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    • 专利摘要:
    The present invention provides novel compounds having excellent Na + channel inhibitory activity. That is, the compound or its salt, or its hydrate represented by following formula (I) is provided. (I) In the formula, ring A is A ring or the like represented by (R 1 represents a hydrogen atom or the like; R 2 represents a hydrogen atom or the like); W represents a C 1-6 alkylene group etc. which may be substituted; Z represents a C 6-14 aromatic hydrocarbon ring group which may be substituted; l represents the integer of 0-6.
    公开号:KR20020080378A
    申请号:KR1020027009265
    申请日:2001-01-18
    公开日:2002-10-23
    发明作者:후미히로 오자키；도시히코 가네코；무쓰코 다바타；요시노리 다카하시；가즈키 미야자키；준이치 가마타；이치로 요시다；마사유키 마쓰쿠라；히로유키 스즈키；다카시 요시나가；히로키 이시하라；히로시 가토；고헤이 사와다；다쓰히로 오노기；기요아키 고바야시；미유키 오쿠보
    申请人:에자이 가부시키가이샤；
    IPC主号:
    专利说明:

    New Piperidine Compounds and Their Medicines {NOVEL PIPERIDINE COMPOUNDS AND DRUGS CONTAINING THE SAME}
    [2] Atrial fibrillation, which is one of the arrhythmias, is classified into paroxysmal atrial fibrillation and chronic atrial fibrillation, in which the atrium does not perform regular contraction of excitability in response to the stimulation from the freezing node, and often repeats the excitement disorderly. In most cases, isolated atrial fibrillation, which manifests itself as a complication of organic cardiac diseases such as mitral valve disease, ischemic heart disease, hypertensive heart disease, hyperthyroidism (also referred to as quadriplegic disease), has been reported. In addition, in addition to palpitation, palpitation, and chest discomfort, there are not many heart failure states, and a thrombus is formed in the left atrium, which causes thromboembolism in various organs throughout the body. Treatment of atrial fibrillation (seizure arrest, prevention of recurrence, etc.) cannot be said to be effective for non-drug treatments due to seizure atrial fibrillation and chronic atrial fibrillation. It is. Vaughan Williams Class I drugs (Class I: drugs that inhibit the regression circuit by inhibiting conduction in the atrial muscle by selective blocking of Na + channels), and Class II drugs (Class II: β adrenergic receptor blockers Antiarrhythmic drugs, such as this group III drug (Class III: drugs that selectively block K + channels to prolong the action potential duration), and this class IV drug (Class IV: Ca + channel blockers). Although it is known, a drug that inhibits the regression circuit of intracardiac potential is effective for stopping atrial fibrillation, and antiarrhythmic drugs of group I and antiarrhythmic drugs of group III are considered to be effective. A large number of reports have been made regarding this type of antiarrhythmic medicine, for example, Japanese Patent Application Laid-Open No. 9-505597, Japanese Patent Application Laid-Open No. 8-511014, and International Publication No. WO96 / 13479. In addition to the disclosed antiarrhythmic drugs, Japanese Patent Application Laid-Open No. 62-281858, Japanese Patent Laid-Open No. 6-501242, Japanese Patent Laid-Open Publication No. 7-502273, Japanese Patent Laid-Open Publication No. 8-511014, etc. An invention relating to ferridine derivatives is disclosed.
    [3] However, antiarrhythmic drugs of group I have a negative metabolic action (decrease in the pump function of the heart) due to Na + channel inhibitory activity, and thus have a problem of worsening or aggravating heart failure. On the other hand, although group III antiarrhythmic drugs are excellent in extending only refractory without exhibiting such an effect, the conventional group III antiarrhythmic drugs are not necessarily effective in atrial fibrillation arrest rate, and the ventricle Muscle infertility was also prolonged, and in many cases, the infertility of ventricular muscles was strongly extended (reverse frequency dependence) at normal time than in tachycardia, and causing a ventricular arrhythmias at doses showing drug efficacy.
