acid

2.8 g of ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetate, 20 ml of 2 N. aqueous sodium hydroxide and 20 ml of methanol was stirred at 70°C for 1.5 hours. Then add 8 ml of 5 N. aqueous hydrochloric acid and the solvent is evaporated. To the residue is added ethanol and the sodium chloride is filtered off. The ethanol is evaporated and obtain 2.9 g of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ to 1.35 and 1.80 (6N, m), 2,25-to 2.40 (2H, m), 2,60-2,70 (2H, m), 2,92-of 3.00 (1H, m), 3,49 (1H, d, J=15.6 Hz), of 3.77 (1H, d, J=15.6 Hz), 3,90 (3H, s), 7,00 (1H, DD, J=7,6 4,8 Hz), of 7.70 (1H, DD, J=7,6 2,0 Hz), 8,08 (1H, d, J=4,8 2,0 Hz).

Comparative example 35

2-[(2R)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinyl]acetic acid

of 29.3 g of 2-[(2R)-hexahydro-2-pyridinyl]acetic acid, 8 g of sodium hydroxide, to 44.7 g of di-tert-butylboronic, 240 ml of water and 180 ml of tert-butanol was stirred at room temperature overnight. The reaction solution is washed with ethyl acetate. The aqueous layer was adjusted to a pH of 1.5 by addition of an aqueous potassium bisulfate and then extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and then utilize the al is evaporated to obtain 18.6 g of the target compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ to 1.35 and 1.75 (15 NM, m), 2,52-of 2.66 (2H, m), 2,73-2,84 (1H, m), 3,97-4,06 (1H, m), 4,67-of 4.75 (1H, m).

Comparative example 36

tert-Butyl(2R)-2-[2-(di(2-propylamino)-2-oxoethyl]hexahydro-1-pyridinecarboxylic

of 7.4 g of 2-[(2R)-1-(tert-butoxycarbonyl)hexahydro-2-pyridinyl]acetic acid, 2.7 g of diprophylline, 1.2 g WSC (hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), 2.0 g HOBt (1-hydroxy-1H-benzotriazole) and 50 ml of DMF was stirred at room temperature for 2 hours. Then add a saturated solution of salt. The mixture is extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Anhydrous sodium sulfate is filtered off and the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=4:1 then 2:1), resulting in a gain of 7.7 g of the desired product as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,36-1,75 (15 NM, m), 2,22 (1H, s), 2,30 (1H, s), 2,50-2,60 (1H, m), 2,73-to 2.85 (2H, m), 3,93-of 4.05 (1H, m), 4,18-4,30 (2H, m), 4,30-4,45 (2H, m), 4,58 with 4.65 (1H, m).

Comparative example 37

N1,N1-Di(2-PROPYNYL)-2-[(2R)-hexahydro-2-pyridinyl]ndimethylacetamide

of 7.7 g of tert-butyl(2R)-2-[2-(di(2-propylamino)-2-oxoethyl]hexahydro-1 pyridinecarboxylic, 100 ml of 5 N. aqueous hydrochloric acid and 50 ml of methyl alcohol is stirred at room temperature for one hour. Then add 110 ml of 5 N. aqueous sodium hydroxide. The mixture is then extras is Giroud with ethyl acetate and dried over anhydrous sodium sulfate. After removing anhydrous sulfate sodium and evaporation of the organic solvent to obtain 4.4 g of the desired product as oil.

[α]D=-23,4° (C=0,74, Meon, 28°).

1H-NMR (400 MHz, CDCl3) δ 1,15-1,50 (3H, m), 1.56 to and 1.63 (2H, m), 1,72 and 1.80 (1H, m), of 2.21 (1H, s), 2,28 (1H, s), 2.40 a-2,48 (2H, m), 2,63-of 2.72 (1H, m), 2,93-3,03 (2H, m), 4,10-4,39 (4H, m).

Comparative example 38

1-[(2-Methoxy-3-pyridyl)methyl]-2-piperidinecarboxylic

17 g of triacetoxyborohydride sodium is added to the reaction solution of 8.7 g of 2-methoxynicotinate aldehyde, 5.8 g of 2-piperidinemethanol, 3 ml of acetic acid and 100 ml of tetrahydrofuran (THF) at room temperature and the mixture is stirred over night. Then add dilute sodium hydroxide and the mixture extracted with ethyl acetate. The solvent is evaporated and the residue purified by chromatography on silica gel (hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=4:1) obtaining of 5.4 g of oil. A solution of 8.0 g of a complex of pyridine - sulfur trioxide dissolved in DMSO, supporting the bulk temperature of 20°s or less, dropwise, with stirring, add in a solution of 5.4 g of the obtained oil, 14 ml of triethylamine and 20 ml of DMSO. After stirring at room temperature for 3 hours add the cooled sodium bicarbonate and the mixture extracted with ethyl acetate. The solvent is evaporated and the residue eyes which indicate chromatography on silica gel (hexane:ethyl acetate=4:1, then 3:2, and then 2:1), resulting in a gain of 2.7 g of a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,28 and 1.80 (6H, m), 2.05 is with 2.14 (1H, m), 2,85-2,96 (2H, m), 3,50 (1H, d, J=14,8 Hz), 3,62 (1H, d, J=14,8 Hz), of 3.94 (3H, s), 6,85 (1H, DD, J=6,8, 6,8 Hz), the 7.65 (1H, d, J=6.8 Hz), 8,07 (1H, d, J=6,8 Hz), a 9.60 (1H, s).

Comparative example 39

Ethyl(E)-3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-2-propenoate

2.4 g of tert-butoxide potassium, mixing, add at room temperature to a solution of 4.2 ml of triethylphosphate dissolved in 40 ml of THF. After 10 minutes stirring at room temperature, add a solution of 5 g of 1-[(2-methoxy-3-pyridyl)methyl]-2-piperidinecarboxylate dissolved in THF. After stirring for one hour, water is added and the mixture extracted with ethyl acetate. After drying over anhydrous sodium sulfate the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=4:1 then 2:1) to obtain 3.4 g of oil.

1H-NMR (400 MHz, CDCl3) δ of 1.27 (3H, t, J=7.2 Hz), 1,28-1,80 (6N, m), 1,94-2,02 (1H, m), 2,82-of 2.97 (2H, m), 3,19 (1H, d, J=14,8 Hz), 3,70 (1H, d, J=14,8 Hz), of 3.94 (3H, s), 4,19 (2H, q, J=7.2 Hz), 5,98 (1H, d, J=16.0 Hz), 6,85 (1H, DD, J=6,8, 6,8 Hz), of 6.96 (1H, DD, J=16,0, 7,0 Hz), to 7.67 (1H, d, J=6.8 Hz), 8,02 (1H, d, J=6,8 Hz).

Comparative example 40

Ethyl-3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-2-propanoate

3.4 g of ethyl(E)-3-[1-(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-2-propenoate dissolved in ethanol, add Aut 1 g of Pd-C (product, containing water) and the mixture is catalytically hydronaut overnight at normal pressure. The catalyst is filtered off and the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the 1,58 g of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ of 1.03 (3H, t, J=7.2 Hz), 1.30 and 1,73 (6N, m), 1,88-of 1.95 (2H, m), 2,09-2,17 (1H, m), 2,23 at 2.45 (3H, m), of 2,75 2,80 (1H, m), 3,26 (1H, d, J=14,8 Hz), 3,83 (1H, d, J=14,8 Hz), of 3.95 (3H, s), 4,10 (2H, q, J=7,2 Hz), at 6.84 (1H, DD, J=6,8, 6,8 Hz), to 7.67 (1H, d, J=6.8 Hz), 8,02 (1H, d, J=6,8 Hz).

Comparative example 41

(2-Methoxy-3-pyridyl)methyl

4 g (2-methoxy-3-pyridyl)methyl chloride, 2.5 g of sodium cyanide and 10 ml of DMF is stirred under heating for 10 minutes. Then water is added and the mixture extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant is removed and the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain 2.5 g of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ the 3.65 (2H, s)to 3.99 (3H, s), 6,93 (1H, DD, J=6,8 Hz), 7,66 (1H, d, J=6.8 Hz), 8,15 (1H, d, J=6,8 Hz).

Comparative example 42

2-(2-Methoxy-3-pirical)acetic acid

2.2 g (2-methoxy-3-pyridyl)methyl cyanide, 35 ml of 5 N. aqueous sodium hydroxide solution and 35 ml of methanol is stirred under heating at 100°C for 1.5 hours. The mixture is cooled to room temperature, and then to it was added 35 ml of 5 N. water solenoidality and the solvent is evaporated. To the residue is added ethanol and the solid is filtered off. The ethanol is evaporated and to the residue again add the ethanol, after which the solid is filtered off. The ethanol is evaporated and obtain 2.4 g of white crystals.

1H-NMR (400 MHz, DMSO-d6) δ of 3.53 (2H, s), 3,86 (3H, s), to 6.95 (1H, DD, J=6,8 6,8 Hz), 7,60 (1H, d, J=6.8 Hz), 8,07 (1H, d, J=6,8 Hz).

Comparative example 43

2-(2-Methoxy-3-pyridyl)ethanol

2.4 g (2-methoxy-3-pyridyl)acetic acid, 550 mg of lithium aluminum hydride and 20 ml of THF was stirred at room temperature for 0.5 hours. Then add 0,27 ml of water, 3,9 ml 3.8 N. aqueous sodium hydroxide and 0.78 ml of water, after which the solid is filtered off. The filtrate is evaporated and the residue purified by chromatography on silica gel (hexane:ethyl acetate=2:1 then 1:1) to obtain 1.2 g of a yellow oil.

1H-NMR (400 MHz, DMSO-d6) δ and 2.83 (3H, t, J=7.2 Hz), a-3.84 (2H, q, J=7.2 Hz), of 3.97 (3H, s), 6,83 (1H, DD, J=6,8 6,8 Hz), 7,42 (1H, d, J=6.8 Hz), 8,03 (1H, d, J=6,8 Hz).

Comparative example 44

2-(2-Methoxy-3-pyridyl)acetaldehyde

A solution of 2.7 g of a complex of pyridine-sulfur trioxide dissolved in DMSO, is added dropwise, at 20°s or less are added to a solution of 1.2 g of 2-(2-methoxy-3-pyridyl)ethanol and 4.8 ml of triethylamine, dissolved in DMSO. After stirring for 0.5 hours add the cooled sodium bicarbonate and the mixture extracted with ethyl is the Etat. After drying over sodium sulfate, the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain 200 mg of a yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 3.60 (2H, s), of 3.95 (3H, s), 6,85 (1H, d, J=6,8 6,8 Hz), 7,40 (1H, d, J=6.8 Hz), 8,10 (1H, d, J=6,8 Hz).

Comparative example 45

Chloride [[(2-(cyclohexylmethoxy)phenyl)methyl] triphenylphosphane

of 3.06 g of 2-(cyclohexylmethoxy)benzyl alcohol are dissolved in 30 ml of toluene, the solution is added of 1.52 ml of thionyl chloride and 5 drops of N,N-dimethylformamide and the mixture is stirred for 70 minutes under ice cooling. To the reaction solution was added aqueous sodium carbonate, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solution is filtered through alumina and the solvent is evaporated, resulting in a gain of a light-yellow oil. The oil obtained is dissolved in 3 ml of acetonitrile, add the 3.65 g of triphenylphosphine and the mixture was stirred at 110°C for 1 hour and 45 minutes. To the reaction solution was added ethyl acetate, and the product is collected by filtration, resulting in a gain 6,51 g specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ of 0.75 to 0.89 (2H, m), 1.06 a-to 1.38 (4H, m)and 1.51 is 1.58 (2H, m), 1,641,84 (3H, m), 3,21 (2H, d, J=6.4 Hz), of 5.34 (2H, d, J=14,0 Hz), 6,59 (1H, d, J=8.0 Hz), to 6.80 (1H, dt, J=8,0, 0.8 Hz), 7,22 (1H, m), 7,32 (1H, m), 7,58-7,68 (N, m), 7,73-7,81 (3H, m).

Comparative example 46

Methyl-5-methyl-2-methoxy-3-pyridinecarboxylic

1.2 g of methyl 5-bromo-2-methoxy-3-pyridinecarboxylic dissolved in 20 ml of N,N-dimethylformamide, added 440 mg methylboronic acid, 4,79 g of anhydrous cesium carbonate and 564 mg of tetrakis(triphenylphosphine)palladium and the mixture was stirred at 120°C for 2 hours in nitrogen atmosphere. To the reaction solution was added ice water and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (hexane:ethyl acetate=20:1), resulting in a gain 461 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ to 2.29 (3H, s), 3,90 (3H, s), was 4.02 (3H, s), to 7.99 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=2,4 Hz).

Comparative example 47

Methyl-5-phenyl-2-methoxy-3-pyridinecarboxylic

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 46.

1H-NMR (400 MHz, CDCl3) δ of 3.94 (3H, s), 4,10 (3H, s), 7,38 (1H, m), 7,44-7,50 2H, m), 7,54-7,58 (2H, m), 8,39 (1H, d, J=2,8 Hz), 8,54 (1H, d, J=2,8 Hz).

Comparative example 48

Methyl-5-(3-pyridinyl)-2-methoxy-3-pyridinecarboxylic

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 46.

1H-NMR (400 MHz, CDCl3) δ of 3.95 (3H, s), 4,11 (3H, s), 7,41 (1H, DD, J=8,0, to 4.8, 1.2 Hz), 7,86 (1H, DDD, J=8.0 a, 2,4, and 1.6 Hz), 8,39 (1H, d, J=2,8 Hz), 8,55 (1H, d, J=2,8 Hz), 8,64 (1H, DD, J=4,8, and 1.6 Hz), 8,83 (1H, DD, J=2,4, 1,2 Hz).

Comparative example 49

Methyl-5-(4-pyridinyl)-2-methoxy-3-pyridinecarboxylic

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 46.

1H-NMR (400 MHz, CDCl3) δ of 3.95 (3H, s), of 4.12 (3H, s), 7,47-7,53 (2H, m), 8,44 (1H, d, J=2,8 Hz), 8,61 (1H, d, J=2,8 Hz), 8,67-8,73 (2H, m).

Comparative example 50

6-Methyl-2-methoxy-3-pyridinemethanol

0.9 g of lithium aluminum hydride are suspended in 60 ml of tetrahydrofuran and to this suspension is added dropwise while cooling with ice and with stirring a solution to 4.41 g of 6-methyl-2-methoxy-3-pyridinecarboxylic dissolved in 20 ml of tetrahydrofuran. After stirring for 30 minutes to a solution successively added to 0.9 ml of water, 0.9 ml of 15% aqueous sodium hydroxide and 2.7 ml of water. Then dobavlaut celite and anhydrous magnesium sulfate and the mixture is stirred at room temperature. After filtering the reaction solution, the solvent is evaporated and receive of 3.78 g specified in the title compound as a white solid.

1H-NMR (400 MHz, CDCl3) δ and 2.26 (1H, m), is 2.44 (3H, s), 3,98 (3H, s), 4,60 (2H, d, J=5,2 Hz), of 6.71 (1H, d, J=7,2 Hz), 7,42 (1H, d, J=7,2 Hz).

Comparative example 51

5-Chloro-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ of 3.97 (3H, s), 4,63 (2H, s), to 7.59-the 7.65 (1H, m), 8,03 (1H, d, J=2,4 Hz).

Comparative example 52

5-Bromo-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ of 3.96 (3H, s), 4,63 (2H, s), 7,73 (1H, d, J=2.4 Hz), 8,13 (1H, d, J=2,4 Hz).

Comparative example 53

5-Methyl-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ of 2.25 (3H, s), of 3.97 (3H, s), 4.26 deaths (2H, s)to 7.50 (1H, d, J=2.4 Hz), 7,89 (1H, d, J=2,4 Hz).

Comparative example 54

5-Phenyl-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ Android 4.04 (1H, s), 4.72 in (2N, C)of 7.36 (1H, m), 7,42-of 7.48 (2H, m), 7,52-7,56 (2H, m), 7,82 (1H, d, J=2.4 Hz), 8,32 (1H, d, J=2,4 Hz).

Comparative example 55

5-(3-Pyridinyl)-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ of 4.05 (3H, s), 4,74 (2H, s), 7,39 (1H, DDD, J=8.0 a, 4,8, 0,4 Hz), the 7.85-7,88 (2H, m), 8,32 (1H, d, J=2.4 Hz), 8,61 (1H, DD, J=4,8, and 1.6 Hz), 8,11 (1H, DD, J=2,4, and 0.4 Hz).

Comparative example 56

5-(4-Pyridinyl)-2-methoxy-3-pyridinemethanol

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 50.

1H-NMR (400 MHz, CDCl3) δ of 2.38 (1H, s)4,06 (3H, s), and 4.75 (2H, s), 7,47-to 7.50 (2H, m), to $ 7.91 (1H, m), 8,40 (1H, d, J=2.4 Hz), 8,64-8,68 (2H, m).

Comparative example 57

6-Methyl-2-methoxy-3-(chloromethyl)pyridine

of 3.78 g of 6-methyl-2-methoxy-3-pyridinemethanol dissolved in 60 ml of carbon tetrachloride, the solution add 6,48 g of triphenylphosphine and the mixture is refluxed for 6 hours and 30 minutes. The solvent in perigaut, to the residue is added n-hexane and any insoluble matter is filtered off. The solvent is evaporated and the crude product is purified by chromatography on silica gel (n-hexane:ethyl acetate=100:1) getting to 2.29 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ of 2.45 (3H, s), 3,98 (3H, s), 4,58 (2H, s), 6,72 (1H, d, J=7,2 Hz), to 7.50 (1H, d, J=7,2 Hz).

Comparative example 58

5-Chloro-2-methoxy-3-(chloromethyl)pyridine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 57.

1H-NMR (400 MHz, CDCl3) δ 3,98 (3H, s)4,55 (2H, s), 7,63-to 7.68 (1H, m), 8,07 (1H, d, J=2,4 Hz).

Comparative example 59

5-Bromo-2-methoxy-3-(chloromethyl)pyridine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 57.

1H-NMR (400 MHz, CDCl3) δ 3,98 (3H, s), of 4.54 (2H, s), 7,78 (1H, d, J=2.4 Hz), to 8.12 (1H, d, J=2,4 Hz).

Comparative example 60

5-Methyl-2-methoxy-3-(chloromethyl)pyridine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 57.

1H-NMR (400 MHz, CDCl3) δ and 2.26 (3H, s), of 3.97 (3H, s), 4,58 (N, C)of 7.48 (1H, d, J=2.0 Hz), to 7.93 (1H, d, J=2.0 Hz).

Comparative example 61

5-Phenyl-2-methoxy-3-(chloromethyl)pyridine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 57.

1H-NMR (400 MHz, CDCl3) δ of 4.05 (3H, s), of 4.66 (2H, s), 7,37 (1H, m), 7,43-of 7.48 (2H, m), 7,52-7,56 (2H, m), 7,88 (1H, d, J=2.4 Hz), at 8.36 (1H, d, J=2,4 Hz).

Comparative example 62

5-(4-Pyridinyl)-2-methoxy-3-pyridinecarboxamide

321 mg of 5-(4-pyridinyl)-2-methoxy-3-pyridinemethanol dissolved in 10 ml of chloroform, add 1.6 g of manganese dioxide and the mixture is stirred at room temperature for 14 hours. After filtration through celite the solvent is evaporated. The crude product is purified by chromatography on silica gel (toluene:ethyl acetate=3:1) to give 329 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ to 4.17 (3H, s)of 7.48-7,56 (2H, m), 8,40 (1H, d, J=2,8 Hz), 8,66-8,76 (3H, m), 10,45 (1H, s).

Comparative example 63

5-(3-Pyridinyl)-2-methoxy-3-pyridinecarboxamide

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 62.

1H-NMR (400 MHz, CDCl3) δ 4,15 (3H, s), 7,41 (1H, DDD, J=0,8, 48, 8.0 Hz), 7,87 (1H, DDD, J=8.0 a, 2,4, and 1.6 Hz), with 8.33 (1H, d, J=2.4 Hz), 8,63 (1H, d, J=2.4 Hz), 8,65 (1H, DD, J=4,8, and 1.6 Hz), 8,84 (1H, DD, J=2,4, and 0.8 Hz), 10,44 (1H, s).

Comparative example 64

Dimethylacetal 5-bromo-2-methoxy-3-pyridinecarboxamide

2.58 g of 5-bromo-2-methoxy-3-pyridinecarboxamide dissolved in 30 ml of dichloromethane, add a mixture of 9 ml of triethylorthoformate and montmorillonite K-10 (3 g) and the mixture is stirred at room temperature for 2 hours.

After filtering the reaction solution, the filtrate is evaporated. To the residue is added ethyl acetate, and then filtered through alumina. The filtrate is evaporated and get to 3.09 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 3,36 (6N, (C), of 3.96 (3H, s), the 5.51 (1H, s), of 7.90 (1H, DD, J=2,4, 0,4 Hz), 8,18 (1H, d, J=2,4 Hz).

Comparative example 65

Dimethylacetal 5-(methylsulphonyl)-2-methoxy-3-pyridinecarboxamide

20 ml of tetrahydrofuran is cooled to -78°add to 4.17 ml of n-utility (1.6 M solution in hexane) and the mixture is stirred. Then added dropwise a solution of 1.59 g of dimethylacetal 5-bromo-2-methoxy-3-pyridinecarboxamide dissolved in 5 ml of tetrahydrofuran. After 30 minutes, added dropwise to 0.66 ml of dimethyl disulfide, and the mixture is stirred for another 1.5 hours. To the reaction solution we use the t water and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and get a pale yellow oil. The oil obtained is dissolved in 30 ml of dichloromethane, add 5,12 g of sodium bicarbonate and 2,32 g of m-chloroperbenzoic acid and the mixture is stirred for 30 minutes under ice cooling. To the reaction solution was added aqueous sodium thiosulfate and the mixture is extracted with ethyl acetate. The organic layer is washed with water, 1 N. aqueous sodium hydroxide and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to obtain the 0,81 g specified in the title compound as a white solid.

1H-NMR (400 MHz, CDCl3) δ is 3.08 (3H, s), 3,38 (6N, C)4,08 (3H, s), the 5.51 (1H, s), 8,29 (1H, DD, J=2,8, 0.8 Hz), 8,71 (1H, d, J=2,8 Hz).

Comparative example 66

5-(Methylsulphonyl)-2-methoxy-3-pyridinecarboxamide

0,81 g dimethylacetal 5-(methylsulphonyl)-2-methoxy-3-pyridinecarboxamide dissolved in 8 ml of acetone, add 2 ml of 5 N. hydrochloric acid and the mixture is stirred at room temperature for 30 minutes. To the reaction solution was added aqueous sodium carbonate and the mixture extracted with ethyl acetate. About the organic layer washed with water and saturated salt solution, and then dried over anhydrous magnesium sulfate. The solvent is evaporated, to the residue is added n-hexane and the resulting product is collected by filtration to obtain 0,62 g specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ the 3.11 (3H, s), of 4.12 (3H, s), 8,58 (1H, d, J=2,8 Hz), 8,93 (1H, d, J=2,8 Hz), 10,38 (1H, s).

Comparative example 67

5-fluoro-2-methoxy-3-pyridinecarboxamide

20 ml of tetrahydrofuran is cooled to -78°add to 2.41 ml n-utility (2.6 M solution in hexane) and the mixture is stirred. Then added dropwise a solution of 1.50 g of dimethylacetal 5-bromo-2-methoxy-3-pyridinecarboxamide dissolved in 5 ml of tetrahydrofuran. After 25 minutes, dropwise within 20 minutes, add a solution of 2.16 g of N-forbindelseshastighed dissolved in 20 ml of tetrahydrofuran, and the mixture is stirred for 55 minutes. To the reaction mixture is added a saturated solution of salt and 20 ml of 2 N. hydrochloric acid, and then stirred at room temperature. After 40 minutes to the reaction solution add dilute ammonia and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and receives a yellow oil. The oil obtained is dissolved in 16 ml of acetone, add 4 ml of 5 is. hydrochloric acid and the mixture is left for 30 minutes at room temperature. To the reaction solution was added aqueous potassium carbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give 234 mg specified in the title compound as a pale yellow solid.

1H-NMR (400 MHz, CDCl3) δ 4,07 (3H, s), to 7.84 (1H, d, J=3.2, and a 7.6 Hz), 8,24 (1H, d, J=3.2 Hz), 10,33 (1H, d, J=2,8 Hz).

Comparative example 68

5-Cyano-2-methoxy-3-pyridinecarboxamide

a 2.00 g of dimethylacetal 5-bromo-2-methoxy-3-pyridinecarboxamide dissolved in 25 ml of propionitrile. To this mixture 449 mg of sodium cyanide, 152 mg of copper iodide and 462 mg of tetrakis(triphenylphosphine)palladium, and then stirred at 100°C for 45 minutes under nitrogen atmosphere. To the reaction solution add dilute ammonia and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain an oil. The oil obtained is dissolved in 16 ml of acetone, add 4 ml of 5 N. hydrochloric acid and the mixture is left for 30 minutes p is at room temperature. To the reaction solution was added an aqueous solution of sodium carbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (toluene:ethyl acetate=1:1) to obtain 843 mg specified in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ to 4.17 (3H, s), a 8.34 (1H, d, J=2.4 Hz), 8,67 (1H, d, J=2.4 Hz), 10,33 (1H, s).

Comparative example 69

1-(Benzyloxycarbonyl)-4-[(E)-2-[2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

of 1.75 g of the chloride [[2-(cyclohexylmethoxy)phenyl]methyl] triphenylphosphine dissolved in 10 ml of dimethyl sulfoxide, add 144 mg of 60% sodium hydride and the mixture was stirred at 70°C. After cooling to room temperature, added dropwise a solution of 800 mg of 1-(benzyloxycarbonyl)-4-piperidinecarboxylate dissolved in 3 ml of tetrahydrofuran, and the mixture is stirred at room temperature for one hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with 1 N. hydrochloric acid, aqueous saturated sodium bicarbonate and saturated saline solution and then dried over anhydrous magnesium sulfate. Solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1), resulting in getting 554 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 0,98 of 1.50 (7H, m), 1,63-of 1.92 (8H, m), 2,34 (3/4H, m), 2,66 (1/4H, m), 2,73-of 2.97 (2H, m), 3,66 (1/2H, d, J=6.0 Hz), 3,68 (3/2H, d, J=6.0 Hz), 4,20 (2H, m), 5,13 (1/2H, s), 5,14 (3/2H, C)5,46 (1/4H, DD, J=11,6, 10,0 Hz), 6,15 (3/4H, DD, J=16,0, 6.4 Hz), 6,50 (1/4H, d, J=11,6 Hz), 6,72 (3/4H, d, J=16.0 Hz), for 6.81-6,94 (2H, m), 7,14-7,41 (7H, m).

Comparative example 70

(2 Cyclohexylmethoxy)bramasol

5,00 ml of 2-bromophenol dissolved in 90 ml of N,N-dimethylformamide, add 7,21 ml (methyl bromide)cyclohexane and to 7.15 g of potassium carbonate and the mixture was stirred at 100°C for 5 hours. To the reaction solution was added water and the mixture extracted with n-hexane. The organic layer is washed with water, 5 N. sodium hydroxide and saturated saline solution and then dried over anhydrous magnesium sulfate. The mixture is filtered through alumina and the solvent is evaporated from the receipt of 10.47 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,04-to 1.38 (5H, m), 1,67-1,95 (6N, m), 3,81 (2H, d, J=6.0 Hz), to 6.80 (1H, dt, J=7,6, 1.2 Hz), 6.87 in (1H, DD, J=8,0, 1.2 Hz), 7.23 percent (1H, DDD, J=8,0, to 7.6, 2.0 Hz), 7,52 (1H, d, J=7,6, 2.0 Hz).

Comparative example 71

1-Benzyl-4-[2-hydroxy-2-[(2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

10 ml of tetrahydrofuran is cooled to -7° To add 5,11 ml n-utility (1.6 M solution in hexane) and the mixture is stirred. Then added dropwise a solution of 2000 (2 cyclohexylmethoxy)bromine benzol, dissolved in 5 ml of tetrahydrofuran. After one hour added dropwise a solution of 1.93 g of 1-benzyl-4-piperidinylidene dissolved in 5 ml of tetrahydrofuran and the mixture is stirred for further 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on NH form silica gel (n-hexane:ethyl acetate=4:1) to obtain 2,986 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,03-1,44 (7H, m), 1,47-1,90 (11N, m), 1,92-2,02 (2H, m), 2,83 of 2.92 (2H, m), 3,50 (2H, s), 3,76 (1H, DD, J=8,8, 6,0 Hz), 3,82 (1H, DD, J=8,8, 5.6 Hz), 4,99 (1H, DD, J=9,2, a 7.6 Hz), at 6.84 (1H, DD, J=8,0, 0.8 Hz), 6,93 (1H, dt, J=7,6, 1.2 Hz), 7.18 in-7,34 (7H, m).

Comparative example 72

1-Benzyl-4-[(E)-2-[(2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

2,986 g of 1-benzyl-4-[2-hydroxy-2-[(2-(cyclohexylmethoxy) phenyl]ethyl]piperidine are dissolved in 70 ml of toluene. To the mixture of 1.38 g of p-toluensulfonate acid and then refluxed for one hour. To the reaction rastv the Roux add aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and get 2,848 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,02-of 1.42 (5H, m), 1,48-of 1.92 (10H, m), 2,01 is 2.10 (2H, m)of 2.16 (1H, m), 2,89-2,96 (2H, m), 3,53 (2H, s), 3,76 (2H, d, J=6.4 Hz), to 6.19 (1H, DD, J=16,0, 7,2 Hz), 6,70 (1H, d, J=16.0 Hz), PC 6.82 (1H, DD, J=8,8, 0.8 Hz), 6.87 in (1H, dt, J=8,8, 0.8 Hz), 7,14 (1H, dt, J=8,8, 0.8 Hz), 7,22 and 7.36 (5H, m), 7,40 (1H, DD, J=8,8, 0.8 Hz).

Comparative example 73

1-Benzyl-4-[2-[(2-(cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine

1.19 g of 1-benzyl-4-ethynylpyridine dissolved in 20 ml of N,N-dimethylformamide, add 1,774 g (2 cyclohexylmethoxy)bromine benzol, 114 mg of copper iodide, to 0.92 ml of triethylamine and 347 mg of tetrakis(triphenylphosphine)palladium and the mixture was stirred at 100°C for 3.5 hours under nitrogen atmosphere. To the reaction solution was added ice water and dilute ammonia and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. After filtration through alumina and silica gel, the solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give 316 mg specified in the connection header in the form with which ETLO-yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.36 (5H, m), 1,64-1,98 (10H, m), 2,22-of 2.34 (2H, m), 2,64-of 2.81 (3H, m), 3,52 (2H, s), 3,80 (2H, d, J=6.0 Hz), PC 6.82 (1H, d, J=8,4, 1.2 Hz), at 6.84 (1H, dt, J=8,4, 1.2 Hz), 7.18 in and 7.36 (7H, m).

Comparative example 74

1-(Vinyloxycarbonyl)-4-[(E)-2-[(2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

2,848 g of 1-benzyl-4-[(E)-2-[(2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine was dissolved in 15 ml of 1,2-dichloroethane, add 0,93 ml vinylnorbornene and the mixture is stirred at room temperature for 50 minutes and refluxed for one hour. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=50:1) to obtain 2,026 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,03-1,52 (7H, m), 1,67-of 1.92 (8H, m), is 2.37 (1H, m), 2,84-3,03 (2H, m), of 3.78 (2H, d, J=6.4 Hz), 4,16-4,27 (2H, m), of 4.45 (1H, DD, J=6,4, and 1.6 Hz), 4,78 (1H, DD, J=13,2, and 1.6 Hz), x 6.15 (1H, DD, J=16,0, 6,8 Hz), was 6.73 (1H, d, J=16.0 Hz), at 6.84 (1H, DD, J=8,4, 1.2 Hz), to 6.88 (1H, dt, J=8,4, 1.2 Hz), 7,17 (1H, dt, J=8,4, 1.2 Hz), 7,24 (1H, DD, J=13,2, 6.4 Hz), 7,39 (1H, DD, J=8,4, 1.2 Hz).

Comparative example 75

1-(Vinyloxycarbonyl)-4-[(E)-2-[(2-(forfinal)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 74.

1H-NMR (400 MHz, CDCl3) δ 1,39-of 1.52 (2H, m)and 1.83 (2H, sird, J=15.6 Hz), is 2.37 (1H, m), 2,83-a 3.01 (2H, m), 4.09 to be 4.29 (2H, m), 4,46 (1H, DD, J=6,4, and 1.6 Hz), 4,78 (1H, DD, J=10,4, 1,6 Hz), 6,21 (1H, DD, J=16,0, 6,8 Hz), 6,56 (1H, d, J=16.0 Hz), 7,02 (1H, DDD, J=10,8, and 8.4, 1.2 Hz), was 7.08 (1H, dt, J=8,0, 1.2 Hz), 7,15-7,26 (2H, m), 7,42 (1H, dt, J=8,0, 1.2 Hz).

Comparative example 76

1-(Vinyloxycarbonyl)-4-[2-[(2-cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 74.

1H-NMR (400 MHz, CDCl3) δ of 1.03 and 1.35 (5H, m), 1,65-of 1.93 (10H, m), 2,98 (1H, m), 3,56-of 3.64 (2H, m), 3,67-with 3.79 (2H, m), with 3.79 (2H, d, J=6.4 Hz), of 4.45 (1H, d, J=6,4, and 1.6 Hz), 4,78 (1H, DD, J=11,6, 1,6 Hz), 6,83 (1H, DD, J=8,0, 1.2 Hz), 6,86 (1H, dt, J=8,0, 1.2 Hz), 7,21-7,27 (2H, m), 7,34 (1H, DD, J=11,6, 1,6 Hz).

Comparative example 77

1-(Vinyloxycarbonyl)-4-[(E)-2-(2-(chlorophenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 74.

1H-NMR (400 MHz, CDCl3) δ 1,40-and 1.54 (2H, m), of 1.85 (2H, sird, J=13,2 Hz)to 2.41 (1H, m), 2,83-to 3.02 (2H, m), 4,19-the 4.29 (2H, m), 4,46 (1H, DD, J=6,0, 1,6 Hz), 4,79 (1H, DD, J=14,4, and 1.6 Hz), 6,12 (1H, DD, J=16,0, 7,2 Hz), 6,56 (1H, DD, J=16,0, 0.8 Hz), 7,13-7,28 (3H, m), 7,34 (1H, DD, J=7,6, 1.2 Hz), to 7.50 (1H, DD, J=7,6, 2.0 Hz).

Comparative example 78

1-(Vinyloxycarbonyl)-4-[(E)-2-(2-were)-1-FL the Neil]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 74.

1H-NMR (400 MHz, CDCl3) δ 1,39-of 1.53 (2H, m)of 1.84 (2H, sird, J=12,8 Hz), of 2.33 (3H, s), a 2.36 (1H, m), 2,83-to 3.02 (2H, m), 4,19-the 4.29 (2H, m), of 4.45 (1H, DD, J=6,4, and 1.6 Hz), 4,78 (1H, DD, J=14,0, and 1.6 Hz), 6,01 (1H, DD, J=16,0, 7,2 Hz), 6,60 (1H, DD, J=16,0, 0.8 Hz), 7,10-7,19 (3H, m), 7,34 (1H, DD, J=14,0, 6.4 Hz), 7,40 (1H, d, J=8.0 Hz).

Comparative example 79

4-[2-[(Cyclohexylmethoxy)phenyl]piperidine

398 mg of 1-benzyl-4-[2-(2-cyclohexylmethoxy)phenyl]-3,4-dihydropyridine dissolved in 10 ml of ethanol, add 150 mg of powdery 20% palladium hydroxide on coal (product containing water) and the mixture is stirred at room temperature overnight under normal pressure in a hydrogen atmosphere. To the reaction solution was added ethyl acetate and the mixture filtered. The filtrate is evaporated and get 315 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.38 (5H, m), 1,54-of 1.92 (10H, m), 2,74-2,82 (2H, m), 3,10 (1H, TT, J=12,0, a 3.2 Hz), 3,16 is 3.23 (2H, m), 3,76 (2H, d, J=6.0 Hz), 6,83 (1H, DD, J=8,0, 1.2 Hz), 6,91 (1H, dt, J=8,0, 1.2 Hz), to 7.15 (1H, dt, J=8,0, 1.2 Hz), 7,19 (1H, DD, J=8,0, 1.2 Hz).

Comparative example 80

4-[2-[2-(Cyclohexylmethoxy)phenyl]ethyl]piperidine

554 mg of 1-(Benzino dicarbonyl)-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine dissolved in 10 ml of ethanol, add 250 mg powder 10% palladium hydroxide on coal (product containing water) and the mixture is stirred at room temperature overnight under normal pressure in a hydrogen atmosphere. The reaction solution is filtered and the filtrate is evaporated to obtain 379 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.76 (8H, m), 1,67-1,96 (10H, m), 2,56-to 2.67 (4H, m), 3,06-3,13 (2H, m in), 3.75 (2H, d, J=5.6 Hz), for 6.81 (1H, d, J=8.0 Hz), 6,85 (1H, dt, J=8,0, 1.2 Hz), 7,09-7,16 (2H, m).

Comparative example 81

4-[2-[2-Isobutyryloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 80.

1H-NMR (400 MHz, CDCl3) δ 1,05 (6N, d, J=6.8 Hz), 1,12-1,24 (2H, m)of 1.42 (1H, m), 1,48-of 1.56 (2H, m), 1,73-of 1.81 (2H, m), 2,10 (1H, m), 2,56-to 2.67 (4H, m), 3,06-3,14 (2H, m), and 3.72 (2H, d, J=6.4 Hz), to 6.80 (1H, d, J=8.0 Hz), 6,86 (1H, dt, J=1,2, 7,6 Hz), 7,09-7,17 (2H, m).

Comparative example 82

4-[[2-(2-Phenylethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 80.

1H-NMR (400 MHz, CDCl3) δ 1,13-of 1.26 (2H, m), 1,39-of 1.55 (3H, m), 1,72-to 1.79 (2H, m), 2,56-of 2.66 (4H, m), 2,84-to 2.94 (4H, m), 3,06-3,14 (2H, m), 7,12-7,33 (N, m).

Comparative example 83

[2-[2-(Cyclohexylmethyl)amino]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 80.

1H-NMR (400 MHz, CDCl3) δ 0,95-1,08 (2H, m), 1,12-of 1.34 (5H, m), 1,40 is 1.86 (7H, m), 1,87-2,04 (4H, m), 2,43-of 2.50 (2H, m), 2,62 (2H, dt, J=12,0, 2.4 Hz), 2,98 (2H, d, J=6.8 Hz), is 3.08-3,14 (2H, m), 3,61 (1H, m), 4,22 (2H, m), 6,61 (1H, DD, J=1,2, 7,6 Hz), of 6.65 (1H, dt, J=7,6, 1.2 Hz), 7,02 (1H, DD, J=7,6, 1.2 Hz), 7,11 (1H, dt, J=7,6, 1.2 Hz).

Comparative example 84

[2-[2-[N-(Cyclohexylmethyl)-N-methylamino]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 80.

1H-NMR (400 MHz, CDCl3) δ 0,95-1,08 (2H, m), 1,12-of 1.34 (5H, m), 1,40 is 1.86 (8H, m), 1,87-2,04 (4H, m), 2,43-of 2.50 (2H, m), 2,62 (2H, dt, J=12,0, 2.4 Hz), 2,98 (2H, d, J=6.8 Hz), is 3.08-3,14 (2H, m), 3,61 (1H, m), is 6.61 (1H, DD, J=the 1.2 and 7.6 Hz), of 6.65 (1H, dt, J=7,6, 1.2 Hz), 7,02 (1H, DD, J=7,6, 1.2 Hz), 7,11 (1H, dt, J=7,6, 1.2 Hz).

Comparative example 85

4-[[2-(Cyclohexylethyl)phenoxy]methyl]piperidine

at 1,138 g of 1-(tert-butoxycarbonyl)-4-[[2-cyclohexylethyl)phenoxy]methyl]piperidine was dissolved in 3 ml of dichloromethane, add 3 ml triperoxonane acid and the mixture is left for 1 hour 30 minutes at room temperature. To the reaction solution was added aqueous sodium carbonate and the mixture extracted with ethyl acetate, the m The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and to the residue is added n-hexane, resulting in a gain 899 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ 0,86 to 0.97 (2H, m), 1,09-1,22 (4H, m), of 1.40 to 1.48 (2H, m), 1,61 and 1.80 (7H, m), 2.05 is-of 2.20 (3H, m), 2,56-2,63 (2H, m), 2,96 (2H, dt, J=of 12.8, 2.4 Hz), 3,50 (2H, sird, J=11,6 Hz), a-3.84 (2H, d, J=6.4 Hz), 6,78 (1H, d, J=8.0 Hz), 6.89 in (1H, dt, J=7,6, 0.8 Hz), 7,16 (1H, d, J=7,6 Hz), to 7.15 (1H, DD, J=7,6, and 0.8 Hz).

Comparative example 86

4-[(E)-2-[2-(Cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

2,026 g of 1-(vinyloxycarbonyl)-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine suspended in 20 ml of 10% solution of hydrogen chloride in methanol and the mixture is stirred for 20 minutes under ice cooling. After stirring for 15 minutes at room temperature the mixture is refluxed for one hour and 10 minutes. The solvent is evaporated and to the residue add aqueous saturated sodium bicarbonate. The mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and to the residue is added n-heptane. Any insoluble matter is filtered off and the filtrate is evaporated to item is the receiving 1,556 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,03-1,46 (6N, m)of 1.66-1.93 and (N, m), 2,28 (1H, m), 2,68 (2H, dt, J=2,4, 12.0 Hz), 3,12 (2H, dt, J=12,0, a 3.2 Hz), of 3.77 (2H, d, J=6.0 Hz), 6,18 (1H, DD, J=16.0 Hz), 6,70 (1H, d, J=16.0 Hz), PC 6.82 (1H, DD, J=7,6, 0.8 Hz), to 6.88 (1H, dt, J=7,6, 0.8 Hz), to 7.15 (1H, dt, J=7,6, 0.8 Hz), 7,41 (1H, DD, J=7,6, and 0.8 Hz).

Comparative example 87

4-[(E)-2-(2-Forfinal)-1-ethynyl]piperidine

904 mg of 1-(vinyloxycarbonyl)-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine suspended in 5 ml of 10% solution of hydrogen chloride in methanol. After stirring for 15 minutes at room temperature, the mixture is heated at 70°C for one hour. The solvent is evaporated and to the residue is added water and ethyl acetate to separate the water layer. The aqueous layer was alkalinized with dilute ammonia and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain 660 mg of the indicated in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.47 (2H, m), 1,75-of 1.84 (2H, m)to 2.29 (1H, m), 2,64-by 2.73 (2H, m), of 3.13 (2H, sird, J=12,4 Hz), 6,24 (1H, DD, J=16,0, 6.4 Hz), is 6.54 (1H, d, J=16.0 Hz), 6,97-7,11 (2H, m), 7,16 (1H, m), 7,44 (1H, m).

Comparative example 88

4-[(E)-2-(2-Chlorophenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding is of similar material by the method, described in comparative example 87.

1H-NMR (400 MHz, CDCl3) δ 1,34 of 1.46 (2H, m), a 1.75-to 1.86 (2H, m), 2,31 (1H, m), 2,68 (2H, dt, J=8,4, 2,8 Hz), 3,12 (2H, dt, J=11,6, a 3.2 Hz), x 6.15 (1H, DD, J=16,0, 6,8 Hz), to 6.75 (1H, DD, J=16,0, 0.8 Hz), 7,13 (1H, dt, J=8,0, 2.0 Hz), then 7.20 (1H, DD, J=8.0 a, 1,6 Hz), 7,33 (1H, DD, J=8.0 a, 1,6 Hz), 7,51 (1H, DD, J=8,0, 2.0 Hz).

Comparative example 89

4-[(E)-2-(2-Were)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 87.

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.47 (2H, m), 1,75-of 1.84 (4H, m)to 2.29 (1H, m), 2,64-by 2.73 (2H, m), of 3.13 (2H, sird, J=12,4 Hz), 6,24 (1H, DD, J=16,0, 6.4 Hz), is 6.54 (1H, d, J=16.0 Hz), 6,97-7,11 (2H, m), 7,16 (1H, m), 7,41-of 7.48 (2H, m,).

Comparative example 90

4-[2-[(2-Cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in comparative example 87.

1H-NMR (400 MHz, CDCl3) δ 1,03-of 1.42 (5H, m), 1,64-1,96 (10H, m), is 2.74 (2H, DDD, J=3.2, and an 8.4, 12.0 Hz), of 2.81 (1H, m), 3,10-3,17 (2H, m), 3,80 (2H, d, J=6.4 Hz), PC 6.82 (1H, DD, J=8,4, 2.0 Hz), 6,85 (1H, dt, J=8,4, 1.2 Hz), 7,21 (1H, DDD, J=8,4, to 7.6, 2.0 Hz), 7,35 (1H, dt, J=7,6, 1.2 Hz).

Example 1

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(methylsulphonyl)phenethyl]piperidine

3,90 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, of 8.92 g of chloride (2-methylsulfonyl nil)triphenylphosphine and 1.96 g of tert-butoxide potassium suspended in 80 ml of N,N-dimethylformamide and the mixture is stirred for 3 hours at room temperature. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography with NH-silica gel (ethyl acetate:hexane=1:4). Received the product and 440 mg powder 10% palladium on coal (product containing water) are suspended in 80 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature under normal pressure for 30 minutes. The reaction solution is filtered and the filtrate is evaporated from the receipt of 4.05 g specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1,61 by 1.68 (2H, m), 1,74-of 1.81 (2H, m), 2,02 is 2.10 (2H, m), 2,88-2,96 (2H, m), 3.00 and-is 3.08 (2H, m), is 3.08 (3H, s)to 3.49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,1, 5.0 Hz), 7,33-7,42 (2H, m)of 7.55 (1H, DDD, J=7,7, and 7.7, 1.3 Hz), the 7.65 (1H, DD, J=7,1, 1.8 Hz), 8,00-8,08 (2H, m).

Example 2

1-[(2-Methoxy-3-pyridyl)methyl]-4-(3,4-methylenedioxyphenethyl)piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ to 1.22 to 1.37 (3H, m), 1,47 is 1.58 (2H, m), 1,64-to 1.77 (2H, m), 1,96-2,07 (2H, m), 2,50 at 2.59 (2H, m), 2,84-to 2.94 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 5,91 (2H, s), is 6.61 (1H, DD, J=7,8, and 1.6 Hz), to 6.67 (1H, d, J=1,6 Hz), 6,72 (1H, d, J=7.8 Hz), 6.87 in (1H, DD, J=7,2, 5,2 Hz), 64 (1H, DD, J=7,2, 1.8 Hz), with 8.05 (1H, DD, J=5,2, 1.8 Hz).

Example 3

1-[(2-Methoxy-3-pyridyl)methyl]-4-finetipped

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.39 (3H, m), 1,52-to 1.61 (2H, m), 1,68-to 1.77 (2H, m), 1,96-2,07 (2H, m), 2,58-of 2.66 (2H, m), 2,85-of 2.93 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,14-7,21 (3H, m), 7.23 percent-7,31 (2H, m), the 7.65 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 4

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-hydroxyphenethyl)piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.42 (3H, m), 1,46-and 1.54 (2H, m), 1,69-to 1.77 (2H, m), 2.00 in of 2.10 (2H, m), 2.57 m) 2.63 in (2H, m), 2,73-of 3.00 (2H, m), 3,55 (2H, s), 3,90 (3H, s), to 6.58 (1H, DD, J=7,5, 1.1 Hz), 6,79 (1H, DDD, J=7,5, 7,5, 1,1 Hz), 6,86 (1H, DD, J=7,2, 5,1 Hz), 7,00 (1H, DDD, J=7,5, to 7.5, 1.6 Hz), 7,07 (1H, DD, J=7,5, and 1.6 Hz), a 7.62 (1H, DD, J=7,2, 1.9 Hz), 8,07 (1H, DD, J=5,1, 1.9 Hz).

Example 5

1-[(2-Methoxy-3-pyridyl)methyl]-4-(3-florfenicol)piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,21-of 1.40 (3H, m)and 1.51-of 1.61 (2H, m), 1,65-to 1.77 (2H, m), 1,95-of 2.08 (2H, m), 2.57 m)-2,66 (2H, m), 2,85-to 2.94 (2H, m), of 3.48 (2H, s), of 3.95 (3H, s), 6,83-6,91 (2H, m), 6.87 in (1H, DD, J=7,1, 4,9 Hz)6,94 (1H, m), 7.18 in-7,26 (1H, m), of 7.64 (1H, DD, J=7,1, 2.0 Hz), with 8.05 (1H, DD, J=4,9, 2.0 Hz).

Example 6

1-[(2-M is toxi-3-pyridyl)methyl]-4-(2-cryptomaterial)piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.42 (3H, m)and 1.51-of 1.61 (2H, m), was 1.69 and 1.80 (2H, m), 1,99-2,11 (2H, m), 2,73-2,82 (2H, m), 2,87-2,95 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,1, 4.9 Hz), 7,26 (1H, DD, J=7,7, 7,6 Hz), 7,31 (1H, d, J=7.5 Hz), was 7.45 (1H, DD, J=7,6, 7.5 Hz), 7,60 (1H, d, J=7,7 Hz), the 7.65 (1H, DD, J=7,1, 1.9 Hz), with 8.05 (1H, DD, J=4,9, 1.9 Hz).

Example 7

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(1-pyrazolo)phenethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,10-of 1.23 (3H, m), 1.32 to 1.39 in (2H, m), 1,49-of 1.57 (2H, m), 1,90 of 1.99 (2H, m), 2,52 at 2.59 (2H, m), 2,78-to 2.85 (2H, m), 3,44 (2H, s), 3,93 (3H, s), 6.42 per (1H, DD, J=2,0, 2,0 Hz), 6,85 (1H, DD, J=7,2, 4,8 Hz), 7,24-7,38 (4H, m), 7,56 (1H, d, J=2.0 Hz), to 7.61 (1H, DD, J=7,2, 2.0 Hz), of 7.70 (1H, d, J=2.0 Hz), of 8.04 (1H, DD, J=4,8, 2.0 Hz).

Example 8

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(4-acetylpiperidine)phenethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.39 (3H, m), 1,52-to 1.61 (2H, m), 1,71-to 1.79 (2H, m), 1,97-2,07 (2H, m), and 2.14 (3H, s), 2,65-of 2.72 (2H, m), 2,81-2,94 (6N, m)of 3.48 (2H, s), 3,55-3,61 (2H, m), 3,70-of 3.78 (2H, m), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 4,8 Hz),? 7.04 baby mortality (1H, d, J=7,6 Hz), 7,07 (1H, DD, J=7,6, 7,2 Hz), 7,17 (1H, DD, J=7,6, 7,2 Hz), 7,21 (1H, d, J=7,6 Hz), to 7.64 (1H, DD, J=7,2, 1,6 Hz), with 8.05 (1H, DD, J=4,8, 1,6 Hz).

Note the R 9

1-[(2-Methoxy-3-pyridyl)methyl]-4-[6-(methylsulphonyl)-2,3-methylenedioxyphenethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1.56 to of 1.66 (2H, m), 1,73-of 1.81 (2H, m), 2,02 is 2.10 (2H, m), 2,88-to 2.99 (4H, m), 3.04 from (3H, s)to 3.49 (2H, s), of 3.95 (3H, s), between 6.08 (2H, s), is 6.78 (1H, d, J=8,3 Hz), 6.87 in (1H, DD, J=7,2, 5.0 Hz), a 7.62 (1H, d, J=8,3 Hz), 7,66 (1H, DD, J=7,2, 1.8 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 10

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-thienyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,59 is 1.75 (4H, m), 1,95 e 2.06 (2H, m), 2,80-of 2.93 (4H, m), 3,47 (2H, s), of 3.94 (3H, s), 6,77 (1H, d, J=3.5 Hz), 6,85 (1H, DD, J=7,1, 4.9 Hz), make 6.90 (1H, DD, J=5,1, 3.5 Hz), to 7.09 (1H, d, J=5,1 Hz), to 7.64 (1H, DD, J=7,1, 1.8 Hz), of 8.04 (1H, DD, J=4,9, 1.8 Hz).

Example 11

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-methoxy-2-thienyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ to 1.24 to 1.37 (3H, m), 1,52-to 1.59 (2H, m), 1,67-to 1.77 (2H, m), 1,96-2,07 (2H, m), 2,67-to 2.74 (2H, m), 2,85 of 2.92 (2H, m), 3,47 (2H, s), of 3.80 (3H, s), of 3.94 (3H, s), to 6.80 (1H, d, J=5.5 Hz), 6,86 (1H, DD, J=7,1, 4.9 Hz), 6,98 (1H, d, J=5.5 Hz), to 7.64 (1H, DD, J=7,1, 1.8 Hz), of 8.04 (1H, DD, J=4,9, 1.8 Hz).

Example 12

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-cyano-2-ment who yl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,40 (3H, m), 1,62-to 1.77 (4H, m), 1,98-of 2.09 (2H, m), 2,87-2,95 (2H, m), 2,99-of 3.06 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,1, 4.9 Hz), 7,11 (1H, d, J=5.3 Hz), 7,17 (1H, d, J=5.3 Hz), to 7.64 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 13

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-phenyl-2-thienyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ to 1.21 to 1.31 (3H, m), 1,55 was 1.69 (4H, m), 1,91 is 2.01 (2H, m), 2,80 of 2.92 (4H, m), of 3.46 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,00 (1H, d, J=5,2 Hz), to 7.15 (1H, d, J=5,2 Hz), 7,27-the 7.43 (5H, m), a 7.62 (1H, DD, J=7,1, 2.0 Hz), of 8.04 (1H, DD, J=4,9, 2.0 Hz).

Example 14

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-thienyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,25-to 1.38 (3H, m), 1,54-of 1.64 (2H, m), of 1.66 to 1.76 (2H, m), 1,96-2,07 (2H, m), 2,62 of 2.68 (2H, m), 2,85-to 2.94 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 6.87 in (1H, DD, J=7,2, 5,2 Hz), 6.90 to-6,95 (2H, m), 7,24 (1H, DD, J=5,2, 3.0 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 15

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-methanesulfonyl-3-thienyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material of the method is om, described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.41 (3H, m), 1.56 to of 1.66 (2H, m), 1,68 and 1.80 (2H, m), 1,97 is 2.10 (2H, m), 2,85-to 2.99 (4H, m), 3,14 (3H, s), of 3.48 (2H, s), of 3.95 (3H, s), (3H, s)6,86 (1H, DDD, J=7,1, 4.9 Hz), 7,01 (1H, d, J=5,0 Hz), 7,56 (1H, d, J=5.0 Hz), to 7.64 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 16

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(benzo[b]thiophene-2-yl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.41 (3H, m), 1,65-of 1.78 (4H, m), 1,96-2,07 (2H, m), 2,85-of 2.97 (4H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5,1 Hz), of 6.99 (1H, s), from 7.24 (1H, DD, J=7,5, 7,1 Hz), 7,30 (1H, DD, J=7,9, 7,1 Hz), to 7.64 (1H, DD, J=7,3, 2.0 Hz), 7,66 (1H, d, J=7.5 Hz), of 7.75 (1H, d, J=7.9 Hz), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 17

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-methylsulphonyl-3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,40 (3H, m), 1,60 by 1.68 (2H, m), 2,02 is 2.10 (2H, m), 2,88-2,95 (2H, m), is 3.08-3,14 (2H, m), 3,37 (3H, m), 3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 4,8 Hz), the 7.43 (1H, DD, J=7,8, and 4.8 Hz), 7,66 (1H, DD, J=7,2, 1.8 Hz), 7,71 (1H, DD, J=7,8, 1.8 Hz), with 8.05 (1H, DD, J=4,8, 1.8 Hz), to 8.41 (1H, DD, J=4,8, 1.8 Hz).

Example 18

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-n-butyl-3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described the data in example 1.

1H-NMR (400 MHz, CDCl3) δ to 0.96 (3H, t, J=7,3 Hz), of 1.30 to 1.48 (5H, m), 1,48-of 1.56 (2H, m), 1,63 and 1.80 (4H, m), 2,00-2,11 (2H, m), 2.57 m)-2,66 (2H, m), 2,77 (2H, t, J=8.1 Hz), 2,88-of 2.97 (2H, m), 3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7,03 (1H, DD, J=7,6, 4,8 Hz), 7,39 (1H, DD, J=7,2, 1.8 Hz), the 7.65 (1H, DD, J=7,6, 1.8 Hz), of 8.06 (1H, DD, J=5.0 and 1.8 Hz).

Example 19

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.40 (3H, m), 1,54-of 1.62 (2H, m), 1,67 to 1.76 (2H, m), 1,98-of 2.08 (2H, m), 2,60-of 2.66 (2H, m), 2,87-2,96 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=8,0, 5.0 Hz), 7,20 (1H, DD, J=8.0 a, 5,0 Hz), 7,49 (1H, DDD, J=8.0 a, 2,0, 2,0 Hz), the 7.65 (1H, d, J=8.0 Hz), of 8.06 (1H, DD, J=5.0 and 2.0 Hz), 8,42-8,46 (2H, m).

Example 20

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-phenoxy-3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.40 (3H, m), 1,55 by 1.68 (2H, m), 1,70-1,80 (2H, m), 1,98-of 2.08 (2H, m), 2,90-2,77 (2H, m), 1,98-of 2.08 (2H, m), 2,70-2,77 (2H, m), 2,86-to 2.94 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 5.0 Hz), 6,93 (1H, DD, J=7,1, 5.0 Hz), 7,07-7,11 (2H, m), 7,17 (1H, m), of 7.36-7,42 (2H, m), 7,52 (1H, DD, J=7,1, 2.0 Hz), to 7.64 (1H, DD, J=7,1, 2.0 Hz), 8,00 (1H, DD, J=5.0 and 2.0 Hz), with 8.05 (1H, DD, J=5.0 and 2.0 Hz).

Example 21

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(5-methoxy-2-pyridyl)ethyl]piperidine

310 mg specified in the connection header in the form of a demon who Vatan oil is obtained from 300 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 592 mg chloride [(5-methoxy-2-pyridyl)methyl]triphenylphosphane the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.41 (3H, m), 1,59 by 1.68 (2H, m), 1,71 of-1.83 (2H, m), 1,97-of 2.08 (2H, m), 2,79-to 2.94 (4H, m), 3,49 (2H, s), 3,82 (3H, m), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,1, 4.9 Hz), to 7.09 (1H, d, J=2,9 Hz), to 7.09 (1H, d, J=2,9 Hz), the 7.65 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz), 8,11 (1H, DD, J=2,9, 2,9 Hz).

Example 22

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(4-methoxyphenyl-3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,11-of 1.23 (3H, m), 1.41 to 1,49 (2H, m)and 1.51-of 1.59 (2H, m), 1,90 of 1.99 (2H, m), 2,62-2,69 (2H, m), 2,78-is 2.88 (2H, m)2,44 (2H, s), 3,85 (3H, s), 6,85 (1H, DD, J=7,2, 4,8 Hz), of 6.96 (2H, d, J=8,4 Hz), 7,17 (1H, DD, J=8.0 a, 4,8 Hz), 7,49 (2H, d, J=8,4 Hz), EUR 7.57 (1H, DD, J=8.0 a, 1,6 Hz), to 7.61 (1H, DD, J=7,2, 2.0 Hz), of 8.04 (1H, DD, J=4,8, 2.0 Hz), 8,49 (1H, DD, J=4,8, 1,6 Hz).

Example 23

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(1,3-thiazol-2-ileti]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,29-of 1.40 (3H, m), 1,69-of 1.81 (4H, m), 1,97-2,07 (2H, m), 2,85-of 2.93 (2H, m), 3,01-is 3.08 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5,1 Hz), 7,18 (1H, d, J=3.5 Hz), to 7.64 (1H, DD, J=7,3, 2.0 Hz), 7,66 (1H, d, J=3.5 Hz), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 24

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-(1-morpholino)3-pyridyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.39 (3H, m), 1.56 to of 1.64 (2H, m), 1.70 to of 1.78 (2H, m), 1,99-2,07 (2H, m), 2,60-of 2.66 (2H, m), 2,86-to 2.94 (2H, m), 3,10 (4H, t, J=4,7 Hz), 3,49 (2H, s), 3,85 (4H, J=4,7 Hz), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,4, 4,8 Hz), 6,93 (1H, DD, J=7,4, 4,8 Hz), 7,46 (1H, DD, J=7,4, 1.9 Hz), to 7.64 (1H, DD, J=7,4, 1.9 Hz), of 8.06 (1H, DD, J=4,8, 1.9 Hz), 8,18 (1H, DD, J=4,8, 1.9 Hz).

Example 25

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-aminoethanethiol)piperidine

255 mg specified in the title compounds as colorless crystals obtained from 310 mg of 1-[ (2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 767 mg of bromide (2-nitrobenzyl)triphenylphosphane the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,40 (3H, m), 1,52-of 1.66 (2H, m), 1,72-to 1.82 (2H, m), 2.00 in of 2.10 (2H, m), 2,46-of 2.54 (2H, m), 2,87-2,96 (2H, m), 3,49 (2N, C)and 3.59 (2H, Sirs), of 3.95 (3H, s), of 6.68 (1H, DD, J=8,3, 1.1 Hz), was 6.73 (1H, DD, J=7,4, 1.1 Hz), 6.87 in (1H, DD, J=7,1, 4.9 Hz), 7,01-7,06 (2H, m), the 7.65 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 26

1-[(2-Methoxy-3-pyridyl)methyl]-4-[(2-methylsulfonylamino)phenethyl]piperidine

255 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(2-aminopentyl)piperidine, 110 mg methylsulfonylamino and 0.13 ml of pyridine are dissolved in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 3 hours. The reaction mixture paddel which allow the addition of 1 N. an aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate chromatography on NH form silica gel (ethyl acetate:hexane=1:1), resulting in getting 286 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.41 (3H, m), 1,50-1,60 (2H, m), 1,68-of 1.78 (2H, m), 2,00-2,09 (2H, m), 2,61 of 2.68 (2H, m), 2,88-2,95 (2H, m), 3,03 (3H, s)to 3.49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,3, 5.0 Hz), 7,15-7,26 (3H, m), was 7.45 (1H, m), the 7.65 (1H, DD, J=7,3, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 27

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-6-methyl-3-pyridyl)ethyl]piperidine

445 mg specified in the title compound as a colourless oil is obtained from 500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 1.01 g of chloride [(2-chloro-6-methyl-3-pyridyl)methyl]triphenylphosphane the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.39 (3H, m), 1,50-to 1.59 (2H, m), 1.70 to of 1.78 (2H, m), 1,98-2,07 (2H, m), 2.49 USD (3H, s), 2.63 in-a 2.71 (2H, m), 2,86-2,95 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,1, 4.9 Hz), 7,01 (1H, d, J=7.9 Hz), 7,41 (1H, d, J=7.9 Hz), the 7.65 (1H, DD, J=7,1, 2.0 Hz), with 8.05 (1H, DD, J=4,9, 2.0 Hz).

Example 28

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(6-chloro-3-pyridyl)ethyl]piperidine

600 mg indicated in the title the connection information in the form of a colourless oil is obtained from 504 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 1.01 g of chloride [(6-chloro-3-pyridyl)methyl]triphenylphosphane the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1,23-to 1.38 (3H, m), 1,50-to 1.59 (2H, m), 1,66-of 1.74 (2H, m), 1,96 e 2.06 (2H, m), 2.57 m-to 2.65 (2H, m), 2,85-to 2.94 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, d, J=7,1, 5.0 Hz), 7,24 (1H, d, J=8,3 Hz), 7,46 (1H, d, J=8,3, 2.4 Hz), 7,63 (1H, DD, J=7,1, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz), to 8.20 (1H, d, J=2,4 Hz).

Example 29

1-[(2-Methoxy-3-pyridyl)methyl]-4-[(E)-2-(2-pyridyl)-1-ethynyl]piperidine

488 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, 1.07 g of chloride (2-pyridylmethyl)triphenylphosphine and 561 mg of tert-butoxide potassium suspended in 10 ml of N,N-dimethylformamide and the mixture is stirred for 1 hour at room temperature. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:9), resulting in a gain 453 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,55-1,70 (3H, m), 1,75-of 1.85 (2H, m), 2,08-of 2.20 (2H, m), 2.91 in is 3.00 (2H, m), 3,53 (2H, s), of 3.96 (3H, s), 6.48 in (1H, DD, J=15,8, 1.3 Hz), of 6.71 (1H, DD, J=15,8 and 6.9 Hz), to 6.88 (1H, DD, J=7,2, 5.0 Hz) 7,10 (1H, DDD, J=7,6, to 4.8, 1.1 Hz), 7,25 (1H, m), 7,60 (1H, DDD, J=7,6, to 7.6, 1.8 Hz), to 7.67 (1H, DD, J=7,2, 1.9 Hz), of 8.06 (1H, DD, J=5.0 and 1.9 Hz), 8,53 (1H, m).

Example 30

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-pyridyl)ethyl]piperidine

332 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(E)-2-(2-pyridyl)-1-ethynyl]piperidine obtained in example 29, and 79 mg powder 10% palladium on coal (product containing water) suspended in 5 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at normal temperature and under normal pressure for 30 minutes. The reaction solution is filtered and the filtrate is evaporated to obtain 234 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.41 (3H, m), 1,62-of 1.78 (4H, m), 1,98-of 2.09 (2H, m), was 2.76-2,84 (2H, m), 2,86-2,95 (2H, m), 3,49 (2H, s), of 3.94 (3H, s), 6.87 in (1H, DD, J=7,5, 5.0 Hz), 7,10 (1H, DDD, J=7,5, 5,0, 1.2 Hz), 7,14 (1H, d, J=7.5 Hz), 7,58 (1H, DDD, J=7,5, 7,5, 2,0 Hz), the 7.65 (1H, DD, J=7,5, 2.0 Hz), with 8.05 (1H, DD, J=5.0 and 2.0 Hz), charged 8.52 (1H, m).

Example 31

1-[(2-Methoxy-3-pyridyl)methyl]-4-[(E)-(2,3-(methylenedioxyphenyl)-1-ethynyl]piperidine

324 mg specified in the title compound as a colourless oil is obtained from 784 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 1.76 g of chloride (3,4-methylenedioxybenzyl)triphenylphosphane by the method described in example 29.

1H-NMR (400 MHz, CDCl3) δ 1,48-of 1.62 (3H, m), 1.70 to to 1.79 (2H, m), 2,062,18 (2H, m), 2,90-to 2.99 (2H, m), 3,52 (2H, s), of 3.96 (3H, s)5,94 (2H, s), 6,00 (1H, DD, J=15,8, 7,2 Hz), of 6.29 (1H, d, J=15,8 Hz), 6,70-6,79 (2H, m), 6,83-6,92 (2H, m), to 7.67 (1H, DD, J=7,0, 1.8 Hz), of 8.06 (1H, DD, J=5,2, 1.8 Hz).

Example 32

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine

of 2.35 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, 4.68 g of chloride [(2-chloro-3-pyridyl)methyl]triphenylphosphine and 1.24 g of tert-butoxide potassium suspended in 50 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:19). The product obtained 330 mg of platinum oxide are suspended in a mixed solvent consisting of 20 ml of ethanol and 40 ml of tetrahydrofuran. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 20 hours. The reaction solution is filtered and the filtrate is evaporated. Then the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:19), resulting in a gain 1,89 g specified the title compound as a colourless oil.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.44 (3H, m), 1,54-of 1.62 (2H, m), 1.70 to is 1.81 (2H, m), 2.00 in a 2.12 (2H, m), 2,70-2,77 (2H, m), 2,88 are 2.98 (2H, m), 3,51 (2H, s), 3,95 (ZN, C), to 6.88 (1H, DD, J=7,4, 5,2 Hz), 7,17 (1H, DD, J=7,4, 5.0 Hz), 7,53 (1H, DD, J=7,4, 2.0 Hz), 7,66 (1H, DD, J=5,2, 2.0 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz), 8,24 (1H, DD, J=5.0 and 2.0 Hz).

Example 33

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[4-(methylsulphonyl)-3-(1,3-thiazol-2-yl)-2-thienyl]ethyl]piperidine

250 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, 680 mg bromide [[4-(methylsulphonyl)-3-bromo-2-thienyl)]methyl]triphenylphosphine and 258 mg of tert-butoxide potassium suspended in 5 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:4). The resulting product, 408 mg of 2-(tributylstannyl)thiazole and 39 mg of tetrakis(triphenylphosphine)palladium suspended in 5 ml of toluene and the mixture refluxed for 8 hours in a stream of nitrogen. The solvent is evaporated and then the residue purified and allocate column chromatography on silica gel (ethyl acetate). Received the product and 00 mg powder 10% palladium on coal (product, containing water) suspended in 10 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 3 hours. The reaction solution is filtered and the filtrate is evaporated to obtain 230 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,18-of 1.32 (3H, m), 1,54-of 1.65 (4H, m), 1,92-2,02 (2H, m), was 2.76-2,90 (4H, m), 3,24 (3H, s), 3,44 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,4, 5.0 Hz), 7,55 (1H, d, J=3,4 Hz), the 7.65 (1H, DD, J=7,4, 2,0 Hz), 7,94 (1H, d, J=3,4 Hz), with 8.05 (1H, DD, J=5.0 and 2.0 Hz), 8,10 (1H, s).

Example 34

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[3-(1,3-thiazol-2-yl)-2-thienyl]ethyl]piperidine

230 mg specified in the title compound as a colourless oil is obtained from 400 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 974 mg bromide [(Z-bromo-2-thienyl)methyl]triphenylphosphane by the method described in example 33.

1H-NMR (400 MHz, CDCl3) δ 1,29 was 1.43 (3H, m), 1,65-of 1.78 (4H, m), 1,98-of 2.09 (2H, m), 2,87-2,95 (2H, m), 3,21-of 3.27 (2H, m), 3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, d, J=7,5, a 4.9 Hz), 7,13 (1H, d, J=5,2 Hz), 7,29 (1H, d, J=3,4 Hz), 7,40 (1H, d, J=5,2 Hz), 7,66 (1H, DD, J=7,5, 2.0 Hz), 7,83 (1H, d, J=3,4 Hz), with 8.05 (1H, DD, J=4,9, 2.0 Hz).

Example 35

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(1,3-thiazol-2-yl)phenethyl]piperidine

233 mg specified in the title compound as a colourless oil is obtained from 293 mg of 1-[(2-methoxy-3-pyridyl)IU is Il]-4-piperidinecarboxylate, obtained as described in comparative example 2, and bromide (2-bromobenzyl)triphenylphosphane by the method described in example 33.

1H-NMR (400 MHz, CDCl3) δ 1,15 of 1.28 (3H, m), 1,42 of 1.50 (2H, m), 1.56 to of 1.66 (2H, m), 1.93 and-2,02 (2H, m), 2,80-2,89 (2H, m), 2.91 in are 2.98 (2H, m), of 3.45 (2H, s), of 3.94 (3H, s), 6,85 (1H, DD, J=6,8, 4,8 Hz), 7,26 (1H, DD, J=7,6, 7,6 Hz), 7,30 (1H, d, J=7,6 Hz), 7,35 (1H, DD, J=7,6, 7,6 Hz), 7,39 (1H, d, J=3.2 Hz), EUR 7.57 (1H, d, J=7,6 Hz), a 7.62 (1H, DD, J=6,8, 2.0 Hz), 7,88 (1H, d, J=3.2 Hz), of 8.04 (1H, DD, J=4,8, 2.0 Hz).

Example 36

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

591 mg of 4-(2,3-methylenedioxyphenethyl)piperidine, 404 mg of 3-(chloromethyl)-2-methoxypyridine and 415 mg of potassium carbonate are suspended in 5 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 12 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:9) to obtain 809 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,53-to 1.61 (2H, m), 1,68-of 1.78 (2H, m), 1,97-to 2.06 (2H, m), 2,56-2,62 (2H, m), 2,85 of 2.92 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), of 5.92 (2H, s), 6,63-6,70 (2H, m), of 6.75 (1H, DD, J=7,7, 7,7 Hz), 6,86 (1H, DD, J=7,1, 5.0 Hz), to 7.64 (1H, DD, J=7,1, 1.9 Hz), with 8.05 (1H, d is, J=5,0, 1.9 Hz).

Example 37

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-cyanophenyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1,57-of 1.65 (2H, m), 1,72 and 1.80 (2H, m), 1,98-of 2.09 (2H, m), 2,81-2,95 (4H, m), of 3.48 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,3, 5,1 Hz), 7,27 (1H, DDD, J=7,7, and 7.7, 0.9 Hz), 7,31 (1H, DD, J=7,7, 1.5 Hz), to 7.50 (1H, DDD, J=7,7, and 7.7, 1.5 Hz), 7,60 (1H, DD, J=7,7, 0.9 Hz), the 7.65 (1H, DD, J=7,3, 2.0 Hz), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 38

1-[(2-Methoxy-3-pyridyl)methyl]-4-(3-cyanophenyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1,52-to 1.61 (2H, m), 1,66-of 1.78 (2H, m), 1,97-2,07 (2H, m), 2,61-2,70 (2H, m), 2,86-to 2.94 (2H, m), of 3.48 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,3, 5,1 Hz), 7,33-to 7.50 (4H, m), of 7.64 (1H, DD, J=7,3, 1.8 Hz), with 8.05 (1H, DD, J=5,1, 1.8 Hz).

Example 39

1-[(2-Methoxy-3-pyridyl)methyl]-4-(4-phenylphenate)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.40 (3H, m), 1,57-of 1.64 (2H, m), 1,70-1,80 (2H, m), 2.00 in of 2.08 (2H, m), 2,64-2,70 (2H, m), 2,86-to 2.94 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7,22-7,27 (2H, m), 7,32 (1H, m), 7,40 was 7.45 (2H, m), 7,49-7,53 (2H, m), 7,56-of 7.60 (2H, m), the 7.65 (1H, DD, J=7,2, 1.8 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 40

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-phenylphenate)piperidine

181 mg of 4-(2-phenylphenate)piperidine synthesized from the corresponding starting material as described above, 150 mg of 2-methoxy-Z-pyridinecarboxamide and 226 mg of triacetoxyborohydride sodium suspended in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 20 hours. The reaction mixture is otshelushivaet adding 1 to N. aqueous sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:19) to give 213 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,07 is 1.20 (3H, m), 1,37-to 1.45 (2H, m), 1,45-of 1.53 (2H, m), 1,87-of 1.97 (2H, m), 2,55-2,62 (2H, m), 2,75-and 2.83 (2H, m), of 3.43 (2H, s), 3,93 (3H, s), 6,85 (1H, DD, J=7,6, 5.0 Hz), 7.18 in-7,42 (N, m), 7,60 (1H, DD, J=7,6, 2.0 Hz), of 8.04 (1H, DD, J=5.0 and 2.0 Hz).

Example 41

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-methylthiophenyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1,52-of 1.62 (2H, m), 1,71-to 1.82 (2H, m), 2,02 and 2.13 (2H, m), the 2.46 (3H, s), 2,68-to 2.74 (2H, m), 2,87-of 2.97 (2H, m), 3,51 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5,2 Hz),? 7.04 baby mortality-7,14 (2H, m), 7,16-7,21 (2H, m), 7,66 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 42

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-methoxyphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,23-to 1.38 (3H, m), 1,48-of 1.57 (2H, m), 1.70 to to 1.79 (2H, m), 1,97-2,07 (2H, m), 2.57 m-to 2.65 (2H, m), 2,85-of 2.93 (2H, m), of 3.48 (2H, s), 3,81 (3H, s), of 3.94 (3H, s), at 6.84 (1H, DD, J=8,0, 1.2 Hz), 6,86 (1H, DD, J=7,2, 5.0 Hz), to 6.88 (1H, DDD, J=7,6, to 7.6, 1.2 Hz), 7,12 (1H, DD, J=7,6, and 1.6 Hz), 7,17 (1H, DDD, J=8,0, to 7.6, 1.6 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5.0 and 2.0 Hz).

Example 43

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-methylsulphonyl-2-thienyl)ethyl]piperidine

to 4.41 g of the hydrochloride of 4-[2-(3-methylsulphonyl-3-thienyl)ethyl]piperidine, of 2.36 g of 3-(chloromethyl)-2-methoxypyridine and 5,90 g of potassium carbonate are suspended in 30 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 12 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain 809 mg specified in the title compounds as colorless oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.42 (3H, m), 1,66-of 1.78 (4H, m), 2,00-2,09 (2H, m), 2,88-to 2.94 (2H, m), 3,06 (3H, s), 3,17-of 3.23 (2H, m), 3,49 (2H, s), of 3.94 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7,18 (1H, d, J=5.4 Hz), 7,30 (1H, d, J=5.4 Hz), to 7.64 (1H, DD, J=7,2, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 44

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulphonyl)-2-thienyl]-1-ethynyl]piperidine

500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(1-ethynyl)piperidine, 530 mg of 2-bromo-3-(methylsulphonyl)thiophene, 21 mg of anhydrous copper iodide and 127 mg of tetrakis(triphenylphosphine)palladium suspended in a mixed solvent consisting of 2.2 ml of triethylamine and 2.2 ml of N,N-dimethylformamide, and the mixture was stirred at 100°C for 2 hours in a stream of nitrogen. To the reaction solution was added ethyl acetate, and the resulting precipitates is filtered off. To the filtrate we use the t water and the mixture extracted with ethyl acetate. The solvent is evaporated, and then the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate), resulting in a gain of 450 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,77-1,89 (2H, t), 1.93 and-2,03 (2H, m), 2,25-is 2.37 (2H, m), 2,70-2,84 (3H, m), 3,19 (3H, m), 3,51 (2H, s), of 3.95 (3H, s), 6.87 in (1H, d, J=7,2, 5.0 Hz), 7,21 (1H, d, J=7,1 Hz), 7,38 (1H, d, J=7,1 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5.0 and 2.0 Hz).

Example 45

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulphonyl)-2-thienyl]ethyl]piperidine

450 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulphonyl)-2-thienyl]-1-ethinyl]piperidine and 250 mg powder 10% palladium on coal (product containing water) suspended in 10 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 8 hours. The reaction solution is filtered and the filtrate is evaporated to obtain specified in the title compound as a yellow oil (quantitative yield).

The data of the NMR spectrum is specified in the header connections coincide with the NMR data of the compound of example 42.

Example 46

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(methylsulphonyl)-3,4-methylenedioxyphenethyl]piperidine

800 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, 1,90 g bromide [2-(methylsulphonyl)-3,4-methylenedioxybenzyl]triphenyl Estonia and 384 mg of tert-butoxide potassium suspended in 10 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:4). Received the product and 400 mg powder 10% palladium on coal (product containing water) are suspended in 40 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 30 minutes. The reaction solution is filtered and the filtrate is evaporated to obtain specified in the title compounds as colorless oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ 1,30-1,40 (3H, m), 1,52 is 1.60 (2H, m), 1,68-of 1.78 (2H, m), 2,00-2,09 (2H, m), 2,86-of 2.93 (2H, m), 2,96-to 3.02 (2H, m), 3,21 (3H, s)to 3.49 (2H, s), of 3.95 (3H, s), 6,12 (2H, s), of 6.75 (1H, d, J=8.1 Hz), 6,86 (1H, d, J=7,1, 5.0 Hz), 6,93 (1H, d, J=8.1 Hz), to 7.64 (1H, DD, J=7,1, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 47

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine

500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, 905 mg chloride [ (2-chloro-3-pyridyl)methyl]triphenylphosphine and 340 mg of tert-butoxide potassium suspended in 15 ml of N,N-dimethylformamide and the mixture is stirred in to the room temperature for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:19). The resulting product is added to the solution in which 116 mg of benzyl alcohol and 35 mg of 60% sodium hydride suspended in the oil, dissolved in 5 ml of N,N-dimethylformamide and stirred at room temperature for 1 hour, after which the mixture was stirred at 120°C for 2 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:19). Received the product and 50 mg powder 5% palladium on coal (product containing water) are suspended in 20 ml of methanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 3 hours. The reaction solution is filtered and after evaporation of the filtrate him washed with ethyl acetate, resulting in a gain of 130 mg specified in the header is the connection in the form of colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.39 (3H, m), 1,49-to 1.59 (2H, m), 1,70-1,80 (2H, m), 1,97-of 2.09 (2H, m), 2,50-of 2.58 (2H, m), 2,84-of 2.93 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), of 6.20 (1H, DD, J=6,8, 6,8 Hz)6,86 (1H, DD, J=7,2, 4,8 Hz), 7,20 (1H, DD, J=6,8, 2.0 Hz), 7,26 (1H, DD, J=6,8, 2.0 Hz), to 7.64 (1H, DD, J=4,8, 2.0 Hz), of 8.04 (1H, DD, J=4,8, 2.0 Hz).

Example 48

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[2-(1,3-thiazol-2-yl)-3-pyridyl]ethyl]piperidine

150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-[[(trifluoromethyl)sulfonyl]oxy]-3-pyridyl]ethyl]piperidine, 180 mg of 2-(tributylstannyl)thiazole and 20 mg of tetrakis(triphenylphosphine)palladium suspended in 4 ml of toluene and the mixture refluxed for 2 hours in a stream of nitrogen. The solvent is evaporated and then the residue purified and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:4) to obtain 39 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.41 (3H, m), 1,52-of 1.62 (2H, m), 1,72-of 1.78 (2H, m), 1,99-of 2.09 (2H, m), 2,86-to 2.94 (2H, m), 3.27 to to 3.34 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7.23 percent (1H, DD, J=8.0 a, 4,8 Hz), 7,40 (1H, d, J=3,4 Hz), to 7.61 (1H, DD, J=8.0 a, 1,6 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), to $ 7.91 (1H, d, J=3,4 Hz), with 8.05 (1H, DD, J=5.0 and 2.0 Hz), of 8.47 (1H, DD, J=4,8, 1,6 Hz).

Example 49

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[2-(4-hydroxy)piperidino]-3-pyridyl)ethyl]piperidine

269 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-[(trifluoromethyl)sulfonyl]oxy]-3-pyridyl]ethyl]piperidine, obtained as described in compare enom example 18, 178 mg of 4-hydroxypiperidine and 243 mg of potassium carbonate are suspended in 5 ml of N,N-dimethylformamide and the mixture is stirred at 130°C for 3 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:1) to give 70 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (3H, m), 1,54-1,80 (6N, m), 1,98-of 2.08 (4H, m), 2,58-of 2.64 (2H, m), 2,84-2,95 (4H, m), 3.25 to to 3.33 (2H, m), 3,49 (2H, s), a-3.84 (1H, m), of 3.95 (3H, s), 6,85-6,92 (2H, m), 7,44 (1H, d, J=7,2, 1,9 Hz), to 7.64 (1H, d, J=7,2 Hz), of 8.06 (1H, DD, J=4,9, 1.9 Hz), 8,15 (1H, DD, J=4,9, 1.9 Hz).

Example 50

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[2-(3-cyanopropyl)-3-pyridyl]ethyl]piperidine

200 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine obtained as described in comparative example 47, 95 mg γ-bromobutyronitrile and 169 mg of potassium carbonate are suspended in 5 ml of N,N-dimethylformamide and the mixture is stirred at 60°C for 4 hours. To the mixture is added ethyl acetate, the obtained salt is filtered off and the solvent is evaporated. The crude product was then purified and allocate column chromatography on NH form silica gel (ethylacetate=1:4) to obtain 77 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1,47-of 1.56 (2H, m), 1,68-to 1.77 (2H, m), 1,97-2,07 (2H, m), 2,11-of 2.21 (2H, m), of 2.51-2,61 (4H, m), 2,86-of 2.93 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 4,40-of 4.45 (2H, m), PC 6.82 (1H, DD, J=7,2, 5.0 Hz), 6.87 in (1H, DD, J=7,2, 4,8 Hz), 7,38 (1H, DD, J=7,2, 2.0 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), of 7.97 (1H, DD, J=5.0 and 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 51

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[1-(2-terbisil)-2-oxo-1,2-dihydro-3-pyridinyl]ethyl]piperidine

87 mg specified in the title compound obtained as a colorless oil of 100 mg 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine obtained in example 47, and 61 mg of 2-ftorangidridy the method described in example 49.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.36 (3H, m), 1,47-of 1.56 (2H, m), 1,68-of 1.78 (2H, m), 1,97-to 2.06 (2H, m), of 2.51-of 2.58 (2H, m), 2,84 of 2.92 (2H, m), 3,47 (2H, s), of 3.94 (3H, s)to 5.17 (2H, s), between 6.08-6,13 (1H, m)6,86 (1H, DD, J=7,2, 5,2 Hz), 7.03 is-7,16 (3H, m), 7.24 to 7,31 (2H, m), 7,40-7,46 (1H, m), of 7.64 (1H, DD, J=7,2, 2.0 Hz), of 8.04 (1H, DD, J=5,2, 2.0 Hz).

Example 52

1-[(2-Benzyloxy-3-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

369 mg specified in the title compound as a colourless oil is obtained from 478 mg of 1-[(2-chloro-3-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine by the method described below in example 120.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.36 (3H, m), 1,54-of 1.62 (2H, m), 1,69-to 1.77 (2H, m), 1,98-2,07 (2H, m), 2,56-2,63 (2H, m), 2,86 of 2.92 (2H, m), 3,53 (2H, s)5,41 (2H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,8, 1.0 Hz), of 6.68 (1H, DD, J=7,8, 1.0 Hz), to 6.75 (1H, DD, J=7,8,7,8 Hz), 6,89 (1H, DD, J=7,2, 5.0 Hz), 7,32 (1H, m), 7,35-7,41 (2H, m), 7,45 is 7.50 (2H, m), 7,68 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5.0 and 2.0 Hz).

Example 53

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-hydroxy-2-(2-thienyl)ethyl]piperidine

48,4 ml of 1.0 M (2-thienyl)lithium in tetrahydrofuran is dissolved in 40 ml of tetrahydrofuran at -78°and to this solution is added dropwise a mixed solution consisting of 10.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in example 24, and 40 ml of tetrahydrofuran. After completion of adding dropwise, the mixture is stirred for further 20 minutes at -78°C. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:3) to give 12.1 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.55 (3H, m), 1,65-2,08 (6N, m), 2,83-2,90 (2H, m), 3,47 (2H, s), of 3.94 (3H, s), of 5.03 (1H, d, J=8,3, 5,6), 6,86 (1H, DD, J=7,1, 4.9 Hz), 6,94-6,99 (2H, m), 7,25 (1H, m), 7,63 (1H, DD, J=7,1, 2,0 Hz), of 8.04 (1H, DD, J=4,9, 2.0 Hz).

Example 54

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine

12.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-hydroxy-2-(2-thienyl)ethyl]piperidine and 30.2 ml of triethylamine are dissolved in 72 ml dimethylsulfoxide to this solution under ice cooling are added dropwise a mixed solution, consisting of of 17.2 g of a complex of sulfur trioxide - pyridine and 90 ml of dimethylsulfoxide. After completion of adding dropwise, the mixture is stirred for further 30 minutes at room temperature. To the reaction solution was added aqueous sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 9.6 g specified in the title compounds as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.48 (2H, m), was 1.69 and 1.80 (2H, m), 1,94-of 2.15 (3H, m), 2,82 (2H, d, J=7,0 Hz), 2,84-of 2.93 (2H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5.0 Hz), 7,13 (1H, DD, J=4,9, 3,9 Hz), 7,63 (1H, DD, J=4,9, 1.3 Hz), to 7.64 (1H, DD, J=7,3, 1.9 Hz), of 7.70 (1H, DD, J=3,9, 1.3 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 55

N1-Methoxy, N1-methyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]ndimethylacetamide

2.6 g of ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-(piperidyl)acetate and 1.3 g of the hydrochloride of N,O-dimethylhydroxylamine suspended in 18 ml of tetrahydrofuran and to this suspension is added dropwise to 13.2 ml of 2 M solution chloropropylamine in diethyl ether at -23°C. After completion of adding dropwise, the mixture is stirred for further 30 minutes at room temperature. To the reaction solution was added aqueous saturated holdem is rid of the ammonia and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:2) to obtain 2.3 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,29-of 1.42 (2H, m), 1,69-of 1.78 (2H, m), a 1.88 (1H, m), 2.05 is-of 2.15 (2H, m), 2,32-to 2.40 (2H, m), 2,85-to 2.94 (2H, m), 3,18 (3H, s)to 3.49 (2H, s)to 3.67 (3H, s), of 3.95 (3H, s)6,86 (1H, DD, J=7,2, 5.0 Hz), of 7.64 (1H, DD, J=7,2, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 56

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine

0.50 g of N1-methoxy, N1-ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]ndimethylacetamide, obtained in example 55, dissolved in 3 ml of tetrahydrofuran and the solution added dropwise 1.8 ml of 1.0 M solution of (2-thienyl)lithium in tetrahydrofuran at -78°C. After completion of adding dropwise, the mixture is stirred for further 1 hour at -78°C. To the reaction solution was added aqueous saturated ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate) to obtain 0,22 g specified in the title compound as a pale yellow maslamani of the NMR spectrum is specified in the header connections coincide with the NMR data of the compound of example 54.

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.48 (2H, m), was 1.69 and 1.80 (2H, m), 1,94-of 2.15 (3H, m), 2,82 (2H, d, J=7,0 Hz), 2,84-of 2.93 (2H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5.0 Hz), 7,13 (1H, DD, J=4,9, 3,9 Hz), 7,63 (1H, DD, J=4,9, 1.3 Hz), to 7.64 (1H, DD, J=7,3, 1.9 Hz), of 7.70 (1H, DD, J=3,9, 1.3 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 57

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-hydroxy-2-phenylethyl)piperidine

2.2 g specified in the title compound as a yellow oil is obtained from 2.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in the comparative example, and 10.0 ml cyclohexane/diethylamino solution of 0.97 M finelite the method described in example 53.

1H-NMR (400 MHz, CDCl3) δ 1,24 is 1.60 (4H, m), 1,64-to 1.82 (3H, m), 1,96-2,07 (2H, m), 2,82-only 2.91 (2H, m), of 3.46 (2H, s)to 3.92 (3H, s), 4,71-4,78 (1H, m), at 6.84 (1H, DD, J=7,1, 4.9 Hz), 7.23 percent-7,37 (5H, m), a 7.62 (1H, DD, J=7,1, 2.0 Hz), 8,03 (1H, DD, J=4,9, 2.0 Hz).

Example 58

1-[(2-Methoxy-3-pyridyl)methyl]-4-(2-oxo-2-phenylethyl)piperidine

2.2 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-(2-hydroxy-2-phenylethyl)piperidine and 8.6 g of manganese dioxide are suspended in 35 ml of toluene and the mixture refluxed for 2 hours. The reaction solution is filtered and the filtrate is evaporated. Then the residue purified and allocate column chromatography on silica gel (ethyl acetate) to give 1.54 g specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.32 to 1.47 (2H, m), 1,70-1,80 (2H, m), 1,92-,17 (3H, m), and 2.83 vs. 2.94 (4H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5,1 Hz), 7,42-7,49 (3H, m), 7,52-to 7.59 (1H, m), of 7.64 (1H, DD, J=7,3, 2.0 Hz), 7,92-7,98 (2H, m), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 59

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidine

1.0 g of 2-bromchlorenone dissolved in 11 ml of tetrahydrofuran and the solution added dropwise at -78°add 10.0 ml of 1.54 M solution of n-utility in hexane. After stirring for 20 minutes, to the mixture are added dropwise a mixed solution consisting of 1.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in comparative example 22, and 4 ml of tetrahydrofuran. After completion of adding dropwise, the mixture is stirred 10 minutes at -78°C. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:3) to obtain 0,90 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1.32 to to 1.45 (2H, m), 1,52-of 1.95 (5H, m), 2,83-of 2.97 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), 5,19 at 5.27 (1H, m)6,86 (1H, DD, J=7,2, 5.0 Hz), 7,19 (1H, DDD, J=7,6, to 7.6, 1.6 Hz), 7,28 (1H, DD, J=7,6, and 1.6 Hz), 7,31 (1H, DDD, J=7,6, to 7.6, 1.6 Hz), EUR 7.57 (1H, DD, J=7,6, and 1.6 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), of 8.04 (1H, DD, J=5.0 and 2.0 Hz).

Example 60

-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chlorophenyl)-2-oxoethyl]piperidine

720 mg specified in the title compound as a pale yellow oil is obtained from 900 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chlorophenyl)-2-hydroxyethyl]piperidine by the method described in example 54.