    [4] On the other hand, compounds having Na + channel inhibitory activity are also known to be useful for the treatment of various neuralgias (for example, post-herpetic neuralgia, diabetic neuralgia, HIV neuralgia, etc.). For example, Lidoderm in the treatment of post-herpetic neuralgia, Carbamazepine in trigeminal neuralgia, Na + channel inhibitors (eg, Mexiletin, etc.) as antiarrhythmic drugs, Na as an antidepressant or anticonvulsant etc. + channel inhibitor (e.g. Amitriptyline, Carbamazepine, etc.), are already used as neuralgia various drugs. In addition, there have been several reports on the effectiveness of arrhythmia (Mexiletine, Lidocaine) as an analgesic (Pain. 83 (1999) 389-400; European Journal of Pain. 2 (1998) 3-14; Pain. 73 (1997) 123-139).
    [5] However, in the conventional neuralgia therapeutic drug, since the actions of the conventional Na + channel inhibitors on the heart and nerves are equivalent, it is not possible to increase the dose of the Na + channel inhibitory compounds and could not exhibit a clear analgesic effect.
    [6] Drugs that exhibit excellent Na + channel inhibitory action, satisfy pharmacological activity, dosage, safety, and the like as drugs, and are effective in clinical practice, have not yet been found. Accordingly, an object of the present invention is to provide an excellent Na + channel inhibitory compound that satisfies the above problem.
    [1] The present invention relates to a pharmaceutical composition comprising the new piperidine derivatives and salts thereof, these hydrates, their preparation methods, these compounds and the like, and the pharmaceuticals thereof.
    [7] The present inventors have made diligent research in view of the above object, and as a result, a whole new piperidine derivative (I)
    [8] (I)
    [9] [Wherein, ring A is a formula
    [10]
    [11]
    [12] (In the formula,
    [13] R 1 represents (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted, (5) a C 2-6 alkenyl group which may be substituted, (6) substituted C 2-6 alkynyl group, (7) substituted C 3-8 cycloalkyl group, (8) substituted C 3-8 cycloalkenyl group, (9) substituted It could be C 1-6 alkoxy group, (10) a C 1-6 alkyl which may be substituted, (11) which may be substituted with C 1-6 alkylsulfinyl group, (12) may be substituted A C 1-6 alkylsulfonyl group, (13) a substituted C 6-14 aromatic hydrocarbon ring group, or (14) a substituted 5 to 14 membered aromatic heterocyclic group;
    [14] R 2 is (1) hydrogen atom, (2) C 1-6 alkyl group which may be substituted, (3) C 2-6 alkenyl group which may be substituted, (4) C 2-6 which may be substituted Alkynyl groups, (5) substituted C 3-8 cycloalkyl groups, (6) substituted C 3-8 cycloalkenyl groups, (7) substituted amino groups, (8) substituted A C 6-14 aromatic hydrocarbon ring group which may be substituted, or (9) a 5 to 14 membered aromatic heterocyclic group which may be substituted;
    [15] R 3 is (1) a substituted C 1-6 alkoxy group, (2) a substituted C 2-6 alkenyloxy group, (3) a substituted C 3-7 cycloalkyloxy group Or (4) a C 3-7 cycloalkenyloxy group which may be substituted;
    [16] W is (1) single bond, (2) C 1-6 alkylene group which may be substituted, (3) C 2-6 alkenylene group which may be substituted, (4) C 2- which may be substituted 6 alkynylene group, (5) -UV-, wherein U is (i) single bond, (ii) oxygen atom, (iii) sulfur atom, (iv) group represented by formula -NH-, (v) C 1-6 alkylene group, which may be substituted (vi) C 2-6 alkenyl which may be substituted seen group or (vii) C 2-6 alkynylene group which may be substituted, V is selected from: (i) single A bond, (ii) a substituted C 1-6 alkylene group, (iii) a substituted C 2-6 alkenylene group, (iv) a substituted C 2-6 alkynylene group, ( v) an oxygen atom, (vi) a sulfur atom, (vii) a group represented by the formula -CO-, (viii) -SO- or (ix) -SO 2- ;