1H-NMR (400 MHz, CDCl3) δ 1,32 of 1.46 (2H, m), 1,71 and 1.80 (2H, m), 1.93 and-of 2.16 (3H, m), 2,84-of 2.93 (4H, m), 3,50 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,2, 5.0 Hz), 7,26-7,44 (4H, m), of 7.64 (1H, d, J=7,2, 1.8 Hz), with 8.05 (1H, d, J=5,0, a 1.8 Hz).

Example 61

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-hydroxyethyl]piperidine

of 0.26 ml of 2-chloropyridine, 2,9 ml cyclohexane/diethylamino solution of 0.97 M finelite and 0,039 ml Diisopropylamine dissolved in 9 ml of tetrahydrofuran and the mixture is stirred for 1 hour at -45°C. To this mixture is added dropwise a mixed solution consisting of 500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in comparative example 22, and 2 ml of tetrahydrofuran, and the mixture is stirred for further 20 minutes at -45°C. To the reaction solution was added water and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:2) to give 420 mg specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,33-,47 (2H, m), 1,55-of 1.95 (5H, m), 2,01 with 2.14 (2H, m), 2,83-of 2.97 (2H, m), 3,49 (2H, s), of 3.94 (3H, s), 5,12-5,20 (1H, m)6,86 (1H, DD, J=7,3, 5.0 Hz), 7,28 (1H, DD, J=7,7, 5.0 Hz), the 7.65 (1H, DD, J=7,3, 2.0 Hz), 7,94 (1H, DD, J=7,7, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz), 8,29 (1H, DD, J=5.0 and 2.0 Hz).

Example 62

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-oxoethyl]piperidine

463 mg specified in the title compound as a pale yellow oil is obtained from 610 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-hydroxyethyl]piperidine by the method described in example 54.

1H-NMR (400 MHz, CDCl3) δ of 1.33 to 1.47 (2H, m), 1.70 to to 1.79 (2H, m), 1.93 and-2,17 (3H, m), 2,84-of 2.97 (4H, m), 3,50 (2H, s), of 3.95 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,33 (1H, DD, J=7,7, a 4.9 Hz), 7,63 (1H, DD, J=7,1, 1.8 Hz), to 7.77 (1H, DD, J=7,7, 1.9 Hz), with 8.05 (1H, DD, J=4,9, 1.9 Hz), 8,48 (1H, DD, J=4,9, 1.8 Hz).

Example 63

1-[(2-Methoxy-Z-pyridyl)methyl]-4-[2-oxo-2-(2-triptoreline)ethyl]piperidine

482 mg of 2-bromo-N-(TRIFLUOROACETYL)aniline was dissolved in a mixed solvent consisting of 1.8 ml of tetrahydrofuran and 1.8 ml of diethyl ether, and to this solution dropwise at 0°add 1,14 M solution metallice in diethyl ether. After stirring for 10 minutes the mixture is slowly upload via cannula into a solution consisting of 2.4 ml 1,51 M tert-utility and 4 ml of diethyl ether and cooled to -78°C. the Mixture is stirred for 1 hour. Then to the mixture is added dropwise a mixed solution consisting of 500 mg of N1-methoxy,N1-ethyl-2-[1-[(2-what ethoxy-3-pyridyl)methyl]-4-piperidyl]ndimethylacetamide, obtained in example 54, and 2 ml of tetrahydrofuran, and the mixture is stirred for another 20 minutes. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is produce by purification column chromatography on silica gel (ethyl acetate) to obtain 150 mg of the above compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.35 to 1.48 (2H, m), 1,70-1,80 (2H, m), 1,94-to 2.18 (3H, m), 2,87-2,95 (2H, m), 2,98 (2H, d, J=6.4 Hz), 3,51 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 4.9 Hz), 7,29 (1H, DD, J=8,6, 7,7 Hz), a 7.62 (1H, DD, J=7,2, 1.9 Hz), to 7.64 (1H, DD, J=8,1, 7,7 Hz), 8,00 (1H, d, J=8.1 Hz), of 8.06 (1H, DD, J=4,9, 1.9 Hz), to 8.70 (1H, d, J=8.6 Hz).

Example 64

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-AMINOPHENYL)-2-oxoethyl]piperidine

150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-triptoreline)ethyl]piperidine obtained as described in comparative example 63 and 141 mg of potassium carbonate are suspended in a mixed solvent consisting of 3 ml methanol and 3 ml of water, and the mixture is stirred at room temperature for 1 hour. The reaction solution is extracted with ethyl acetate and the organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain specified in the connection header in the IDA yellow oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ of 1.33 to 1.47 (2H, m), 1.70 to to 1.79 (2H, m), 1,90-2,03 (1H, m), 2.06 to 2,17 (2H, m), 2,82-to 2.94 (4H, m), 3,50 (2H, s), of 3.94 (3H, s), only 6.64 (1H, DD, J=8.0 a, 7,0 Hz), of 6.65 (1H, d, J=7,2 Hz), 6,86 (1H, DD, J=7,2, 5.0 Hz), 7,26 (1H, DDD, J=8,0, to 7.2, 1.5 Hz), to 7.64 (1H, DD, J=7,2, 1.8 Hz), 7,73 (1H, DD, J=7,0, 1.5 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 65

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-methylsulfonylamino)-2-oxoethyl]piperidine

120 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-AMINOPHENYL)-2-oxoethyl]piperidine, obtained as described in comparative example 64, 0.1 ml of triethylamine and 0,041 ml methanesulfonanilide dissolved in 2 ml of dichloromethane and the mixture is stirred for 2 hours under ice cooling. To the reaction solution was added aqueous sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate) to obtain 90 mg specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ of 1.36 to 1.47 (2H, m), 1,76-of 1.85 (2H, m), 1,99-2,22 (3H, m), 2,83-2,96 (4H, m), 3,50 (3H, s), 3,52 (2H, s), of 3.95 (3H, s)6,86 (1H, DD, J=7,3, 5.0 Hz), 7,40 (1H, DD, J=5,9, 3,4 Hz), 7,54 (1H, d, J=3,4 Hz), 7,56 (1H, d, J=3,4 Hz), the 7.65 (1H, DD, J=7,3, 1.9 Hz), to 7.67 (1H, DD, J=5,9, 3,4 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 66

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-[(2-methylsulphonyl)f the Nile]-2-oxoethyl]piperidine

953 mg of N-(tert-butoxycarbonyl)-4-[2-[2-(methylsulfinylphenyl)]-2-oxoethyl]piperidine and 19.2 ml of 4 M solution of hydrogen chloride in ethyl acetate is dissolved in 15 ml of ethyl acetate and the mixture is stirred at room temperature for 4 hours. The solvent is evaporated and the residue recrystallized from ethyl acetate to obtain 800 mg of the hydrochloride of 4-[2-(2-methylsulfinylphenyl)-2-oxoethyl]piperidine. Then the resulting product is suspended in 400 mg of 3-(chloromethyl)-2-methoxypyridine, 1.0 g of potassium carbonate and 15 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 12 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate) to give 1.07 g specified in the connection header in the form of settle-yellow oil (quantitative yield).

1H-NMR (400 MHz, CDCl3) δ of 1.33 to 1.47 (2H, m), 1,80-1,89 (2H, m), 2,02-of 2.20 (3H, m), 2,85-2,95 (4H, m)of 3.25 (3H, s), 3,50 (2H, s), of 3.95 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,41 (1H, d, J=7.5 Hz), to 7.61 (1H, DD, J=7,9, 7.5 Hz,), to 7.64 (1H, d, 3=1,1, 1.8 Hz), 7,69 (1H, DD, J=7,5, 7.5 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz), 8,07 (1H, d, J=7.9 Hz).

Example 67

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-methoxyphenyl)-2-oxoethyl]piperidine

2.4 g of 1-[(2-IU is hydroxy-3-pyridyl)methyl]-4-[2-(hydroxy-2-methoxyphenyl)ethyl]piperidine obtained by way described in example 59, from 2.1 g of 2-bromoanisole, 7,4 ml of 1.54 M solution of n-utility in hexane and 2.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in comparative example 22. Then the product is treated as described in example 54, and get 0,93 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,29 was 1.43 (2H, m), 1,65-to 1.77 (2H, m), 1,89-of 2.15 (3H, m), 2,81-2,95 (4H, m), of 3.48 (2H, s)to 3.89 (3H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), to 6.95 (1H, d, J=8,4 Hz), of 6.99 (1H, DD, J=7,5, 7.5 Hz,), 7,44 (1H, DDD, J=8,4, to 7.5, 1.5 Hz), to 7.61 (1H, DD, J=7,5, 1.5 Hz), 7,63 (1H, DD, J=7,1, 1.8 Hz), of 8.04 (1H, DD, J=4,9, 1.8 Hz).

Example 68

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(2-cyclopropylmethoxy)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 0,32 to 0.39 (2H, m), and 0.62 to 0.70 (2H, m), to 1.22 to 1.47 (3H, m), was 1.69 and 1.80 (2H, m), 1,92-2,19 (3H, m), 2,70-2,96 (2H, m), 3,01 (2H, d, J=6.9 Hz), 3,50 (2H, s), 3,88 (2H, d, J=6.5 Hz), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), to 6.88 (1H, d, J=8,4 Hz), 6,97 (1H, DD, J=7,5, 7,4 Hz), 7,40 (1H, DDD, J=8,4, to 7.4, 1.8 Hz), to 7.64 (1H, DD, J=7,5, 1.8 Hz), the 7.65 (1H, DD, J=7,1, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 69

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-triptoreline)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,29 was 1.43 (2H, m), 1,73 of-1.83 (2H, m), 1,96-to 2.18 (3H, m), and 2.79 (2H, d, J=6.6 Hz), 2,85-to 2.94 (2H, m), 3,50 (2H, s), of 3.95 (3H, s)6,86 (1H, DD, J=7,2, 4.9 Hz), 7,39 (1H, d, J=7.5 Hz), 7,54 (1H, DD, J=to 7.5, 7.5 Hz), 7,60 (1H, DD, J=7,5, 7.5 Hz), 7,63 (1H, DD, J=7,2, 1.8 Hz), 7,71 (1H, d, J=7.5 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 70

1-[(2-Methoxy-3-pyrid the l)methyl]-4-[2-oxo-2-(3-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,33 of 1.46 (2H, m), 1,68 and 1.80 (2H, m), 1,92-of 2.15 (3H, m), 2,78-to 2.94 (4H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 4.9 Hz), 7,31 (1H, DD, J=5,1, 2,9 Hz), 7,54 (1H, DD, J=5,1, 1.3 Hz), 7,63 (1H, DD, J=7,1, 1.8 Hz), 8,03 (1H, DD, J=2,9, 1.3 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 71

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,37-is 1.51 (2H, m), 1,71 and 1.80 (2H, m), 1,97-of 2.16 (3H, m), 2,85-of 2.93 (2H, m), 3,10 (2H, d, J=6.8 Hz), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,1, 5.0 Hz), to 7.64 (1H, DD, J=7,1, 1.8 Hz), to 7.67 (1H, d, J=3.0 Hz), 8,00 (1H, DD, J=3.0 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 72

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3,4-methylenedioxyphenyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,38 was 1.43 (2H, m), by 1.68 to 1.76 (2H, m), is 2.09 (1H, m) 2,80 (2H, d, J=6.8 Hz), 2,84 of 2.92 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 6,04 (2H, s), 6,85 (1H, d, J=8,2 Hz), 6,86 (1H, DD, J=7,2, 4.9 Hz), the 7.43 (1H, d, J=1,8 Hz), 7,55 (1H, d, J=8,2, 1.8 Hz), 7,63 (1H, d, J=7,2, 1.8 Hz), with 8.05 (1H, DD, J=4,9, 1.8 Hz).

Example 73

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.48 (2H, m), 1,72-to 1.82 (2H, m), 1,95-2,17 (3H, m), 2,84-to 2.99 (4H, m), 3,49 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,3, 5,1 Hz), 7,11 (1H, d, J=5,1 Hz)to 7.50 (1H, d, J=5,1 Hz), to 7.64 (1H, DD, J=to 7.3, 2.0 Hz), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 74

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-[3-(1,3-thiazol-2-yl)-3-thienyl]ethyl]piperidine

300 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine obtained in example 73, 438 mg of 2-(tributyl is nil)thiazole and 42 mg of tetrakis(triphenylphosphine)palladium suspended in 4 ml of toluene and the mixture refluxed for 2 hours in a stream of nitrogen. The solvent is evaporated and then the residue purified and allocate column chromatography on silica gel (ethyl acetate) to obtain 300 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,29 was 1.43 (2H, m), 1,66 is 1.96 (2H, m), 1,94 with 2.14 (3H, m), was 2.76-2.91 in (4H, m), of 3.48 (2H, s), of 3.94 (3H, s), 6,85 (1H, DD, J=7,3, 5,1 Hz), 7,46 (1H, d, J=3.3 Hz), 7,53 (1H, d, J=5,2 Hz), a 7.62 (1H, DD, J=to 7.3, 2.0 Hz), 7,82 (1H, d, J=5,2 Hz), to 7.93 (1H, d, J=3.3 Hz), with 8.05 (1H, DD, J=5,1, 2.0 Hz).

Example 75

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(3-phenyl-2-thienyl)ethyl]piperidine

290 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(3-bromo-2-thienyl)-2-oxoethyl]piperidine obtained in example 73, 173 mg of phenylboric acid and 42 mg of tetrakis(triphenylphosphine)palladium suspended in 5.6 ml of toluene, 1,4 ml of methanol and 2.8 ml of 2 M sodium carbonate and the mixture is refluxed for 3 hours in a stream of nitrogen. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on silica gel (ethyl acetate) to give 290 mg specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,09-1,24 (2H, m), 1,48-to 1.59 (2H, m)and 1.83 (1H, m), 1,98-2,11 (2H, m), 2,42 (2H, d, J=6.8 Hz), 2,75-2,87 (2H, m), 3,42 (2H, s), 6,30 (1H, d is, J=7,5, 6,0 Hz), 7,06 (1H, d, J=4.9 Hz), 7,33 (1H, d, J=6.0 Hz), 7,34-7,46 (5H, m), of 7.48 (1H, d, J=7.5 Hz), 7,54 (1H, d, J=4,9 Hz).

Example 76

1-[(2-Methoxy-3-pyridyl)methyl]-4-(3-phenylpropyl)piperidine

214 mg specified in the title compound as a colourless oil is obtained from 332 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in comparative example 22, and 491 mg chloride benzyltriphenylphosphonium the method described in example 46.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (5H, m), 1,57 is 1.70 (4H, m), 1,76 e 2.06 (2H, m)at 2.59 (2H, t, J=7,7 Hz), 2,84-only 2.91 (2H, m), 3,47 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,2, 5.0 Hz), 7,14-7,20 (3H, m), 7.24 to 7,30 (2H, m), of 7.64 (1H, DD, J=7,2, 1.9 Hz), of 8.04 (1H, DD, J=5.0 and 1.9 Hz).

Example 77

1-[(2-Methoxy-3-pyridyl)methyl]-4-(3-(2-thienyl)propyl)piperidine

206 mg specified in the title compound as light brown oil is obtained from 261 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinylidene obtained in comparative example 22, and 499 mg chloride (2-thienylmethyl)triphenylphosphine.

1H-NMR (400 MHz, CDCl3) δ of 1.20 and 1.35 (5H, m), 1,62-of 1.74 (4H, m), 1,76 e 2.06 (2H, m), of 2.81 (2H, t, J=7,6 Hz), 2,84 of 2.92 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 6,77 (1H, DD, J=3,4, 1,1 Hz)6,86 (1H, DD, J=7,2, 5.0 Hz), 6,91 (1H, DD, J=5,1, 3,4 Hz), 7,10 (1H, DD, J=5,1, 1.1 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), of 8.04 (1H, DD, J=5.0 and 2.0 Hz).

Example 78

1-[(2-Methoxy-3-pyridyl)methyl]-4-benzylpiperidine

472 mg specified in the title compound as a pale yellow oil is obtained from 292 mg 4-benzyl is peridine way described in example 43.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.40 (2H, m)of 1.53 (1H, m), 1,58 by 1.68 (2H, m), 1,95-2,04 (2H, m), of 2.54 (2H, d, J=7,0 Hz), 2,84-only 2.91 (2H, m), 3,47 (2H, s), 3,93 (3H, s)6,86 (1H, DD, J=7,2, 5.0 Hz), 7,12-7,21 (3H, m), 7.24 to 7,30 (2H, m), 7,63 (1H, DD, J=7,2, 2.0 Hz), of 8.04 (1H, DD, J=5.0 and 2.0 Hz).

Example 79

1-[(2-Methoxy-3-pyridyl)methyl]-4-(4-phenylbutyl)piperidine

150 ml specified in the title compound as a colourless oil is obtained from 220 mg of 3-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]propanal obtained in comparative example 30, and 407 mg chloride benzyltriphenylphosphonium the method described in example 46.

1H-NMR (400 MHz, CDCl3) δ 1,18-1,38 (7H, m), 1,55-1,70 (4H, m), 1,96 e 2.06 (2H, m)2,60 (2H, t, J=7,7 Hz), 2,84-of 2.93 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s)6,86 (1H, DD, J=7,2, 5.0 Hz), 7,14-7,20 (3H, m), 7.24 to 7,30 (2H, m), of 7.64 (1H, DD, J=7,2, 1.8 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 80

1-[(2-Methoxy-3-pyridyl)methyl]-4-[oxo(2-thienyl)methyl)piperidine

101 mg specified in the title compounds as colorless crystals obtained from 210 mg of 4-[oxo(2-thienyl)methyl]piperidine by the method described in example 43.

1H-NMR (400 MHz, CDCl3) δ 1,82-to 1.98 (4H, m), 2,14-of 2.23 (2H, m), 2,94-3,03 (2H, m)to 3.09 (1H, m), 3,52 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7,12 (1H, DD, J=5.0 and 3.8 Hz), a 7.62 (1H, DD, J=5.0 and 1.0 Hz), to 7.67 (1H, DD, J=7,2, 1.8 Hz), 7,72 (1H, DD, J=3,8, 1.0 Hz), with 8.05 (1H, DD, J=5.0 and 1.8 Hz).

Example 81

1-[(2-Methoxy-3-pyridyl)methyl]-4-piperidinecarboxylic

832 mg specified in the connection header in VI is e colorless crystals obtained from 496 mg isonipecotamide way described in example 43.

1H-NMR (400 MHz, CDCl3) δ 1,73 is 1.91 (4H, m), 2,04-2,22 (3H, m), 2,90 are 2.98 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), to 5.35 (1H, Sirs), vs. 5.47 (1H, Sirs), 6,87 (1H, DD, J=7,2, 5.0 Hz), the 7.65 (1H, DD, J=7,2, 1.9 Hz), of 8.06 (1H, DD, J=5,0, 1,9 Hz).

Example 82

N4-[(2-Phenyl)benzyl-1-[(2-methoxy-3-pyridyl)methyl]]-4-piperidinecarboxylic

212 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperazinecarboxamide, 0.16 ml of 2-(methyl bromide)biphenyl and 46 mg of 60% sodium hydride suspended in 5 ml of N,N-dimethylformamide and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate:hexane=1:3) to give 92 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,60-of 1.78 (4H, m), 1,96-of 2.08 (3H, m), 2,86-to 2.94 (2H, m), 3,47 (2H, s), of 3.94 (3H, s), 4,43 (2H, d, J=5.5 Hz), of 5.48 (1H, t, J=5.5 Hz), 6.87 in (1H, DD, J=7,2, 5.0 Hz), 7.24 to 7,45 (N, m), 7,63 (1H, DD, J=7,2, 1.9 Hz), with 8.05 (1H, DD, J=5.0 and 1.9 Hz).

Example 83

1-[(2-Methoxy-3-pyridyl)methyl]-4-[[(2-bromo-3-pyridyl)oxy]methyl]piperidine

1.18 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinemethanol obtained in comparative example 1, and 0.87 g of 2-bromo-3-hydroxypyridine restauraut 50 ml of tetrahydrofuran. When cooled at 10°With added 1.12 g of diisopropylcarbodiimide and 1.44 g of triphenylphosphine and the mixture is stirred at room temperature for 20 hours. The solvent is evaporated and the residue purified and allocate column chromatography on silica gel (dichloromethane-methanol) to obtain 550 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,40-of 1.52 (2H, m), 1,84-to 1.98 (3H, m), 2,08-2,17 (2H, m), 2,92-a 3.01 (2H, m), 3,53 (2H, s), a 3.87 (2H, d, J=6.4 Hz), of 3.96 (3H, s), to 6.88 (1H, DD, J=6,8, 4,8 Hz), 7,11 (1H, DD, J=8.0 a, 1,6 Hz), 7,19 (1H, DD, J=8,0, 4,8 Hz), the 7.65 (1H, DD, J=6,8, 2.0 Hz), of 7.97 (1H, DD, J=4,8, and 1.6 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 84

1-[(2-Methoxy-3-pyridyl)methyl]-4-[[[2-(1,3-thiazol-2-yl)-3-pyridyl]oxy]methyl]piperidine

238 mg specified in the title compound as a colourless oil is obtained from 250 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[[(2-bromo-3-pyridyl)oxy]methyl]piperidine by the method described in example 33.

1H-NMR (400 MHz, CDCl3) δ 1,44-to 1.59 (2H, m), 1,92-of 2.20 (5H, m), 2,93-to 3.02 (2H, m), of 3.54 (2H, s), of 3.96 (3H, s), Android 4.04 (2H, d, J=6.4 Hz), to 6.88 (1H, DD, J=7,2, 4,8 Hz), 7,31 (1H, DD, J=8,4, 4,4 Hz), 7,37 (1H, DD, J=8,4, 1.2 Hz), of 7.48 (1H, d, J=3.2 Hz), 7,66 (1H, DD, J=7,2, 1,6 Hz), of 8.04 (1H, d, J=3.2 Hz), of 8.06 (1H, DD, J=4,8, and 1.6 Hz), 8,39 (1H, DD, J=4,4, 1.2 Hz).

Example 85

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(3,4-methylenedioxyphenyl)ethyl]piperidine

227 mg specified in the title compound as a colourless oil is obtained from 200 mg of 4-[2-cyano-2-(3,4-is atlanticcity)ethyl]piperidine way described in example 33.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (2H, m), USD 1.43-of 1.56 (1H, m), 1,63 and 1.80 (3H, m), 1,86 is 1.96 (1H, m), 2.00 in of 2.10 (2H, m), 2,84-of 2.93 (2H, m), of 3.48 (2H, s), 3,71-of 3.77 (1H, m), of 3.94 (3H, s), 5,98 (2H, s), 6.73 x-to 6.80 (3H, m)6,86 (1H, DD, J=7,2, 4,8 Hz), a 7.62 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 86

1-[(2-Methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine

191 mg specified in the title compound as a colourless oil is obtained from 242 mg of 4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine by the method described in example 80.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (2H, m), 1,52-of 1.74 (3H, m), 1,80 is 1.91 (2H, m), 2,01-2,12 (2H, m), 2,83-2,95 (2H, m), of 3.48 (2H, s), of 3.84 (3H, s), of 3.95 (3H, s), 4,22-to 4.28 (1H, m)6,86 (1H, DD, J=7,2, 5,2 Hz), to 6.88 (1H, d, J=8.0 Hz), 6,98 (1H, DD, J=8.0 a, 7,6 Hz), 7,29 (1H, DD, J=8.0 a, 7,6 Hz), 7,40 (1H, d, J=8.0 Hz), a 7.62 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 87

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(methylsulphonyl)phenethyl]piperidine

479 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(methylsulphonyl)phenethyl]piperidine obtained in comparative example 1 and 2 ml of thionyl chloride dissolved in 50 ml of ethanol and the mixture refluxed for 2 hours. The reaction mixture was alkalinized by addition of 1 N. aqueous sodium hydroxide and the mixture extracted with dichloromethane. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is t clean and allocate column chromatography on silica gel (ethyl acetate) to give 368 mg specified in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ of 1.32 to 1.48 (3H, m), 1,62 by 1.68 (2H, t), a 1.75-to 1.82 (2H, t), 2.06 to of 2.16 (2H, t), 2.91 in-2,99 (2H, t), 3,02-of 3.07 (2H, t), is 3.08 (3H, s), of 3.48 (2H, s), 6,33 (1H, DD, J=6,5, 6.5 Hz), 7,35-7,40 (3H, t), 7,53-7,58 (2H, t), 8,03 (1H, DD, J=8,3, 1,4 Hz).

Example 88

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(3,4-methylenedioxyphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,25-to 1.38 (3H, m), 1,49-of 1.57 (2H, m), 1,68-to 1.77 (2H, m), 2,02-2,12 (2H, m), 2,52-of 2.58 (2H, m), 2,88-2,96 (2H, m), 3,47 (2H, s), of 5.92 (2H, s), 6,34 (1H, DD, J=6,6, and 6.6 Hz), is 6.61 (1H, DD, J=7,9) and 1.7 Hz), to 6.67 (1H, d, J=1.7 Hz), 6,72 (1H, d, J=7.9 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,53 (1H, d, J=6,6 Hz).

Example 89

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-finetipped

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (3H, m), 1,53-of 1.62 (2H, m), 1,69-to 1.79 (2H, m), 2,01 and 2.13 (2H, m), 2,58-to 2.67 (2H, m), 2,88-of 2.97 (2H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,14-7,21 (3H, s), 7.24 to 7,31 (2H, s), of 7.36 (1H, d, J=6.6 Hz), 7,54 (1H, d, J=6,6 Hz).

Example 90

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-hydroxyphenethyl)piperidine

1H-NMR (400 MHz, DMSO-d6) δ 1,12-1,24 (3H, m), of 1.40 to 1.48 (2H, m), 1,64-1,71 (2H, m), 1,87 is 1.96 (2H, m), 2,48 is 2.55 (2H, m), 2,75-2,82 (2H, m), up 3.22 (2H, s), 6,16 (1H, DD, J=6,6, and 6.6 Hz), 6,69 (1H, DDD, J=7,5, to 7.5, 1.2 Hz), to 6.75 (1H, DD, J=7,5, 1.2 Hz), of 6.96 (1H, DDD, J=7,5, of 7.5 and 1.7 Hz), 7,02 (1H, DD, J=7,5) and 1.7 Hz), 7,24 (1H, DD, J=6,6 and 2.2 Hz), 7,37 (1H, DD, J=6,6 and 2.2 Hz).

Example 91

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(3-florfenicol)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.40 (3H, m), 1,52-to 1.61 (2H, m), 1,68-to 1.77 (2H, m), 2,02-2,12 (2H, m), 2,58-of 2.66 (2H, m), 2,88-of 2.97 (2H, m), 3,47 (2H, s),6,33 (1H, DD, J=6,8, 6,8 Hz), 6,83-6,91 (2H, m)6,94 (1H, m), 7,19-7,26 (1H, m), of 7.36 (1H, d, J=6.8 Hz), 7,54 (1H, d, J=6,8 Hz).

Example 92

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-cryptomaterial)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,29-of 1.45 (3H, m)and 1.51-of 1.61 (2H, m), 1.70 to is 1.81 (2H, m), 2,04-of 2.16 (2H, m), 2,73-2,82 (2H, m), 2,89-to 2.99 (2H, m), 3,49 (2H, s), 6,34 (1H, DD, J=6,8, 6,8 Hz), 7,26 (1H, DD, J=7,7, a 7.6 Hz), 7,31 (1H, d, J=7.5 Hz), was 7.36 (1H, d, J=6.8 Hz), was 7.45 (1H, DD, J=7,6, 7.5 Hz), 7,54 (1H, d, J=6.8 Hz), 7,60 (1H, d, J=7,7 Hz).

Example 93

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(1-pyrazolo)phenethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,12-1,24 (3H, m), 1,31-of 1.40 (2H, m), 1,50-to 1.59 (2H, m), 1,94-2,04 (2H, m), of 2.51 at 2.59 (2H, m), 2,81-2,89 (2H, m), 3,42 (2H, s), 6,30 (1H, DD, J=6,4, 6.4 Hz), 6.42 per (1H, DD, J=2,4, 2.0 Hz), 7.23 percent-7,38 (5H, m), 7,52 (1H, d, J=6.4 Hz), 7,56 (1H, d, J=2.4 Hz), of 7.70 (1H, d, J=2.0 Hz).

Example 94

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(4-acetylpiperidine)phenethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.40 (3H, m), 1,53-to 1.61 (2H, m), 1,73-of 1.81 (2H, m), 2,03-2,12 (2H, m)to 2.13 (3H, s), 2,65-of 2.72 (2H, m), 2,81-2,97 (6N, m), of 3.46 (2H, s), 3,55-3,61 (2H, m), 3,68-of 3.77 (2H, m), 6,34 (1H, DD, J=6,4, 6.4 Hz),? 7.04 baby mortality (1H, d, J=7,6 Hz), 7,07 (1H, DD, J=7,6, 7,6 Hz), 7,17 (1H, DD, J=7,6, 7,6 Hz), 7,21 (1H, d, J=7,6 Hz), was 7.36 (1H, d, J=6.4 Hz), 7,51 (1H, d, J=6,4 Hz).

Example 95

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[6-(methylsulphonyl)-2,3-methylenedioxyphenethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1.32 to the 1.44 (3H, m), 1,58-to 1.67 (2H, m), 1,74-of 1.84 (2H, m), 2.06 to to 2.15 (2H, m), 2,90 are 2.98 (4H, m), 3,05 (3H, s)to 3.49 (2H, s)6,09 (2H, s), 6,34 (1H, DD, J=6,5, 6,5 Hz), is 6.78 (1H, d, J=8,4 Hz), 7,37 (1H, d, J=6.5 Hz), 7,54 (1H, d, J=6.5 Hz), a 7.62 (1H, d, J=8,4 Hz).

Example 96

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.40 (3H, m), 1.60-to or 1.77 (4H, m), 2,02-2,12 (2H, m), 2,81-of 2.97 (4H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,9 and 6.9 Hz), 6,78 (1H, d, J=3.5 Hz), 6,91 (1H, DD, J=5,1, 3.5 Hz), 7,11 (1H, d, J=5,1 Hz), of 7.36 (1H, d, J=6.9 Hz), 7,52 (1H, d, J=6,9 Hz).

Example 97

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-methoxy-2-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,25-to 1.38 (3H, m), 1,52-to 1.61 (2H, m), 1.70 to to 1.79 (2H, m), 2,01-2,12 (2H, m), 2,67 is 2.75 (2H, m), 2,87-2,96 (2H, m), of 3.46 (2H, s), 3,81 (3H, s), 6,33 (1H, DD, J=6,4, 6.4 Hz), for 6.81 (1H, d, J=5,2 Hz), 6,99 (1H, d, J=5,2 Hz), was 7.36 (1H, d, J=6.4 Hz), 7,54 (1H, d, J=6,4 Hz).

Example 98

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-cyano-2-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.31-1.42 (3H, m), 1,63-of 1.81 (4H, m), 2,03-of 2.15 (2H, m), 2,90-to 2.99 (2H, m), 3.00 and-of 3.07 (2H, m), of 3.48 (2H, s), 6,33 (1H, DD, J=6,5, 6.5 Hz), 7,11 (1H, d, J=5.3 Hz), 7,17 (1H, d, J=5.3 Hz), 7,35 (1H, d, J=6.5 Hz), 7,53 (1H, d, J=6.5 Hz).

Example 99

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-phenyl-2-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.20 and 1.33 (3H, m), 1.56 to of 1.66 (4H, m), 1,96-2,07 (2H, m), 2,83 of 2.92 (4H, m), 3,44 (2H, s), 6,32 (1H, DD, J=6,4, 6.4 Hz), 7,00 (1H, d, J=5,2 Hz), to 7.15 (1H, d, J=5,2 Hz), 7,27-7,43 (6N, m), 7,52 (1H, d, J=6,4 Hz).

Example 100

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,26-to 1.38 (3H, m), 1,55-of 1.62 (2H, m, 1,66-of 1.78 (2H, m), 2,01-2,12 (2H, m), 2,62 of 2.68 (2H, m), 2,88-2,96 (2H, m), 3,47 (2H, s), 6,34 (1H, DD, J=6.4 Hz), 6,91-to 6.95 (2H, m), 7,24 (2H, DD, J=4,8, 2,8 Hz), 7,34 (1H, d, J=6.4 Hz), 7,52 (1H, d, J=6,4 Hz),

Example 101

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(methylsulphonyl)-3-thienyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,34 of 1.46 (3H, m), 1,57-of 1.66 (2H, m), 1,73-to 1.82 (2H, m), 2,10-2,22 (2H, m), 2,92-3,03 (4H, m), 3,14 (3H, s), of 3.54 (2H, s), 6,34 (1H, DD, J=6,6, and 6.6 Hz), 7,01 (1H, d, J=5.0 Hz), was 7.36 (1H, d, J=6,6 Hz), 7,54 (1H, d, J=6.6 Hz), EUR 7.57 (1H, d, J=5.0 Hz).

Example 102

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(benzo[b]thiophene-2-yl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,29 was 1.43 (3H, m), 1,66 and 1.80 (4H, m), 2,02 and 2.13 (2H, m), 2,89-of 2.97 (4H, m), 3,47 (2H, s), (4H, m), 2,02 and 2.13 (2H, m), 2,89-of 2.97 (4H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,4, 6.4 Hz), 7,00 (1H, s), from 7.24 (1H, DD, J=7,2, 7,1 Hz), 7,30 (1H, DD, J=7,6, 7,1 Hz), was 7.36 (1H, d, J=6.4 Hz), 7,53 (1H, d, J=6.4 Hz), 7,66 (1H, d, J=7,2 Hz), 7,76 (1H, d, J=7,6 Hz).

Example 103

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(methylsulphonyl)-3-pyridyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32 of 1.46 (3H, m), 1,62 is 1.70 (2H, m), 1,74 of-1.83 (2H, m), 2.06 to 2,17 (2H, m), 2.91 in-2,99 (2H, m), 3,07 is 3.15 (2H, m), 3,37 (3H, s)to 3.49 (2H, s), 6,34 (1H, DD, J=6,6, and 6.6 Hz), 7,37 (1H, d, J=6.6 Hz), 7,43 (1H, DD, J=7,8, and 4.6 Hz), 7,56 (1H, d, J=6.6 Hz), 7,72 (1H, DD, J=7,8, 1,6), 8,42 (1H, DD, J=4,8, 1,6 Hz).

Example 104

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-n-butyl-3-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ to 0.96 (3H, t, J=7,3 Hz), 1,34-1,49 (5H, m), 1,49 is 1.60 (2H, m), 1,63 and 1.80 (4H, m), 2.06 to 2,17 (2H, m), 2,59-of 2.66 (2H,m), 2,77 (2H, t, J=8.1 Hz), 2,92-of 3.00 (2H, m), 3,50 (2H, s), 6,34 (1H, DD, J=6,4, 6.4 Hz),? 7.04 baby mortality (1H, DD, J=7,6, 4,8 Hz), 7,33-7,42 (2H, m), 7,53 (1H, d, J=6.4 Hz), of 8.37 (1H, DD, J=4,8, 1.8 Hz).

Example 105

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.40 (3H, m), 1.56 to of 1.62 (2H, m), 1.70 to of 1.78 (2H, m), 2,04-2,12 (2H, m), 2,60-of 2.66 (2H, m), 2,90-of 2.97 (2H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,21 (1H, DD, J=7,8, and 4.8 Hz), was 7.36 (1H, d, J=6, 6 Hz), 7,49 (1H, DDD, J=7,8, 2,0, 2,0 Hz), 7,54 (1H, d, J=6.6 Hz), 8,42-8,46 (2H, m).

Example 106

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-phenoxy-3-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32-of 1.40 (3H, m), 1,60 by 1.68 (2H, m), 1,72-to 1.82 (2H, m), 2,04-2,12 (2H, m), 2,70-2,77 (2H, m), 2,90-of 2.97 (2H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,4, 6.4 Hz), 6,94 (1H, DD, J=7,2, 5.0 Hz), 7,07 for 7.12 (2H, m), 7,17 (1H, m), 7,33-7,42 (3H, m), 7,50-of 7.55 (2H, m), 8,00 (1H, DD, J=5.0 and 1.8 Hz).

Example 107

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(5-methoxy-2-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1,61 is 1.70 (2H, m), 1,74-of 1.84 (2H, m), 2.05 is-of 2.16 (2H, m), 2,80-2,87 (2H, m), 2.91 in-2,99 (2H, m), 3,49 (2H, s), 3,83 (3H, m), 6,34 (1H, DD, J=6,4, 6.4 Hz), to 7.09 (1H, d, J=2,8 Hz), 7,09 (1H, d, J=2,8 Hz), 7,37 (1H, d, J=6.4 Hz), EUR 7.57 (1H, d, J=6.4 Hz), 8,11 (1H, DD, J=2,8, 2,8 Hz).

Example 108

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(4-methoxyphenyl-3-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,13-of 1.29 (3H, m), 1.41 to a 1.50 (2H, m), 1,52-of 1.62 (2H, m), 1,96-of 2.09 (2H, m), 2,62-2,70 (2H, DD, J=6,4, 6.4 Hz), of 6.96 (2H, d, J=8,8 Hz), 7,18 (1H, DD, J=7,8, and 4.8 Hz), 7,33 (1H, d, J=6.4 Hz), 7,40 (2 is, d, J=8,8 Hz), 7,55 (1H, d, J=6.4 Hz), EUR 7.57 (1H, DD, J=7,8, and 1.6 Hz)and 8.50 (1H, DD, J=4,8, 1,6 Hz).

Example 109

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(1,3-thiazol-2-yl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,29-of 1.42 (3H, m), 1,69 of-1.83 (4H, m), 2,03 and 2.13 (2H, m), 2,89-of 2.97 (2H, m), 3,02-3,10 (2H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,19 (1H, d, J=3.3 Hz), 7,35 (1H, d, J=6.6 Hz), 7,53 (1H, d, J=6, 6 Hz), to 7.67 (1H, d, J=3.3 Hz).

Example 110

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(1-morpholino)-3-pyridyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1.56 to of 1.64 (2H, m), 1,72 and 1.80 (2H, m), 2,04-2,12 (2H, m), 2,60-of 2.66 (2H, m), 2,72-2,78 (2H, m), 3,10 (4H, t, J=4,7 Hz), of 3.48 (2H, s), 3,85 (4H, t, J=4,7 Hz), 6,34 (1H, DD, J=6,6, and 6.6 Hz), 6,93 (1H, DD, J=7,4, 4,8 Hz), was 7.36 (1H, d, J=6, 6 Hz), 7,47 (1H, DD, J=7,4, 1.9 Hz), 7,54 (1H, m), 8,19 (1H, DD, J=4,8, 1.9 Hz).

Example 111

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[(methylsulphonyl)amino]phenethyl]piperidine

155 mg specified in the title compounds as colorless crystals obtained from 286 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(2-methylsulphonyl)amino]phenethyl]piperidine obtained in example 26, the same way as in example 87.

1H-NMR (400 MHz, CDCl3) δ 1,31-of 1.40 (3H, m), 1,52 is 1.60 (2H, m), 1,72 and 1.80 (2H, m), 2,04 and 2.13 (2H, m), 2,64-a 2.71 (2H, m), 2,90-of 2.97 (2H, m), 3,03 (3H, s), 3,47 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,15-7,28 (3H, m), 7,34 (1H, d, J=6.6 Hz), 7,45 (1H, m), 7,54 (1H, m).

Example 112

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methoxy-6-methyl-3-pyridyl)ethyl]piperidine

1-[(2-Oxo-12-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-6-methyl-3-pyridyl)ethyl]piperidine obtained by way described in example 87, 275 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-6-methyl-3-pyridyl)ethyl]piperidine obtained in example 27. Then the product is dissolved in 5 ml of 28% aqueous sodium methoxide and the mixture is refluxed for 3 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The extract was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and receive 80 mg specified in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ 1,21-of 1.39 (3H, m), 1,45-1,55 (2H, m), 1,68-of 1.78 (2H, m), 1,97-of 2.08 (2H, m), is 2.41 (3H, s), 2,48-of 2.56 (2H, m), 2,85-2,95 (2H, m), 3,49 (2H, s)to 3.92 (3H, s), of 3.95 (3H, s), 6.35mm (1H, DD, J=6,6, and 6.6 Hz), 6,63 (1H, d, J=7,3 Hz), 7.23 percent (1H, d, J=7,3 Hz), 7,37 (1H, d, J=6.6 Hz), 7,53 (1H, d, J=6,6 Hz).

Example 113

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(6-methoxy-3-pyridyl)ethyl]piperidine

86 mg specified in the connection header in the form of white crystals is obtained from 300 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(6-chloro-3-pyridyl)ethyl]piperidine obtained in example 28, the method described in example 112.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.44 (3H, m), 1,47-to 1.59 (2H, m), 1,67-of 1.78 (2H, m), 2,04-2,17 (2H, m), of 2.51-of 2.58 (2H, m), 2,90-a 3.01 (2H, m), 3,51 (2H, s)to 3.92 (3H, m), 6.35mm (1H, DD, J=6,6, and 6.6 Hz), of 6.68 (1H, d, J=8,3 Hz), of 7.36 (1H, d, J=6.6 Hz), 7,39 (1H, d, J=8,3, 2.4 Hz), 7,55 (1H, d, J=6, 6 Hz), 7,95 (1H, d, J=2,4 Hz).

Example 114

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl-4-[(E)-2-(2-pyridyl)-1-ethynyl]piperidine

110 mg specified in the title compounds as colorless crystals obtained from 121 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(E)-2-(2-pyridyl)-1-ethynyl]piperidine obtained in example 29, the method described in example 87.

1H-NMR (400 MHz, CDCl3) δ 1,57-1,72 (3H, m), 1.77 in-a 1.88 (2H, m), 2,15-of 2.28 (2H, m), 2.95 and was 3.05 (2H, m), 3,52 (2H, s), 6.35mm (1H, DD, J=6,6, and 6.6 Hz), of 6.49 (1H, d, J=15,9 Hz), was 6.73 (1H, DD, J=15,9, 7,0 Hz), 7,11 (1H, DD, J=7,5, 5,0 Hz), 7,25 (1H, d, J=7.5 Hz), 7,37 (1H, d, J=6.6 Hz), 7,56-the 7.65 (2H, m), 8,54 (1H, m).

Example 115

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-pyridyl)ethyl]piperidine

128 mg specified in the connection header in the form of colorless crystals is obtained from 150 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-pyridyl)ethyl]piperidine obtained in example 30, the method described in example 114.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.42 (3H, m), 1,64-to 1.82 (4H, m), 2,03-of 2.15 (2H, m), 2.77-to 2,85 (2H, m), 2,90-to 2.99 (2H, m), of 3.48 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,10 (1H, DDD, J=7,8, 4,4, 1.2 Hz), 7,14 (1H, d, J=7.8 Hz), of 7.36 (1H, d, J=6.6 Hz), 7,53 to 7.62 (2H, m), 7,52 (1H, DD, J=4,4, 1.2 Hz).

Example 116

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2,3-methylenedioxyphenyl)-1-ethynyl]piperidine

64 mg specified in the title compounds as colorless crystals obtained from 99 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(E)-(2,3-methylenedioxyphenyl)-1-ethynyl]piperidine obtained in example 31, by the method described in example 114.

1H-NMR (400 MHz, CDCl3) δ 1,50-of 1.64 (3H, m), 1.70 to to 1.83 (2H, m, 2,12-of 2.24 (2H, m), 2,94-to 3.02 (2H, m), 3,51 (2H, s)5,94 (2H, s), 6,01 (1H, DD, J=15,8, 7,0 Hz), of 6.29 (1H, d, J=15,8 Hz), 6,34 (1H, DD, J=6,8, 6,8 Hz), 6,74 (1H, d, J=8.1 Hz), 6,77 (1H, DD, J=8,1, 1,4 Hz), 6.90 to (1H, d, J=1.4 Hz), 7,35 (1H, d, J=6.8 Hz), 7,56 (1H, d, J=6,8 Hz).

Example 117

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine

1,15 g specified in the title compounds as colorless crystals get out of 1.37 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 32, the method described in example 1.

1H-NMR (400 MHz, CDCl3) δ 1.32 to the 1.44 (3H, m), 1,54-of 1.64 (2H, m), 1,72-of 1.84 (2H, m), 2,07-to 2.18 (2H, m), 2,69-2,78 (2H, m), 2,92-a 3.01 (2H, m), 3,51 (2H, s), 6,34 (1H, DD, J=6, 6, and 6.6 Hz), 7,18 (1H, DD, J=7,2, 4,8 Hz), 7,37 (1H, d, J=6.4 Hz), 7,54 (1H, DD, J=7,2, 1.8 Hz), EUR 7.57 (1H, d, J=6, 4 Hz), of 8.25 (1H, DD, J=4,8, 1.8 Hz).

Example 118

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methoxy-3-pyridyl)ethyl]piperidine

192 mg specified in the title compounds as colorless crystals obtained from 220 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, the method described in example 112.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.40 (3H, m), 1,49-of 1.57 (2H, m), 1,72 and 1.80 (2H, m), 2,03 and 2.13 (2H, m), 2,54-2,60 (2H, m), 2,89 are 2.98 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 6,33 (1H, DD, J=6.6 Hz), to 6.80 (1H, DD, J=7,2, 5.0 Hz), 7,34-7,39 (2H, m), EUR 7.57 (1H, d, J=6.6 Hz), 8,01 (1H, DD, J=5,2, 1.8 Hz).

Example 119

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methylthio-3-pyridyl)ethyl]piperidin the

168 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and 354 mg of timelocked sodium suspended in 5 ml of 1-methyl-2-pyrrolidinone and the mixture is stirred at 150°C for 2 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (methanol:ethyl acetate=1:19), resulting in a gain of 20 mg indicated in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1,54-of 1.64 (2H, m), 1,72 of-1.83 (2H, m), 2.05 is-of 2.16 (2H, m), to 2.57 (3H, s), 2.57 m)-2,66 (2H, m), 2,90-of 3.00 (2H, m), 3,49 (2H, s), 6,34 (1H, DD, J=6.6 Hz), 6,94 (1H, DD, J=7,4, 4,8 Hz), 7,31 (1H, DD, J=7,4, 1.9 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,56 (1H, d, J=6.6 Hz), 8,32 (1H, DD, J=4,8, 1.9 Hz).

Example 120

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-2-[(2-methoxyethoxy-3-pyridyl)ethyl]piperidine

183 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and 226 mg dispersed in oil, 60% sodium hydride suspended in 3 ml of 2-methoxyethanol and the mixture is stirred at 150°C for 2 hours. To the reaction solution was added water and the mixture extracted with dichloromethane. The organic layer PR is myauth saturated salt solution, and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (methanol:ethyl acetate=1:19), resulting in a gain of 135 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.42 (3H, m), 1,50-1,60 (2H, m), 1,72-to 1.82 (2H, m), 2,03-of 2.15 (2H, m), 2,56-to 2.65 (2H, m), 2,89-of 3.00 (2H, m), 3.43 points (3H, s), of 3.48 (2H, s), 3,76 (2H, t, J=4,8 Hz), 4,48 (2H, t, J=4,8 Hz), 6,34 (1H, DD, J=6.6 Hz), to 6.80 (1H, DD, J=7,2, 4,8 Hz), 7,34-7,41 (2H, m), 7,56 (1H, d, J=6.6 Hz), of 7.97 (1H, DD, J=4,8, 1.8 Hz).

Example 121

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-cyclopropylmethoxy-3-pyridyl)ethyl]piperidine

179 mg of 1-[(2-oxo-1,2-dihydro-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and 0.44 ml of cyclopropanemethanol and 246 mg dispersed in oil, 60% sodium hydride suspended in 5 ml of 1-methylpyrrolidone and the mixture is stirred at 150°C for 1 hour. To the reaction solution was added water and the mixture extracted with dichloromethane. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (methanol:ethyl acetate=1:19), resulting in a gain of 147 mg specified in the title compound as a colorless crystal is s.

1H-NMR (400 MHz, CDCl3) δ at 0.31 to 0.70 (2H, m), of 0.54 to 0.60 (2H, m), 1,22-of 1.42 (4H, m), 1,52 is 1.60 (2H, m), 1,74-to 1.82 (2H, m), 2.05 is with 2.14 (2H, m), 2,56-of 2.64 (2H, m), 2,90-to 2.99 (2H, m), of 3.48 (2H, s), 4,14 (2H, d, J=7,0 Hz), 6,34 (1H, DD, J=6,6, and 6.6 Hz), 6,78 (1H, DD, J=7,2, 5.0 Hz), 7,32-7,42 (2H, m), 7,55 (1H, d, J=6.6 Hz), of 7.96 (1H, DD, J=5.0 and 1.9 Hz).

Example 122

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-triptoreline-3-pyridyl)ethyl]piperidine

373 mg specified in the title compounds as colorless crystals obtained from 404 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and 0.88 ml of triptoreline the method described in example 120.

1H-NMR (400 MHz, CDCl3) δ 1,25-1,40 (3H, m), 1,50 is 1.58 (2H, m), 1,70-1,80 (2H, m), 2,02 with 2.14 (2H, m), 2,56-of 2.64 (2H, m), 2,89 are 2.98 (2H, m), of 3.48 (2H, s), was 4.76 (2H, q, J=8,4 Hz), 6,34 (1H, DD, J=6,6, and 6.6 Hz), make 6.90 (1H, DD, J=7,2, 5.0 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,44 (1H, DD, J=7,2, 2.0 Hz), 7,55 (1H, d, J=6.6 Hz), 7,98 (1H, DD, J=5.0 and 2.0 Hz).

Example 123

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-hydroxyethoxy)-3-pyridyl)ethyl]piperidine

72 mg specified in the title compounds as colorless crystals obtained from 213 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and 395 mg of ethylene glycol by the method described in example 121.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.41 (3H, m), 1,50-to 1.59 (2H, m), 1.70 to to 1.79 (2H, m), 2,03 and 2.13 (2H, m), 2,56-2,63 (2H, m), 2,90-of 2.97 (2H, m), 3,47 (2H, s), 3,92-of 3.97 (2H, m), 4,47-to 4.52 (2H, m), 6,33 (1 is, DD, J=6,6, and 6.6 Hz), 6,85 (1H, DD, J=7,2, 5.0 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,42 (1H, DD, J=7,2, 1.8 Hz), 7,55 (1H, m), 7,95 (1H, DD, J=5.0 and 1.8 Hz).

Example 124

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(N,N-dimethylamino)ethoxy-3-pyridyl]ethyl]piperidine

220 mg specified in the title compounds as colorless crystals obtained from 254 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in example 117, and of 0.77 ml of N,N-dimethylaminoethanol the method described in example 121.

1H-NMR (400 MHz, CDCl3) δ 1,25-1,40 (3H, m), 1,50 is 1.58 (2H, m), 1,72 and 1.80 (2H, m), 2,04 and 2.13 (2H, m), 2,36 (6N, (C), 2,53-2,61 (2H, m), was 2.76 (2H, t, J=5.8 Hz), 2,90 are 2.98 (2H, m), of 3.48 (2H, s), of 4.44 (2H, t, J=5.8 Hz), 6.35mm (1H, DD, J=6,4, 6.4 Hz), to 6.80 (1H, DD, J=7,2, 5,2 Hz), 7,34-7,40 (2H, m), 7,54 (1H, d, J=6.4 Hz), to 7.99 (1H, DD, J=5.0 and 2.0 Hz).

Example 125

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[4-(methylsulphonyl)-3-(1,3-thiazol-2-yl)-2-thienyl]ethyl]piperidine

90 mg specified in the title compounds as colorless crystals obtained from 230 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[4-(methylsulphonyl)-3-(1,3-thiazol-2-yl)-2-thienyl]ethyl]piperidine obtained in example 33, the method described in example 87.

1H-NMR (400 MHz, CDCl3) δ of 1.18 and 1.33 (3H, m), 1,54-of 1.65 (4H, m), 1,97-of 2.09 (2H, m), was 2.76 vs. 2.94 (4H, m), 3,24 (3H, s), 3,44 (2H, s), of 6.31 (1H, DD, J=6,7, 6,7 Hz), 7,34 (1H, d, J=6,7 Hz), 7,52 (1H, d, J=6,7 Hz), 7,55 (1H, d, J=3,4 Hz), 7,94 (1H, d, J=3,4 Hz), 8,10 (1H, s).

Example 126

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[3-(1,3-thiazol-2-the l)-2-thienyl]ethyl]piperidine

156 mg specified in the title compounds as colorless crystals obtained from 230 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[3-(1,3-thiazol-2-yl)-2-thienyl]ethyl] piperidine obtained in example 34, the method described in example 87.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,45 (3H, m), 1,65-of 1.81 (4H, m), 2.05 is-of 2.16 (2H, m), 2,90-to 2.99 (2H, m), 3,21-3,29 (2H, m), 3,49 (2H, s), 6,34 (1H, DD, J=6,8, 6,8 Hz), 7,13 (1H, d, J=5,2 Hz), 7,29 (1H, d, J=3,4 Hz), was 7.36 (1H, d, J=6, 8 Hz), 7,40 (1H, d, J=5,2 Hz), 7,54 (1H, d, J=6.8 Hz), 7,83 (1H, d, J=3,4 Hz).

Example 127

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(1,3-thiazol-2-yl)phenethyl]piperidine

171 mg specified in the title compounds as colorless crystals obtained from 233 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(1,3-thiazol-2-yl)phenethyl]piperidine obtained in example 35, the method described in example 87.

1H-NMR (400 MHz, CDCl3) δ of 1.18 and 1.33 (3H, m), USD 1.43-of 1.52 (2H, m), 1,58 was 1.69 (2H, m), 1,98-of 2.09 (2H, m), 2,82 are 2.98 (4H, m), of 3.45 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,26 (1H, DD, J=7,6, 7,6 Hz), 7,30 (1H, d, J=7,6 Hz), was 7.36 (1H, DD, J=7,6, 7,6 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,39 (1H, d, J=3.2 Hz), 7,51 (1H, d, J=6.6 Hz), EUR 7.57 (1H, d, J=7,6 Hz), 7,89 (1H, d, J=3.2 Hz).

Example 128

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.40 (3H, m), 1,54-of 1.62 (2H, m), 1,70-1,80 (2H, t), 2,02-2,12 (2H, t), of 2.56 2.63 in (2H, t), 2,88-2,96 (2H, t), of 3.46 (2H, s), of 5.92 (2H, s), 6,33 (1H, DD, J=6.5 Hz), 6,64-6,70 (2H, m), of 6.75 (1H, DD, J=7,8, and 7.8 Hz), was 7.36 (1H, d, J=6.5 Hz), 7,54 (1H, d, J=6.5 Hz).

Example 129

1-[(2-OK, what about the-1,2-dihydro-3-pyridinyl)methyl]-4-(2-cyanophenyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,31-of 1.45 (3H, m), 1,57-to 1.67 (2H, m), 1,72-to 1.82 (2H, m), 2,03-of 2.15 (2H, m), 2,81-to 2.99 (4H, m), 3,47 (2H, s), 6,32 (1H, DD, J=6,9, and 6.3 Hz), 7,27 (1H, DD, J=7,6, 7,6 Hz), 7,32 (1H, d, J=7,6 Hz), was 7.36 (1H, d, J=6, 3 Hz), to 7.50 (1H, DD, J=7,6, 7,6 Hz), 7,58 (1H, d, J=6, 9 Hz), 7,60 (1H, d, J=7,6 Hz).

Example 130

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(3-cyanophenyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.41 (3H, m), 1,52-of 1.62 (2H, m), 1,68-to 1.77 (2H, m), 2,01 and 2.13 (2H, m), 2,62-a 2.71 (2H, m), 2,89-to 2.99 (2H, m), 3,47 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), of 7.36-to 7.50 (4H, m), of 7.36 (1H, d, J=6,6 Hz), EUR 7.57 (1H, d, J=6,6 Hz).

Example 131

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(4-phenylphenate)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32-of 1.42 (3H, m), 1,58-of 1.65 (2H, m), 1,73-of 1.81 (2H, m), 2.05 is with 2.14 (2H, m), 2,64-2,70 (2H, m), 2.91 in are 2.98 (2H, m), of 3.48 (2H, s), 6,34 (1H, DD, J=6,4, 6.4 Hz), 7.23 percent-7,28 (2H, m), 7,32 (1H, m), 7,37 (1H, d, J=6.4 Hz), 7,40 was 7.45 (2H, m), 7,49-of 7.60 (5H, m).

Example 132

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-phenylphenate)piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.10-1.20 (3H, m), 1,37-to 1.45 (2H, m), 1,46-and 1.54 (2H, m), 1,94-2,03 (2H, m), 2,56-2,62 (2H, m), 2,79-of 2.86 (2H, m), of 3.43 (2H, s), 6,32 (1H, DD, J=6,4, 6.4 Hz), 7.18 in-7,42 (10H, m), of 7.48 (1H, d, J=6,4 Hz).

Example 133

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-methylphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32 was 1.43 (3H, m), 1,53-of 1.62 (2H, m), 1,73-of 1.84 (2H, m), 2.06 to 2,17 (2H, m), the 2.46 (3H, s), 2,67 is 2.75 (2H, m), 2,90-of 3.00 (2H, m), 3,49 (2H, s), 6,34 (1H, DD, J=6.6 Hz), 7,06-7,16 (2H, m), 7.18 in-7,21 (2H, m), 7,37 (1H, d, J=6.6 Hz), EUR 7.57 (1H, d, J=6,6 Hz).

Example 134

1-[(2-ACS is -1,2-dihydro-3-pyridinyl)methyl]-4-(2-methoxyphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,25-1,40 (3H, m), 1,48-of 1.57 (2H, m), 1,72-to 1.82 (2H, m), 2,02 with 2.14 (2H, m), 2,58-of 2.66 (2H, m), 2,88-of 2.97 (2H, m), of 3.48 (2H, s), 3,81 (3H, s), 6.35mm (1H, DD, J=6,6, and 6.6 Hz), at 6.84 (1H, d, J=8,2 Hz), 6,88 (1H, DD, J=7,6, 7,6 Hz), 7,12 (1H, DD, J=7,6, 2.0 Hz), 7,17 (1H, DDD, J=8,2, 7,6, 2,0 Hz), 7,38 (1H, d, J=6.6 Hz), 7,53 (1H, d, J=6,6 Hz).

Example 135

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3-methylsulphonyl-2-thienyl)ethyl]piperidine

6,09 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[3-(methylsulphonyl)-2-thienyl]ethyl]piperidine obtained in example 43, and 2 ml of thionyl chloride dissolved in 50 ml of ethanol, and the mixture is refluxed for 2 hours. The reaction mixture was alkalinized by addition of 1 N. aqueous sodium hydroxide, and then extracted with dichloromethane. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate) to obtain the 4,89 g specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1,67 and 1.80 (4H, m), 2,04 and 2.13 (2H, m), 2,90-of 2.97 (2H, t), 3,06 (3H, s), 3,18-3,24 (2H, t), of 3.46 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), 7,18 (1H, d, J=5.5 Hz), 7,31 (1H, d, J=5,5 Hz), was 7.36 (1H, DD, J=6,6, 2.0 Hz), 7,56 (1H, DD, J=6,6, 2.0 Hz).

Example 136

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(methylsulphonyl)-3,4-methylenedioxyphenethyl]piperidine/p>

875 mg specified in the title compounds as colorless crystals obtained from 1.45 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(methylsulphonyl)-3,4-methylenedioxyphenethyl] piperidine obtained in comparative example 1 by the method described in example 135.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1,52 is 1.60 (2H, m), 1,72 and 1.80 (2H, m), 2,07-of 2.16 (2H, m), 2,90-2,96 (2H, m), 2,96-to 3.02 (2H, m), 3,21 (3H, s), of 3.48 (2H, s), 6,12 (2H, s), 6,34 (1H, DD, J=6,5, 6.5 Hz), to 6.75 (1H, d, J=8.1 Hz), 6,93 (1H, d, J=8.1 Hz), 7,37 (1H, d, J=6.5 Hz), 7,53 (1H, d, J=6.5 Hz).

Example 137

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(1,3-thiazol-2-yl)-3-pyridyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32 of 1.46 (3H, m), 1,54-to 1.63 (2H, m), 1,73-to 1.82 (2H, m), 2.06 to of 2.16 (2H, m), 2,90 are 2.98 (2H, m), 3.27 to to 3.34 (2H, m), 3,49 (2H, s), 6,34 (1H, DD, J=6,4, 6.4 Hz), 7.23 percent (1H, DD, J=7,6, 4,4 Hz), 7,37 (1H, d, J=6.4 Hz), 7,40 (1H, d, J=3.6 Hz), 7,56 (1H, d, J=6.4 Hz), to 7.61 (1H, DD, J=7,6, and 1.6 Hz), to $ 7.91 (1H, d, J=3.6 Hz), of 8.47 (1H, DD, J=4,4, 1,6 Hz).

Example 138

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[1-(4-hydroxy)piperidino]-3-pyridyl]ethyl]piperidine

49 mg specified in the title compound as a colourless oil is obtained from 70 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[1-(4-hydroxy)piperidino]-3-pyridyl)ethyl]piperidine obtained in example 49, by the method described in example 135.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.42 (3H, m), 1,54-of 1.62 (2H, m), 1,64-to 1.82 (4H, m), 1,96 with 2.14 (4H, m), 2,58-to 2.65 (2H, m), 2,84-to 2.99 (4H, m), 3.25 to to 3.34 (2H, m), of 3.48 (2H, s), a-3.84 (1H, m), 6,33 (1H, DD, J=6,6, and 6.6 Hz), make 6.90 (1H, DD, J=74, a 4.9 Hz), 7,37 (1H, d, J=6.6 Hz), 7,44 (1H, DD, J=7,4, 1.9 Hz), 7,55 (1H, d, J=6.6 Hz), 8,15 (1H, DD, J=4,9, 1.9 Hz).

Example 139

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(3-cyanopropyl)-3-pyridyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.40 (3H, m), 1,48-of 1.57 (2H, m), 1.70 to is 1.81 (2H, m), 2,03-of 2.20 (4H, m), of 2.51-2,61 (4H, m), 2,89-of 2.97 (2H, m), 3,47 (2H, s), 4,40-4,47 (2H, m), 6,33 (1H, DD, J=6,4, 6.4 Hz), PC 6.82 (1H, DD, J=7,2, 5,2 Hz), 7,35 (1H, d, J=6.4 Hz), 7,38 (1H, DD, J=7,2, 2.0 Hz), 7,55 (1H, d, J=6.4 Hz), of 7.97 (1H, DD, J=5,2, 2.0 Hz).

Example 140

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[1-(2-terbisil)-2-oxo-1,2-dihydro-3-pyridinyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.41 (3H, m), 1,48-of 1.57 (2H, m), 1,71-to 1.82 (2H, m), 2,01-of 2.15 (2H, m), 2,52-of 2.58 (2H, m), 2,88 are 2.98 (2H, m), 3,49 (2H, s)to 5.17 (2H, s), between 6.08-6,13 (1H, m), 6,34 (1H, DD, J=6,4, 6.4 Hz), 7.03 is-7,17 (3H, m), 7.24 to 7,31 (2H, m), of 7.36 (1H, d, J=6.4 Hz), 7,40-7,46 (1H, m), 7,55 (1H, d, J=6,4 Hz).

Example 141

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine

9.6 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-oxo-2-(2-thienyl)ethyl]piperidine obtained in example 54, and 8.5 ml of thionyl chloride dissolved in 60 ml of ethanol and the mixture refluxed for 3 hours. The solvent is evaporated and then the residue is dissolved in chloroform and 1 N. aqueous sodium hydroxide. The organic layer is separated, washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product paracrystalline is to see from ethanol to obtain 9.0 g specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,36-1,49 (2H, m), 1,72-of 1.81 (2H, m), 2,03 (1H, m), 2,09-of 2.20 (2H, m), 2,82 (2H, d, J=7,0 Hz), 2,87-2,96 (2H, m), 3,47 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), 7,13 (1H, DD, J=4,9, 3,9 Hz), 7,35 (1H, d, J=6.6 Hz), 7,54 (1H, d, J=6.6 Hz), 7,63 (1H, DD, J=4,9, 1.1 Hz), of 7.70 (1H, DD, J=3,9, 1,1 Hz).

Example 142

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-phenylethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,35-1,49 (2H, m), 1,72-to 1.82 (2H, m), 1,97-2,22 (3H, m), 2,87-of 2.97 (3H, m), of 3.48 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,46 (1H, DD, J=8,0, 8.0 Hz), 7,55 (1H, d, J=6.6 Hz), 7,56 (1H, DD, J=8,0, 8.0 Hz), 7,95 (1H, d, J=8.0 Hz).

Example 143

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chlorophenyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.33 to 1.47 (2H, m), 1,72-to 1.82 (2H, m), a 2.01 (1H, m), 2,09-of 2.21 (2H, m), 2,85-2,96 (4H, m), 3,47 (2H, s), 6,32 (1H, DD, J=6,8, 6,8 Hz), 7,29-7,34 (1H, m), 7,35 (1H, d, J=6.8 Hz), 7,35-7,44 (3H, m), 7,54 (1H, d, J=6,8 Hz).

Example 144

1-[(2-Oxo-1,2-dihydro-Z-pyridinyl)methyl]-4-[2-(2-methoxyphenyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,32 of 1.46 (2H, m), 1,69-to 1.79 (2H, m), 1,99 (1H, m), 2,09-of 2.20 (2H, m), 2,86-2,96 (3H, m), of 3.48 (2H, s)to 3.89 (3H, s), 6,33 (1H, DD, J=7,0, 5.8 Hz), of 6.99 (1H, DD, J=7,5, 7,2 Hz), to 6.95 (1H, d, J=8,4 Hz), 7,37 (1H, d, J=5.8 Hz), 7,44 (1H, DDD, J=8,4, to 7.2, 1.8 Hz), 7,53 (1H, d, J=7,0 Hz), a 7.62 (1H, DD, J=7,5, 1.8 Hz).

Example 145

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methylsulfinylphenyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,35-1,49 (2H, m), 1,81 is 1.91 (2H, m), 2.05 is was 2.25 (3H, m), 2,85-to 2.99 (4H, m)of 3.25 (3H, s)to 3.49 (2H, s, 6,32 (1H, DD, J=6,6, 6.2 Hz), was 7.36 (1H, d, J=6.2 Hz), 7,41 (1H, d, J=7.5 Hz), 7,55 (1H, d, J=6.6 Hz), to 7.61 (1H, DD, J=7,7, 7.5 Hz), 7,69 (1H, DD, J=7,5, 7.5 Hz), 8,07 (1H, d, J=7,7 Hz).

Example 146

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-cyclopropylmethoxy)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 0,32 is 0.38 (2H, m), is 0.63 to 0.70 (2H, m), 1,24 of 1.46 (3H, m), 1,70-1,80 (2H, m), 2,02 (1H, m), 2,08-2,19 (2H, m), 2,86-to 2.94 (2H, m), to 3.02 (2H, d, J=6.8 Hz), 3,47 (2H, s)to 3.89 (2H, d, J=7,2 Hz), 6,32 (1H, DD, J=6,9, 5,9 Hz), to 6.88 (1H, d, J=8,2 Hz), 6,97 (1H, DD, J=7,7, 7,4 Hz), was 7.36 (1H, d, J=5,9 Hz), 7,41 (1H, DD, J=8,2, 7,4 Hz), 7,53 (1H, d, J=6.9 Hz), the 7.65 (1H, d, J=7,7 Hz).

Example 147

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-(2-triptoreline)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,31-to 1.45 (2H, m), 1,75-of 1.85 (2H, m), 1,95-of 2.24 (3H, m), 2,80 (2H, d, J=6.6 Hz), 2,88 are 2.98 (2H, m), of 3.48 (2H, s), 6,32 (1H, DD, J=7,1, 6.2 Hz), was 7.36 (1H, d, J=6.2 Hz), 7,40 (1H, d, J=7,3 Hz), 7,54 (1H, d, J=7,1 Hz), 7,55 (1H, DD, J=7,8, and 7.1 Hz), 7,60 (1H, DD, J=7,8, and 7.3 Hz), 7,71 (1H, d, J=7,1 Hz).

Example 148

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-(3-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.48 (2H, m), 1,71-of 1.81 (2H, m), 2,02 (1H, m), 2,09-of 2.21 (2H, m), 2,80 (2H, d, J=6.8 Hz), 2,88-of 2.97 (2H, m), 3,47 (2H, s), 6,32 (1H, DD, J=6,8, 6,8 Hz), 7,31 (1H, DD, J=5,1, 2,9 Hz), was 7.36 (1H, d, J=6,8 Hz), 7,54 (1H, d, J=6.8 Hz), 7,545 (1H, d, J=5,1 Hz), of 8.04 (1H, d, J=2,9 Hz).

Example 149

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,39-of 1.52 (2H, m), 1,73-to 1.82 (2H, m), 2,01-of 2.21 (3H, m), 2,87-2,96 (2N, is), the 3.11 (2H, d, J=6.8 Hz), 3,47 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), 7,34 (1H, d, J=6.6 Hz), 7,54 (1H, d, J=6.6 Hz), to 7.67 (1H, d, J=3.1 Hz), 8,00 (1H, DD, J=3.1 Hz).

Example 150

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3,4-methylenedioxyphenyl)-2-oxoethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,34-to 1.45 (2H, m), 1,71 and 1.80 (2H, m), a 2.01 (1H, m), 2,10-of 2.20 (2H, m), of 2.81 (2H, d, J=6.8 Hz), 2,88-2,96 (2H, m), 3,47 (2H, s), 6,04 (2H, s), 6,33 (1H, DD, J=6,5, 6.5 Hz), 6,85 (1H, d, J=8,2 Hz), of 7.36 (1H, d, J=6.5 Hz), the 7.43 (1H, d, J=1.7 Hz), 7,52 (1H, d, J=6.5 Hz), 7,55 (1H, DD, J=8,2) and 1.7 Hz).

Example 151

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-[3-(1,3-thiazol-2-yl)-2-thienyl]ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,31-to 1.45 (2H, m), 1,69-of 1.78 (2H, m), 1,96-2,19 (3H, m), 2,80 (2H, d, J=6.8 Hz), 2,85-to 2.94 (2H, m), of 3.46 (2H, s), of 6.31 (1H, DD, J=6,9, 5,9 Hz), 7,35 (1H, d, J=5,9 Hz), 7,47 (1H, d, J=3.3 Hz), 7,52 (1H, d, J=6.9 Hz), 7,54 (1H, d, J=5,2 Hz), 7,82 (1H, d, J=5,2 Hz), to 7.93 (1H, d, J=3.3 Hz).

Example 152

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-oxo-2-(3-phenyl-2-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,09-1,24 (2H, m), 1,48-to 1.59 (2H, m)and 1.83 (1H, m), 1,98-2,11 (2H, m), 2,42 (2H, d, J=6.8 Hz), 2,75-2,87 (2H, m), 3,42 (2H, s), 6,30 (1H, DD, J=7,5, 6,0 Hz), 7,06 (1H, d, J=4.9 Hz), 7,33 (1H, d, J=6,0 Hz), 7,34-7,46 (5H, m), of 7.48 (1H, d, J=7.5 Hz), 7,54 (1H, d, J=4,9 Hz).

Example 153

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridinyl)-2-oxoethyl]piperidine

In acetonitrile (4 ml) dissolve 100 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-oxoethyl]piperidine obtained in example 62, and 0.35 ml of 4 M solution of chloric the oho hydrogen in ethyl acetate, and then refluxed for 1 hour. The solvent is evaporated and then the residue is dissolved in ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is recrystallized from ethanol to obtain 46 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ of 1.34 to 1.48 (2H, m), 1,71-of 1.81 (2H, m), 2,02 (1H, m), 2,09-of 2.21 (2H, m), 2,87 are 2.98 (4H, m), 3,47 (2H, s), of 6.31 (1H, DD, J=6,6, and 6.6 Hz), 7,33 (1H, DD, J=7,5, 4,8 Hz), 7,35 (1H, d, J=6.6 Hz), 7,54 (1H, d, J=6.6 Hz), to 7.77 (1H, DD, J=7,5, 1.9 Hz), 8,48 (1H, DD, J=4,8, 1.9 Hz).

Example 154

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methylsulfonylamino)-2-oxoethyl]piperidine

In acetonitrile (4 ml) dissolved 90 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-methylsulfonylamino)-2-oxoethyl]piperidine obtained in example 65, and 0.30 ml of concentrated hydrochloric acid and then refluxed for 5 hours. The solvent is evaporated, then the residue is dissolved in ethyl acetate and 1 N. aqueous sodium hydroxide solution. The organic layer is separated, washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is recrystallized from et the Nola with receiving 45 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ of 1.33 to 1.47 (2H, m), 1,75-1,89 (2H, m), 2,01 was 2.25 (3H, m), 2,83 are 2.98 (4H, m), 3,50 (5H, m), 6,33 (1H, DD, J=6,6, and 6.6 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,40 (1H, DD, J=5,6, and 3.2 Hz), 7,52 (1H, d, J=6.6 Hz), at 7.55 (1H, d, J=3.2 Hz), EUR 7.57 (1H, DD, J=3,4 Hz), to 7.67 (1H, DD, J=5,6, 3,4 Hz).

Example 155

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(3-phenylpropyl)piperidine

161 mg specified in the title compounds as colorless crystals obtained from 214 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(3-phenylpropyl)piperidine obtained in example 76, the method described in example 141.

1H-NMR (400 MHz, CDCl3) δ to 1.22 to 1.34 (5H, m), 1,58-1,72 (4H, m), 2.00 in of 2.10 (2H, m)at 2.59 (2H, t, J=7.8 Hz), 2,86-to 2.94 (2H, m), of 3.45 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), 7,14-7,20 (3H, m), 7.24 to 7,30 (2H, m), of 7.36 (1H, d, J=and 6.6 Hz), 7,53 (1H, m).

Example 156

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-benzylpiperidine

365 mg specified in the title compounds as colorless crystals obtained from 472 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-benzylpiperidine obtained in example 78, the method described in example 141.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (2H, m), and 1.56 (1H, m), 1,60 by 1.68 (2H, m), 2,02 is 2.10 (2H, m)to 2.55 (2H, d, J=7,0 Hz), 2,89-2,96 (2H, m), of 3.46 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), 7,12-7,21 (3H, m), 7.24 to 7,30 (2H, m), 7,35 (1H, d, J=6.6 Hz), 7,54 (1H, d, J=6,6 Hz).

Example 157

1-[(2-Oxo-1,2-dihydro-Z-pyridinyl)methyl]-4-(4-phenylbutyl)piperidine

105 mg specified in the connection header in the form of colorless crystals is obtained from 150 mg of 1-[(2-labels and-3-pyridyl)methyl]-4-(4-phenylbutyl)piperidine, obtained in example 79, the method described in example 141.

1H-NMR (400 MHz, CDCl3) δ 1,20-1,40 (7H, m), 1.56 to to 1.70 (4H, m), 2,02-2,12 (2H, m)2,60 (2H, t, J=7,7 Hz), 2,88-2,96 (2H, m), 3,47 (2H, s), 6,33 (1H, DD, J=6,5, 6.5 Hz), 7,14-7,20 (3H, m), 7.24 to 7,30 (2H, m), 7,37 (1H, d, J=6, 5 Hz), 7,54 (1H, d, J=6.5 Hz).

Example 158

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[oxo-(2-thienyl)methyl]piperidine

101 mg specified in the title compounds as colorless crystals obtained from 273 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[oxo(2-thienyl)methyl]piperidine obtained in example 80, the method described in example 172.

1H-NMR (400 MHz, CDCl3) δ 1,86-2,02 (4H, m), 2,20-of 2.30 (2H, m), 3.00 and-of 3.07 (2H, m), of 3.13 (1H, m), 3,52 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 7,14 (1H, DD, J=5.0 and 4.0 Hz), 7,33 (1H, DD, J=6,6, 2.0 Hz), to 7.61 (1H, m), of 7.64 (1H, DD, J=5.0 and 1.0 Hz), 7,74 (1H, DD, J=4,0, 1.0 Hz).

Example 159

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(3-oxo-3-phenylpropyl)]piperidine

414 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-piperidinecarboxylate, obtained as described in comparative example 2, and 0.46 ml of diethyl(2-oxo-2-phenylethyl)phosphonate and 78 mg suspended in oil, 60% sodium hydride are suspended in 8 ml of tetrahydrofuran and then stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate, the mixture was washed with 1 N. aqueous sodium hydroxide solution and a saturated saline solution and then dried over anhydrous magnesium sulfate. Rast is oritel is evaporated and obtained and 160 mg powder 10% palladium on coal (product, containing water) suspended in 10 ml of ethanol. After replacing the atmosphere of the vessel with hydrogen, the mixture is stirred at room temperature and under normal pressure for 4 hours. The reaction solution is filtered and the filtrate is evaporated. The crude product was then purified and allocate column chromatography on silica gel (methanol:ethyl acetate=1:9). Received the product and 0.15 ml of thionyl chloride dissolved in ethanol (2 ml)and then refluxed for 2 hours. The mixture is alkalinized by adding 1 N. aqueous sodium hydroxide solution and then extracted with dichloromethane. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is distilled and allocate column chromatography on NH form silica gel (ethyl acetate), resulting in a gain of 104 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1,67-of 1.78 (4H, m), 2,04 with 2.14 (2H, m), 2,90-of 2.97 (2H, m)of 3.00 (2H, t, J=7.5 Hz), of 3.46 (2H, s), 6,32 (1H, DD, J=6,6, and 6.6 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,44-7,49 (2H, m), 7,53-to 7.59 (2H, m)of 7.96-to 7.99 (2H, m).

Example 160

N4-(2-Phenyl)benzyl-1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-piperidinecarboxylic

47 mg specified in the title compounds as colorless crystals obtained from 92 mg of N4-[(2-phenyl)benzyl-1-[(2-IU is hydroxy-3-pyridyl)methyl]-4-piperazinecarboxamide, obtained in comparative example 82, the method described in example 141.

1H-NMR (400 MHz, DMSO-d6) δ 1,52 by 1.68 (4H, m), 1,90-to 1.98 (2H, m), and 2.14 (1H, m), 2,78-to 2.85 (2H, m), 3,23 (2H, s), 4,17 (2H, d, J=5.8 Hz), 6,17 (1H, DD, J=6,7, 6,7 Hz), 7,19-7,27 (2H, m), 7,29-7,40 (7H, m), 7,41-7,47 (2H, m), 8,18 (1H, t, J=5.8 Hz).

Example 161

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[[[2-(1,3-thiazol-2-yl)-3-pyridyl]oxy]methyl]piperidine

200 mg indicated in the title compounds as colorless crystals obtained from 238 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[[[2-(1,3-thiazol-2-yl)-3-pyridyl]oxy]methyl] piperidine obtained in example 84, the method described in example 141.

1H-NMR (400 MHz, CDCl3) δ 1,47-to 1.61 (2H, m), 1.93 and-of 2.26 (5H, m), 2,97-of 3.06 (2H, m), 3,52 (2H, s), Android 4.04 (2H, d, J=6.4 Hz), 6,32 (1H, DD, J=6,4, 6.4 Hz), 7,30 (1H, DD, J=8,4, 4,4 Hz), 7,35 (1H, d, J=6.4 Hz), was 7.36 (1H, DD, J=8.4 and, 1.2 Hz), of 7.48 (1H, d, J=3.0 Hz), EUR 7.57 (1H, d, J=6.4 Hz), 8,03 (1H, d, J=3.0 Hz), 8,40 (1H, DD, J=4,4, 1.2 Hz).

Example 162

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-cyano-2-(3,4-methylenedioxyphenyl)ethyl]piperidine

183 mg specified in the title compounds as colorless crystals obtained from 227 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(3,4-methylenedioxyphenyl)ethyl] piperidine obtained in example 85, the method described in example 141.

1H-NMR (400 MHz, CDCl3) δ 1,27-of 1.42 (2H, m), 1,45 is 1.58 (1H, m), 1,63-to 1.79 (3H, m), 1.85 to 1,95 (1H, m), 2,04-of 2.15 (2H, m), 2,88-of 2.97 (2H, m), 3,47 (2H, s), 3,70-of 3.77 (1H, m), 5,97 (2H, s), 6,30 (1H, DD, J=6,4, 6.4 Hz), 6,72-for 6.81 (3H, m) 7,34 (1H, d, J=6.4 Hz), 7,54 (1H, d, J=6,4 Hz).

Example 163

The dihydrochloride of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine

191 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine obtained in example 86, dissolved in ethanol (2 ml). To the mixture is added 0.3 ml of 4 n solution of hydrochloric acid in ethyl acetate, and then refluxed for 2 hours. The solvent is evaporated to obtain 199 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, DMSO-d6) δ 1,43-to 1.67 (4H, m), 1,80 is 1.96 (3H, m), 2,87-to 2.99 (2H, m), 3,28-3,37 (2H, m), 3,81 (3H, s), of 4.00 (2H, s), 4,27-to 4.33 (1H, m), 6,27 (1H, DD, J=6,4, 6.4 Hz), 6,98 (1H, DD, J=7,6, 7,6 Hz), 7,06 (1H, d, J=8.0 Hz), 7,32 (1H, d, J=6.4 Hz), 7,35 (1H, DD, J=8.0 a, 7,6 Hz), 7,51 (1H, d, J=6.4 Hz), to 7.77 (1H, d, J=7,6 Hz).

Example 164

1-[(6-Methoxy-2-pyridyl)methyl]-4-(3,4-methylenedioxyphenethyl)piperidine

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,47-of 1.56 (2H, m), 1,66-of 1.74 (2H, m), 2,01 is 2.10 (2H, m), 2,50-to 2.57 (2H, m), 2,90 are 2.98 (2H, m), of 3.56 (2H, s), 3,91 (3H, s), 5,91 (2H, s), to 6.58 (1H, d, J=8,2 Hz), is 6.61 (1H, DD, J=of 7.9, 1.6 Hz), of 6.66 (1H, d, J=1.6 Hz), 6,72 (1H, d, J=7.9 Hz), 6,98 (1H, d, J=7,2 Hz), 7,52 (1H, DD, J=8,2, 7,2 Hz).

Example 165

1-[(6-Methoxy-2-pyridyl)methyl]-4-[2-(3-thienyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.39 (3H, m), 1,54-to 1.63 (2H, m), 1,68-to 1.77 (2H, m), 2,01-2,11 (2H, m), 2,61-2,69 (2H, m), 2.71 to and 2.79 (2H, m), of 3.57 (2H, s)to 3.92 (3H, s), 6,59 (1H, d, J=8,2 Hz), 6,92 (1H, d, J=2,9 Hz), 6,93 (1H, d, J=7,7 Hz), 6,98 (1H, d, J=7,3 Hz), 7,24 (N, DD, J=7,7, 2,9 Hz), 7,52 (1H, DD, J=8,2, 7,3 Hz).

Example 166

1-[(6-Methoxy-2-pyridyl)methyl]-4-[2-(2-methoxy-3-pyridyl)ethyl]piperidine

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.40 (3H, m), 1,48-of 1.56 (2H, m), 1.70 to of 1.78 (2H, m), 2,02-2,12 (2H, m), 2,53-2,60 (2H, m), 2,92-to 2.99 (2H, m), of 3.57 (2H, s)to 3.92 (3H, s), of 3.94 (3H, s), 6,59 (1H, d, J=8,2 Hz), to 6.80 (1H, DD, J=7,1, 5,1 Hz), of 6.99 (1H, d, J=7,1 Hz), was 7.36 (1H, DD, J=7,1, 1.8 Hz), 7,52 (1H, DD, J=8,2, 7,1 Hz), 8,00 (1H, DD, J=5,1, 1.8 Hz).

Example 167

1-[(6-Methoxy-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

A 28% solution of sodium methoxide in methanol (2 ml) dissolved 218 mg of 1-[(6-bromo-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine obtained in comparative example 19, and then refluxed for 1 hour. To the reaction solution was added water and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is evaporated, resulting in a gain of 144 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,54-to 1.60 (2H, m), 1.70 to 1.77 in (2H, m), 2,02 is 2.10 (2H, m), 2,56-2,62 (2H, m), 2,92 are 2.98 (2H, m), of 3.56 (2H, s), 3,91 (3H, s), of 5.92 (2H, s), to 6.58 (1H, d, J=8,2 Hz), of 6.66 (1H, DD, J=of 7.8, 1.2 Hz), of 6.68 (1H, DD, J=7,8, 1.2 Hz), to 6.75 (1H, DD, J=7,8, and 7.8 Hz), 6,98 (1H, d, J=7,4 Hz), 7,52 (1H, DD, J=8,2, 7,4 Hz).

Example 168

1-[[6-(2-Hydroxyethoxy)-2-pyridyl]methyl]-4-(2,3-methylenedioxyphenethyl)piperidine

226 mg of the specified reception in the e connection in the form of colorless crystals is obtained from 320 mg of 1-[(3-bromo-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine, obtained in comparative example 19, the method described in example 123.

1H-NMR (400 MHz, CDCl3) δ 1,25-to 1.38 (3H, m), 1,54-to 1.61 (2H, m), of 1.62 and 1.75 (2H, m), 1,98 e 2.06 (2H, m), 2,55-2,62 (2H, m), 2,85 of 2.92 (2H, m), 3,52 (2H, s), 3,90-of 3.94 (2H, m), 4,45-4,50 (2H, m), of 5.92 (2H, s), 6,64-6,69 (3H, m), to 6.75 (1H, DD, J=7,8, and 7.8 Hz), 6,97 (1H, d, J=7,2 Hz), 7,56 (1H, DD, J=7,8, 7,2 Hz).

Example 169

1-[(6-Oxo-1,6-dihydro-2-pyridinyl)methyl]-4-(3,4-methylenedioxyphenethyl)piperidine

186 mg of 4-(3,4-methylenedioxyphenethyl)piperidine obtained in comparative example 4, 228 mg of 6-tert-butyldimethylsilyloxy-2-pyridinecarboxamide and 203 mg of triacetoxyborohydride sodium suspended in 2 ml of tetrahydrofuran and then stirred at room temperature for 20 hours. To the reaction solution was added aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is evaporated. The crude product was then purified and allocate column chromatography on NH form silica gel (ethyl acetate), resulting in a gain of 160 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.36 (3H, m), 1,48-to 1.61 (2H, m), of 1.66 and 1.75 (2H, m), 2,03 and 2.13 (2H, m), of 2.51-of 2.58 (2H, m), 2,73-of 2.81 (2H, m)to 3.34 (2H, s), of 5.92 (2H, s), of 5.99 (1H, d, J=6.8 Hz), to 6.43 (1H, d, J=9.3 Hz), 6,62 (1H, DD, J=7,9, and 1.6 Hz), to 6.67 (1H, d, J=1.6 Hz), was 6.73 (1H, d, J=7.9 Hz), 7,31 (1H, DD, J=9,3, 6,8 Hz).

Example 170

1-[(6-Oxo-1,6-dihydro-2-pyridinyl)methyl]-4-[2-(3-thienyl)ethyl]piperidine

Specified in the header of the compound obtained by the method described in example 169.

1H-NMR (400 MHz, CDCl3) δ to 1.22 to 1.37 (3H, m), 1,53-to 1.63 (2H, m), 1,67 to 1.76 (2H, m), 2,03 and 2.13 (2H, m), 2,61-2,69 (2H, m), 2,74-2,82 (2H, m)to 3.35 (2H, s), 5,95 (1H, d, J=6.8 Hz), to 6.43 (1H, d, J=9,2 Hz), 6,92 (1H, d, J=2,9 Hz), 6,94 (1H, d, J=4,8 Hz), 7,25 (1H, DD, J=4,8, 2,9 Hz), 7,31 (1H, DD, J=9,2, 6,8 Hz).

Example 171

1-[(6-Oxo-1,6-dihydro-2-pyridinyl)methyl]-4-[2-(2-methoxy-3-pyridyl)ethyl]piperidine

Specified in the header of the compound obtained by the method described in example 169.

1H-NMR (400 MHz, CDCl3) δ 1,23-to 1.38 (3H, m), 1,49 is 1.58 (2H, m), 1,71-to 1.79 (2H, m), 2,04 with 2.14 (2H, m), 2,53-2,61 (2H, m), 2,75-and 2.83 (2H, m)to 3.36 (2H, s), of 3.95 (2H, s), 5,95 (1H, d, J=6.8 Hz), to 6.43 (1H, d, J=9.3 Hz), for 6.81 (1H, DD, J=7,1, 5,1 Hz), 7,32 (1H, DD, J=9,3, 6,8 Hz), was 7.36 (1H, DD, J=7,1, 1.8 Hz), 8,01 (1H, DD, J=5,1, 1.8 Hz).

Example 172

1-[(6-Oxo-1,6-dihydro-2-pyridinyl)methyl]-4-[2,3-methylenedioxyphenethyl]piperidine

In tert-butanol (5 ml) suspended 316 mg of 1-[(6-bromo-2-pyridyl)methyl]-4-(2,3-methylenedioxyphenethyl)piperidine obtained in comparative example 19, and 880 mg of tert-butoxide potassium, and then refluxed for 8 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent volume is more and the crude product is isolated and purified column chromatography on NH form silica gel (ethyl acetate) to obtain 96 mg specified in the title compounds as colorless crystals.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.36 (3H, m), 1,54-of 1.64 (2H, m), 1,71-of 1.78 (2H, m), 2,04-2,12 (2H, m), 2,56-2,62 (2H, m), 2,75-2,82 (2H, m)to 3.35 (2H, s), to 5.93 (2H, s), of 5.99 (1H, d, J=6.8 Hz), to 6.43 (1H, d, J=7,2 Hz), 6,66 (1H, DD, J=7,6, 1.2 Hz), 6,69 (1H, DD, J=7,6, 1.2 Hz), 6,76 (1H, DD, J=7,6, 7,6 Hz), 7,31 (1H, DD, J=7,2, 6,8 Hz).

Example 173

N1-Benzyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidinyl]ndimethylacetamide

1.0 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetic acid, 0,41 ml benzylamine, 950 mg of WSC and 260 mg of HOBt are suspended in DMF and then stirred for 2 hours at room temperature. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate. The drying agent is filtered off, the solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate:methanol=10:1 and then 5:1) to obtain 500 mg specified in the title compound as white crystals.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (2H, m), 1,52-of 1.85 (4H, m), 2,03-2,10 (1H, m), 2,47 (1H, DD, J=16,4, 4,8 Hz), 2,66-by 2.73 (1H, m), was 2.76-to 2.85 (2H, m)to 3.33 (1H, d, J=13,6 Hz), 3,86 (3H, s), of 3.94 (1H, d, J=13,6 Hz), 4,30 (1H, DD, J=14,8, 5,2 Hz), of 4.54 (1H, DD, J=14,8, 6.4 Hz), to 6.67 (1H, DD, J=7,2, 4,8 Hz), 7,17 (1H, DD, J=7,2, 2 Hz), 7.24 to 7,34 (5H, m), 8,02 (1H, DD, J=4,8, 2 Hz), to 8.70 (1H, Sirs).

Example 174

N1-(3-Terbisil)-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 173.

1H-I Is R (400 MHz, CDCl3) δ 1,30-1,45 (2H, m), 1,52-of 1.65 (2H, m), 1,67-of 1.84 (2H, m), 2,08-2,17 (1H, m), of 2.51 (1H, DD, J=16,8, 5,2 Hz), 2,69-2,90 (3H, m), 3,35 (1H, d, J=13,6 Hz), 3,85 (3H, s), of 3.97 (1H, d, J=13,6 Hz), 4,28 (1H, DD, J=14,8, 5,2 Hz)to 4.52 (1H, DD, J=14,8, 6.4 Hz), 6,72 (1H, DD, J=7,2, 4.8 Hz), 6.90 to-was 7.08 (3H, m), 7,22-to 7.32 (2H, m), of 8.04 (1H, DD, J=4,8, 2.0 Hz), 8,03 (1H, Sirs).

Example 175

N1,N1-Di(2-PROPYNYL)-2-[(R)-1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]ndimethylacetamide

4.4 g of N1,N1-di(2-PROPYNYL)-2-[(2R)-hexahydro-2-pyridinyl]acetamide", she 3.8 g of 3-(chloromethyl)-2-methoxypyridine, 16.6 g of potassium carbonate and 50 ml of DMF was stirred at room temperature overnight. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate. After filtration anhydrous sodium sulfate the organic solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1-1:1, then ethyl acetate, then ethyl acetate:methanol=9:1), resulting in a gain of 640 mg of oil.

[α]D=+31,8° (C=0.99, and the Meon, 28°).