    [17] However, in the above definition, except that when U and V represent the same group, one of U and V is a single bond, a C 1-6 alkylene group which may be substituted, C 2- may be substituted A 6 alkenylene group or a C 2-6 alkynylene group which may be substituted;
    [18] Z is (1) a substituted C 6-14 aromatic hydrocarbon ring group, (2) a substituted 5 to 14 membered aromatic heterocyclic group or (3) formula -N (R 4 ) R 5 (wherein R 4 and R 5 are the same or different and are (i) a hydrogen atom, (ii) a C 1-6 alkyl group which may be substituted, (iii) a C 2-6 alkenyl group which may be substituted, (iv) substituted C 2-6 alkynyl group which may be present, (v) C 3-8 cycloalkyl group which may be substituted, (vi) C 3-8 cycloalkenyl group which may be substituted, (vii) C which may be substituted 6-14 aromatic hydrocarbon ring group, (viii) a 5 to 14 membered aromatic heterocyclic group which may be substituted or (ix) a C 1-6 aliphatic acyl group, or (x) R 4 and R 5 are bonded to To an 8-membered nitrogen-containing cyclic group);
    [19] l represents an integer of 0 to 6], or a salt thereof or a hydrate thereof, and these compounds and the like have excellent Na channel inhibitory activity, and Na + channel inhibitory effect is treated. Diseases effective for prevention (for example, arrhythmia (other, symptoms caused by atrial fibrillation, such as palpitations, palpitations, chest discomfort, heart failure, left thrombosis, thromboembolism, removal of stress from the patient by seizures, etc.), The present invention has been found to be useful for the treatment and prevention of various neuralgias (for example, diabetic neuralgia, HIV-neuralgia, post-herpetic neuralgia, etc.).
    [20] That is, the present invention,
    [21] [1] A compound represented by the formula (I) or a salt thereof or a hydrate thereof. [2] In the above [1], W is a formula -CH 2- , -CH 2 -CH 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5- , -CH = CH-, -C≡ C-, -CO-, -O-, -O-CH 2- , -CH 2 -O-, -CH 2 -CO-,-(CH 2 ) 2 -CO-, -CH 2 -CH (CN)-, -CH 2 -CH (OH)-, -SO 2- , -CH 2- SO 2 -, -NH-CO-, -CH 2 -NH-CO-, -NH-SO 2 - or -CH 2 -NH-SO 2 - group may be represented as, [3] [1] In W, W may be a group represented by the formula -CH 2 -CH 2- , -CH = CH-, -CH≡CH- or -CH 2 -O-, [4] In the above [1], Z may be a substituted C 6-14 aromatic hydrocarbon ring group or a substituted 5 to 14 membered aromatic heterocyclic group. [5] In the above [1], Z may be each substituted. in the phenyl group, pyridyl group or thienyl group may be, carbonyl [6] the pharmaceutical composition of [1], Z is C 6-14 aromatic hydrocarbon ring group or 5- I To 14-membered aromatic heterocyclic group, and wherein said ring (1) hydroxyl group, (2) a halogen atom, (3) a cyano group, (4) C 1-6 alkyl group which may be substituted, (5) C which may be substituted 3-8 cycloalkyl group, (6) substituted C 1-6 alkoxy group, (7) substituted C 3-8 cycloalkyloxy group, (8) substituted C 1-6 Alkylthio group, (9) substituted C 6-14 aryloxy group, (10) substituted 5-14 membered hetero aryloxy group, (11) substituted amino group, (12) A 5- to 14-membered aromatic heterocyclic group which may be substituted, (13) a 5- to 14-membered non-aromatic heterocycle which may be substituted, (14) C 1-6 alkylsulfonyl group and (15) C 1-4 alkylene one or more groups selected from dioxolanyl group may be substituted, respectively, according to [7] above [1], Z is a formula -N (R 4) R 5 in formula [, R 4 and R 5 are each May be groups represented by the group they are the same as defined], in [8] above [7], R 4 and R 5 is optionally substituted C 1-6 alkyl group, which may be the same or different and represent hydrogen atoms, It may be a C 2-6 alkynyl group which may be substituted, a C 6-14 aryl C 1-6 alkyl group which may be substituted, or a heteroaryl C 1-6 alkyl group which may be substituted, [9] In R 4 and R 5 may be bonded to each other to form a 3- to 8-membered nitrogen-containing ring group which may be substituted,