1H-NMR (400 MHz, CDCl3) δ 1,40-1,70 (5H, m), 1,75-of 1.85 (1H, m), of 2.23 (1H, m), and 2.26 (1H, m), 2,47-2,84 (1H, m), of 2.51 (1H, DD, J=15,6, and 8.4 Hz), 2,69 is 2.75 (1H, m), and 2.83 (1H, DD, J=15,6 4.0 Hz), 3,11-3,18 (1H, m), 3,42 (1H, d, J=16,0 Hz), 3,68 (1H, d, J=16.0 Hz), of 3.94 (3H, s), is 4.21 (2H, s)to 4.33 (2H, s)6,86 (1H, DD, J=6,8 6,8 Hz), of 7.70 (1H, DD, J=6,8 2,0 Hz), of 8.04 (1H, DD, J=6,8 2,0 Hz).

Example 176

N1,N1-Di(2-PROPYNYL)-3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]propanamide

500 mg of ethyl-3-[1-[(2-methoxy-pyridyl)methyl]-2-piperidyl]propanoate, 2 ml of 2 N. aqueous sodium hydroxide and 2 ml of methanol was stirred at 60°C for 2 hours. After cooling to room temperature, add 4 ml of 1 N. aqueous hydrochloric acid and the solvent is evaporated. To the residue is added ethanol, any insoluble matter is filtered off and the solvent is evaporated. The obtained oil (500 mg), 170 mg of diprophylline, 450 mg of WSC and 240 mg of HOBt dissolved in DMF and then stirred at room temperature for 3 hours. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1-1:1, then ethyl acetate), resulting in a gain of 300 mg of oil.

1H-NMR (400 MHz, CDCl3) δ 1,32-of 1.52 (4H, m), 1,60-1,75 (2H, m), 1.91 a-2,02 (2H, m), 2,10-of 2.25 (3H, m), 2,44 of $ 2.53 (3H, m), was 2.76-and 2.83 (1H, m), 3,29 (1H, d, J=14,8 Hz), 3,83 (1H, d, J=14,8 Hz), of 3.94 (3H, s), 4,99 (2H, s), 4,30 (2N with), 6,83 (1H, DD, J=6,8 Hz, 6.8 Hz), 7,69 (1H, d, J=6.8 Hz), 8,02 (1H, d, J=6,8 Hz).

Example 177

N1-(3-Terbisil)-2-[1-[2-(2-methoxy-3-pyridyl)ethyl]-2-piperidyl]ndimethylacetamide

200 mg of 2-(2-methoxy-3-pyridyl)acetaldehyde, 400 mg N1-(3-terbisil)-2-(2-piperidyl)ndimethylacetamide, 440 mg triacetoxyborohydride sodium and 0.12 ml of acetic acid are suspended in THF and then stirred at room temperature for 1 hour. Then add aqueous sodium bicarbonate and the mixture extracted with what dilatatum. The extract is dried over sodium sulfate. After filtering off the desiccant, the solvent is evaporated. The residue is purified column chromatography on silica gel (ethyl acetate:methanol=8:1 and then 4:1), resulting in a gain of 370 mg of a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,28-1,75 (6N, m), 2.26 and-of 2.34 (1H, m), is 2.37 (1H, DD, J=16,8, 4,4 Hz), 2.57 m) is 2.80 (5H, m), 2.93 which is 3.00 (1H, m), 3,06-3,13 (1H, m), 3,91 (3H, s), 4,20 (1H, DD, J=15,2 5,2 Hz), 4,46 (1H, DD, J=15,2 6,4 Hz), 6,77 (1H, DD, J=7,2 5,2 Hz), 6,88-6,98 (2H, m), 7,01 (1H, DD, J=7,6 1,0 Hz), 7,22-7,30 (2H, m), 8,01 (1H, DD, J=5,2 2,0 Hz), 8,81 (1H, Sirs).

Example 178

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-2-[3-(2-pyridyl)propyl]piperidine

In DMF was dissolved 2.1 g of the dihydrochloride of triphenyl(2-pyridylmethyl)of phosphonium, and then add, stirring at room temperature, 1.4 g of tert-butoxide potassium. After 15 minutes in the above solution at room temperature and with stirring, added dropwise a solution of 1.25 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetaldehyde dissolved in DMF, and the mixture is left overnight. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1, then ethyl acetate, then ethyl acetate:methanol=4:1). 760 mg of the obtained brown oil of 0.56 ml of thionyl chloride and 10 ml of ethanol is stirred at the boiling milk products is the first refrigerator for 30 minutes. The reaction mixture is cooled to room temperature, add 2 N. aqueous sodium hydroxide and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1, then ethyl acetate, then ethyl acetate:methanol=4:1). The obtained yellow oil (350 mg) was dissolved in 10 ml of ethanol, add 100 mg of 10% palladium on coal (product containing water) and the mixture is catalytically recover at normal pressure and under stirring for 1.5 hours. The catalyst is filtered off and the solvent is evaporated. The residue is purified by chromatography on NH-silica gel (ethyl acetate, then ethyl acetate:methanol=4:1) and obtain 310 mg of oil.

1H-NMR (400 MHz, CDCl3) δ 1,28 is 1.86 (10H, m), 2,16-of 2.24 (1H, m), 2.40 a-2,48 (1H, m), 2,73-2,82 (3H, m), 3,30 (1H, d, J=16.0 Hz), of 3.77 (1H, d, J=16.0 Hz), 6,33 (1H, DD, J=6,8, 6,8 Hz), 7,05-7,13 (2H, m), 7,35 (1H, d, J=6.8 Hz), at 7.55 (1H, DDD, J=7,0, 7,0, 2.0 Hz), 7,63 (1H, d, J=6,8 Hz)and 8.50 (1H, d, J=5 Hz).

Example 179

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-2-(2-phenylethyl)piperidine

Specified in the title compound is obtained using the compound obtained in comparative example 31, by the method described in example 163.

1H-NMR (400 MHz, CDCl3) δ 1,36 of 1.46 (1H, m), 1,48-of 1.64 (3H, m), 1,66-to 1.98 (4H, m), 2,20-of 2.28 (1H, m), 2,48-2,77 (3H, m), 2,78-of 2.86 (1H, m)to 3.34 (1H, d, J=16 Hz), 3,85 (1H, d, J=16.0 Hz), 6,32 (1H, DD, J=6,8, 68 Hz), 7,13-7,34 (6N, m), 7,63 (1H, d, J=6,8 Hz).

Example 180

1-[(2-Oxo-1-cyclopropylmethyl-1,2-dihydro-3-pyridinyl)methyl]-2-[(3-pyridyl)propyl]piperidine

300 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-[3-(2-pyridyl)propyl]piperidine obtained in example 178, 0.2 ml (methyl bromide)cyclopropane and 610 mg of potassium carbonate are suspended in 5 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at 80°C for 4 hours. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate. The drying agent is filtered off and the solvent is evaporated. The residue is purified column chromatography on NH-silica gel (hexane:ethyl acetate=2:1, then 1:1, then ethyl acetate) to obtain 150 mg of the target oil.

1H-NMR (400 MHz, CDCl3) δ 0,36 at 0.42 (2H, m), 0,57-of 0.64 (2H, m), 1,20-1,90 (11N, m), 2,15-of 2.23 (1H, m), 2,39-2,47 (1H, m), 2,72-2,82 (3H, m), 3,29 (1H, d, J=16.4 Hz in), 3.75 (1H, d, J=16.4 Hz), 3,81 (2H, d, J=7,2 Hz), to 6.19 (1H, DD, J=6,8, 6,8 Hz), 7,05-7,14 (2H, m), 7,27 (1H, DD, J=6,8, 2 Hz), 7,50-7,58 (2H, m), 8,48-charged 8.52 (1H, m).

Example 181

N1-Benzyl-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

To an ethanol (5 ml) is added 250 mg of N1-benzyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidinyl]ndimethylacetamide, obtained in example 173, and 0.11 ml of thionyl chloride, and then stirred at 100°C for 1.5 hours. The solvent is evaporated, to the residue add dilute aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, and then is evaporated to obtain 180 mg of the target oil.

1H-NMR (400 MHz, CDCl3) δ 1,30 was 1.43 (2H, m), 1,50-to 1.82 (4H, m), 2,07-of 2.16 (1H, m), 2,50-2,60 (1H, m), 2,67 is 2.80 (2H, m), 2,83-2,90 (1H, m), 3,30 (1H, d, J=14.4 Hz), with 3.89 (1H, d, J=14.4 Hz), 4,33 (1H, DD, J=14,8 2,8 Hz), 4,51 (1H, DD, J=14,8 2,0 Hz), equal to 6.05 (1H, DD, J=6,8 6,8 Hz), 7,06 (1H, DD, J=6,8 2,0 Hz), 7,11 (1H, DD, J=6,8 2,0 Hz), 7.18 in-to 7.32 (5H, m), 8,67-a total of 8.74 (1H, m).

Example 182

N1-(2-Cyclopropylethyl)-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-pyridinyl]ndimethylacetamide

500 mg N1-(3-terbisil)-2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]ndimethylacetamide, obtained in example 174, and 2 N. aqueous hydrochloric acid was stirred at 90°C for 3.5 hours. After cooling to room temperautre the mixture is alkalinized by adding 2 N. aqueous sodium hydroxide and extracted with ethyl acetate. The extract is dried over sodium sulfate. The drying agent is filtered off and the solvent is evaporated. The residue is purified column chromatography on NH form silica gel (hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=4:1) to give 270 mg of a colorless oil.

1H-NMR (400 MHz, CDCl3) δ 1,32-1,88 (6N, m), 2,10-of 2.21 (1H, m), 2,52-2,63 (1H, m), 2,69 is 2.80 (2H, m), 2,87-2,95 (1H, m), 3,29 (1H, d, J=13,6 Hz), of 3.94 (1H, d, J=13,6 Hz), 4,30 (1H, DD, J=15,2, 5,2 Hz), 4,51 (1H, DD, J=15,2, 6,4 Hz) 6,11 (1H, DD, J=6,8, 6,8 Hz), 6,85-7,10 (4H, m), 7,17-7,26 (2H, m), 8,86-to 8.94 (1H, m).

Example 183

N1-(2-Cyclopropylethyl)-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

400 mg 2-1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl)acetic acid, obtained in example 34, 200 mg of 2-cyclopropylalanine, 370 mg of WSC, 100 mg of HOBt, of 0.42 ml of triethylamine and 10 ml of DMF was stirred at room temperature overnight. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and the solvent is evaporated. 310 mg of the obtained oil was added to 0,23 ml of thionyl chloride and 5 ml of ethanol and the mixture is stirred at the boil under reflux at room temperature for 1 hour. Then add water dilute sodium hydroxide and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate and then the solvent is evaporated. The residue is purified column chromatography on NH form silica gel (hexane:ethyl acetate=2:1, then ethyl acetate, then ethyl acetate:methanol=10:1, then 4:1) to give 290 mg of a yellow oil.

1H-NMR (400 MHz, CDCl3) δ -0,08-0,08 (2H, m), of 0.35-0.40 (2H, m), of 0.58 and 0.68 (1H, m), of 1.30 and 1.80 (8H, m), 2,10-of 2.20 (1H, m), 2,45 of $ 2.53 (1H, s), 2,65-to 2.74 (2H, m), 2,88-2,95 (1H, m), 3,13-up 3.22 (1H, m)to 3.33 (1H, d, J=14.4 Hz), 3,35-of 3.45 (1H, m), 3,91 (1H, d, J=14.4 Hz), 6,30 (1H, DD, J=6,8, 6,8 Hz), 7,33 (1H, DD, J=6,8, 2.0 Hz), 7,44 (1H, DD, J=6,8, 2.0 Hz).

Example 184

N1-Cyclopropylmethyl-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 183.

1H-NMR (400 MHz, CDCl3) δ 0,25-0,30 (2 is, m), 0,40 of 0.47 (2H, m), 0.88 to 1.00 and (1H, m), of 1.30 and 1.80 (6N, m), 2,10-of 2.20 (1H, m), 2,42-of 2.50 (1H, m), 2,67-2,78 (2H, m), 2,90-to 3.02 (2H, m), 3,19-of 3.27 (1H, m)to 3.34 (1H, d, J=14.4 Hz), of 3.94 (1H, d, J=14.4 Hz), 6,30 (1H, DD, J=6,8, 6,8 Hz), 7,35 (1H, DD, J=6,8, 2 Hz), 7,49 (1H, DD, J=6,8, 2.0 Hz), to 8.20 (1H, m).

Example 185

N1-(4-Forfinal)-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 183.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,84 (6N, m), 2.49 USD (1H, DD, J=16,4, 4,4 Hz), 2.57 m-to 2.65 (1H, m), 2,97-of 3.06 (2H, m), 3,11 (1H, DD, J=16,4, 4 Hz), 4,22 (1H, d, J=12,8 Hz)6,09 (1H, DD, J=6,8, 6,8 Hz), only 6.64 (1H, DD, of 6.8, 2.0 Hz), for 6.81-6,89 (2H, m), 7,35 (1H, DD, J=6,8, 2.0 Hz), 7,50-7,58 (2H, m), is 10.68 (1H, s).

Example 186

N1-(2-Pyridylmethyl)-2-[1-(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 183.

1H-NMR (400 MHz, CDCl3) δ of 1.30 and 1.80 (6N, m), 2,13-2,22 (1H, m), 2.05 is-2,63 (1H, m), 2,70-2,82 (2H, m), 2,88-2,95 (1H, m), 3,35 (1H, d, J=14,8, 2.0 Hz), 3,92 (1H, d, J=14,8, 2.0 Hz), 4,49 (1H, DD, J=16,0, 5,2 Hz), with 4.64 (1H, DD, 16,0, 2.0 Hz), 6,16 (1H, DD, J=6,8, 6,8 Hz), 7,12-7,17 (1H, m), 7,22 (1H, DD, of 6.8, 2.0 Hz), 7,25-to 7.32 (1H, m), 7,45 (1H, DD, J=6,8, 2.0 Hz), 7,58-to 7.64 (1H, m), of 8.47-charged 8.52 (1H, m), 8,86-8,93 (1H, m).

Example 187

N1-(2-Cyclopropylethyl)-2-[1-[[1-(cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl]-2-piperidyl]ndimethylacetamide

300 mg of N1-(2-cyclopropylethyl)-2-[1-(2-oxo-1,2-dihydro-3-pyridine is l)methyl]-2-pyridinyl]acetamide", she obtained in example 183, 0.2 ml (methyl bromide)cyclopropane and 470 mg of a solution of potassium carbonate are suspended in 5 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at 80°C for 4 hours. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate. The drying agent is filtered off and the solvent is evaporated. The residue is purified by chromatography on NH-silica gel (hexane:ethyl acetate=2:1, then 1:1, then ethyl acetate) to obtain 150 mg of the target oil.

1H-NMR (400 MHz, CDCl3) δ 0,02-0,08 (2H, m), from 0.37 to 0.45 (4H, m), 58-0,74 (3H, m), 1,20-1,84 (N, m), 2,02-of 2.21 (1H, m), 2,49-by 2.73 (3H, m), 2,87-2,96 (1H, m), 3,17-of 3.27 (1H, m)to 3.33 (1H, d, J=14.4 Hz), 3,32-of 3.43 (1H, m), 3,81 (1H, d, J=6.8 Hz), 3,90 (1H, d, J=14.4 Hz), to 6.19 (1H, DD, J=6,8, 6,8 Hz), 7,31 (1H, DD, J=6,8, 2 Hz), was 7.36 (1H, DD, J=6,8, 2 Hz), 8,14-to 8.20 (1H, m).

Example 188

N1-(3-Terbisil)-2-[1-[[1-(cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 187.

1H-NMR (400 MHz, CDCl3) δ (1H, m), 1.30 and 1,85 (6N, m), 2,09-to 2.18 (1H, m), 2,55-2,78 (3H, m), 2,87-2,96 (1H, m), with 3.27 (1H, d, J=14.6 Hz), 3,56-3,70 (2H, m), 3,98 (1H, d, J=14.6 Hz), to 4.38 (1H, DD, J=15,2, 5,2 Hz), of 4.57 (1H, DD, J=15,2, 6.4 Hz), 6,09 (1H, DD, J=6,8, 6,8 Hz), 7,00-7,26 (5H, m), 7,29 (1H, DD, J=6,8, 2.0 Hz), 8,98-9,06 (1H, m).

Example 189

N1-(4-Forfinal)-2-[1-[[1-(cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl]-2-piperidyl]ndimethylacetamide

At asanee the title compound is obtained using the appropriate connection method, described in example 187.

1H-NMR (400 MHz, CDCl3) δ 0,30-0,40 (2H, m), of 0.56 to 0.63 (2H, m), 1,15-1,25 (1H, m), 1.30 and 1,87 (6N, m), 2,16-of 2.24 (1H, m), 2,60-by 2.73 (2H, m), 2,89 (1H, DD, J=15,2, 4.0 Hz), 2,99-of 3.06 (1H, m), 3,35 (1H, d, J=13,6 Hz), 3,76 (2H, DD, J=7,2, 1,6 Hz), 3,99 (1H, d, J=13,6 Hz), 6,17 (1H, DD, J=6,8, 6,8 Hz), 6,93-7,00 (2H, m), 7,31 (1H, DD, J=6,8, 2.0 Hz), was 7.36 (1H, DD, J=6,8, 2.0 Hz), 7,55-7,63 (2H, m), 10,49 (1H, s).

Example 190

N1-(2-Pyridylmethyl)-2-[1-[(1-benzyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 187.

1H-NMR (400 MHz, CDCl3) δ 1,33-1,80 (6N, m), 2,17-of 2.24 (1H, m), 2,60-of 2.75 (2H, m), was 2.76 (1H, m), is 2.40 (1H, m), 3,39 (1H, d, J=6.8 Hz), 3,92 (1H, d, J=6.8 Hz), 4,50 (1H, DD, J=16,0, 5,2 Hz), with 4.64 (1H, DD, J=16,0, 6,0 Hz), 5,00 (1H, d, J=14.4 Hz), 5,07 (1H, d, J=14.4 Hz), the 6.06 (1H, DD, J=6,8, 6,8 Hz), 7,10-7,35 (N, m), 7,55 (1H, DDD, J=7,6, to 7.6, 1.6 Hz), 8,48-charged 8.52 (1H, m), 8,87-8,93 (1H, m).

Example 191

N1,N1-Di(2-PROPYNYL)-2-[(2R)-1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

600 mg of N1,N1-di(2-PROPYNYL)-2-[(R)-1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]ndimethylacetamide, obtained in example 175, and 0.45 ml of thionyl chloride dissolved in 20 ml of ethanol and the mixture refluxed for 1.5 hours. After cooling to room temperature, add 2 N. aqueous sodium hydroxide and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous Sul is the sodium atom. Anhydrous sodium sulfate is filtered off and the ethyl acetate is evaporated. The residue is purified by chromatography on silica gel (ethyl acetate:methanol=9:1) to give 530 mg of the target oil.

[α]D=+37,9° (C=0,23, MeOH, 26°C).

1H-NMR (400 MHz, CDCl3) δ 1,40-1,70 (5H, m), is 1.81 (1H, m), 2,22 (1H, s), 2,28 (1H, s), is 2.37 (1H, m), 2,53 (1H, DD, J=15,6, and 8.4 Hz), a 2.75 (1H, m), is 2.88 (1H, DD, J=15,6, 4.0 Hz), 3,19 (1H, m), 3,40 (1H, d, J=16.0 Hz), 3,68 (1H, d, J=16.0 Hz), 4,16-and 4.40 (4H, m), 6,32 (1H, t, J=6.8 Hz), 7,34 (1H, d, J=6.8 Hz), 7,60 (1H, d, J=6,8 Hz).

Example 192

N1,N1-Di(2-PROPYNYL)-2-[(2R)-1-[(1-cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl)methyl]hexahydro-2-pyridinyl]ndimethylacetamide

200 mg of N1,N1-di(2-PROPYNYL)-2-[(2R)-1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide, obtained in example 95, and 0.09 ml (methyl bromide)cyclopropane and 510 mg of potassium carbonate are suspended in 10 ml of DMF and the mixture is stirred at 80°C for 1.5 hours. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate. Anhydrous sodium sulfate is filtered off and utilized is evaporated. The residue is purified column chromatography on NH-silica gel (hexane:ethyl acetate=2:1, then 1:1) to obtain 100 mg of the target oil.

1H-NMR (400 MHz, CDCl3) δ 0,35-0,42 (2H, m), 0,57-of 0.64 (2H, m), 1,19-of 1.30 (1H, m), 1,40-1,85 (6N, m)of 2.21 (1H, s), 2,28 (1H, s), 2,34 is 2.43 (1H, m), 2,50-2,60 (1H, m), 2,69 was 2.76 (1H, m), 2,85-of 2.93 (1H, m), 3,19 (1H, Sirs), 3,40 (1H, d, J=14,8 Hz), 3,68 (1H, d, J=14,8 Hz), 3.75 to 3,86 (2 is, m), 4,18-and 4.40 (4H, m), of 6.20 (1H, t, J=6.8 Hz), 7,29 (1H, d, J=6.8 Hz), to 7.50 (1H, d, J=6,8 Hz).

Example 193

N1,N1-Di(2-PROPYNYL)-2-[(2R)-1-[[1-(2-methoxyethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl]hexahydro-2-piperidinyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 192.

1H-NMR (400 MHz, CDCl3) δ 1,40-1,83 (6N, m)of 2.21 (1H, s), 2,28 (1H, s), 2,33-to 2.42 (1H, m), 2,49-of 2.58 (1H, m), 2,69 was 2.76 (1H, m), 2,83-2,90 (1H, m), 3,17 (1H, Sirs), of 3.32 (3H, s), 3,39 (1H, d, J=15,5 Hz), 3,64-3,71 (3H, m), 4,06-4,17 (2H, m), 4,20 is 4.35 (4H, m), 6,16 (1H, DD, J=6,8, 6,8 Hz), 7.23 percent (1H, DD, J=6,8, 2 Hz), 7,49 (1H, DD, J=6,8, 2 Hz).

Example 194

N1,N1-Di(2-PROPYNYL)-2-[(2R)-1-[[2-oxo-1-(2,2,2-triptorelin)-1,2-dihydro-3-pyridinyl]methyl]hexahydro-2-pyridinyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method described in example 192.

1H-NMR (400 MHz, CDCl3) δ 1,40-1,70 (5H, m), 1,75-of 1.85 (1H, m), of 2.21 (1H, s), 2,28 (1H, s), 2,32-to 2.42 (1H, m), 2,52 (1H, DD, J=15,2, and 8.4 Hz), 2,68 was 2.76 (1H, m), and 2.83 (1H, DD, J=15,2, 4.0 Hz), 3,20 (1H, Sirs), to 3.38 (1H, d, J=16.4 Hz), 3,66 (1H, d, J=16.4 Hz), 4,17-and 4.40 (4H, m), to 4.62 (2H, q, J=8,8 Hz) and 6.25 (1H, DD, J=6,6, 6,8 Hz), 7,17 (1H, d, J=6.8 Hz), 7,53 (1H, d, J=6,8 Hz).

Example 195

N1,N1-Di(2-PROPYNYL)-2-[(2R)-1-[1-[2-(diisopropylamino)ethyl]-2-oxo-1,2-dihydro-3-pyridinyl)methyl]hexahydro-2-pyridinyl]ndimethylacetamide

Specified in the title compound is obtained using the appropriate connection method, is written in example 192.

1H-NMR (400 MHz, CDCl3) δ 0,93 (6N, d, J=6.8 Hz), 1,40-of 1.65 (5H, m), 1,74 of-1.83 (1H, m) of 2.20 (1H, s), and 2.27 (1H, s), 2,30-of 2.38 (1H, m), 2,53 (1H, DD, J=15,2, 9,2 Hz), 2,65 was 2.76 (3H, m), 2,83-2,90 (1H, m), 2,92-to 3.02 (2H, m), 3,13-3,20 (1H, m)to 3.38 (1H, d, J=15.6 Hz), to 3.67 (1H, d, J=15.6 Hz), 3,80-to 3.92 (2H, m), 4,17-4,39 (4H, m), 6,13 (1H, DD, J=6,8, 6,8 Hz), 7,16 (1H, DD, J=6,8, 2.0 Hz), 7,46 (1H, DD, J=6,8, 2.0 Hz).

Example 196

N1,N1-Di(2-PROPYNYL)-3-[1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]ndimethylacetamide

300 mg of N1,N1-di(2-PROPYNYL)-3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]propanamide obtained in example 176, 0.4 ml of thionyl chloride and 5 ml of ethanol is stirred at the boil under reflux for 1 hour and then the mixture is left overnight. After that add water dilute sodium hydroxide and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate. The sodium sulfate is removed and the solvent is evaporated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate=3:1, then ethyl acetate:methanol=9:1) to give 300 mg of a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,33-of 1.57 (4H, m), of 1.62 and 1.75 (2H, m), 1,87 is 2.00 (2H, m), 2,17-of 2.27 (2H, m), 2,30 at 2.59 (4H, m), 2,80-is 2.88 (1H, m), and 3.31 (1H, d, J=16.0 Hz), 3,82 (1H, d, J=16.0 Hz), 4,20 (2H, s), or 4.31 (2H, s), of 6.31 (1H, DD, J=6,8 Hz), 7,33 (1H, d, J=6.8 Hz), to 7.59 (1H, d, J=6,8 Hz).

Example 197

N1,N1-Di(2-PROPYNYL)-3-[1-[(1-cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-2-piperidyl]propanamide

300 mg of N1,N1-di(2-PROPYNYL)-3-[1-[(2-oxo-1,2-dihydro-3-pyridinylmethyl]-2-piperidyl]propanamide, 0.1 ml of cyclopropanemethylamine, 620 mg of potassium carbonate and 5 ml of DMF is heated, with stirring, at 60°C for 1 hour and at 80°C for 1 hour. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over magnesium sulfate. The drying agent is filtered off and the solvent is evaporated. The residue is purified column chromatography on MN-silica gel (hexane:ethyl acetate=4:1, then 2:1, then ethyl acetate) to obtain 150 mg of oil.

1H-NMR (400 MHz, CDCl3) δ 0,35-0,75 (2H, m), 0,57 is 0.71 (2H, m), 1,20-1,30 (1H, m), 1.30 and of 1.55 (4H, m), 1,61 is 1.75 (2H, m), 1,90-of 1.97 (2H, m), 2,15-of 2.28 (3H, m), 2,43-of 2.58 (3H, m), 2,80-2,87 (1H, m), 3,29 (1H, d, J=16.0 Hz), 3,79 (1H, d, J=16.0 Hz), 3,80 (2H, d, J=7,2 Hz), 4,22 (2H, s), 4,30 (2H, s), 6,17 (1H, DD, J=6,8, 6,8 Hz), 7,28 (1H, DD, J=6,8, 2.0 Hz), of 7.48 (1H, DD, J=6, 8, 2.0 Hz).

Example 198

N1-(3-Terbisil)-2-[1-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]ndimethylacetamide

370 mg of N1-(3-terbisil)-2-[1-[2-(2-methoxy-3-pyridyl)ethyl]-2-piperidyl]ndimethylacetamide, obtained in example 177, of 0.44 ml of thionyl chloride and 5 ml of ethanol is stirred for 2 hours at 100°C. the Solvent is evaporated and to the residue add aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate and dried over sodium sulfate. Then, the drying agent is filtered off and the solvent is evaporated, resulting in a gain of 330 mg of white crystals.

1H-NMR (400 MHz, CDCl3) δ of 1.30-1.77 in (6N, m), 2,30-of 2.58 (3H, m), 2,69 is 2.80 (4H, m), 2,88-of 2.97 (1H, m), 3.00 and-a 3.06 (1H, m), 4,32 (1H, DD, J=15,2, 56 Hz), 4,48 (1H, DD, J=15,2, 6,0 Hz), 6,16 (1H, DD, J=6,8, 6,8 Hz), 6,86-6,93 (1H, m), 6,97-7,03 (1H, m),? 7.04 baby mortality (1H, d, J=7,6 Hz), 7,16-7,26 (3H, m), 8,80-8,86 (1H, m).

Example 199

N1-(3-Terbisil)-2-[1-[2-(1-cyclopropylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]ndimethylacetamide

230 mg of N1-(3-terbisil)-2-[1-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]ndimethylacetamide, obtained in example 102, and 0.08 ml of cyclopropylmethanol, 450 mg of potassium carbonate and 5 ml of DMF was stirred at 60°C for 1 hour. Then water is added and the mixture extracted with ethyl acetate. The extract is dried over sodium sulfate. Then, the drying agent is filtered off and the solvent is evaporated. The residue is purified column chromatography on NH-silica gel (hexane:ethyl acetate=1:1, then ethyl acetate) resulting in a gain 180 mg of colorless oil.

1H-NMR (400 MHz, CDCl3) δ 0,30-0,35 (2H, m), of 0.54 to 0.60 (2H, m), 1,12-1,22 (1H, m), of 1.28 to 1.48 (6N, m), 2,32-to 2.40 (1H, m), a 2.45-2.63 in (3H, m), 2,67-only 2.91 (4H, m), 2.95 and-to 3.02 (1H, m), 3,65-of 3.77 (2H, m), the 4.29 (1H, DD, J=15,2, 5,2 Hz), of 4.49 (1H, DD, J=15,2, 5.6 Hz), between 6.08 (1H, DD, J=6,8, 6,8 Hz), 6.87 in-7,11 (4H, m), 7,20-7,27 (1H, m), 8,86 (1H, Sirs).

Example 200

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[3-(2-thienyl)propyl]piperidine

159 mg specified in the title compound obtained as colorless crystals from 206 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(3-(2-thienyl)propyl)piperidine, which was obtained in example 77.

1H-NMR (400 MHz, CDCl3) δ 1,20-of 1.36 (5H, m), 1,62 to 1.76 (4H, m), 2,02 is 2.10 (2H, m), 2,1 (2H, t, J=7,6 Hz), 2,87-to 2.94 (2H, m), of 3.46 (2H, s), 6,33 (1H, DD, J=6,6, and 6.6 Hz), 6,77 (1H, DD, J=3.3, which is 1.1 Hz), 6,91 (1H, DD, J=5,1, 3,3 Hz), 7,10 (1H, DD, J=5,1, 1.1 Hz), was 7.36 (1H, d, J=6.6 Hz), 7,52 (1H, m).

Example 201

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(2-methoxyphenoxy)methyl]piperidine

200 mg of 2-methoxy-3-(chloromethyl)pyridine, 380 mg of 4-[(2-methoxyphenoxy)methyl]piperidine and 235 mg of potassium carbonate are added to 10 ml of acetonitrile and the mixture is stirred at room temperature for 3 hours and 15 minutes. After filtering the reaction solution, the solvent is evaporated and the crude product is purified column chromatography on silica gel (hexane:ethyl acetate=3:2) to give 359 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,36 is 1.48 (2H, m), 1,84-of 1.97 (3H, m), 2.05 is with 2.14 (2H, m)to 2.94 (2H, sird, J=11,6 Hz), 3,51 (2N), 3,86 (3H, s), a 3.87 (2H, s), 3,95 (ZN, C), 6,85-6,94 (5H, m), 7,66 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 202

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(2-pertenece)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,36-of 1.52 (2H, m)to 1.86 (3H, sird, J=8,8 Hz), 2,10 (2H, shirt, J=12.0 Hz), to 2.94 (2H, sird, J=8,4 Hz), 3,51 (2H, s), a 3.87 (2H, d, J=6.0 Hz), of 3.95 (3H, s), 6,84-6,93 (2H, m), 6.90 to-7,00 (1H, m),? 7.04 baby mortality (1H, t, J=7,6 Hz), 7,00-7,14 (1H, m), 7,66 (1H, DD, J=7,6, 2.0 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 203

1-[(5-Chloro-2-methoxy-3-PIR is dinyl)methyl]-4-[(2-pertenece)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,36-of 1.52 (2H, m)to 1.87 (3H, sird, J=8,8 Hz), 2,12 (2H, shirt, J=10,8 Hz), of 2.92 (2H, sird, J=11,6 Hz), of 3.46 (2H, s), 3,88 (2H, d, J=6.0 Hz), 3,93 (3H, s), 6,84-6,93 (1H, m), to 6.95 (1H, t, J=8.0 Hz), 7,00-7,14 (2H, m), of 7.64-of 7.70 (1H, m), 7,98 (1H, d, J=2.0 Hz).

Example 204

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(2-cyclohexylmethoxy)phenoxymethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,01 by 1.12 (2H, m), 1,13-of 1.36 (3H, m), 1,38 of 1.50 (2H, m), 1,64-1,94 (N, m), 2.06 to to 2.15 (2H, m)to 2.94 (2H, sird, J=11,6 Hz), 3,51 (2H, s), of 3.78 (2H, d, J=6.0 Hz), a-3.84 (2H, d, J=6.0 Hz), of 3.95 (3H, s), 6,84-6,92 (5H, m), to 7.67 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 205

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[[2-(2-cyclohexylethyl)phenoxy]methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 0,87 is 0.99 (2H, m), with 1.009 is 1.34 (4H, m), 1,42-and 1.54 (4H, m), 1.60-to 1,90 (8H, m), 2,08-of 2.16 (2H, m), 2,58-of 2.64 (2H, m), 2,96 (2H, sird, J=11.2 Hz), 3,52 (2H, s), 3,80 (2H, d, J=5.6 Hz), of 3.96 (3H, s), to 6.80 (1H, d, J=7,6 Hz), 6,83-of 6.90 (2H, m), 7,10-7,16 (2H, m), 7,68 (1H, DD, J=4,8, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 206

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)phenoxyl the Teal]piperidine

150 mg of 5-chloro-2-methoxy-3-pyridinecarboxamide and 291 mg of 4-[2-(cyclohexylmethoxy)phenoxymethyl]piperidine was dissolved in 5 ml of 1,2-dichloroethane. To the mixture is added 0.06 ml of acetic acid and 214 mg of triacetoxyborohydride sodium, and then the mixture is stirred over night at room temperature. To the reaction solution was added aqueous saturated sodium bicarbonate, and the mixture is then extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give 285 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,01-of 1.36 (5H, m), 1,39-of 1.52 (2H, m), 1,65-1,94 (N, m), 2,08-of 2.16 (2H, m), of 2.92 (2H, sird, J=11,6 Hz), of 3.46 (2H, s), of 3.78 (2H, d, J=6.4 Hz), 3,85 (2H, d, J=6.4 Hz), 3,93 (3H, s), 6,86-6,92 (4H, m), to 7.67 (1H, d, J=2.4 Hz), 7,98 (1H, d, J=2,4 Hz).

Example 207

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[(2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

To acetonitrile (10 ml) is added 500 mg of 2-methoxy-3-(chloromethyl)pyridine, 1.04 g of 4-[(E)-2-[(2-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine and 531 mg of potassium carbonate and then stirred at room temperature overnight. To the reaction solution was added ethyl acetate and the mixture filtered through a mixture of the TRC aluminum-silica gel. Then the solvent is evaporated and the crude product is purified column chromatography on silica gel (hexane:ethyl acetate=8:1) to obtain 961 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,02-to 1.38 (5H, m), 1,52-of 1.92 (10H, m), 2,10-of 2.23 (3H, m), 2,92 are 2.98 (2H, m), 3,53 (2H, s), of 3.77 (2H, d, J=6.0 Hz), of 3.96 (3H, s), to 6.19 (1H, DD, J=16,0, 7,2 Hz), of 6.71 (1H, d, J=16.0 Hz), 6,80-6,92 (3H, m), to 7.15 (1H, dt, J=7,2, 1.2 Hz), 7,41 (1H, DD, J=7,2, 1,6 Hz), to 7.67 (1H, DD, J=7,6, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 208

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-[(2-(2-forfinal)-1-ethynyl]piperidine

200 mg of 5-chloro-2-methoxy-3-pyridinecarboxamide and 263 mg of 4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine was dissolved in 5 ml of 1,2-dichloroethane. To the mixture of 0.09 ml of acetic acid and 339 mg of triacetoxyborohydride sodium, and then the mixture is stirred at room temperature for 2.5 hours. The reaction solution is filtered through NH form silica gel and the filtrate is evaporated. To the residue is added ethyl acetate, the mixture is filtered through alumina and the filtrate is evaporated. The crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give 245 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,53 was 1.69 (2H, m), a 1.75 of-1.83 (2H, m), 2,10-of 2.24 (3H, m), 2,85-2,96 (2H, m), 3,47 (2H, s), 3,93 (3H, s), and 6.25 (1H, DD, J=16,0, 6,8 Hz), 6,55 (1H, d, J=16.0 Hz), 7,01 (1 is, DDD, J=10,8, to 8.0, 1.2 Hz), 7,07 (1H, dt, J=8,0, 1.2 Hz), 7,16 (1H, m), 7,44 (1H, dt, J=8,0, 1.2 Hz), to 7.68 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=2,4 Hz).

Example 209

1-[(5-Cyano-2-methoxy-3-pyridinyl)methyl]-4-[(E)-(2-forfinal)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,53-of 1.66 (2H, m), 1,76-of 1.84 (2H, m), 2,12-of 2.26 (3H, m), 2,85 of 2.92 (2H, m), of 3.48 (2H, s)to 4.01 (3H, s), of 6.26 (1H, DD, J=16,0, 6,8 Hz), 6,56 (1H, d, J=16.0 Hz), 7,01 (1H, DDD, J=11,2, an 8.4, 1.2 Hz), was 7.08 (1H, dt, J=8,4, 1.2 Hz), 7,17 (1H, m), 7,45 (1H, dt, J=8,4, 1.2 Hz), 7,95 (1H, d, J=2.4 Hz), of 8.37 (1H, d, J=2,4 Hz).

Example 210

1-[(5-fluoro-2-methoxy-3-pyridyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine

117 mg of 5-fluoro-2-methoxy-3-pyridinecarboxamide and 291 mg of 4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine was dissolved in 3 ml of 1,2-dichloroethane, added 0.06 ml of acetic acid and 238 mg of triacetoxyborohydride sodium and the mixture is stirred at room temperature overnight. To the reaction solution was added aqueous saturated sodium carbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=8:1) to give 221 mg specified in the title compound as a colourless oil is.

1H-NMR (400 MHz, CDCl3) δ 1,53 was 1.69 (2H, m), a 1.75 of-1.83 (2H, m), 2,11-of 2.25 (3H, m), 2,89-2,96 (2H, m), of 3.48 (2H, s), 3,93 (3H, s), of 6.26 (1H, DD, J=16,0, 6,8 Hz), 6,55 (1H, d, J=16.0 Hz), 7,01 (1H, DDD, J=10,4, to 8.0, 1.2 Hz), 7,07 (1H, dt, J=8,0, 1.2 Hz), 7,16 (1H, m), 7,44 (1H, dt, J=8,0, 1.2 Hz), 7,53 (1H, DD, J=8,4, and 3.2 Hz), 7,87 (1H, d, J=3.2 Hz).

Example 211

1-[(5-fluoro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,03-to 1.38 (5H, m), 1,52-of 1.93 (10H, m), 2,12-of 2.24 (3H, m), 2,89-2,96 (2H, m), of 3.48 (2H, s), of 3.78 (2H, d, J=6.0 Hz), 3,93 (3H, s), of 6.20 (1H, DD, J=16,0, 7,2 Hz), 6,72 (1H, d, J=16.0 Hz), 6,83 (1H, d, J=8.0 Hz), to 6.88 (1H, dt, J=7,6, and 1.6 Hz), to 7.15 (1H, dt, J=7,6, 2.0 Hz), 7,41 (1H, DD, J=7,6, and 1.6 Hz), 7,53 (1H, DD, J=8,4, 2,8 Hz), 7,87 (1H, d, J=2,8 Hz).

Example 212

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-chlorophenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,54-of 1.66 (2H, m), 1,76-of 1.84 (2H, m), of 2.15 (2H, dt, J=2,4, 12.0 Hz), of 2.21 (1H, m), 2,89-2,96 (2H, m), 3,47 (2H, s), 3,93 (3H, s), 6,17 (1H, DD, J=16,0, 7,2 Hz), 6,77 (1H, d, J=16.0 Hz), 7,14 (1H, dt, J=to 8.0, 2.0 Hz), 7,20 (1H, dt, J=8,0, 2.0 Hz), 7,33 (1H, DD, J=8,0, 2.0 Hz), 7,51 (1H, dt, J=8,0, 2.0 Hz), to 7.68 (1H, d, J=2,8 Hz).

Example 213

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-were)-1-ethynyl]piperidine

Specified in the header is the connection obtained from the corresponding starting material way, described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,53-to 1.67 (2H, m), a 1.75 of-1.83 (2H, m), 2,10-of 2.24 (3H, m), of 2.33 (3H, s), 2,89-2,96 (2H, m), 3,47 (2H, s), 3,93 (3H, s), the 6.06 (1H, DD, J=16,0, 7,2 Hz), 6.48 in (1H, DD, J=16,0, 0.8 Hz), 7,08-to 7.18 (3H, m), 7,41 (1H, d, J=6.8 Hz), to 7.68 (1H, d, J=2,8 Hz), 7,98 (1H, d, J=2,8 Hz).

Example 214

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-were)-1-ethynyl]piperidine

In N,N-dimethylformamide (10 ml) are suspended to 1.15 g of the bromide [(2-were)methyl]triphenylphosphine. To the suspension is added 288 mg of tert-butoxide potassium, and then stirred for 15 minutes under ice cooling. Then added dropwise a solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxylate dissolved in 3 ml of N,N-dimethylformamide, and then stirred at room temperature overnight. To the reaction solution was added ice water and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 473 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,48 by 1.68 (2H, m), 1,74 of-1.83 (2H, m), 1,96-2,22 (3H, m), 2,19 (3/4H), 2,32 (9/4H, s), 2,86 (1/2H, sird, J=7,6 Hz), 2,99 (3/2H, sird, J=12 Hz), 3,47 (1/2N), 3,52 (3/2H, s), 3,93 (3/4H with), 3,96 (9/4H, s), 5,55 (1/4H, DD, J=11,6, 10,0 Hz), 6,05(3/4H, DD, J=15,6, a 7.6 Hz), 6,37 (1/4H, d, J=11,6 Hz), 6,57 (3/4H, d, J=15.6 Hz), 6,84-6,92 (1H, m), 7,00-7,20 (3H, m), 7,41 (1H, d, J=6.4 Hz), 7,63 (1/4H, DD, J=7,2, 2.0 Hz), to 7.67 (3/4H, DD, J=6,8, 2.0 Hz), 8,03-of 8.09 (1H, m).

Example 215

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[3-(benzyloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,50-1,80 (4H, m), 2,02-2,20 (11/5H, m), 2,56 (4/5H, m), 2,85 are 2.98 (2H, m), 3,49 (2/5H, s), 3,52 (8/5H, s), 3,94 (3/5H, s), 3.96 points (12/5H, s), 5,07 (2H, s), 5,50 (1/5H, DD, J=11,2, 6,0 Hz), 6,17 (4/5H, DD, J=16,0, 6,8 Hz), 6,34 (1/5H, d, J=11.2 Hz), 6.35mm (4/5H, d, J=16.0 Hz), 6,80-of 6.90 (3H, m), 6,93-7,00 (2H, m), 7.18 in-to 7.25 (1H, m), 7,20-7,46 (4H, m), 7,65 (1/5H, sird, J=6.4 Hz), to 7.67 (4/5H, sird, J=6.4 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 216

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-phenylmethyl)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,52-of 1.66 (2H, m), 1,74-1,83 (11/6N, m)2,01 (1/6N, m), 2,10-2,24 (17/6N, m), 2,36 (1/6N, m), 2,78-3,00 (6N, m), 3,47 (1/3H, s), 3,53 (5/3H, s), 3,53 (1/2H, s), 3.96 points (5/2H, s), 5,91 (1/6N, DD, J=11,2, 10,0 Hz), 6,07 (5/6N, DD, J=the 15.6, 6.8 Hz), 6,46 (1/6N, d, J=11.2 Hz), 6,64 (5/6N, d, J=15.6 Hz), 6,84-6,92 (1H, m), 7,09-7,24 (6N, m), 7,25-7,33 (2H, m), the 7.43 (1H, DD, J=6,8, 2.0 Hz), 7,63 (1/5H, sird, J=6,8 Hz), 7,68 (5/6N, sird, J=6,8 Hz), 8,05 (1/5H, DD, J=5,2, 2.0 Hz), 8,06 (5/6N, DD, J=5,2, 2.0 Hz).

Example 217

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(isobutoxy)the dryer is l]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,02 (6/5H, d, J=6.8 Hz), 1.05 of (24/5H, d, J=6.8 Hz), 1,48-of 1.64 (2H, m), 1,74 of-1.83 (2H, m), 2.00 in 2,22 (19/5H, m), of 2.51 (1/5H, m), 2,84 are 2.98 (2H, m), 3,48 (2/5H, s), 3,52 (8/5H, m), 3.72 points 2/5H, d, J=6.4 Hz), 3,74 (8/5H, d, J=6.4 Hz), 3,94 (3/5H, s), 3.96 points (12/5H, s), 5,12 (1/5H, DD, J=11,6, 10,0 Hz), 6,21 (4/5H, DD, J=16,0, 7,2 Hz), 6,50 (1/5H, d, J=11,6 Hz), 6.73 x (4/5H, d, J=16.0 Hz), 6,80-6,93 (3H, m), 7,12-7,24 (1H, m), 7,41 (1H, DD, J=7,6, and 1.6 Hz), 7,65 (1/5H, DD, J=6,8, 2.0 Hz), to 7.67 (4/5H, DD, J=6,8, 2.0 Hz), 8,05 (1/5H, DD, J=5,2, 2.0 Hz), 8,06 (4/5H, DD, J=5,2, 2.0 Hz).

Example 218

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[3-(cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 0,98-to 1.38 (5H, m), 1,49-of 1.92 (10H, m), 2,03-2,20 (11/4H, m)2,60 (1/4H, m), 2,86 are 2.98 (2H, m), 3,49 (1/2H, s), 3,51 (3/2H, m), 3,74 (1/2H, d, J=6.4 Hz), 3,75 (3/2H, d, J=6.4 Hz), 3,94 (3/4H, s), 3.96 points (9/4H, s)5,49 (1/4H, DD, J=11,6, 10,0 Hz), 6,17 (4/5H, DD, J=16,0, 6,8 Hz), 6,32 (1/4H, d, J=11,6 Hz), 6,33 (3/4H, d, J=16.0 Hz), 6,72-6,93 (4H, m), 7,16-7,28 (1H, m), 7,55 (1/4H, DD, J=7,2, 2.0 Hz), EUR 7.57 (3/4H, DD, J=7,2, 2.0 Hz), 8,07 (1H, DD, J=5,6, 2.0 Hz).

Example 219

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(2-phenylethane)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400MHz, CDCl3) δ 1,48-of 1.81 (4H, m), 2,00-2,20 (17/6N, m), 2,48 (1/6N, m), 2,85-of 3.00 (2H, m), 3,09 (1/3H, t, J=6.8 Hz), 3,13 (5/3H, t, J=6.8 Hz), 3,48 (1/3H, s), 3,53 (5/3H, s), 3,94 (1/2H, s), 3.96 points (5/2H, s)4,179 (1/3H, t, J=6.8 Hz), 4,19 (5/3H, t, J=6.8 Hz), 5,52 (1/6N, DD, J=11,6, 10,0 Hz), 6,15 (5/6N, DD, J=16,0, 7,2 Hz), 6,44 (1/6N, d, J=11,6 Hz), 6,67 (5/6N, d, J=16.0 Hz), 6,80-6,94 (3H, m), 7,11-7,37 (6N, m), 7,40 (1H, DD, J=8.0 a, 1,6 Hz), 7,65 (1/6N, sird, J=6,8 Hz), 7,69 (5/6N, sird, J=6,8 Hz), 8,05 (1/6N, DD, J=4,8, 2.0 Hz), 8,06 (5/6N, DD, J=4,8, 2.0 Hz).

Example 220

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(phenoxymethyl)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,46-of 1.78 (4H, m), 1,95-2,20 (17/6N, m), 2,31 (1/6N, m), 2,82-2,96 (2H, m), 3.43 points (1/3H, s), 3,50 (5/3H, s), 3,93 (1/2H, s), 3,95 (5/2H, s)5,00 (1/3H, s), 5,07 (5/3H, s), 5,61 (1/6N, DD, J=11,6, 10,0 Hz), 6,11 (5/6N, DD, J=16,0, 6,8 Hz), 6.48 in (1/6N, DD, J=11,6 Hz), 6,62 (5/6N, DD, J=16.0 Hz), 6,85-of 6.90 (1H, m), 6,92-7,02 (2H, m), 7,17 and 7.36 (5H, m), 7,41 (1H, DD, J=6,0, 2.0 Hz), 7,50 (1H, DD, J=7,6, 1.2 Hz), 7,63 (1/6N, sird, J=7,2 Hz), 7,65 (5/6N, sird, J=7,2 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 221

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclopentyloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (2H, m), 1,50-of 1.73 (8H, m), 1,74 is 1.91 (11/4H, m), 2.00 in 2,22 (9/4H, m), 2,39 (3/4H, m), of 2.51 (1/4H, m), 2,98 (1/2H, sird, J=11,6 Hz), 2,95 (3/2H, sird, J=11,6 Hz, 3,48 (1/2H, s), 3,52 (3/2H, s), 3,84 (1/2H, d, J=6.8 Hz), 3,85 (3/2H, d, J=6.8 Hz), 3,94 (3/4H, d, J=6.8 Hz), 3.96 points (9/4H, s), 5,51 (1/4H, DD, J=12,0, 10,0 Hz), 6,21 (3/4H, DD, J=15,6, 7,2 Hz), 6,48 (1/4H, d, J=12.0 Hz), 6,70 (4/5H, d, J=15.6 Hz), 6,80-6,94 (3H, m), 7,12-of 7.23 (1H, m), 7,40 (1H, DD, J=7,6, 1.2 Hz), 7,65 (1/4H, DD, J=7,2, 2.0 Hz), to 7.67 (3/4H, DD, J=7,2, 2.0 Hz), 8,06 (1/4H, DD, J=5,2, 2.0 Hz), 8,07 (3/4H, DD, J=5,2, 2.0 Hz).

Example 222

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-[2-(2-cyclohexylethyl)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ of 0.85 to 1.00 (2H, m), 1,10-1,83 (15 NM, m), 1,65-2,04 (3/4H, m), 2,10-of 2.23 (2H, m), 2,32 (1/4H, m), 2,53-2,59 (1/2H, m), 2,60-2,67 (3/2H, m), 2,82-2,88 (1/2H, m), 2.91 in-2,99 (3/2H, m), 3.46 in (1/2H, s), 3,53 (3/2H, s), 3,93 (3/4H, s), 3.96 points (9/4H, s)5,54 (1/4H, DD, J=11,2, 10,0 Hz), 6,04 (3/4H, d, J=16,0, 6,8 Hz), 6,44 (1/4H, d, J=11.2 Hz), 6,60 (3/4H, d, J=16.0 Hz), 6,84-6,92 (1H, m), 7,06-7,22 (3H, m), 7,38-7,44 (1H, m), 7,63 (1/4H, DD, J=7,2, 2.0 Hz), to 7.67 (1/4H, DD, J=7,2, 2.0 Hz), 8,05 (1/4H, DD, J=4,8, 2.0 Hz), 8,06 (3/4H, DD, J=4,8, 2.0 Hz).

Example 223

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclohexylmethoxy)-5-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 0,97-to 1.38 (5H, m), 1,48-of 1.92 (10H, m), 2,01-2,23 (8/3H, m), 2,48 (1/3H, m), 2,85 are 2.98 (2H, m), 3,48 (2/3H, s), 3,52 (4/3H, s), 3,71 (2/3H, d, J=6.4 Hz), 3.72 points 4/3H, d, J=6.4 Hz), 3,94 (1H, s), of 3.96 (2H, s), 5,55 (1/3H, t, J=11,6 Hz), 6,20 (2/3H, DD, J=16,0, 6,8 Hz), 6,3 (1/3H, d, J=11,6 Hz), 6,67 (2/3H, d, J=16.0 Hz), of 6.71-6,93 (3H, m), 7,11 (1H, DD, J=a 9.6, 3.2 Hz), 7,62-of 7.70 (1H, m), of 8.06 (1H, m).

Example 224

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclohexylmethoxy)-4-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 0,97-to 1.38 (5H, m), 1,47-of 1.81 (10H, m), 1,99-of 2.21 (8/3H, m), 2,43 (1/3H, m), 2,85-of 2.97 (2H, m), 3,47 (2/3H, s), 3,51 (4/3H, s), and 3.72 (2/3H, d, J=6.8 Hz), to 3.73 (4/3H, d, J=6.0 Hz), 3,94 (1H, s), of 3.96 (2H, s), 5,50 (1/3H, DD, J=11,6, 10,0 Hz), 6,12 (2/3H, DD, J=16,0, 7,2 Hz), 6,38 (1/3H, d, J=11,6 Hz), 6,52-6,66 (8/3H, m), 6,84-6,93 (1H, m), 7,11 (1/3H, t, J=7,6 Hz), 7,33 (2/3H, DD, J=8,4, 6,8 Hz), 7,62-of 7.70 (1H, m), 78,03-8,11 (1H, m).

Example 225

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclohexylmethoxy)-6-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,04-1,38 (6N, m)of 1.44 (1H, m), 1,52-of 1.65 (2H, m), 1,68 is 1.91 (6N, m), 2,10-2,22 (3H, m), 2,90 are 2.98 (2H, m), 3,52 (2H, s), of 3.78 (2H, d, J=6.0 Hz), of 3.96 (3H, s), 6,48 of 6.68 (4H, m), to 6.88 (1H, DD, J=of 7.6, 5.2 Hz),7,05 (1H, dt, J=8,0, 6.4 Hz), to 7.67 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 226

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-methoxy-5-were)-1-ethynyl]piperidine

The compound in free form is obtained from the corresponding starting material in the manner described in example 214, and this connection is their standard way converted into the oxalate with obtaining specified in the connection header.

1H-NMR (400 MHz, CDCl3) δ 1,54-1,72 (2H, m), 1,89 (2H, sird, J=11,6 Hz), of 2.23 (3H, s), 2,30-of 2.54 (1H, m), 2,90-of 3.06 (2H, m)to 3.35 (2H, sird, J=10,8 Hz in), 3.75 (3H, s), of 3.94 (3H, s), 4,20 (2H, s), 6,10-of 6.26 (1H, m), 6,62 (1H, d, J=16.4 Hz), 6,86 (1H, d, J=8,4 Hz), 7,02 (1H, DD, J=8,4, and 1.6 Hz), 7,10 (1H, DD, J=7,2, 4,8 Hz), 7,27 (1H, s), 7,88 (1H, d, J=6.4 Hz), 7,27 (1H, d, J=4.4 Hz).

Example 227

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(3-bromophenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 226.

1H-NMR (400 MHz, CDCl3) δ 1.56 to around 1.74 (2H, m), 1.91 a (2N, sird, J=12,8 Hz), a 2.36-of 2.50 (1H, m), 2,90-of 3.06 (2H, m)to 3.35 (2H, sird, J=11.2 Hz), of 3.94 (3H, s) 4,19 (2H, s), 6.30-in-6,48 (2H, m), 7,06-7,14 (1H, m), 7.24 to 7,38 (1H, m), 7,38-7,50 (2H, m), the 7.65 (1H, s), 7,88 (1H, d, J=7,6 Hz), of 8.27 (1H, d, J=4.4 Hz).

Example 228

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclopentyloxy)phenyl]-1-ethynyl]piperidine

786 mg diethyl-2-(cyclopentyloxy)benzylphosphonic acid dissolved in 10 ml of tetrahydrofuran. To the resulting mixture 281 mg of tert-butoxide potassium, and then stirred under ice cooling for 15 minutes. Then added dropwise a solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxylate dissolved in 3 ml of tetrahydrofuran, followed by stirring at room temperature for 2 hours. To the reaction solution was added ice water and the mixture extracted with ethyl acetate the Organic layer was washed with water and saturated salt solution, and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product was then purified column chromatography on silica gel (n-hexane:ethyl acetate=1:1), resulting in a gain 473 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,48-1,94 (N, m), 2.00 in 2,22 (11/4H, m), 2,50 (1/4H, m), 2,85-of 3.00 (2H, m), 3,48 (1/2N), 3,52 (3/2H, s), 3,94 (3/4H), 3.96 points (9/4H, s), 4,78 (1H, m), 5,48 (1/4H, DD, J=12,0, 10,0 Hz), 6,18 (3/4H, DD, J=15,6, 7,2 Hz), 6,44 (1/4H, d, J=12.0 Hz), 6,66 (3/4H, d, J=15.6 Hz), 6,82-6,92 (11/4H, m), 7,10-7,22 (5/4H, m), 7,40 (1H, DD, J=7,2, 1,6 Hz), 7,63-7,52 (1H, m), 8,03-of 8.09 (1H, m).

Example 229

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-phenoxyphenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 228.

1H-NMR (400 MHz, CDCl3) δ 1,44-of 1.74 (4H, m), 1,98-of 2.16 (2H, m), 2.40 a is 2.55 (1H, m), 2,84-to 2.94 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), of 6.20 (1H, DD, J=16, 7,2 Hz), 6,63 (1H, d, J=16 Hz), 6,84-7,40 (10H, m), 7,60-7,66 (1H, m), 8,02-of 8.06 (1H, m).

Example 230

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[3-(cyclopentyloxy)phenylphenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 228.

1H-NMR (400 MHz, CDCl3) δ 1,48 is 1.96 (N, m), 2,04-2,18 (14/5H, m), 2,61 (1/5H, m), 2,86-to 2.99 (2H, m), 3,50 (2/5H), 3,52 (8/5H, s), 3,94 (3/5H), 3.96 points (12/5H, s), 4.72 in-4,80 (1H, m), 5,49 (1/5H, DD, J=11,6, 10, Hz), 6,16 (4/5H, DD, J=the 15.6, 6.8 Hz), 6,33 (4/5H, d, J=15.6 Hz), 6,34 (1/5H, d, J=11,6 Hz), 6,70-6,94 (4H, m), 7,15-of 7.25 (1H, m), 7,63-of 7.70 (1H, m), 8,04-8,08 (1H, m).

Example 231

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(E)-2-[2-(benzyloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 228.

1H-NMR (400 MHz, CDCl3) δ 1,48-to 1.82 (4H, m), 2.00 in 2,23 (14/5H, m), 2,50 (1/5H,m), 2,85 are 2.98 (2H, m), 3,48 (2/5H), 3,51 (8/5H, s), 3,94 (3/5H, s), 3,95 (12/5H, s), 5,10 (2H, s), 5,55 (1/5H, DD, J=11,6, 10,0 Hz), 6,18 (4/5H, DD, J=16,0, 7,2 Hz), 6,54 (1/5H, d, J=11,6 Hz), 6,78 (4/5H, d, J=16.0 Hz), 6,84-6,97 (3H, m), 7,12-7,24 (2H, m), 7,28-of 7.48 (5H, m), of 7.64 (1/5H, sird, J=6,8 Hz), 7,66 (4/5H, sird, J=6.8 Hz), 8,05 (1/5H, DD, J=4,8, and 2.4 Hz), 8,06 (4/5H, DD, J=4,8, 2,4 Hz).

Example 232

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2,5-dimetilfenil)-1-ethynyl]piperidine

The method described in example 228, get a connection in a free form from the appropriate starting material and the connection is a standard way converted into the oxalate with obtaining specified in the connection header.

1H-NMR (400 MHz, CDCl3) δ 1,54-of 1.74 (2H, m), a 1.88 (2H, sird, J=13,2 Hz), 2,22 (3H, in), 2.25 (3H, s), 2,30-of 2.50 (1H, m), 2,64-2,90 (2H, m), 3,26 (2H, sird, J=10,8 Hz)to 3.92 (3H, s)4,06 (2H, s)6,09 (1H, DD, J=16,0, 6,8 Hz), 6,57 (1H, d, J=16.0 Hz), 6,94 (1H, d, J=7,6 Hz), 7,03 (1H, d, J=7,6 Hz), was 7.08 (1H, DD, J=7,6, 5,2 Hz), 7,26 (1H, s), a 7.85 (1H, DD, J=7,6, 1.2 Hz), 8,23 (1H, DD, J=5,2, 1.2 Hz).

Example 233

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(3,5-dim is terphenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 232.

1H-NMR (400 MHz, CDCl3) δ 1.56 to around 1.74 (2H, m), 1,90 (2H, sird, J=12.0 Hz), 2,24 (6N, (C), 2,30-of 2.50 (1H, m), 2,90-is 3.08 (2H, m)to 3.35 (2H, sird, J=11.2 Hz), 3,93 (3H, s), 4,20 (2H, s), 6,10-of 6.26 (1H, m), 6.30-in-6,40 (1H, m)6,86 (1H, ), 7,01 (2H, s), 7,06-7,14 (1H, m), 7,89 (1H, d, J=7,2 Hz), of 8.27 (1H, d, J=4,8 Hz).

Example 234

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(Z)-4-[2,3-(methylenedioxy)phenyl]-1-butenyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.46 (4H, m), 1,98-of 2.08 (2H, m), 2,19 (1H m), and 2.26-to 2.42 (2H, m), 2.63 in (2H, t, J=8.0 Hz), 2,84 (2H, sird, J=11,6 Hz), 3,47(2N)of 3.95 (3H, s), of 5.24 (1H, DD, J=10,4, 9.6 Hz), of 5.34 (1H,m), to 5.93 (2H, C)of 6.66 (1H, DD, J=8,0, 2.0 Hz), 6,78 (1H, DD, J=8,0, 2.0 Hz), 6,74 (1H, t, J=8.0 Hz), 6.87 in (1H, DD, J=7,2, 4,8 Hz), 7,63 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 235

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[(Z)-4-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

To dichlormethane (5 ml) is added 2,355 g chloride [[(2-cyclohexylmethoxy)phenyl]methyl]triphenylphosphine, 650 mg of potassium carbonate and 18-crown-6 (11 mg). In the mixture, boiling under reflux for 20 minutes, added dropwise to 1,000 g of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxylate dissolved in 10 ml of dichloromethane. After boiling with reverse what holodilniki within 6 hours to the reaction solution was added ethyl acetate and filtered through NH form silica gel. The filtrate is evaporated and the crude product was then purified column chromatography on silica gel (n-hexane:ethyl acetate=6:1) obtaining at 1,047 g light yellow oil. The oil obtained is dissolved in ethyl acetate, add 944 mg di-O-benzoyl-D-tartaric acid and the resulting crystals are filtered. To the filtrate add aqueous saturated sodium carbonate and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution and then dried over anhydrous magnesium sulfate. The solution is filtered through alumina and the filtrate is evaporated to obtain 374 mg specified in the title compound as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 0,98-of 1.36 (5H, m), 1,52-of 1.92 (10H, m), 2.00 in of 2.10 (2H, m), of 2.51 (1H, m), 2,84 of 2.92 (2H, m), of 3.48 (2H, in), 3.75 (2H, d, J=6.4 Hz), of 3.94 (3H, s)5,52 (1H, DD, J=11,6, 10.4 Hz), of 6.49 (1H, d, J=11,6 Hz), 6,80-6,94 (3H, m), 7,15-of 7.25 (2H, m), the 7.65 (1H, sird, J=7,2 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 236

1-[(2-Methoxy-3-pyridinyl)methyl]-4-(2,2-diphenyl)-1-ethynyl)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 214.

1H-NMR (400 MHz, CDCl3) δ 1,52 by 1.68 (4H, m), 1,90-2,02 (2H, m), and 2.14 (1H, m), of 2.86 (2H, sird, J=10,8 Hz), 3.46 in (2N)3,93 (3H)of 5.92 (1H, d, J=10.0 Hz), 6.87 in (1H, DD, J=7,2, 4,8 Hz), 7,14-7,40 (10H, m), of 7.64 (1H, sird, J=6,8 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 237

1-[(2-Methoxy-3-pyridinyl)methyl]4-[3-[2,3-(methylenedioxy)phenyl]propyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ of 1.18 to 1.34 (4H, m), 1,58-of 1.62 (5H, m), a 2.01 (2H, shirt, J=10,8 Hz)to 2.55 (2H, t, J=7,6 Hz), 2,89 (2H, sird, J=11.2 Hz), 3,48 (2N)of 3.94 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,6, 2.0 Hz), of 6.68 (1H, DD, J=to 7.6, 2.0 Hz), to 6.75 (1H, t, J=7,6 Hz)6,86 (1H, DD, J=7,2, 4,8 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 238

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[5-[2,3-(methylenedioxy)phenyl]pentyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,16-to 1.38 (8H, m), 1,55-1,70 (5H, m), a 2.01 (2H, shirt, J=11,6 Hz), of 2.56 (2H, t, J=8.0 Hz), 2,89 (2H, sird, J=11,6 Hz), 3,48 (2N)3,93 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=8,0, 1.2 Hz), of 6.68 (1H, DD, J=to 8.0, 1.2 Hz), to 6.75 (1H, t, J=8.0 Hz), 6,86 (1H, DD, J=7,2, 4,8 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 239

1-[(6-Methyl-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,52-to 1.59 (2H, m), 1,67 to 1.76 (2H, m)to 1.99 (2H, m), 2,42 (3H, s), 2,55-2,62 (2H, m), is 2.88 (2H, sird, J=11,6 Hz), of 3.45 (2H), 3,92 (3H, s), of 5.92 (2H, s), 6,07 (1H, sird, J=6,8 Hz), 6,65 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), to 6.75 (1H, t, J=7,6 Hz), 7,49 (1H, d, J=7,2 Hz).

Example 240

p> 1-[(2-Methoxy-3-pyridinyl)methyl]-4-(2,2-diphenylether)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,17 (1H, m), 1,24-of 1.40 (2H, m), rate of 1.67 and 1.75 (2H, m), 1,87-2,02 (4H, m), 2,84 (2H, sird, J=11,6 Hz), 3,44 (2H, s)to 3.92 (3H, s), Android 4.04 (1H, t, J=7,6 Hz), 6,85 (1H, DD, J=6,8, 4,8 Hz), 7,14-7,30 (10H, m), a 7.62 (1H, sird, J=6,8 Hz), of 8.04 (1H, DD, J=5,2, 2.0 Hz).

Example 241

1-[(5-Bromo-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.40 (3H, m), 1,54-of 1.65 (2H, m), 1,68-to 1.79 (2H, m), 1,98-of 2.09 (2H, m), 2,56-of 2.64 (2H, m), of 2.86 (2H, sird, J=11,6 Hz), of 3.43 (2H, s), 3,91 (3H, s), to 5.93 (2H, s), of 6.66 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), 6,76 (1H, t, J=7,6 Hz), 7,78 (1H, sird, J=1.2 Hz), 8,07 (1H, d, J=2,8 Hz).

Example 242

1-[(5-Methyl-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.40 (3H, m), 1,54-of 1.62 (2H, m), 1,68-to 1.79 (2H, m), a 2.01 (2H, shirt, J=11.2 Hz), 2,24 (3H, s), 2,59 (2H, shirt, J=8.0 Hz), 2,89 (2H, sird, J=11,6 Hz), of 3.45 (2H), 3,91 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), to 6.75 (1H, t, J=7,6 Hz), 7,47 (1H, Sirs), to 7.84 (1H, Sirs).

Example 243

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-(2-benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1,52 is 1.60 (2H, m), of 1.66-1.77 in (2H, m), 1,96-of 2.08 (2H, m), 2,65-of 2.72 (2H, m), 2,87 (2H, sird, J=10,8 Hz), of 3.48 (2H, s), of 3.95 (3H, s), to 5.08 (2H, s), 6,85-6,93 (3H, m), 7,12-to 7.18 (2H, m), 7,28-7,46 (5H, m), 7,66 (1H, sird, J=6,8 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 244

1-[(5-Phenyl-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.40 (3H, m), 1,52-of 1.78 (4H, m), 2.00 in of 2.10 (2H, m), 2,55-2,62 (2H, m), 2,90-2,96 (2H, m), of 3.54 (2H, s)to 3.99 (3H, s), of 5.92 (2H, s), of 6.65 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), 6.75 in (1H, t, J=7,6 Hz), 7,35 (1H, m), 7,42-of 7.48 (2H, m), 7,53-7,58 (2H, m), 7,89 (1H, d, J=2.4 Hz), of 8.28 (1H, d, J=2,4 Hz).

Example 245

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[[2-(2-piperidino-2-oksidoksi)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,26-to 1.38 (2H, m)and 1.51-1,78 (11N, m), 1,98-of 2.08 (2H, m), 2,62 of 2.68 (2H, m), 2,90 (2H, sird, J=10,8 Hz), 3,45-3,60 (6N, m), of 3.95 (3H, s), of 4.67 (2H, s), 6,84-to 6.95 (3H, m), 7,12-to 7.18 (2H, m), 7,66 (1H, shirt, J=6.8 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 246

1-[(2-Methoxy-pyridinyl)methyl]-4-[[2-(4-piperidinyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,15-of 1.32 (3H, m), 1,45-and 1.54 (2H, m), 1,57 by 1.68 (2H, m), 1,99 (2H, sird, J=10.4 Hz), 2,48 is 2.55 (2H, m), 2,87 (2H, sird, J=10.4 Hz), of 3.48 (2H, s), of 3.94 (3H, s), 6,74-6,79 (2H, m)6,86 (1H, DD, J=7,2, 5,2 Hz), of 7.00 (1H, DD, J=7,6, and 1.6 Hz), 7,17-7,34 (3H, m), of 7.64 (1H, sird, J=6,8 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz), to 8.41-8,46 (2H, m).

Example 247

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(1-(dimethylcarbamoyl)cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.41 (3H, m), 1,47 is 1.58 (2H, m), 1,68-1,82 (6N, m), 1,98 is 2.10 (2H, m), 2,11-of 2.20 (2H, m), 2,38-to 2.40 (2H, m), 2,56-of 2.64 (2H, m), 2.91 in (2H, m), of 2.92 (3H, s)to 3.09 (3H, s), 3,51 (2H, s), of 3.95 (3H, C)to 6.67 (1H, DD, J=7,6, 1.2 Hz), 6,82-6,91 (2H, m),? 7.04 baby mortality (1H, DD, J=7,6, and 1.6 Hz), 7,11 (1H, DD, J=7,6, and 1.6 Hz), 7,66 (1H, sird, J=6.0 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 248

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1,52 is 1.60 (2H, m), of 1.66-1.77 in (2H, m), 1,96-of 2.08 (2H, m), 2,65-of 2.72 (2H, m), 2,87 (2H, sird, J=10,8 Hz), of 3.48 (2H, s), of 3.95 (3H, s), to 5.08 (2H, s), 6.87 in-6,94 (2H, m), 7,13-7,20 (2H, m), 7,29-7,46 (5H, m), 7,66 (1H, Sirs), 7,98 (1H, d, J=2.0 Hz).

Example 249

1-[(-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(2-methoxyethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,20-1,40 (3H, m), 1,50-1,60 (2H, m), 1,70-1,80 (2H, m), 2.00 in of 2.10 (2H, m)to 2.65 (2H, t, J=8.0 Hz), 2,87 (2H, sird, J=10,8 Hz), 3,44 (2H, s), of 3.46 (3H, s), 3,76 (2H, t, J=4,8 Hz)to 3.92 (3H, s), 4,12 (2H, t, J=4,8 Hz), at 6.84 (1H, d, J=8.0 Hz), 6.89 in (1H, t, J=7,6 Hz), 7,10-to 7.18 (2H, m), 7,66 (1H, d, J=2,8 Hz), of 7.97 (1H, d, J=2,4 Hz).

Example 250

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(benzylamino)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1.55V and 1.80 (4H, m), 1,98-of 2.08 (2H, m), 2,46-of 2.54 (2H, m), 2,89 (2H, sird, J=11.2 Hz), 3,49 (2H, s), of 3.94 (3H, s), 4,37 (2H, s), 6,62 (1H, d, J=9.6 Hz), 6,70 (1H, dt, J=8,0, 1.2 Hz), 6,87 (1H, DD, J=7,2, 5,2 Hz), 7,05-7,14 (2H, m), 7.24 to 7,42 (5H, m), of 7.64 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 251

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(N-benzyl-N-methylamino)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (3H, m), 1,47-of 1.65 (2H, m), 1,71-of 1.78 (2H, m), 1,98-of 2.08 (2H, m), of 2.56 (3H, s), 2,75-of 2.81 (2H, m), 2,89 (2H, sird, J=11.2 Hz), 3,49 (2H, s), of 3.95 (3H, s), of 4.00 (2H, s), 6.87 in (1H, DD, J=8,8, 5,2 Hz), 7,02-7,07 (1H, m), 7,13-7,40 (8H, m), 7,66 (1H, DD, J=7,2, 1,6 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 252

1-[(2-Methoxy-3-pyrid the Nile)methyl]-4-[2-[2-[(cyclohexylmethyl)amino]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 0,95-1,08 (2H, m), 1,12-of 1.42 (5H, m), 1,52 is 1.86 (11N, m), 2.00 in a 2.12 (2H, m), 2,43-2,49 (2H, m), of 2.92 (2H, sird, J=7,2 Hz), 2,98 (2H, d, J=6.4 Hz), 3,50 (2H, s), of 3.95 (3H, s), 6,60 (1H, DD, J=1,2, 7,6 Hz), of 6.65 (1H, dt, J=7,6, 1.2 Hz), 6.87 in (1H, DD, J=7,2, 4,8 Hz), 7,02 (1H, DD, J=7,6, 1.2 Hz), 7,11 (1H, dt, J=7,6, 1.2 Hz), the 7.65 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 253

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-[N-(cyclohexylmethyl)-N-methylamino]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 0,81 with 0.93 (2H, m), 1,08-1,40 (6N, m), 1,44 is 1.60 (3H, m), 1,61-1,78 (6N, m), 1,79-to 1.87 (2H, m), 1,99-of 2.08 (2H, m), of 2.56 (3H, s), 2,65 (2H, d, J=7,2 Hz), 2,68-to 2.74 (2H, m), 2,90 (2H, sird, J=11.2 Hz), 3,49 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 4,8 Hz), 7,01 (1H, dt, J=7,6, 2.0 Hz), 7,08-7,20 (3H, m), 7,66 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 254

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)phenyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.38 (5H, m), 1.60-to 1,90 (10H, m), 2,18-of 2.26 (2H, m), of 2.97 (1H, m), 3,01-of 3.07 (2H, m), of 3.56 (2H, s), 3,76 (2H, d, J=6.0 Hz), of 3.97 (3H, s), 6,83 (1H, DD, J=8,0, 1.2 Hz), 6,86-6,94 (2H, m), 7,15 (1H, dt, J=8,0, 1.2 Hz), 7,21 (1H, dt, J=8,0, 1.2 Hz), ,71 (1H, DD, J=7,2, 2.0 Hz), 8,07 (1H, DD, J=7,2, 2.0 Hz).

Example 255

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-(2-phenoxyphenyl)ethyl]piperidine

Loose coupling is obtained from the corresponding starting material by the method described in example 201, and turn it into oxalate standard method.

1H-NMR (400 MHz, DMSO-d6) δ 1,20-1,50 (3H, m), 1,40-of 1.55 (2H, m)of 1.75 (2H, sird, J=12,8 Hz), of 2.56 (2H, t, J=8.0 Hz), 2,60 is 2.80 (2H, m), 3,18 (2H, sird, J=11.2 Hz), 3,90 (3H, s), Android 4.04 (2H, s), 6.89 in (3H, d, J=8,4 Hz),? 7.04 baby mortality-to 7.18 (3H, m), of 7.23 (1H, dt, J=1,4, and 7.6 Hz), 7,35 (3H, d, J=8.0 Hz), 7,81 (1H, DD, J=7,6, and 1.6 Hz), by 8.22 (1H, DD, J=5,2, 1,6 Hz).

Example 256

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-(2-were)ethyl]piperidine

In ethanol (10 ml) dissolved 473 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-were)-1-ethynyl]piperidine. To the mixture was added 100 mg of powdery 10% palladium on coal (product containing water), then stirred at room temperature and under normal pressure during the night, and then in an atmosphere of hydrogen for 1.5 hours. The reaction solution is filtered, then the filtrate is evaporated to obtain 465 mg specified in the title compounds as colorless oils.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.42 (2H, m), 1,47-of 1.55 (2H, m), 1,66-of 1.84 (3H, m)to 2.06 (2H, m)to 2.29 (3H, s), 2,56-of 2.64 (2H, m), of 2.92 (2H, sird, J=11.2 Hz), 3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=8,8, 4,2 Hz), 7,06-7,16 (4H, m), 7,66 (1H, DD, J=8,8, 2.0 Hz), of 8.06 (1H, DD, J=4.2, and 2.0 Hz).

Example 257

1-[(2-IU is hydroxy-3-pyridinyl)methyl]-4-[4-[2,3-(methylenedioxy)phenyl]butyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,16-1,39 (6N, m, 1,55 by 1.68 (4H, m), 1,72 (1H, m)2,00 (2H, t, J=11.2 Hz), to 2.57 (2H, t, J=8.0 Hz), is 2.88 (2H, sird, J=11.2 Hz), of 3.48 (2H, s), of 3.94 (3H, s), of 5.92 (2H, s), of 6.65 (1H, DD, J=8,0, 2.0 Hz), of 6.68 (1H, DD, J=8,0, 2.0 Hz), to 6.75 (1H, d, J=8.0 Hz), 6,86 (1H, DD, J=7,2, 4,8 Hz), to 7.64 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 258

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(triptoreline)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,20-of 1.45 (3H, m), 1,48 is 1.60 (2H, m)of 1.73 (2H, sird, J=9.6 Hz), 2,04 (2H, sird, J=10,8 Hz)to 2.66 (2H, t, J=8,4 Hz), 2.91 in (2N, sird, J=11.2 Hz), 3,50 (2H, s), of 3.94 (3H, s), 6.87 in (1H, DD, J=7,2, 5,2 Hz), 7,14-to 7.32 (3H, m), 7,66 (1H, DD, J=7,2, 1.2 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 259

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,22-to 1.38 (3H, m), 1,46-and 1.54 (2H, m), 1,55-of 1.94 (10H, m), 1,98 is 2.10 (2H, m), 2,54-2,62 (2H, m), 2,90 (2H, sird, J=11.2 Hz), 3,50 (2H, s), of 3.95 (3H, s), of 4.77 (1H, m), 6,78-of 6.90 (3H, m), 7,08-7,16 (2H, m), 7,66 (1H, sird, J=6,8 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 260

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[3-(cyclopentyloxy)phenyl]et the l]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,52-1,95 (N, m), 1,96-of 2.08 (2H, m), 2,54-2,62 (2H, m), 2,90 (2H, sird, J=11.2 Hz), 3,49 (2H, s), of 3.94 (3H, s), and 4.75 (1H, m), 6,66-6,76 (3H, m), at 6.84 (1H, DD, J=7,2, 4,8 Hz), 7,16 (1H, m), 7,66 (1H, sird, J=6,8 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 261

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(3-pyridinyl)phenyl]ethyl]piperidine

In methanol (50 ml) dissolve 0.3 g of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(3-bromophenyl)-1-ethynyl]piperidine and 0.3 g of 3-pyridineboronic acid. To the mixture is added 0.3 ml of aqueous sodium carbonate and 0.1 g of tetrakis(triphenylphosphine)palladium, and then refluxed for 3 hours in a stream of nitrogen gas. The reaction solution is cooled to room temperature and the solvent is evaporated. The residue is purified column chromatography on silica gel to obtain 0.3 g of a yellow oil. The oil obtained is treated in the manner described in example 256, and obtain 0.3 g specified in the title compound as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.44 (3H, m), 1.44MB and 1.80 (2H, m), 1.60-to of 1.84 (2H, m), 1,96 is 2.10 (2H, m), 2,64-to 2.74 (2H, m), 2,86-2,96 (2H, m), 3,49 (2N, C) of 3.94 (3H, s), 6,84-of 6.90 (1H, m), 7.18 in-7,30 (1H, m), 7,32-7,44 (4H, m), 7,65 (1H, d, J=6.8 Hz), 7,87 (1H, d, J=7,6 Hz), with 8.05 (1H, d, J=5,2 Hz), 8,58 (1H, d, J=4.4 Hz), 8,84 (1H, d, J=2.0 Hz).

Example 262

1-[(2-Methoxy-3-pyridine is l)methyl]-4-[2-[3-[(tetrahydropyran-2-yl)metiloksi]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,10-2,00 (15 NM, m), 2,20-2,40 (2H, m), 2,55-2,63 (2H, m)3,00-3,20 (2H, m), 3,40-4,10 (5H, m), of 3.96 (3H, s)6,70-to 6.80 (2H, m), 6,86-6,98 (1H, m), 7,14-7,22 (1H, m), 7,42-7,52 (1H, m), 7,62-7,72 (1H, m,), 8,06-8,16 (1H, m).

Example 263

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-[(tetrahydropyran-2-yl)metiloksi]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,20-1,40 (3H, m), 1,40-2,00 (10H, m), 1,97 is 2.10 (2H, m), 2.57 m) of 2.68 (2H, m), 2,90 (2H, sird, J=11.2 Hz), 3,49 (2H, s) 3,45-3,55 (1H, m), 3,65 of 3.75 (1H, m), 3,80-are 3.90 (1H, m), of 3.95 (3H, s), 3,93-4,10 (2H, m,), 6,78-6,92 (3H, m, 7,08-to 7.18 (2H, m), 7,66 (1H, DD, J=7,6, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 264

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[3-[(benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,22-to 1.38 (3H, m)of 1.52 to 1.76 (4H, m), 1,96-of 2.08 (2H, m), 2,56-of 2.64 (2H, m), 2,85-to 2.94 (2H, m), 3,49 (2H, s), of 3.95 (3H, s), of 5.05 (2H, s), 6,76-6,83 (3H, m), 6.87 in (1H, DD, J=7,2, 5,2 Hz), 7,19 (1H, t, J=8,4 Hz), 7,28-7,46 (5H, m), 7,66 (1H, sird, J=6,8 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 265

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[[2-(2-phenylethyl)phenyl]ethyl]piperidine

Specified in the header connection receive is from the appropriate starting material way, described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.40 (3H, m), 1,48-of 1.56 (2H, m), 1.70 to of 1.78 (2H, m), 2.00 in of 2.10 (2H, m), 2,58-of 2.64 (2H, m), 2,84-2,94 (6N, m)3,50 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=7,2, 5,2 Hz), 7,11-7,33 (N, m), 7,66 (1H, shirt, J=7,2 Hz), with 8.05 (1H, DD, J=4, 8, and 1.6 Hz).

Example 266

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.40 (8H, m), 1,49 is 1.58 (2H, m), 1,65-1,90 (8H, m), 1,99 is 2.10 (2H, m), 2,58-of 2.66 (2H, m), 2,86-2,95 (2H, m), 3,50 (2H, s), 3,74 (2H, d, J=6.0 Hz), of 3.95 (3H, s), 6,78-of 6.90 (3H, m), 7,08-7,16 (2H, m), 7,66 (1H, sird, J=7,6 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 267

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,04 (6N, d, J=6.8 Hz), 1,26-to 1.38 (3H, m), 1,50 is 1.58 (2H, m), 1.70 to of 1.78 (2H, m), 1,99-of 2.15 (3H, m), 2,60-to 2.67 (2H, m), 2,86-to 2.94 (2H, m), 3,49 (2H, s), and 3.72 (2H, d, J=6.4 Hz), of 3.95 (3H, s), to 6.80 (1H, d, J=8.0 Hz), 6,82-of 6.90 (2H, m), 7,08-7,16 (2H, m), 7,66 (1H, sird, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 268

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[3-(cyclohexylmethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 0,98-1,11 (2H, m), 1,14-1,38 (6N, m, 1,52 is 1.60 (2H, m), 1,62 is 1.91 (8H, m), 1,97-of 2.08 (2H, m), 2,54-2,62 (2H, m), 2,85-of 2.93 (2H, m), of 3.48 (2H, s), of 3.73 (2H, d, J=6.4 Hz), of 3.94 (3H, s), 6,68-6,76 (3H, m), 6.87 in (1H, DD, J=5,2, 7,6 Hz), 7,17 (1H, m), the 7.65 (1H, sird, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz) (2H, m)of 2.64 (2H, t, J=8.0 Hz), 2,90 (2H, sird, J=10.4 Hz), of 3.45 (3H, t), of 3.48 (2H, s), 3,64-of 3.80 (2H, m), of 3.95 (3H, s), 4,11 (2H, t, J=4,8 Hz), 6,80-6,92 (2H, m), 7,10-to 7.18 (1H, m), 7,42-7,74 (3H, m), 8,02-8,08 (1H, m).

Example 269

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(2-methoxyethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,20-of 1.36 (3H, m), USD 1.43-is 1.51 (2H, m), of 1.62 and 1.75 (2H, m), 1,99-of 2.08 (2H, m), 2,54-of 2.26 (2H, m), 2,86-to 2.94 (2H, m), 3,10 (2H, t, J=6.8 Hz), 3,50 (2H, s), of 3.95 (3H, s)to 4.17 (2H, t, J=6.8 Hz), 6,78-6,90 (3H, m), 7,07-7,16 (2H, m), 7,19 and 7.36 (5H, m), to 7.67 (1H, sird, J=7,2 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 270

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(2-phenylethane)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,20-of 1.36 (3H, m), USD 1.43-is 1.51 (2H, m), of 1.62 and 1.75 (2H, m), 1,99-of 2.08 (2H, m), 2,54-of 2.26 (2H, m), 2,86-to 2.94 (2H, m), 3,10 (2H, t, J=6.8 Hz), 3,50 (2H, s), of 3.95 (3H, s)to 4.17 (2H, t, J=6.8 Hz), 6,78-6,90 (3H, m), 7,07-7,16 (2H, m), 7,19 and 7.36 (5H, m), to 7.67 (1H, sird, J=7,2 Hz), of 8.06 (1H, DD, J=5,2, 2.0 Hz).

Example 271

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(proximate the l)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,25-of 1.39 (3H, m), 1,54-of 1.78 (4H, m), 1,96-of 2.08 (2H, m), 2,65-by 2.73 (2H, m), 2,84-of 2.93 (2H, m), of 3.48 (2H, s), of 3.94 (3H, s), 5,04 (2H, s), 6.87 in (1H, DD, J=7,6, 5,2 Hz), 6,95-7,01 (2H, m), 7.18 in-7,34 (6N, m), 7,42 (1H, d, J=7,6 Hz), to 7.64 (1H, sird, J=6.4 Hz), with 8.05 (1H, DD, J=4,8, 2.0 Hz).

Example 272

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.45 (5H, m), 1,49-of 1.88 (10H, m), 1,98 is 2.10 (2H, m), is 2.37 (1H, Sept, J=7,4 Hz), 2,58-of 2.66 (2H, m), 2,86-2,96 (2H, m), 3,50 (2H, s), 3,82 (2H, d, J=6.8 Hz), of 3.95 (3H, s), 6,78-of 6.90 (3H, m), 7,09-7,17 (2H, m), 7,66 (1H, DD, J=7,2, 2.0 Hz), with 8.05 (1H, DD, J=5,2, 2.0 Hz).

Example 273

1-[(2-Methoxy-3-pyridinyl)methyl]-4-[2-[(2-cyclohexylethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 256.

1H-NMR (400 MHz, CDCl3) δ 0,89-a 1.01 (2H, m), 1,10-1,56 (10H, m), 1,62 of-1.83 (8H, m), 2,02-2,11 (2H, m), 2,56-2,63 (4H, m), 2,89-2,96 (2H, m), 3,51 (2H, s), of 3.95 (3H, s), 6.87 in (1H, DD, J=6,8, 4,8 Hz), 7,08-7,16 (4H, m), 7,66 (1H, DD, J=7,2, 2.0 Hz), of 8.06 (1H, DD, J=4,8, 2.0 Hz).

Example 274

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-(2,5-dimetilfenil)ethyl]piperidine

Specified in the header of the connection of the floor is up from the corresponding starting material way, described in example 256.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-of 1.55 (5H, m), 1,80-1,90 (2H, m), are 2.19 (3H, s), 2,22 (3H, s), 2,45 is 2.55 (2H, m), 2,65-to 2.85 (2H, m), 3.15 and is 3.25 (2H, m), 3,91 (3H, s), Android 4.04 (2H, s), 6.87 in (1H, d, J=9,2 Hz), 6,93 (1H, s), 6,99 (1H, d, J=8.0 Hz), 7,07 (1H, DD, J=7,2, 4,8 Hz), 7,80-a 7.85 (1H, m), 8,20 is 8.25 (1H, m).

Example 275

Oxalate of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-(3, 5dimethylphenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 274.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-of 1.55 (5H, m)of 1.84 (2H, sird, J=12,8 Hz), 2,22 (3H, s)of 2.50 (3H, s), 2,45 is 2.55 (2H, m), 2,75-2,90 (2H, m), 3,26 (2H, sird, J=10,8 Hz)to 3.92 (3H, s), of 4.12 (2H, s), 6,79 (3H, s), was 7.08 (1H, DD, J=7,6, 5,2 Hz), 7,82-7,86 (1H, m), of 8.25 (1H, DD, J=5,2, 2.0 Hz).

Example 276

Salt of oxalic acid and 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-(2-methoxy-5-were)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 274.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-of 1.55 (5H, m)to 1.87 (2H, sird, J=11.2 Hz), measuring 2.20 (3H, s), 2,40-2,60 (2H, m), 2,80-3,00 (2H, m), of 3.25 to 3.35 (2H, m), and 3.72 (3H, s), 3,93 (3H, s), 4,10-4,20 (2H, m), for 6.81 (1H, d, J=8,4 Hz), 6.90 to-7,00 (2N, m), 7,10 (1H, DD, J=7,6, 5.6 Hz), the 7.85 (1H, d, J=7,6 Hz), 8,24-8,30 (1H, m).

Example 277

1-[[5-(3-Pyridinyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the relevant source material the way, described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.41 (3H, m), 1,54-of 1.62 (2H, m), 1,70-1,80 (2H, m)2,07 (2H, shirt, J=10.4 Hz), 2,56-of 2.64 (2H, m), with 2.93 (2H, sird, J=11.2 Hz)and 3.15 (2H, s), of 4.00 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,6, and 1.6 Hz), of 6.68 (1H, DD, J=7,6, and 1.6 Hz), to 6.75 (1H, t, J=7,6 Hz), 7,38 (1H, DDD, J=8,0, to 4.8, 1.2 Hz), the 7.85 (1H, DDD, J=8.0 a, 2,4, and 1.6 Hz), 7,92 (1H, Sirs), of 8.27 (1H, d, J=2.4 Hz), 8,59 (1H, DD, J=4,8, and 1.6 Hz), 8,82 (1H, DD, J=2,4, 1.2 Hz).

Example 278

1-[(5-(4-Pyridinyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.41 (3H, m), 1,55-to 1.63 (2H, m), 1,68-to 1.82 (2H, m)2,07 (2H, shirt, J=11.2 Hz), 2,56-of 2.64 (2H, m), of 2.92 (2H, sird, J=11.2 Hz), of 3.54 (2H, s)to 4.01 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=8,0, 1.2 Hz), of 6.68 (1H, DD, J=8,0, 1.2 Hz), to 6.75 (1H, t, J=8.0 Hz), 7,46-7,52 (2H, m), of 7.97 (1H, Sirs), 8,35 (1H, d, J=2.4 Hz), 8,63-8,69 (2H, m).

Example 279

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-(2-forfinal)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,20-1,40 (3H, m), 1,50-of 1.65 (2H, m), 1,70-1,80 (2H, m), 2,04 (2H, shirt, J=10,8 Hz), 2,66 (2H, d, J=7,6 Hz), 2,87 (2H, sird, J=11,6 Hz), of 3.43 (2H, s)to 3.92 (3H, s), of 6.96-was 7.08 (2H, m), 7,12-7,22 (2H, m), 7,66 (1H, d, J=2,8 Hz), of 7.97 (1H, d, J=2,8 Hz).

Example 280

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-cyclohexylmethoxy)the dryer is l]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.40 (7H, m), 1,49 is 1.60 (2H, m), 1,62 is 1.91 (N, m), 1,99-2,11 (2H, m), 2,58-of 2.66 (2H, m), 2,83 of 2.92 (2H, m), 3,44 (2H, in), 3.75 (2H, d, J=6.0 Hz), to 3.92 (3H, s), to 6.80 (1H, d, J=8.0 Hz), 6,85 (1H, dt, J=7,2, 1.2 Hz), 7,09-7,20 (2H, m), to 7.67 (1H, d, J=2.4 Hz), of 7.97 (1H, d, J=2,4 Hz).

Example 281

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,05 (6N, d, J=6.8 Hz), 1,24-of 1.40 (3H, m)and 1.51-of 1.59 (2H, m), 1,72 and 1.80 (2H, m), 2.00 in 2,19 (3H, m), 2,61 of 2.68 (2H, m), 2,84 of 2.92 (2H, m), 3,44 (2H, s), and 3.72 (2H, d, J=6,4 Hz)to 3.92 (3H, s), to 6.80 (1H, d, J=8.0 Hz), 6,86 (1H, dt, J=7,6, 1.2 Hz), 7,10-7,17 (2H, m), 7,66 (1H, d, J=2.4 Hz), 7,98 (1H, d, J=2,4 Hz).

Example 282

1-[(5-Chloro-2-methoxy-3-pyridinyl)methyl]-4-[[2-(2-phenylethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,26-of 1.42 (3H, m), 1,39-of 1.56 (2H, m), 1,70-1,80 (2H, m), 2,02-2,11 (2H, m), 2,58-to 2.65 (2H, m), 2,84-2,95 (6N, m), 3,44 (2H, s)to 3.92 (3H, s), 7,12-7,34 (N, m), 7,66 (1H, d, J=2.4 Hz), 7,98 (1H, d, J=2,4 Hz).

Example 283

1-[(5-Methylsulphonyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

Specified in the header with the Association receives from the corresponding starting material way, described in example 206.

1H-NMR (400 MHz, CDCl3) δ 1,04-of 1.40 (8H, m)and 1.51 is 1.58 (2H, m), 1,64-1,90 (8H, m), 2,04-2,12 (2H, m), 2,60 of 2.68 (2H, m), 2,82-only 2.91 (2H, m), is 3.08 (3H, s), 3,49 (2H, in), 3.75 (2H, d, J=6.0 Hz), Android 4.04 (3H, s), to 6.80 (1H, d, J=8.0 Hz), 6,85 (1H, dt, J=8,0, 1.2 Hz), 7,11 (1H, DD, J=8,0, 1.2 Hz), to 7.15 (1H, dt, J=8,0, 2.0 Hz), 8,18 (1H, d, J=2.4 Hz), 8,61 (1H, d, J=2,4 Hz).

Example 284

1-[(4-Methoxy-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material by the method described in example 201.

1H-NMR (400 MHz, CDCl3) δ 1,20-of 1.39 (3H, m), 1,52-of 1.62 (2H, m), of 1.66 to 1.76 (2H, m), from 2.00 (2H, shirt, J=11.2 Hz), 2,54-of 2.64 (2H, m), of 2.92 (2H, sird, J=12.0 Hz), 3,53 (2H, s), 3,86 (3H, s), of 5.92 (2H, s), of 6.65 (1H, DD, J=7,6, 1.2 Hz), to 6.67 (1H, DD, J=7,6, 1.2 Hz), to 6.75 (1H, t, J=7,6 Hz), 6,77 (1H, d, J=5.6 Hz), 8,40 (1H, d, J=5.6 Hz), to 8.41 (1H, s).

Example 285

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-were)ethyl]piperidine

In ethanol (10 ml) dissolved 465 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-were)ethynyl]piperidine. To the mixture of 1.75 ml solution of 4 G. hydrochloric acid in methanol and then refluxed for 3 hours. The solvent is evaporated, to the residue add aqueous sodium bicarbonate and the mixture extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated. The obtained solid is recrystallized from ethyl acetate and obtain 344 mg specified the CSOs in the title compound as white needle crystals.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.42 (3H, m), 1,47-of 1.56 (2H, m), 1,72 of-1.83 (2H, Shir. d, J=9,2 Hz), 2,10 (2H, shirt, J=10.4 Hz), is 2.30 (3H, s), 2,56-of 2.64 (2H, m), 2,95 (2H, sird, J=11.2 Hz), of 3.48 (2H, s), 6,33 (1H, t, J=6.4 Hz), 7,06-to 7.18 (4H, m), 7,37 (1H, sird, J=5,2 Hz), EUR 7.57 (1H, sird, J=6.0 Hz).

Example 286

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[4-[2,3-(methylenedioxy)phenyl]butyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,18-of 1.40 (7H, m), 1,55-1,70 (4H, m)to 2.06 (2H, t, J=10.4 Hz), to 2.57 (2H, t, J=7, 6 Hz), of 2.92 (2H, sird, J=11.2 Hz), 3,47 (2H, s), to 5.93 (2H, s), 6,34 (1H, t, J=6.8 Hz), of 6.66 (1H, DD, J=8,0, 2.0 Hz), to 6.80 (1H, DD, J=8,0, 2.0 Hz), to 6.75 (1H, t, J=8.0 Hz), 7,38 (1H, m), 7,53 (1H, sird, J=6,8 Hz).

Example 287

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[3-[2,3-(methylenedioxy)phenyl]propyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 28-5.

1H-NMR (400 MHz, CDCl3) δ to 1.22 and 1.35 (4H, m), 1,48-of 1.53 (5H, m), of 2.08 (2H, shirt, J=10.4 Hz), of 2.56 (2H, t, J=8.0 Hz), of 2.92 (2H, sird, J=11.2 Hz), of 3.48 (2H, s), of 5.92 (2H, s), 6,34 (1H, t, J=6.8 Hz), of 6.66 (1H, DD, J=7,6, 1.2 Hz), 6,68 (1H, DD, J=7,6, 1.2 Hz), to 6.75 (1H, t, J=7.2 Hz), 7,37 (1H, m), 7,54 (1H, sird, J=6,4 Hz).

Example 288

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[5-[2,3-(methylenedioxy)phenyl]pentyl]piperidine

Specified in the title compound is obtained from the corresponding starting material of str is obom, described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,16-of 1.36 (8H, m), 1.56 to 1,90 (5H, m)2,07 (2H, shirt, J=10.0 Hz), to 2.57 (2H, t, J=7,6 Hz), of 2.92 (2H, sird, J=10,8 Hz), of 3.48 (2H, s), 3,93 (3H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), to 6.75 (1H, t, J=7,6 Hz), 7,38 (1H, m), 7,54 (1H, sird, J=6.0 Hz).

Example 289

1-[(6-Methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,24-to 1.38 (3H, m), 1,53 is 1.60 (2H, m), 1,68-to 1.77 (2H, m)to 2.06 (2H, m), 2,31 (3H, s), 2,55-2,62 (2H, m), with 2.93 (2H, sird, J=11,6 Hz), 3,45 (2N)of 5.92 (2H, s), 6,07 (1H, sird, J=6,8 Hz), of 6.66 (1H, DD, J=of 7.6, 1.6 Hz), of 6.68 (1H, DD, J=7,6, and 1.6 Hz), to 6.75 (1H, t, J=7,6 Hz), 7,41 (1H, sird, J=6,8 Hz).

Example 290

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2,2-diphenylether)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ of 1.20 (1H, m), 1.30 and of 1.42 (2H, m), 1,69 to 1.76 (2H, m), 1,94-2,04 (4H, m), is 2.88 (2H, sird, J=11,6 Hz), of 3.43 (2H, s), Android 4.04 (1H, t, J=8.0 Hz), of 6.31 (1H, t, J=6.4 Hz), 7,14-7,19 (2H, m), 7,21-7,30 (8H, m), 7,34 (1H, sird, J=5,2 Hz), 7,54 (1H, sird, J=6,4 Hz).

Example 291

1-[(5-Bromo-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material ways the Ohm, described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1.56 to of 1.64 (2H, m), 1,76 is 1.86 (2H, m), 2,09-of 2.20 (2H, m), 2,56-of 2.64 (2H, m), 2,95 (2H, sird, J=11,6 Hz), of 3.57 (2H, s), to 5.93 (2H, s), of 6.65 (1H, DD, J=7,6, 1.2 Hz), of 6.68 (1H, DD, J=7,6, 1.2 Hz), 6,76 (1H, t, J=7,6 Hz), of 7.48 (1H, Sirs), 7,94 (1H, Sirs).

Example 292

1-[(5-Methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,28-of 1.41 (3H, m), 1,54-of 1.62 (2H, m), 1,72 and 1.80 (2H, m), of 2.08 (2H, shirt, J=11.2 Hz), 2,11 (3H, s), 2,56-of 2.64 (2H, m)to 2.94 (2H, sird, J=11.2 Hz), of 3.46 (2H, s), of 5.92 (2H, s), of 6.66 (1H, DD, J=8.0 a, and 1.6 Hz), of 6.68 (1H, DD, J=8.0 a, 1,6 Hz), 6,76 (1H, t, J=8.0 Hz), 7,17 (1H, Sirs), 7,39 (1H, Sirs).

Example 293

1-[(5-Phenyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,25-of 1.44 (3H, m), 1,54-to 1.63 (2H, m), 1,74-to 1.82 (2H, m), and 2.14 (2H, shirt, J=10,8 Hz), 2,56-of 2.64 (2H, m)of 3.00 (2H, sird, J=11.2 Hz), to 3.58 (2H, s), of 5.92 (2H, s), of 6.65 (1H, DD, J=8,0, 1.2 Hz), of 6.68 (1H, DD, J=to 8.0, 1.2 Hz), to 6.75 (1H, t, J=8.0 Hz), 7,33 (1H, m), 7,40-to 7.50 (5H, m), of 7.70 (1H, Sirs), 7,87 (1H, Sirs).

Example 294

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-piperidino-2-oksidoksi)phenyl]ethyl]piperidine

Specified in the header connection receive is from the appropriate starting material way, described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,30-1,40 (2H, m), 1,46-1,81 (11N, m), 2,02 with 2.14 (2H, m), 2,62 of 2.68 (2H, m), 2,90-to 2.99 (2H, m), 3,43-3,60 (6N, m), and 4.68 (2H, s), 6.35mm (1H, m), 6,83-to 6.95 (2H, m), 7,11-7,20 (2H, m), 7,38 (1H, m), 7,58 (1H, m).

Example 295

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[[2-(4-pyridyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,18-of 1.32 (3H, m), 1,46-and 1.54 (2H, m), 1,58 by 1.68 (2H, m), 2,02 (2H, sird, J=10.4 Hz), 2,48-of 2.56 (2H, m), is 2.88 (2H, sird, J=11.2 Hz), 3,44 (2H, s), 6,32 (1H, t, J=6.4 Hz), 6,74-to 6.80 (2H, m), 7,00 (1H, DD, J=1,2, 8.0 Hz), 7.18 in-to 7.32 (3H, m), 7,35 (1H, sird, J=6.0 Hz), 7,52 (1H, sird, J=6.0 Hz), 8,42-8,46 (2H, m).

Example 296

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-[1-(dimethylcarbamoyl)cyclopentyloxy]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,28 was 1.43 (3H, m), 1,47-of 1.56 (2H, m), 1.70 to 1,82 (6N, m), 2.06 to of 2.21 (4H, m), 2,38-of 2.50 (2H, m), 2.57 m-of 2.64 (2H, m), with 2.93 (3H, s), 2,96 (2H, sird, J=11.2 Hz), to 3.09 (3H, s), 3,50 (2H, s), 6,34 (1H, t, J=6,4 Hz), of 6.68 (1H, DD, J=8,4, 1.2 Hz), 6,86 (1H, DD, J=7,6, 1.2 Hz),? 7.04 baby mortality (1H, DD, J=7,6, 2.0 Hz), 7,12 (1H, DD, J=7,6, 2,0, Hz), 7,37 (1H, m), 7,56 (1H, sird, J=5.6 Hz).

Example 297

1-[[5-(3-Pyridinyl)-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-methylenedioxy)phenyl]ethyl]piperidine

Specified in the header of the link is obtained from the corresponding starting material way, described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,28 was 1.43 (3H, m), 1.56 to of 1.64 (2H, m), 1,74 of-1.83 (2H, m), and 2.14 (2H, shirt, J=10,8 Hz), 2,56-of 2.64 (2H, m), is 2.88 (2H, sird, J=10,8 Hz)to 3.58 (2H, s), to 5.93 (2H, s), of 6.66 (1H, DD, J=7,6, and 1.6 Hz), 6,69 (1H, DD, J=to 7.6, 1.6 Hz), 6,76 (1H, t, J=7,6 Hz), 7,37 (1H, DDD, J=8.0 a, 5,2, 0.8 Hz), 7,74 (1H, Sirs), 7,78 (1H, DDD, J=8.0 a, 2,4, and 1.6 Hz), 8,84 (1H, Sirs), 8,58 (1H, DD, J=5,2, 1,6 Hz), 8,76 (1H, DD, J=2,4, and 0.8 Hz).

Example 298

1-[[5-(4-Pyridinyl)-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,30-of 1.44 (3H, m), 1.56 to of 1.64 (2H, m), 1,75-of 1.84 (2H, m), of 2.15 (2H, shirt, J=10.0 Hz), 2.57 m-of 2.64 (2H, m), 2,99 (2H, sird, J=11.2 Hz), to 3.58 (2H, s), to 5.93 (2H, s), of 6.66 (1H, DD, J=7,6, 1.2 Hz), 6,69 (1H, DD, J=to 7.6, 1.2 Hz), 6,76 (1H, t, J=7,6 Hz), 7,38-7,73 (2H, m), 7,73-7,73 (2H, m), 8,63-8,68 (2H, m).

Example 299

1-[5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,23-of 1.39 (3H, m), 1,53-of 1.62 (2H, m), 1,72 and 1.80 (2H, m), is 2.09 (2H, shirt, J=10,8 Hz), 2,65-of 2.72 (2H, m), is 2.88 (2H, sird, J=11,6 Hz), 3,51 (2H, s), to 5.08 (2H, s), 6,88-6,93 (2H, m), 7,13-7,20 (2H, m), 7,29-7,46 (6N, m), to 7.77 (1H, Sirs).

Example 300

1-[2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[3-(cyclohexylmethoxy)phenyl]ethyl]piperidine

The criminal code is mentioned in the title compound is obtained from the corresponding starting material way, described in example 285.

1H-NMR (400 MHz, CDCl3) δ 0,98-1,11 (2H, m), 1,14-1,42 (6N, m, 1,53-of 1.62 (2H, m), 1,65-of 1.92 (8H, m), 2.05 is-of 2.16 (2H, m), 2,55-2,63 (2H, m), 2,90-to 2.99 (2H, m), 3,49 (2H, s), 3,74 (2H, d, J=6.4 Hz), 6,36 (1H, t, J=6.4 Hz), 6,68-6,77 (3H, m), 7,17 (1H, dt, J=7,6, 2.0 Hz), was 7.36 (1H, sird, J=6.0 Hz), 7,58 (1H, sird, J=6,4 Hz).

Example 301

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,05 was 1.43 (N, m, 1,52 is 1.60 (2H, m), 1,66-1,90 (7H, m), 2,10-of 2.20 (2H, m), 2,59-of 2.66 (2H, m)to 2.94 (2H, sird, J=10.4 Hz), of 3.56 (2H, in), 3.75 (2H, d, J=5.6 Hz), to 6.80 (1H, d, J=8.0 Hz), 6,85 (1H, dt, J=8,0, 1,6 Hz), 7,10 (1H, DD, J=8.0 a, 1,6 Hz), 7,14 (1H, dt, J=8.0 a, 1,6 Hz), 7,35 (1H, d, J=2.4 Hz), 7,87 (1H, Sirs).

Example 302

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

In ethanol (4 ml) dissolved 226 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine. To the mixture was added 1 ml of a solution of 4 G. hydrochloric acid in methanol and then refluxed for 1.5 hours. To the reaction solution was added aqueous sodium bicarbonate and the mixture extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated. The oil obtained is dissolved in ethanol, added 49 mg of oxalic KIS is the notes and ethyl acetate, and then, the resulting precipitates are collected by filtration, resulting in a gain of 229 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, DMSO-d6) δ 1,05-1,35 (6N, m), 1,35-of 1.55 (4H, m), 1,62-1,90 (8H, m), of 2.56 (2H, m), is 2.88 (2H, t), 3,23-to 3.36 (2H, t), of 3.77 (2H, d, J=5.6 Hz), of 4.00 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,83 (1H, t, J=7.2 Hz), 6.89 in (1H, d, J=8.0 Hz), 7,09-7,17 (2H, m), 7,52 (1H, sird, J=6.4 Hz), 7,68 (1H, sird, J=6.0 Hz).

Example 303

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[3-(cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,20-to 1.38 (3H, m), 1.44MB and 1.80 (10H, m), 1,82-of 1.94 (2H, m), 2,48-of 2.58 (2H, m), 3,05 (2H, m), 3,49 (2H, Sirs), to 3.64 (2H, Sirs), 4,78 (1H, shirt, J=6.0 Hz), 6,23 (1H, t, J=6.8 Hz), 6,66 to 6.75 (3H, m), to 7.15 (1H, t, J=7,6 Hz), 7,39 (1H, sird, J=5,2 Hz), 7,53 (1H, sird, J=5,2 Hz).

Example 304

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-of 1.44 (5H, m), 1,76 is 1.86 (2H, m)2,60 (2H, shirt, J=7,6 Hz), and 2.83 (2H, m), 3,24 (2H, sird, J=8,8 Hz), 3,98 (2H, s), 5,11 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6.87 in (1H, t, J=7.2 Hz), 7,13 (1H, d, J=8,8 Hz), 7,12-to 7.18 (2H, m), 7,29-7,37 (1H, m), 7,38-of 7.48 (5H, m), 7,52 (1H, DD, J=6,4, 1.2 Hz), to 7.67 (1H, DD, J=6,4, 1.2 Hz).

Example 305

OK, the Alt 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[3-(benzyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,32 is 1.58 (5H, m), 1,76-of 1.88 (2H, m)to 2.55 (2H, m), 2,84 (1H, m), or 3.28 (2H, m), of 3.56 (2H, m), 3,98 (2H, Sirs), to 5.08 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,76-to 6.88 (3H, m), 7,19 (1H, t, J=7,6 Hz), 7.24 to 7,46 (5H, m), 7,52 (1H, sird, J=6.4 Hz), to 7.67 (1H, sird, J=6,4 Hz).

Example 306

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[[2-(2-phenylethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,34 is 1.58 (3H, m), 1,80-1,90 (2H, m), 2.57 m (2N, shirt, J=8.0 Hz), 2,74-2,92 (6N, m), 3,26 (2H, m), 3,62 (2H, m), of 3.94 (2H, Sirs), of 6.29 (1H, d, J=6.4 Hz), 7,08-7,33 (N, m)to 7.50 (1H, sird, J=2.4 Hz), 7,66 (1H, sird, J=6,4 Hz).

Example 307

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,32 of 1.50 (5H, m), 1,55-1,76 (6N, m), 1,78-of 1.93 (4H, m), 2,54-2,62 (2H, m), 2,82 (2H, Sirs), 3,26 (2H m), of 3.95 (2H, Sirs), a 4.83 (1H, shirt, J=5.6 Hz), 6,28 (1H, t, J=6.8 Hz), for 6.81 (1H, t, J=8.0 Hz), 6.90 to (1H, d, J=8.0 Hz), 7,08-7,16 (2H, m)to 7.50 (1H, DD, J=6,4, 2.0 Hz), 7,66 (1H, sird, J=6,4 Hz).

Example 308

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]Pipa is Idina

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,01 (6N, d, J=6, 4 Hz), 1,26-of 1.40 (3H, m), 1,42-is 1.51 (2H, m), 1,72-of 1.81 (2H, m), 2,03 (1H, m), 2,46 (2H, m), 2,53-2,60 (2H, m), 3,06 (2H, sird, J=11.2 Hz), to 3.64 (2H, Sirs), and 3.72 (2H, d, J=6.4 Hz), 6,23 (1H, t, J=6.8 Hz), 6,83 (1H, t, J=7.2 Hz), 6.89 in (1H, d, J=8.0 Hz), 7,09-7,16 (2H, m), 7,40 (1H, sird, J=6,4, 2.0 Hz), 7,54 (1H, d, J=5,2 Hz).

Example 309

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(2-phenylethane)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,28-of 1.44 (5H, m), 1,72-of 1.81 (2H, m), 2,43-of 2.50 (2H, m), of 2.86 (2H, m), 3,03 (2H, t, J=6.4 Hz), or 3.28 (2H, m)4,00 (2H, Sirs), 4,18 (2H, t, J=5,2 Hz), of 6.31 (1H, t, J=6.8 Hz), 6,83 (1H, t, J=7,2 Hz), 6,94 (1H, d, J=7,6 Hz), 7,06-7,16 (2H, m), 7.18 in-to 7.25 (1H, m), 7,28 and 7.36 (3H, m), 7,53 (1H, DD, J=6,0, 2.0 Hz), 7,68 (1H, sird, J=5.6 Hz).

Example 310

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(phenoxymethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,32 is 1.58 (5H, m), 1,78 is 1.86 (2H, m), 2,62 of 2.68 (2H, m), 2,85 (2H, m)to 3.58 (2H, m), 3,98 (2H, Sirs), to 5.08 (2H, s), of 6.29 (1H, t, J=6.8 Hz), to 6.95 (1H, t, J=7.2 Hz), 6,99? 7.04 baby mortality (2H, m), 7.18 in-7,24 (5H, m), 7,42 (1H, DD, J=7,6, 1.2 Hz), 7,52 (1H, DD, J=6,8, 2.0 Hz), 7,66 (1H, sh is R.D., J=6,8 Hz).

Example 311

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclopentyloxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,28-1,67 (11N, m), 1,73 is 1.86 (4H, m), 2,31 (1H, Sept, J=7,3 Hz), 2,52-of 2.58 (2H, m)to 2.67 (2H, m), 3,15-3,24 (2H, m), 3,83 (2H, d, J=6.4 Hz), a-3.84 (2H, Sirs), of 6.26 (1H, t, J=6.4 Hz), PC 6.82 (1H, dt, J=6,8, 1.2 Hz), make 6.90 (1H, d, J=8.0 Hz), 7,09-7,16 (2H, m), 7,46 (1H, DD, J=6,4, 1.2 Hz), to 7.61 (1H, sird, J=5.6 Hz).

Example 312

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[(2-cyclohexylethyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,87 is 0.99 (2H, m), 1,10-1,79 (N, m), 1,83-of 1.92 (2H, m), of 2.51-2,60 (4H, m), of 2.92 (2H, Sirs), to 3.34 (2H, Sirs), Android 4.04 (2H, Sirs), 6,03 (1H, t, J=6.8 Hz), 7,06-7,16 (4H, m), 7,54 (1H, DD, J=6,8, and 2.4 Hz), 7,69 (1H, sird, J=10.0 Hz).

Example 313

The dihydrochloride of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(benzylamino)phenyl]ethyl]piperidine

In ethanol (8 ml) dissolved 294 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(benzylamino)phenyl]ethyl]piperidine. To the mixture add 3 ml solution of 4 G. hydrochloric acid in methanol and then refluxed for 3 hours. After cooling, as described previously received precipitation collect Phi is Tracie and recrystallized from ethanol to obtain 273 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, DMSO-d6) δ 1,42 is 1.58 (4H, m), 1,61 to 1.76 (1H, m), 1,86 is 1.96 (2H, m), of 2.51-2,60 (2H, m), 2,95 (2H, shirt, J=11,6 Hz), or 3.28 (2H, sird, J=12,4 Hz)4,06 (2H, s), 4,36 (2H, s), of 6.31 (1H, t, J=6.4 Hz), 6,53 (1H, m), 6,63 (1H, m)6,94 (1H, shirt, J=7,6 Hz), 7,00 (1H, sird, J=7,2 Hz), 7.18 in-7,37 (5H, m), 7,54 (1H, DD, J=6,4, 2.0 Hz), 7,79 (1H, DD, J=6,8, 2.0 Hz).

Example 314

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(N-benzyl-N-methylamino)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,36-to 1.61 (5H, m), 1,80-of 1.92 (2H, m), of 2.51 (3H, s), 2,68 was 2.76 (2H, m), 2,87 (2H, m), or 3.28 (2H, sird, J=9.6 Hz), 3,98 (2H, s), of 4.00 (2H, s), of 6.29 (1H, t, J=6.8 Hz), 7,01 (1H, dt, J=7,6 Hz), 7,02 (1H, dt, J=7,2, 1,6 Hz), 7,12-7,28 (4H, m), 7,30 and 7.36 (4H, m), 7,52 (1H, DD, J=6,4, 2.0 Hz), to 7.68 (1H, DD, J=6,8, 2.0 Hz).

Example 315

The dihydrochloride of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-[(cyclohexylmethyl)amino]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 313.

1H-NMR (400 MHz, CDCl3) δ 0,93 was 1.06 (2H, m), 1,10-of 1.26 (3H, m), 1,46-of 1.66 (5H, m), 1,66-of 1.81 (4H, m), 1,82 is 1.96 (4H, m)to 2.67 (2H, m), 2,90 totaling 3.04 (2H, m)of 3.00 (2H, d, J=6.4 Hz), 3,34-of 3.42 (2H, m)4,06 (2H, s), of 6.31 (1H, t, J=6, 8 Hz), 7,06-7,42 (4H, m), 7,54 (1H, DD, J=6,8, 2.0 Hz), 7,83 (1H, DD, J=6,8, 2.0 Hz).

Example 316

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-[N-(cyclohexylmethyl)-N-methylamino]phenyl]the Teal]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ of 1.03 to 1.34 (5H, m), 1,63 is 2.00 (10H, m), 3.04 from-3,18 (3H, m), 3,42 (2H, sird, J=12,8 Hz), of 3.78 (2H, d, J=5.6 Hz), 4,08 (2H, s), 6,30 (1H, t, J=6.8 Hz), 6,91 (1H, dt, J=7,6, 1.2 Hz), 6,94 (1H, DD, J=7,6, 1,2 Hz), 7,13 (1H, sird, J=6,8 Hz), 7,18 (1H, dt, J=8,0, 1.2 Hz), 7,54 (1H, DD, J=6,8, 2.0 Hz), 7,73 (1H, DD, J=6,8, 2.0 Hz).

Example 317

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)phenyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, CDCl3) δ the 0.80 to 0.92 (2H, m), 1,08 is 1.23 (3H, m), 1,37-1,56 (6N, m, 1,57 is 1.70 (3H, m), 1,72-of 1.81 (2H, m), 1,81-1,90 (2H, m), of 2.51 (3H, s), 2,62 (2H, d, J=7,2 Hz), 2,62-2,70 (2H, m), of 2.92 (2H, m), 3,26-to 3.38 (2H, m), Android 4.04 (2H, s), of 6.29 (1H, t, J=6.8 Hz), 6,97-7,02 (1H, m), 7,10-7,20 (3H, m), 7,54 (1H, DD, J=6,8, 2.0 Hz), of 7.70 (1H, DD, J=6,8, 2.0 Hz).

Example 318

1-[(5-(Methylsulphonyl)-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine

In ethanol (10 ml) dissolve 138 mg of 1-[(5-(methylsulphonyl)-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(cyclohexylmethoxy)phenyl]ethyl]piperidine. To the mixture was added 1 ml of thionyl chloride and then refluxed for 2.5 hours. To the reaction solution was added an aqueous solution of sodium carbonate and the resulting precipitates are collected, filtrates obtain 127 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ of 1.05 to 1.45 (8H, m), 1,53-to 1.61 (2H, m), 1,67-1,90 (8H, m), 2,15-of 2.27 (2H, m), 2,60 of 2.68 (2H, m), of 2.92 (2H, sird, J=10,8 Hz), is 3.08 (3H, s), of 3.60 (2H, s), 3,76 (2H, d, J=6.0 Hz), for 6.81 (1H, d, J=8.0 Hz), 6,86 (1H, dt, J=8,0, 1.2 Hz), 7,11 (1H, DD, J=8,0, 1.2 Hz), to 7.15 (1H, dt, J=8,0, 2.0 Hz), 7,83 (1H, sird, J=2.4 Hz), 8,35 (1H, SIRM).

Example 319

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,08 is 1.23 (3H, m), 1,42 of 1.50 (2H, m), 1,60-1,70 (2H, m), 1,88 is 2.00 (2H, m), 2,40-2,60 (2H, m), 2,73-and 2.83 (2H, m), 3,24 (2H, s), 5,95 (2H, s), 6,64-6,76 (3H, m), 7,34 (1H, s)to 7.50 (1H, s).

Example 320

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(2-forfinal]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,00-of 1.26 (3H, m), 1,40-and 1.54 (2H, m), 1,67 (2H, sird, J=9.6 Hz), was 1.94 (2H, shirt, J=10.4 Hz), 2,60 (2H, d, J=7,6 Hz), 2,77 (2H, sird, J=11,6 Hz), 3,24 (2H, s), 7,06-7,13 (2H, m), 7,17-7,24 (1H, m), 7,27 (1H, t, J=7,6 Hz), 7,34 (1H, d, J=2.0 Hz), to 7.50 (1H, d, J=3.2 Hz).

Example 321

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(2-methoxyethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR(400 MHz, DMSO-d6) δ 1,10-1,25 (3H, m), of 1.40-1.50 (2H, m), 1,67 (2H, sird, J=8,8 Hz), 1,95 (2H, shirt, J=10,8 Hz)to 2.54 (2H, t, J=8.0 Hz), was 2.76 (2H, sird, J=11.2 Hz), 3,24 (2H, s), and 3.31 (3H, s), the 3.65 (2H, t, J=4.4 Hz), of 4.05 (2H, t, J=4.4 Hz), 6,83 (1H, t, J=7.2 Hz), make 6.90 (1H, d, J=8.0 Hz), 7,10 (1H, d, J=7,6 Hz), 7,06-7,14 (1H, m), 7,34 (1H, d, J=2,8 Hz), to 7.50 (1H, d, J=2,8 Hz).

Example 322

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2,5-dimetilfenil)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,16-of 1.36 (3H, m), 1,32 of 1.46 (2H, m), 1,72 (2H, sird, J=10,8 Hz), 2,03 (1H, Sirs), are 2.19 (3H, s), 2,22 (3H, s), of 2.51 (2H, t, J=7,6 Hz), 2,85 (2H, sird, J=10.4 Hz), 3,20-of 3.42 (2H, m), 6,18 (1H, t, J=6,4 Hz), 6,87 (1H, d, J=7,6 Hz), 6,92 (1H, s), of 6.99 (1H, d, J=7, 6 Hz), 7,28 (1H, d, J=6.4 Hz), 7,41 (1H, d, J=6.0 Hz).

Example 323

Oxalate of 1-[(5-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(isobutoxy)]phenyl]ethyl]piperidine

In ethanol (10 ml) dissolved 443 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]piperidine. To this mixture 0.5 ml of thionyl chloride and then refluxed for 3 hours. To the reaction solution was added aqueous sodium carbonate and the mixture extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated. The oil obtained is dissolved in ethanol, added 99 mg of oxalic acid, and then the precipitation collecting filter is iej, resulting in getting 382 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, DMSO-d6) δ 1,01 (6N, d, J=6, 8 Hz), 1,24-of 1.42 (3H, m), USD 1.43-is 1.51 (2H, m), 1,73-to 1.82 (2H, m), 2,03 (1H, m), of 2.45 (2H, m), 2,54-2,60 (2H, m), is 3.08 (2H, sird, J=11,6 Hz)to 3.64 (2H, Sirs), to 3.73 (2H, d, J=6.4 Hz), 6,83 (1H, dt, J=7,6, 1.2 Hz), 6.89 in (1H, d, J=7,6 Hz), 7,09-7,16 (2H, m), 7,58 (1H, d, J=2.4 Hz), the 7.65 (1H, d, J=2,4 Hz).

Example 324

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(3, 5dimethylphenyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ to 1.48 (5H, Sirs), of 1.84 (2H, sird, J=9,2 Hz), 2,22 (6N, (C), 2,45 is 2.55 (2H, m), 2,85-of 3.00 (2H, m), 3.25 to 3.40 in (2H, m), Android 4.04 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,79 (3H, s), 7,53 (1H, DD, J=6,4, 2.0 Hz), 7,73 (1H, DD, J=6,8, 2.0 Hz).

Example 325

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-methoxy-5-were)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ a 1.45 (5H, Sirs), to 1.86 (2H, sird, J=10.4 Hz), measuring 2.20 (3H, s), 2,44-of 2.54 (2H, m), with 2.93 (2H, Shir,C), 3,24 is 3.40 (2H, m), of 3.73 (3H, s), of 4.05 (2H, s), 6,30 (1H, t, J=6.4 Hz), PC 6.82 (1H, d, J=8.0 Hz), 6,94 (1H, C)to 6.95 (1H, d, J=8,4 Hz), 7,54 (1H, DD, J=6,4, 2.0 Hz), 7,72 (1H, d, J=5,2 Hz).

Example 326

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(triptoreline)phenyl]ethyl]piperidine

The criminal code is mentioned in the title compound is obtained from the corresponding starting material way, described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,34 is 1.60 (5H, Sirs), to 1.86 (2H, sird, J=11.2 Hz), of 2.64 (2H, t, J=7,6 Hz)to 2.94 (2H, Sirs), 3,24-3,44 (2H, m) of 4.05 (2H, s), 6,30 (1H, t, J=6.4 Hz), 7,28-7,40 (3H, m), 7,38-of 7.48 (1H, m), 7,54 (1H, d, J=6,4 Hz), 7,71 (1H, d, J=5.6 Hz).

Example 327

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(3-pyridinyl)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,34-of 1.65 (5H, m), 1,80-of 1.94 (2H, m)to 2.66 (2H, t, J=7,6 Hz), 2,85-of 3.00 (2H, m), 3.25 to 3.40 in (2H, m) 3,95-4,10 (2H, m), 6,28 (1H, t, J=6.4 Hz), 7,26 (1H, d, J=7,2 Hz), 7,40 (1H, d, J=7,2 Hz), 7,47 (1H, DD, J=7,2, 4,8 Hz), 7,40-of 7.60 (3H, m), of 7.69 (1H, d, J=6.4 Hz), 8,00-8,10 (1H, m), 8,55 (1H, DD, J=4,8, and 1.6 Hz), 8,87 (1H, d, J=1.6 Hz).

Example 328

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[3-[(tetrahydropyran-2-yl)metiloksi]phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,20-1,60 (N, m)of 1.62 (1H, sird, J=12,4 Hz), 1,70-1,90 (3H, m), 2,40-2,60 (2H, m), 2,80-3,00 (2H, m) 3,20-of 3.43 (3H, m), 3,50-3,63 (1H, m), 3.75 to of 3.95 (3H, m), was 4.02 (2H, s), 6,27 (1H, t, J=6.4 Hz), 6,66-to 6.80 (3H, m), 7,14 (1H, t, J=8.0 Hz), 7,52 (1H, d, J=6.4 Hz), to 7.68 (1H, d, J=6.0 Hz).

Example 329

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-[(tetrahydropyran-2-yl)metiloksi]phenyl]ethyl]piperidine

Specified in the header connection produces the t from the corresponding starting material way, described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,25-1.55V (N, m)of 1.64 (1H, sird, J=12.0 Hz), 1,75-of 1.93 (3H, m), of 2.53 (2H, t, J=6.4 Hz), 2,80-3,00 (2H, m), 3,20-of 3.43 (3H, m), 3,53-3,63 (1H, m), 3,83-3,93 (3H, m), a 4.03 (2H, s), 6,28 (1H, t, J=6,4 Hz), PC 6.82 (1H, t, J=7.2 Hz), 6.89 in (1H, d, J=8.0 Hz), 7,10 (1H, d, J=7,2 Hz), 7,11 (1H, t, J=7.2 Hz), 7,52 (1H, DD, J=6,0, 2.0 Hz), of 7.64-7,72 (1H, m).

Example 330

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(2-methoxyethoxy)phenyl]ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,34 of 1.50 (5H, m), 1,76-1,90 (2H, m), 2,46-of 2.56 (2H, m), 2,80 are 2.98 (2H, m), 3,20-to 3.38 (2H, m) 3,30 (3H, s)to 3.64 (2H, t, J=4.0 Hz), was 4.02 (2H, s)4,06 (2H, t, J=4.0 Hz), 6,28 (1H, t, J=6.4 Hz), 6,83 (1H, t, J=7.2 Hz), 6,91 (1H, d, J=8.0 Hz), 7,11 (1H, d, J=7,6 Hz), 7,12 (1H, t, J=7,6 Hz), 7,52 (1H, d, J=6.0 Hz), 7,66-7,76 (1H, m).

Example 331

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-phenoxyphenyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,25-to 1.60 (5H, m), of 1.78 (2H, sird, J=12,8 Hz), of 2.56 (2H, t, J=7,6 Hz), 2,66-2,95 (2H, m), 3,20-to 3.35 (2H, m), was 4.02 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,84-6,92 (3H, m), was 7.08 (1H, t, J=7.2 Hz), 7,13 (1H, t, J=7.2 Hz), 7.23 percent (1H, t, J=7.2 Hz), 7,30-7,40 (3H, m), 7,54 (1H, d, J=5,2 Hz), to 7.68 (1H, d, J=6.0 Hz).

Example 332

Oxalate of 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[[2-(2-phenylethyl)phenylethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ of 1.25 to 1.48 (5H, m), 1,74-of 1.84 (2H, m), 2,48 (2H, m), 2,53-2,61 (2H, m), was 2.76-2,89 (4H, m), 3,06 (2H, sird, J=10,8 Hz), the 3.65 (2H, Sirs), 6,98-7,32 (N, m), 7,58 (1H, m), the 7.65 (1H, d, J=2,8 Hz).

Example 333

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2,2-diphenyl-1-ethynyl)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ of 1.52 to 1.76 (4H, m), 1,98-of 2.09 (2H, m)of 2.16 (1H, m), 2,90 (2H, sird, J=10.4 Hz), of 3.46 (2H, s), of 5.92 (1H, d, J=9.6 Hz), 6,33 (1H, shirt, J=6.4 Hz), 7,14-7,40 (11N, m), 7,55 (1H, m).

Example 334

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine

In ethanol (8 ml) dissolved 245 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine. To the mixture is added 7 ml of a solution of 4 G. hydrochloric acid in methanol and then refluxed for 7 hours. To the reaction solution was added aqueous sodium carbonate and the mixture extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and then the solvent is evaporated. To the resulting oil is added ether for crystallization and obtain 116 mg specified in the title compound as a pale yellow powder.

1H-NMR (400 MHz, DCl 3) δ 1,56 by 1.68 (2H, m), 1,80-1,89 (2H, m), 2,18-of 2.30 (3H, m), 2,96-to 3.02 (2H, m), of 3.56 (2H, s), 6,24 (1H, DD, J=7,2, 16.0 Hz), 6,56 (1H, d, J=16.0 Hz), 7,01 (1H, DDD, J=10,8, and 8.4, 1.6 Hz), was 7.08 (1H, dt, J=8,0, 1.2 Hz), 7,17 (1H, m), 7,40-of 7.48 (2H, m), 7,73 (1H, Sirs).

Example 335

1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine

In ethanol (12 ml) dissolved 221 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine. To this mixture (12 ml) solution of 4 G. hydrochloric acid in methanol and then refluxed for 11 hours. To the reaction solution was added aqueous sodium carbonate and the mixture extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and then the solvent is evaporated. To the resulting oil is added ether for crystallization. Specified in the title compound (176 mg) was obtained as a light pink powder.

1H-NMR (400 MHz, CDCl3) δ 1,57 was 1.69 (2H, m), 1,81-1,89 (2H, m), 2,20-2,31 (3H, m), 2,96 totaling 3.04 (2H, m), of 3.60 (2H, s), 6,23 (1H, DD, J=16,0, 7,2 Hz), 6,56 (1H, d, J=16.0 Hz), 7,02 (1H, DDD, J=10,8, to 8.0, 1.2 Hz), was 7.08 (1H, dt, J=8,0, 1.2 Hz), 7,17 (1H, m), 7,28 (1H, DD, J=8.0 a, 2,8 Hz), 7,44 (1H, dt, J=7,6, 2.0 Hz), 7,72 (1H, SIRM).

Example 336

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-chlorophenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,46-,69 (2H, m), 1,82-1,90 (2H, m), 2,18-of 2.34 (3H, m), 2.95 and-to 3.02 (2H, m), 3,55 (2H, s), x 6.15 (1H, DD, J=16,0, 6,8 Hz), 6,78 (1H, d, J=16.0 Hz), to 7.15 (1H, DD, J=8.0 a, 1,6 Hz), 7,20 (1H, dt, J=8.0 a, 1,6 Hz), 7,34 (1H, DD, J=8,0 at 1.6 Hz), was 7.45 (1H, d, J=2,8 Hz), 7,51 (1H, DD, J=8.0 a, 1,6 Hz), 7,69 (1H, Sirs).

Example 337

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-were)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,56 by 1.68 (2H, m), 1,81-of 1.88 (2H, m), 2,16-to 2.29 (3H, m), of 2.33 (3H, s), 2,94-to 3.02 (2H, m), of 3.54 (2H, s), 6,04 (1H, DD, J=16,0, 7,2 Hz), 6,59 (1H, DD, J=16,0, 0.8 Hz), 7,09-7,19 (3H, m), 7,41 (1H, DD, J=of 7.6, 1.6 Hz), was 7.45 (1H, d, J=2.4 Hz), 7,69 (1H, Sirs).

Example 338

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(benzyloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,58-of 1.78 (4H, m), 1,83-of 1.94 (2H, m), 2.40 a (7/8H, m), 2,64 (1/8H,m), 2,82 was 3.05 (2H, m), 3,20-of 3.42 (2H, m)to 4.01 (2H, Sirs), 5,12 (1/4H, s), 5,14 (7/4H, s), 6,18-6,28 (1H, m), 6,30 (1H, t, J=6,4 Hz), 6,50 (1/8H, d, J=11,6 Hz), 6,72 (7/8H, d, J=16.0 Hz), 6.89 in? 7.04 baby mortality (1H, m), 7,05-to 7.15 (1H, m), 7.18 in-of 7.55 (8H, m), 7,66 (1/8H, sird, J=5,2 Hz), 7,69 (7/8H, sird, J=5,2 Hz).

Example 339

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-phenylethyl)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the appropriate source material with the special described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,60-of 1.78 (2H, m), 1,86 is 1.96 (2H, m), of 2.45 (1H, m), 2,52 totaling 3.04 (6N, m), 3,21 (2/7H, sird, J=11.2 Hz), 3,34 (12/7H, sird, J=11.2 Hz), 3,92 (2/7H, Sirs), 4,00 (12/7H, Sirs), 6,06-6,16 (1H, m), 6,27 (1/7H, t, J=6.8 Hz), 6,30 (6/7H, t, J=6.8 Hz), 6,57 (1/7H, d, J=11.2 Hz), 6,68 (6/7H, d, J=16.0 Hz), 7,10-to 7.32 (9H, m), 7,42-7,47 (1H, m), 7,49 (1/7H, DD, J=6,8, 2.0 Hz), 7,52 (6/7H, DD, J=6,8, 2.0 Hz), 7,62 (1/7H, sird, J=6,8 Hz), 7,68 (6/7H, DD, J=6,8, 1,6 Hz).

Example 340

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(isobutyryloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,97 (3/2H, d, J=6.8 Hz), 1,01 (9/2H, d, J=6.8 Hz), 1,58-of 1.94 (4H, m), 1,95-2,10 (1H, m), 2.40 a (1/4H, m), 2,66 (3/4H, m)to 2.94 (2H, m), 3,20-to 3.38 (2H, m), 3,74 (1/2H, d, J=6.8 Hz), 3,76 (3/2H, d, J=6.8 Hz), 3,92-of 4.05 (2H, m), 6,20-6,33 (2H, m), 6.48 in (1/4H, d, J=11,6 Hz), 6,64 (3/4H, d, J=16.0 Hz), 6,86-6,99 (2H, m), 7,15-7,29 (5/4H, m), 7,44 (3/4H, DD, J=8.0 a, 1,6 Hz), 7,50 (1/4H, DD, J=6,4, 2.0 Hz), 7,52 (3/4H, DD, J=6,4, 2.0 Hz), 7,65 (1/4H, sird, J=6.4 Hz), 8,06 (3/4H, sird, J=6,4 Hz).

Example 341

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclopentyloxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,12-1,96 (13H, m), 2,12-of 2.54 (1H, m), 2,64 (1/4H, m), 2,80-3,02 (7/4H, m), is 3.08-3,39 (2H, m), 3,82 (1/2H, d, J=6.8 Hz), 3,83 (3/2 who, d, J=6.8 Hz), 4,00 (2H, m), the 5.45 (1/4H, DD, J=12,0, 10,0 Hz), of 6.20 to 6.35 (7/4H, m), 6,45 (1/4H, d, J=12.0 Hz), 6,62 (3/4H, d, J=15.6 Hz), 6,85-7,00 (2H, m), 7,15-7,30 (7/4H, m), 7,42 (5/4H, d, J=a 7.6 Hz), 7,50 (1/4H, DD, J=7,2, 2.0 Hz), 7,52 (3/4H, DD, J=7,2, 2.0 Hz), to 7.64 (1/4H, DD, J=5,2, 2.0 Hz), 7,65 (3/4H, DD, J=5,2, 2.0 Hz).

Example 342

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(2-cyclohexylethyl)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,85-0,98 (2H, m), 1,07-of 1.29 (4H, s), 1,30-1,40 (2H, m)of 1.57 to 1.76 (7H, m), 1,86-of 1.95 (2H, m), 2,33 (1/7H, m), 2,43 (6/7H, m), of 2.51-2,56 (2/7H, m), 2,58-2,64 (12/7H, m), 3,19-3,27 (2/7H, m), 3,27-3,38 (12/7H, m), 3,92 (2/7H, s), 4.00 points (12/7H, s), 6,05-6,14 (1H, m), 6,27 (1/7H, t, J=6.4 Hz), 6,30 (6/7H, t, J=6.4 Hz), 6,53 (1/7H, d, J=11,6 Hz), 6,62 (6/7H, d, J=15.2 Hz), 7,07-7,22 (3H, m), 7,40-7,46 (1H, m), 7,49 (1/7H, DD, J=6,4, 2.0 Hz), 7,52 (6/7H, DD, J=6,4, 2.0 Hz), 7,63 (1/7H, DD, J=5,6, 2.0 Hz), 7,69 (6/7H, DD, J=5,6, 2.0 Hz).

Example 343

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

In ethanol (16 ml) dissolved 961 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine. To the mixture add 4 ml of 4 n solution of hydrochloric acid in methanol and then refluxed for 3 hours. To the reaction solution was added an aqueous solution of sodium carbonate and the mixture extracted with ethyl acetate. The extract is dried over anhydrous is a Ulfat magnesium and the solvent is evaporated. The oil obtained is dissolved in ethanol, add 207 mg of oxalic acid and ethyl acetate. The obtained precipitates are collected by filtration, resulting in a gain 765 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, DMSO-d6) δ of 1.02 to 1.34 (5H, m), 1,57-of 1.93 (10H, m), 2,39 (1H, m), is 2.88 (2H, m), 3,29 (2H, sird, J=9.6 Hz), with 3.79 (2H, d, J=6.0 Hz), of 3.94 (2H, s), is 6.19-6,32 (2H, m), only 6.64 (1H, d, J=16.4 Hz), to 6.88 (1H, t, J=7,2 Hz), to 6.95 (1H, d, J=7,2 Hz), 7,18 (1H, dt, J=7,2, 1.2 Hz), 7,41 (1H, DD, J=7,2, 1.2 Hz), to 7.50 (1H, DD, J=7,2, 2.0 Hz), to 7.67 (1H, sird, J=5.6 Hz).

Example 344

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(Z)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,97-1,32 (5H, m), 1.60-to 1,84 (10H, m), 2,65 (1H, m), 2.70 height is 3.00 (2H, m), 3,26 (2H, sird, J=12.0 Hz), of 3.77 (2H, d, J=7,2 Hz), of 3.96 (2H, s), vs. 5.47 (1H, m), 6,28 (1H, t, J=6.8 Hz), 6,47 (1H, d, J=11,6 Hz), 6,91 (1H, t, J=7,6 Hz), to 6.95 (1H, d, J=8.0 Hz), 7,18 (1H, DD, J=7,6, 1.2 Hz), 7.23 percent (1H, dt, J=7,6, 1.2 Hz), to 7.50 (1H, DD, J=6,8, 2.0 Hz), 7,66 (1H, sird, J=6.0 Hz).

Example 345

Oxalate of 1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ of 1.03 to 1.34 (5H, m), 1,47-of 1.88 (10H, m) 2,28 (1H, m), 2,42-2,60 (2H, m), 3.00 and-3,18 (2H, m), 3,62-3,74 (2H, m), with 3.79 (2H, d, J=6.0 Hz), of 6.26 (1H, DD, J=16,0, 6,8 Hz), only 6.64 (1H, d, J=16.0 Hz), to 6.88 (1H, t, J=7,6 Hz), of 6.96 (1H, d, J=7,6 Hz), 7,17 (1H, dt, J=of 7.6, 2.0 Hz), 7,42 (1H, DD, J=7,6, 2.0 Hz), the 7.65 (2H, Sirs).

Example 346

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)-5-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,96-1,32 (5H, m), 1,57-of 1.92 (10H, m), 2,41 (7/4H, m), 2,66 (1/4H, m), 2,84-of 3.00 (2H, m), 3,21-to 3.36 (2H, m), 3.75 to (1/2H, d, J=6.4 Hz), of 3.77 (3/2H, d, J=6.4 Hz), 3,94 (1/2H, m), 3,98 (3/2H, m), 5,23 (1/4H, m), 6,25-6,38 (7/4H, m), 6.42 per (1/4H, d, J=11,6 Hz), 6,62 (3/4H, d, J=15.6 Hz), 6,93-7,10 (2H, m), 7,32 (1H, DD, J=10,0, 2,8 Hz), 7,50 (1/4H, DD, J=6,4, 2,0 Hz), 7,52 (3/4H, DD, J=6,4, 2,0 Hz), 7,65 (1/4H, DD, J=6,4, 2,0 Hz), 7,68 (3/4H, DD, J=6,4, 2.0 Hz).

Example 347

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclohexylmethoxy)-4-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ of 0.96 to 1.34 (5H, m), 1,57-of 1.92 (10H, m), of 2.38 (1H, m), 2,59 (1/5H, m), 2,78-3,02 (9/5H, m), 3,20-to 3.38 (2H, m), 3,79 (2/5H, d, J=6.4 Hz), 3,81 (8/5H, d, J=6.0 Hz), 3,94 (2/5H, Sirs), 3,99 (8/5H, Sirs), 5.56mm (1/5H, m), 6,215-6,34 (9/5H, m), 6,38 (1/5H, d, J=11,6 Hz), 6,56 (4/5H, d, J=16.0 Hz), 6,67-6,79 (1H, m), 6,83-6,92 (1H, m), 7,20 (1/5H, t, J=7.2 Hz), 7,26 (1/5H, d, J=7,2 Hz), 7,42-7,56 (8/5H, m), 7,63-7,73 (1H, m).

Example 348

1-[(2-Oxo-1,2-dig the draw-3-pyridinyl)methyl]-4-[(E)-2-[2-(cyclohexylmethoxy)-6-forfinal]-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ the 1.04 to 1.34 (5H, m), 1.56 to of 1.92 (10H, m), 2,39 (1H, m), 2,83 are 2.98 (2H, m), 3,24-to 3.36 (2H, m), a-3.84 (2H, d, J=5.6 Hz), of 3.97 (2H, Sirs), of 6.29 (1H, t, J=6.4 Hz), 6,39-6,51 (2H, m), 7,78 (1H, DD, J=10,8, 8,4 Hz), at 6.84 (1H, d, J=8,4 Hz), 7,19 (1H, DD, J=8,4, 6,8 Hz), 7,51 (1H, DD, J=6,4, 2.0 Hz), 7,68 (1H, sird, J=4,8 Hz).

Example 349

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[(2-cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine

In 1,2-dichloroethane (3 ml) dissolved 111 mg of 4-[2-[2-cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine. To the mixture is added 50 mg of 2-oxo-1,2-dihydro-3-pyridinecarboxamide, of 0.03 ml of acetic acid and 94 mg of triacetoxyborohydride sodium, and then stirred at room temperature for 5.5 hours. To the resulting mixture are added 50 mg of 2-oxo-1,2-dihydro-3-pyridinecarboxamide, of 0.03 ml of acetic acid and 94 mg of triacetoxyborohydride sodium, and then stirred over night. To the reaction solution was added aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified column chromatography on NH form silica gel (ethyl acetate:methanol=30:1), which produces the t 140 mg of colorless oil. The oil obtained is dissolved in ethanol, added 33 mg of oxalic acid and ethyl acetate and the resulting precipitates are collected by filtration, resulting in a gain of 120 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, DMSO-d6) δ 1,02-1,32 (5H, m), 1.60-to of 1.87 (8H, m), 1,99-of 2.08 (2H, m), 2,86 totaling 3.04 (3H, m), 3,11-up 3.22 (2H, m), 3,82 (2H, d, J=6.0 Hz), 3,92, (2H, Sirs), 6,28 (1H, t, J=6.8 Hz), to 6.88 (1H, dt, J=8,0, 0.8 Hz), 7,00 (1H, d, J=8.0 Hz), 7,25-7,33 (2H, m), 7,49 (1H, DD, J=7,6, 2.0 Hz), 7,66 (1H, DD, J=7,6, 2.0 Hz).

Example 350

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-phenoxyphenyl)-1-ethynyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,56-of 1.78 (3H, m), 1,76-of 1.88 (1H, m), 2,10-of 2.50 (1H, m), 2,90-3,10 (2H, m), 3,22 is 3.40 (2H, m), of 4.05 (2H, s), of 6.29 (1H, t, J=6, 4 Hz), 6,39 (0,3H, d, J=11,6 Hz), 6,56 (0,7H, d, J=16.4 Hz), 6,84-7,40 (8H, m), 7,54 (1H, DD, J=6,4, 2.0 Hz), of 7.64-7,74 (1H, m).

Example 351

1-[(5-Cyano-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine

To acetonitrile (10 ml) is added 214 mg of 1-[(5-cyano-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine, 137 mg of sodium iodide and 0.1 ml of chlorotrimethylsilane, and then stirred at room temperature. After 5 hours, add 685 mg of sodium iodide and 0.5 ml of chlorotrimethylsilane, and then stirred at room temperature for 2 minutes. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate, aqueous sodium thiosulfate and a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is suspended in aqueous sodium carbonate and then stirred at room temperature. The crystals are collected by filtration and obtain 185 mg specified in the title compound as a pale yellow powder.

1H-NMR (400 MHz, DMSO-d6) δ 1,41-and 1.54 (2H, m), 1,68-of 1.74 (2H, m), of 2.08 (2H, shirt, J=10,8 Hz), 2,17 (1H, m), 2,85 (2H, sird, J=11,6 Hz), 3,29 (2H, s)6,38 (1H, DD, J=16,0, 6,8 Hz), 6,50 (1H, d, J=16.0 Hz), 7,12-7,21 (2H, m), 7,25 (1H, m), 7,53 (1H, d, J=2.4 Hz), 7,58 (1H, dt, J=8,4, and 1.6 Hz), 8,19 (1H, d, J=2,4 Hz).

Example 352

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)benzyloxy]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 1,00-1,32 (5H, m), 1,62-2,07 (10H, m), 3,01 (2H, m), 3,17 (2H, m), 3,66 (1H, m), with 3.79 (2H, d, J=6.4 Hz), of 4.00 (2H, s), of 4.49 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,91 (1H, t, J=7,6 Hz), to 6.95 (1H, d, J=7,6 Hz), 7,24 (1H, dt, J=7,6, 1.2 Hz), 7,32 (1H, DD, J=7,6, 1.2 Hz), 7,52 (1H, DD, J=6,4, 2.0 Hz), to 7.68 (1H, DD, J=6,4, 2.0 Hz).

Example 353

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(benzyloxy)benzyloxy]piperidine

Specified in the agolove connection is obtained from the corresponding starting material way, described in example 349.

1H-NMR (400 MHz, DMSO-d6) δ 1,72 is 1.86 (2H, m), 1,90-2,02 (2H, m), 2,85 are 2.98 (2H, m), 3,05-3,17 (2H, m)to 3.64 (1H, m), 3,93 (2H, s), a 4.53 (2H, s), 5,14 (2H, s), of 6.29 (1H, t, J=6.8 Hz), to 6.95 (1H, dt, J=7,6, 1.2 Hz), 7,17 (1H, d, J=7,6 Hz), 7,26-7,42 (5H, m), 7,43-of 7.48 (2H, m), 7,51 (1H, DD, J=6,8, 2.0 Hz), the 7.65 (1H, DD, J=6,8, 2,0 Hz.

Example 354

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(chloro-6-forbindelse)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,40-of 1.55 (2H, m), of 1.78-1.90 (2H, m), 2,10 (2H, shirt, J=9,2 Hz), 2,58-2,70 (2H, m), up 3.22 (2H, s), 3.33 and is-3.45 (1H, m), 4,56 (2H, d, J=2.0 Hz), x 6.15 (1H, t, J=6.4 Hz), 7.18 in-7,28 (2H, m), 7,30-7,46 (3H, m), 11,50 (1H, s).

Example 355

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-chloro-6-forbindelse)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,42-of 1.55 (2H, m), 1,80-1,90 (2H, m), and 2.14 (2H, shirt, J=9,2 Hz), 2,58-2,70 (2H, m)of 3.25 (2H, s), 3,30-3,50 (1H, m), 4,56 (2H, d, J=2.4 Hz), 7,20-7,26 (1H, m), 7,31-7,37 (2H, m), 7,37-7,44 (1H, m), 7,50 (1H, d, J=2,8 Hz).

Example 356

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2,6-deferasirox)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,38-of 1.52 (2H, is), of 1.78-1.90 (2H, m), of 2.08 (2H, shirt, J=9.6 Hz), 2,56-2,70 (2H, m), 3,21 (2H, s), 3,30-of 3.43 (1H, m), 4,50 (2H, s), 6,14 (1H, t, J=6.4 Hz), to 7.09 (2H, t, J=8.0 Hz), 7.23 percent (1H, DD, J=6,4, and 1.6 Hz), 7,35 (1H, DD, J=6,4, 1.2 Hz), of 7.36-of 7.48 (1H, m).

Example 357

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2,6-deferasirox)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,40-of 1.53 (2H, m), of 1.78-1.90 (2H, m), 2,13 (2H, shirt, J=9,2 Hz), 2,56-2,70 (2H, m), 3,24 (2H, s), 3,30-of 3.48 (1H, m), 4,50 (2H, s), to 7.09 (2H, t, J=8.0 Hz), 7,35 (1H, d, J=2.0 Hz), 7,38-of 7.48 (1H, m), to 7.50 (1H, d, J=2,8 Hz).

Example 358

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-chlorobenzoyloxy)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,45-to 1.60 (2H, m), 1,82-of 1.93 (2H, sird, J=10.0 Hz), 2,12 (2H, shirt, J=10.0 Hz), 2,60-by 2.73 (2H, m), 3,23 (2H, s), 3,38-3,50 (1H, m), of 4.54 (2H, s), x 6.15 (1H, t, J=6.4 Hz), 7,24 (1H, d, J=6.4 Hz), 7,26-7,44 (4H, m)to 7.50 (1H, d, J=7,6 Hz), 11,50 (1H, s).

Example 359

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-chlorobenzoyloxy)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,47-of 1.62 (2H, m), 1,82-of 1.94 (2H, m)of 2.16 (2H, shirt, J=9.6 Hz), 2,60-of 2.75 (2H, m), 3.27 to (2N, C)of 3.46 (1H, m), of 4.54 (2H, s), 7,26 was 7.45 (4H, m), of 7.48-7,56 2H, m).

Example 360

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-forbindelse)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,70-1,90 (2H, m), 1,90-2,10 (2H, m), 2,90-3,10 (2H, m)3,00-3,20 (2H, m), 3,60-3,70 (1H, m), of 3.97 (2H, s), a 4.53 (2H, s), of 6.26 (1H, t, J=6.4 Hz), 7,10-7,22 (2H, m), 7,30-7,38 (1H,m), 7,45 (1H, t, J=6.8 Hz), 7,49 (1H, d, J=4,8 Hz), to 7.67 (1H, d, J=5,2 Hz).

Example 361

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-forbindelse)piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 323.

1H-NMR (400 MHz, DMSO-d6) δ 1,70-of 1.85 (2H, m), 1,90-of 2.05 (2H, m), 2.77-to of 3.00 (2H, m), 3,05-3,20 (2H, m), 3,60-3,70 (1H, m)to 3.92 (2H, s), of 4.54 (2H, s), 7,14-7,22 (2H, m), 7,31-7,38 (1H, m), 7,45 (1H, dt, J=7,6, 2.0 Hz), 7,73 (1H, d, J=3.2 Hz), 7,74 (1H, d, J=2,8 Hz).

Example 362

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-methoxyphenoxy)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,38-of 1.52 (2H, m), 1.85 to a 2.00 (3H, m), of 2.15 (2H, m), 2,98 (2H, sird, J=11,6 Hz), 3,50 (2N), 3,86 (3H, s), 3,88 (2H, s), 6,33 (1H, d, J=6.8 Hz), 6,86-6,94 (4H, m), of 7.36 (1H, sird, J=6,0, 1.2 Hz), EUR 7.57 (1H, sird, J=6.0 Hz).

Example 363

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)pheno is simetal]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 285.

1H-NMR (400 MHz, CDCl3) δ 1,00-of 1.36 (5H, m), 1.41 to and 1.54 (2H, m), 1,65 is 2.00 (7H, m), 2,16-of 2.26 (2H, m), 2,99 (2H, sird, J=11,6 Hz)to 3.58 (2H, s), of 3.78 (2H, d, J=6.0 Hz), 3,85 (2H, d, J=6.0 Hz), 6,86-6,94 (4H, m), 7,39 (1H, d, J=2,4 Hz), 7,80 (1H, Sirs).

Example 364

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(cyclohexylmethoxy)phenoxymethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,98 by 1.12 (2H, m), 1,12-of 1.30 (3H, m), 1,46-of 1.84 (8H, m), 1,88-of 2.08 (3H, m), of 3.12 (2H, m)to 3.33 (2H, m in), 3.75 (2H, d, J=6.4 Hz), 3,83 (2H, m)to 3.99 (2H, m), 6,30 (1H, t, J=6.8 Hz), 6,82-6,91 (2H, m,), 6,92-7,00 (2H, m), 7,52 (1H, sird, J=5,2 Hz), 7,68 (1H, sird, J=6,4 Hz).

Example 365

Oxalate of 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[[2-(cyclohexylethyl)phenoxy]methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 302.

1H-NMR (400 MHz, DMSO-d6) δ 0,84-to 0.96 (2H, m), 1,06-of 1.27 (4H, m), 1,35 was 1.43 (2H, m), 1,50-to 1.77 (7H, m), 1,86 is 1.96 (2H, m), from 2.00 (1H, m), 2,55-of 2.58 (2H, m), is 2.88 (2H, m), 3.04 from (2H, m), 3,83 (2H, m), of 3.95 (2H, s), of 6.29 (1H, t, J=6.8 Hz), at 6.84 (1H, dt, J=7,6, 0.8 Hz), 6,91 (1H, d, J=7,6 Hz), 7,08-7,16 (2H, m)to 7.50 (1H, sird, J=5,2 Hz), 7,66 (1H, sird, J=4,8 Hz).

Example 366

Oxalate of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl-4-[2-(benzyloxy)phenoxymethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 349.

1H-NMR (400 MHz, DMSO-d6) δ 1,40-of 1.65 (2H, m), 1,86 is 1.96 (2H, m), 2,02 (1H, m), 2,85-2,96 (2H, m), 3,26-to 3.36 (2H, m), 3,88 (2H, d, J=6.4 Hz), of 3.97 (2H, s), 5,10 (2H, s), of 6.29 (1H, t, J=6.4 Hz), 6,84-6,93 (2H, m), 6,97-7,06 (2N, m), 7,28-7,47 (5H, m), 7,51 (1H, DD, J=6,4, 2.0 Hz), to 7.67 (1H, DD, J=6,8, 2.0 Hz).

Example 367

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-pertenece)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,24-to 1.38 (2H, m), 1,72 (3H, sird, J=10 Hz)to 1.98 (2H, shirt, J=10,8 Hz), and 2.83 (2H, sird, J=11.2 Hz)at 3.25 (2H, s), 3,88 (2H, d, J=5.6 Hz), x 6.15 (1H, t, J=6.4 Hz), 6,86-6,94 (1H, m),? 7.04 baby mortality-7,20 (3H, m), 7.24 to (1H, d, J=6.4 Hz), 7,37 (1H, d, J=6.8 Hz), 11,50 (1H, s).

Example 368

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-pertenece)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,24-of 1.40 (2H, m), 1,74 (3H, sird, J=9.6 Hz), a 2.01 (2H, shirt, J=10,8 Hz), 2,82 (2H, sird, J=10,8 Hz), with 3.27 (2H, s), 3,86 (2H, d, J=6.0 Hz), 6,86-6,93 (1H, m), 7,05-7,20 (3H, m), of 7.36 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=3.2 Hz).

Example 369

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,4-divergence)methyl]piperidine

Specified in the header connection receive from the relevant source material way, described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,22-to 1.38 (2H, m), 1,71 (3H, sird, J=10,8 Hz), a 1.96 (2H, shirt, J=10,8 Hz), 2,82 (2H, sird, J=11.2 Hz), 3,23 (2H, s), 3,86 (2H, d, J=5.6 Hz), x 6.15 (1H, t, J=6.4 Hz), 6,93-7,02 (1H, m), 7,12-7,20 (1H, m), 7,20-7,28 (1H, m), of 7.36 (1H, DD, J=6,4, 1.2 Hz), 11,41 (1H, s).

Example 370

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,4-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,24-to 1.38 (2H, m), 1,72 (3H, sird, J=10.4 Hz), a 2.01 (2H, shirt, J=10.4 Hz), 2,82 (2H, sird, J=11,6 Hz), with 3.27 (2H, s), a 3.87 (2H, d, J=6.0 Hz), 6,93-7,01 (1H, m), 7,13-7,21 (1H, m), 7,21-7,28 (1H, m), of 7.36 (1H, d, J=2,8 Hz), to 7.50 (1H, d, J=2,8 Hz).

Example 371

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,5-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,20-to 1.38 (2H, m), 1,65 of-1.83 (1H, m), 1,71 (2H, sird, J=10,8 Hz)of 1.97 (2H, shirt, J=11.2 Hz), 2,82 (2H, sird, J=11.2 Hz), 3,24 (2H, s), 3,90 (2H, d, J=6.0 Hz), x 6.15 (1H, t, J=6.4 Hz), 6,68-6,76 (1H, m), 7,06-7,14 (1H, m), 7,17-7,28 (2H, m), of 7.36 (1H, DD, J=6,4, 1.2 Hz), 11,51 (1H, m).

Example 372

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,5-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in the ore 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,24-of 1.39 (2H, m), 1,67 and 1.80 (1H, m)of 1.73 (2H, sird, J=11.2 Hz), 1,95-of 2.08 (2H, m), 2,82 (2H, sird, J=11.2 Hz), with 3.27 (2H, s), 3,91 (2H, d, J=6.0 Hz), 6,68-6,76 (1H, m), 7,06-7,13 (1H, m), 7.18 in-7,26 (1H, m,), was 7.36 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=2,8 Hz).

Example 373

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,6-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,20-to 1.38 (2H, m), 1,60-1,80 (1H, m), 1,72 (2H, sird, J=12,4 Hz), a 1.96 (2H, shirt, J=11.2 Hz), of 2.81 (2H, sird, J=11.2 Hz), 3,23 (2H, s), 3,93 (2H, d, J=6.0 Hz), x 6.15 (1H, t, J=6.8 Hz),? 7.04 baby mortality-to 7.18 (3H, m), 7.23 percent (1H, d, J=6,4 Hz) of 7.36 (1H, d, J=6.4 Hz), 11,49 (1H, s).

Example 374

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,6-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,22-to 1.38 (2H, m), 1,60-1,80 (1H, m)of 1.73 (2H, sird, J=12,8 Hz), 1,95-of 2.05 (2H, m), of 2.81 (2H, sird, J=11.2 Hz), 3,26 (2H, s), of 3.94 (2H, d, J=6.0 Hz),? 7.04 baby mortality-7,16 (3H, m), 7,35 (1H, d, J=2.0 Hz), to 7.50 (1H, d, J=2,8 Hz).

Example 375

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-methoxyphenoxy)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,22-of 1.36 (2H, m), 1,66 of 1.8 (3H, m), a 2.01 (2H, shirt, J=10.4 Hz), 2,82 (2H, sird, J=11,6 Hz), with 3.27 (2H, s), and 3.72 (3H, s), of 3.78 (2H, d, J=6.0 Hz), 6,80-to 6.88 (2H, m), 6,88-to 6.95 (2H, m), of 7.36 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=3.2 Hz).

Example 376

1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-chlorophenoxy)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,26-of 1.40 (2H, m), 1,74 (3H, sird, J=10,8 Hz)to 1.98 (2H, shirt, J=11.2 Hz), and 2.83 (2H, sird, J=11.2 Hz), 3,24 (2H, s)to 3.89 (2H, d, J=5.6 Hz), 6,16 (1H, t, J=6.8 Hz), 6,91 (1H, t, J=7,6 Hz), 7,11 (1H, d, J=8.0 Hz), 7,20-7,30 (2H, m), 7,34-7,41 (2H, m), and 11.5 (1H, Shir. C).

Example 377

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2-chloro-6-pertenece)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,22-of 1.36 (2H, m), 1,58-of 1.73 (1H, m), 1,74 (2H, sird, J=12 Hz), 1,94-2,04 (2H, m), 2,80 (2H, sird, J=11,6 Hz), 3,26 (2H, s), with 3.79 (3H, s), with 3.79 (2H, d, J=6.0 Hz), to 6.80 (1H, t, J=9.6 Hz), 6,85 (1H, d, J=7,6 Hz), of 6.96-7,05 (2H, m), of 7.36 (1H, d, J=2.0 Hz), to 7.50 (1H, d, J=2,8 Hz).

Example 378

1-[(5-Chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(2,3-divergence)methyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 318.

1H-NMR (400 MHz, DMSO-d6) δ 1,26-to 1.38 (2H, m)of 1.73 (3H, sird, J=12,8 Hz), 1,96 is 2.10 (2H, m), and 2.83 (2H, IRD, J=11,6 Hz), or 3.28 (2H, s), 3,93 (2H, d, J=6.4 Hz), 6.90 to? 7.04 baby mortality (2H, m), 7,06-7,14 (1H, m), of 7.36 (1H, d, J=2,8 Hz), 7,51 (1H, d, J=2,4 Hz).

Example 379

1-[(4-Oxo-1,4-dihydro-3-pyridinyl)methyl]-4-[2-[(2,3-(methylenedioxy)phenyl]methyl]piperidine

259 mg of 1-[(4-methoxy-3-pyridinyl)methyl]-4-[2-(2-were)ethyl]piperidine was dissolved in 5 ml of ethanol. To this mixture at 1.91 ml of 4 n solution of hydrochloric acid in methanol and then refluxed overnight. The solvent is evaporated and to the residue add 2 N. hydrochloric acid (15 ml)and then refluxed for another 7 hours. To the reaction solution was added an aqueous solution of sodium carbonate and the mixture extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated. The crude product is purified column chromatography on NH-silica gel (n-hexane:ethyl acetate=2:1) to give 42 mg specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3) δ 1,24-of 1.44 (3H, m), 1.56 to of 1.64 (2H, m), 1,78-of 1.88 (2H, m), 2,10-of 2.20 (2H, m), 2,56-of 2.64 (2H, m)of 3.00 (2H, sird, J=11,6 Hz), to 3.73 (2H, s), to 5.93 (2H, s), only 6.64 (1H, DD, J=7,6, and 1.6 Hz), 6,69 (1H, DD, J=7,6, 1,6 Hz), 6,69 (1H, d, J=5.6 Hz), 6,76 (1H, t, J=7,6 Hz), 8,10 (1H, s), of 8.25 (1H, d, J=5.6 Hz).

Example 380

1-[(2-Oxo-3,4-dihydro-3-chinoline)methyl]-4-[2-[(2,3-(methylenedioxy)phenyl]ethyl]piperidine

In 50 ml of tetrahydrofuran is dissolved 0.24 g of 2-oxo-3,4-dihydro-3-chinainternational and 0.3 g of 4-[2-[2,3-(methylenedi the si)phenyl]ethyl]piperidine. To the mixture is added 0.5 ml of acetic acid and 0.42 g of triacetoxyborohydride sodium, and then stirred at room temperature for 12 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, and the mixture is then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting solid is collected by filtration Poluchenie 130 mg specified in the title compound as a light brown solid.

1H-NMR (400 MHz, DMSO-d6) δ 1,18 of 1.28 (3H, m), 1,68 (2H, sird, J=7,6 Hz), 1,90-2,00 (2H, m), 2,53 (2H, shirt, J=8.0 Hz), 2,84 (2H, sird, J=10.0 Hz), 3,30 (2H, s), 5,95 (2H, s), 6,66-6,77 (3H, m), 7,14 (1H, t, J=7,6 Hz), 7,27 (1H, d, J=7,6 Hz), the 7.43 (1H, t, J=7,6 Hz), 7,66 (1H, d, J=7,6 Hz), 7,80 (1H, s), 11,74 (1H, s).

Example 381

Oxalate of 1-[(2-oxo-3,4-dihydro-3-chinoline)methyl]-4-[2-(3-(phenylphenyl)ethyl]piperidine

Specified in the title compound is obtained from the corresponding starting material in the manner described in example 349.

1H-NMR (400 MHz, DMSO-d6) δ 1,30-1,70 (5H, m)to 1.86 (2H, sird, J=10,8 Hz), 2,54 was 2.76 (2H, m), is 2.88 (2H, Sirs), to 3.33 (2H, sird, J=10,8 Hz), 4,07 (2H, s), 7,14-7,26 (2H, m), 7,30-7,40 (3H, m), 7,40-to 7.50 (4H, m), 7,55 (1H, t, J=7,6 Hz), 7,60-of 7.70 (3H, m)to 8.14 (1H, s).

Example test 1. Effect of termination and prevention of fibre the ablation fibrillation (AF) in dogs, subjected to thoracotomy in anesthesia.

(1) In this experiment, they used dogs subjected to thoracotomy during anaesthesia. After opening the sternum along the line of the median plane and cutting the epicardium into the free wall of the right and left Atria, respectively sewn bipolar electrodes for determining the waveform of the potential. In addition, in the free wall of the right atrium was introduced wire electrode for fixing and electrical stimulation. After cutting the neck line of the median plane of the exposed right and left wandering nerves. Wire electrodes for stimulation of the vagi were inserted along the surface layers with the respective both sides of the fixing and used for stimulation of the vagi.

(2) electrical Stimulation was carried out under the following conditions: amplitude of stimulation was 0.1 MS (mass microseconds); the stimulation frequency was 20 Hz, and the stimulation intensity ranged from 3 to 7 C. 5 minutes after the beginning of stimulation of the right atrium were subjected to stimulation with high frequency (10 Hz, 1 sec), and efforts were made to induce atrial fibrillation (hereinafter referred to as AF). The intensity of high-frequency stimulation of the right atrium was performed, starting with 1.0, and if the OP was not induced, it tried induzione the ü by increasing the intensity of stimulation to 5.0 Century After induction of AF were observed for 30 minutes, which confirmed the presence of AF (control experiment). If induced AF was not maintained for 30 minutes, the experiment was stopped.

(3) After confirming that the OP is maintained for 30 minutes or more in the control experiment, stimulation of the vagus nerve broke and the dog was left for one hour for recovery. Then again induced AF in the same way. In addition, stimulation of the vagus nerve at this stage was carried out at a higher intensity of stimulation, about 2 higher than in the control experiment. 5 minutes after induction of AF were administered the test substance. The specified test substance was injected in a vein within 5 minutes. After injection were observed for 5 minutes, and if there was no termination of AF, the dose was increased and held similar observations. If the OP stopped, then immediately after stopping again attempted to induce AF. At this stage, if the OP that lasted for a minute or more, were induced again, it testified to the fact that the warning effect is absent, and the experiment was carried out similarly with increased dose.

(4) the Result (see table 1): 1/3 samples prodemos who has demonstrated the effect of termination of atrial dose of 0.3 mg/kg For one sample also confirmed the effect of prevention of atrial at the same dose. For two samples, for which the effect of the termination of fibrillation has not been confirmed at the dose of 0.3 mg/kg, were tested with the increased dose to 1 mg/kg as a result, the effect of termination has been confirmed for 2/2 samples, and confirmed the effect warnings.

Table 1
Example No.DoseEffect of terminationEffects warnings
1350.3 mg/kg1/31/1
1 mg/kg2/22/2

In this table the number in the denominator represents the number of samples used in this test, and the number in the numerator represents the number of samples in which this effect was confirmed.

Example of test 2. The effective refractory period (ETA) in dogs subjected to thoracotomy in anesthesia.

(1) In this experiment, they used dogs subjected to thoracotomy during anaesthesia. After opening the sternum along the line of the median plane and cutting the epicardium into the free wall of the right and left Atria, respectively sewn bipolar electrodes for determining the waveform of the potential. To the ome, free fixed wall of the right ventricle was injected wire electrode for fixing and electrical stimulation.

(2) the Device software for electrical stimulation was connected to the electrode for electrical stimulation in the right atrium, then carried out periodic electrical stimulation with a duration of 500 MS and measured the threshold of electrical stimulation. To implement the stimulation intensity electrical stimulation for these experiments was set at a value that is 3 times higher than this threshold. However, if this threshold was 0.7 or less, the electrical stimulation was performed at 2.0 Century. the Effective refractory period (ETA) provided early premature stimulation (S2) after primary stimulation (S1)conducted 10 times, and the longest period of pairing, in which the potential of the Atria is not generated premature stimulation, called ETA, when the shortening of the period of the pair (S1-S2) to 5 MS. Similar experiments were also performed for the duration of the main stimulation (BCL) 400, 300, 250 and 200 MS (control experiment: 1 series). After making 2 or several control experiments and confirm that the ETA is stable, has introduced the test substance and have the same dimensions. The ZAT is, after a single injection in a vein of the test substance for 5 minutes, in the vein did the maintenance dose. 10 minutes after the beginning of the introduction of the maintenance dose was measured ETA when the frequency of stimulation. After one series of measurements of the concentration of the test substance was increased and the same experiments were repeated. ETA and time of conduction in the atrium when the frequency of stimulation was compared with the different values obtained in control conditions. The results are presented as average values.

(3) Result: the connection of the present invention or its salt or hydrate able to effectively halt or prevent atrial fibrillation and gives an excellent effect of lengthening the effective refractory period of the muscle of the Atria (see tables 2 and 3).

(1) measurement of the value of ETA (MS)

(2) the Coefficient of variation (d%) ETA

Example of test 3. Analysis on sodium channels synaptosome cortex of the rat.

In the present experiment used synaptosome, which was extracted from cerebral cortex of the rat. After you enable injusticeinla dye SBFI, synaptosome was subjected to reaction with the appropriate test substances (3 sample 6 to the ncentrated) at room temperature for 15 minutes in a 96-well pad. Activity inhibition of sodium was measured using devices FDSS2000 from HAMAMATSU Photonics Co., Ltd. The concentration of sodium ions in synaptosomes was measured every 5 seconds using the fluorescence intensity of SBFI as an indicator. After a 10-fold measurement control value added veratridine to a final concentration of 20 μm, after which a measurement was performed 30 times. Then calculate the magnitude of the inhibitory activity of the tested substance in relation to the sodium channel, where the action is only one solution containing no test substance was taken for 0%and inhibitory activity induced by 2 μm TTX, which was used as a positive control, taken as 100%, and where the magnitude of the inhibitory activity corresponding to this action, was measured using an indicator of increasing intensity SBFI fluorescence relative to the control value, which was obtained after adding veratridine. In the result, it was found that the compound of the present invention has excellent action, aimed at the inhibition of sodium channels, as shown in table 4 (the value of SBFI (IC50μm)).

Example of test 4. Analysis of Vmax for the muscles of the Atria of the rabbit.

In the present experiment used a sample of the muscles of the right ventricle the roller, which was subjected to enucleation. Electrical stimulation was carried out for enableireland.ie muscles of the right ventricle under the following conditions: amplitude of stimulation was 1 MS, the stimulation frequency was 4 Hz, and the stimulation intensity was approximately 1.2 times above the threshold. Before the experiment was performed stimulation for 30 - 60 minutes, and the condition of the sample was stabilized. The action potential was detected using thin glass electrode. The glass electrode was loaded with 3 M KCl, was introduced into the sample right atrium and recorded action potential. Vmax is a parameter indicating the maximum increase in the rate of recorded action potential, when it was used the value that was automatically calculated using the program for the analysis of action potential (program SARAH 1.23 developed Physiotec.Co., Ltd.). After registration of the action potential in normal solution Tyrode used as a control, we recorded action potential after continuous injection within 15 minutes of the test substances in relevant concentrations. The effect of a test substance on the Vmax was calculated as the value of the IC50. The result, presented in table 4 (Vmax (IC50μm), has confirmed that the connection of this image is to be placed has a great effect on Vmax.

Example of test 5. Suppression of spontaneous excitation of nerve.

To assess suppressor action on spontaneous nerve stimulation experiment was carried out following the method described in "Burchiel, K.J., Exp. Nuerol., 102, 249-253 (1988)". Namely, for rats that experienced spontaneous excitation, one week before the experiment or more cut left saphenous nerve near the synovial joints of the knee and about 3 mm of the nerve is cut so that the nerve again joined. The left saphenous nerve was treated under anesthesia with urethane (1 g/kg body weight) and about 1 cm adjacent region of the cut part was separated from peripheral tissues. In addition, in the vein of the right side of the neck previously inserted catheter for insertion of the connection. Separated nerve was connected to a platinum hook-like electrode, and it was applied by spraying liquid paraffin to prevent drying of the nerve. This electrode was connected to the amplifier for thin electrodes and magnitude were recorded on a computer through an analog-to-digital (AC) Converter with an oscilloscope. Registered nerve stimulation were analyzed by the number of excitations for 10 seconds using analytical software (AcqKnowledge). The result, presented in table 4 (ectopic excitation (IC50(mg/kg), showed that the connection N. the present invention has excellent suppressor effect on spontaneous excitation of nerve.

Table 4
Example No.Example test 3

SBFI (IC50microns)
Example test 4

Vmax(IC50microns)
Example test 5

Ectopic excitation (IC50, MK/kg)
2857,72,90,13
29114,560,1
2995,3500,1
3016,51000,18
3021,222,50,14
3061,31,90,17
3080,53,10,22
30916,30,19
3110,720,13
3131,58,60,16
31910,2100,082
3201714,80,041
3234,8a 3.90,083

Example No.P the emer test 3 SBFI (IC 50microns)Example test Vmax(IC50microns)Example test 5 Ectopic excitation (IC50, MK/kg)
3261,93,980,18
333of 5.4a 4.90,15
334-of 17.50,03
335-7,80,034
337--0,3
3381,211,40,19
343-300,13
344-300,19
345--0,4
349--0,17
351--0,17
37033,645of 0.081
37221,89,30,11
37620,3-0,07
380a 3.98,60,1
38131000,56

1. Derivatives of piperidine, presents forms the Loy (I), its salt or hydrate

moreover, in the formula, the ring a represents ring represented by the formula

or

where R1means (1) a hydrogen atom, (2) halogen atom, (3) cyano, (4) optionally substituted C1-6alkyl group, (5) optionally substituted C2-6alkenylphenol group, (6) optionally substituted C2-6alkylamino group, (7) optionally substituted C3-8cycloalkyl group, (8) optionally substituted C3-8cycloalkenyl group, (9) optionally substituted C1-6alkoxygroup, (10) optionally substituted C1-6allylthiourea, (11) optionally substituted C1-6alkylsulfonyl group, (12) optionally substituted C1-6alkylsulfonyl group, (13) optionally substituted C6-14aromatic hydrocarbon cyclic group or (14) optionally substituted 5 to 14-membered aromatic heterocyclic group;

R2represents (1) hydrogen atom, (2) optionally substituted C1-6alkyl group, (3) optionally substituted C2-6alkenylphenol group, (4) optionally substituted C2-6alkylamino g is the SCP, (5) optionally substituted C3-8cycloalkyl group, (6) optionally substituted C3-8cycloalkenyl group, (7) optionally substituted by an amino group, (8) optionally substituted C6-14aromatic hydrocarbon cyclic group or (9) optionally substituted 5 to 14-membered aromatic heterocyclic group; and

R3represents (1) optionally substituted C1-6alkoxygroup, (2) optionally substituted C2-6alkenylacyl, (3) optionally substituted C3-7cycloalkylation or (4) optionally substituted C3-7cycloalkanones;

W represents (1) a simple link, (2) optionally substituted C1-6alkylenes group, (3) optionally substituted C2-6alkynylamino group, (4) optionally substituted C2-6alkynylamino group or (5) a group represented by the formula-U-V-, where U means (i) a simple link, (ii) an oxygen atom, (iii) a sulfur atom, (iv) a group represented by the formula-NH-, (v) optionally substituted C1-6alkylenes group, (vi) optionally substituted C2-6alkenylamine group or (vii) optionally substituted C2-6alkynylamino group; V means (i) a simple link, (ii) optionally substituted C1-6alkylenes group, (iii) optionally substituted C2-6alkenylamine group (iv) optionally substituted C 2-6alkynylamino group, (v) an oxygen atom, (vi) a sulfur atom or (vii) a group represented by the formula-CO-, (viii) -SO - or (ix) -SO2-, provided that excluded the case where U and V represent the same group in the above definition, and one of U and V represents a simple bond, optionally substituted C1-6alkylenes group, optionally substituted C2-6alkenylamine group or optionally substituted C2-6alkynylamino group;

Z represents (1) optionally substituted C6-14aromatic hydrocarbon cyclic group, (2) optionally substituted 5 to 14-membered aromatic heterocyclic group or (3) a group represented by formula-N(R4R5(where R4and R5may be the same or different and each represents (i) hydrogen atom, (ii) optionally substituted C1-6alkyl group, (iii) optionally substituted C2-6alkenylphenol group, (iv) optionally substituted C2-6alkylamino group, (v) optionally substituted C3-8cycloalkyl group, (vi) optionally substituted C3-8cycloalkenyl group, (vii) optionally substituted C6-14aromatic hydrocarbon cyclic group, (viii) optionally substituted 5 to 14-membered aromatic heterocyclic group or (ix)1-6aliphatic will stifle acyl group, either (x) R4and R5can be linked together with the formation of a 3-8-membered nitrogen-containing cyclic group; and

l is an integer from 0 to 6.

2. The compound according to claim 1, its salt or hydrate, where W represents a group represented by the formula-CH2-, -CH2-CH2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH -,- ≡ -,- CO-, -O-, -O-CH2-, -CH2-O-, -CH2-CO-, -(CH2)2-CO-, -CH2- CH(CN)-, -CH2-CH(OH)-, -SO2-, -CH2-SO2-, -NH-CO-, -CH2-NH-CO-, -NH-SO2- or-CH2-NH-SO2-.

3. The compound according to claim 1, its salt or hydrate, where W represents a group represented by the formula-CH2-CH2-, -CH=CH -,- ≡C - or-CH2-O-.

4. The compound according to claim 1, its salt or hydrate, where Z represents optionally substituted C6-14aromatic hydrocarbon cyclic group or optionally substituted 5 to 14-membered aromatic heterocyclic group.

5. The compound according to claim 1, its salt or hydrate, where Z is optionally substituted phenyl group, pyridyloxy group or thienyl group.

6. The compound according to claim 1, its salt or hydrate, where Z represents C6-14aromatic hydrocarbon cyclic group or a 5 to 14-membered aromatic heterocyclic group, and the ring may be, but the but substituted by one or more groups selected from (1) hydroxyl group, (2) halogen atom, (3) ceanography, (4) optionally substituted C1-6alkyl group, (5) optionally substituted C3-8cycloalkyl group, (6) optionally substituted C1-6alkoxygroup, (7) optionally substituted C3-8cycloalkylcarbonyl, (8) optionally substituted C1-6allylthiourea, (9) optionally substituted C6-14alloctype, (10) optionally substituted 5 to 14-membered heterokaryosis, (11) optionally substituted amino group, (12) optionally substituted 5 to 14-membered aromatic heterocyclic group, (13) optionally substituted 5 to 14-membered non-aromatic heterocyclic group, (14)1-6alkylsulfonyl group and (15)1-4alkylenedioxy.

7. The compound according to claim 1, its salt or hydrate, where Z represents a group represented by formula-N(R4R5(where R4and R5have the meanings defined above, respectively).

8. The connection according to claim 7, its salt or hydrate, where R4and R5are the same or different and each represents a hydrogen atom, optionally substituted C1-6alkyl group, optionally substituted C2-6alkylamino group, optionally substituted C6-14aryl-C1-6alkyl which the group or optionally substituted heteroaryl-C 1-6alkyl group.

9. The connection according to claim 7, its salt or hydrate, where R4and R5taken together, form an optionally substituted 3-8-membered nitrogen-containing cyclic group.

10. The connection according to claim 9, its salt or hydrate, where Z represents optionally substituted piperidino group, optionally substituted piperazino group or optionally substituted morpholinyl group.

11. The compound according to claim 1, its salt or hydrate, where l is equal to 1.

12. The compound according to claim 1, its salt or hydrate, where the ring And represented by the formula

where R1and R2have the meanings defined above, respectively.

13. The connection section 12, its salt or hydrate, where R1represents a hydrogen atom, a halogen atom or With1-6alkyl group.

14. The connection section 12, its salt or hydrate, where R1represents a hydrogen atom.

15. The connection section 12, its salt or hydrate, where R2represents a hydrogen atom or optionally substituted C1-6alkyl group.

16. The compound according to claim 1, its salt or hydrate, where the specified ring And represented by the formula

where R1and R3has the values defined above, respectively.

17. The compound according to claim 1, its salt or hydrate, where R3is hydroximino group or 1-6alkoxygroup.

18. The compound according to claim 1, its salt or hydrate, where the position of joining the group-W-Z is 2 - or 4-position piperidino rings.

19. The compound according to claim 1, its salt or hydrate, which is represented by the formula

where R1, R2, W, Z and l have the same values that were defined in the above item 1.

20. The compound according to claim 1, its salt or hydrate, which is represented by the formula

where R1W and Z are the same values that were defined in claim 1 above, respectively, a la represents the integer 1 or 2.

21. The compound of formula I according to claim 1, selected from the following compounds:

1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(yclohexanol)phenyl]ethyl]piperidine,

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine,

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(forfinal]ethyl]piperidine,

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-[2-(isobutyryloxy)phenyl]ethyl]piperidine,

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine,

1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-(2-forfinal)-1-ethynyl]piperidine,

1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[2-(b is siloxy)phenyl]-1-ethynyl]piperidine,

1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine,

1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(Z)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine,

1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[(E)-2-[(2-cyclohexylmethoxy)phenyl]-1-ethynyl]piperidine,

1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-cyclohexylmethoxy)phenyl]-1-ethinyl]piperidine,

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,4-(divergence)methyl]piperidine or

1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2,5-(divergence)methyl]piperidine, salt or hydrate.

22. The compound according to claim 1, its salt or hydrate suitable for receiving means having a activity by inhibition of sodium channels or inhibition of potassium channels, means capable of effective termination of the refractory period of the muscle of the Atria, means having a suppressor effect on spontaneous neural discharge.

23. A method of obtaining a compound according to claim 1, its salt or hydrate by condensation piperidinol derivative represented by the formula

where W and Z have the meanings defined above in claim 1, respectively, with the pyridine derivative represented by the formula

where ring a and l have the same values that were defined above in claim 1, respectively, a L is a leaving group;

its salt or reactive derivative in a solvent by the method of reductive amination or by condensation in the presence of a base.

24. Pharmaceutical composition having activity by inhibition of sodium channels or inhibition of potassium channels containing the compound of formula (I), its salt or hydrate.

25. Method of inhibiting sodium channels or potassium channels by introducing the patient a pharmacologically effective amount of the compounds of formula 1 according to claim 1, its salt or hydrate.

26. The method according A.25 suitable for suppression of spontaneous neural discharge.



 

Same patents:

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, chemical technology, explosive substances.

SUBSTANCE: invention relates to a method for preparing 4,4'-bis-[4-aminofurazan-3-yl-N(O)N-azoxy]-3,3'-azofurazane of the general formula (1):

that is a new thermostable explosive substance with improved exploitation indices. Method for preparing compound of the formula (1) involves treatment of 4,4'-diaminoazoxyfurazane with potassium bromate solution (KBrO3) in hydrochloric acid medium or its mixture with organic acid. Proposed compound can be used as a component of explosive compositions, solid rocket fuels and power-consuming compositions of different designations exploited at elevated temperatures (for example, in blast-hole drilling in depth mines).

EFFECT: improved preparing method, valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

Up!