    [22] [10] In the above [9], Z may be a piperidyl group which may be substituted, a piperazyl group which may be substituted, or a morpholinyl group which may be substituted, and [11] the above [1] In Formula 1, l may be an integer 1, and [12] in [1], Ring A is a formula
    [23]
    [24] [Wherein, R 1 and R 2 each represent the same meaning as the above definition], [13] In the above [12], R 1 is a hydrogen atom, a halogen atom or C 1-6 It may be an alkyl group. [14] In [12], R 1 may be a hydrogen atom. [15] In [12], R 2 may be a hydrogen atom or substituted C 1-6. It may be an alkyl group, [16] In the said [1], ring A is a formula
    [25]
    [26] [Wherein, R 1 and R 3 each represent the same meaning as the above definition], and may be a ring represented by [17]. In [16], R 3 may be a hydroxyl group or a C 1-6 alkoxy group. [18] In the above [1], the bonding position of the group -WZ may be the 2 or 4 position of the piperidine ring. Moreover, this invention is a formula of [19]
    [27]
    [28] [Wherein, R 1 , R 2 , W, Z and l represent the same meaning as defined in claim 1], or a salt thereof or a hydrate thereof, [20]
    [29]
    [30] [Wherein R 1 , W and Z represent the same meanings as defined in claim 1 and la represents an integer of 1 or 2] or a salt thereof or a hydrate thereof, [21] 1- [(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) 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-fluorophenyl) ethyl] piperidine, 1-[(5-chloro-2-oxo- 1,2-dihydro-3-pyridinyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine, 1-[(5-chloro-2-oxo-1, 2-dihydro-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine, 1-[(5-fluoro-2- Oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine, 1-[(2-oxo -1,2-dihydro -3-pyridinyl) methyl] -4-[(E) -2- [2- (benzyloxy) phenyl] -1-ethenyl] piperidine, 1-[(2-oxo-1,2-di Hydro-3-pyridinyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine, 1-[(2-oxo-1, 2-dihydro-3-pyridinyl) methyl] -4-[(Z) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine, 1-[(5-fluoro Rho-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine , 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine, 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(2,4-difluorophenoxy) methyl] piperidine, 1- [ (5-chloro-2-oxo-1, 2-dihydro-3-pyridinyl) methyl] -4-[(2,5-difluorophenoxy) methyl] piperidine or salts thereof or hydrates thereof, [22] Expression
    [31]
    [32] [Wherein, the rings A and l each have the same meaning as defined in claim 1, and L represents a leaving group], a salt thereof or a reactive derivative thereof and a formula
    [33]
    [34] [Wherein, W and Z each have the same meaning as defined in the above-mentioned claim 1] or the salt of the compound of the above-mentioned [1], or salts thereof It is a recipe. Moreover, this invention is [23] Formula (I)
    [35] (I)
    [36] [Each symbol in the formula represents the same meaning as defined in the above item 1, respectively] A pharmaceutical composition comprising a compound represented by the salt or a hydrate thereof, [24] The composition in [23] is sodium May be a channel inhibitor or a potassium channel inhibitor, [25] the composition of [23] may be a treatment / prevention agent for arrhythmia, and [26] the composition of [23] is a group of Vaughan Williams class III It may be an antiarrhythmic drug, [27] the composition of [23] may be an analgesic drug, [28] the composition of [23] may be a treatment / preventive agent of neuralgia, 29] The neuralgia in [28] may be diabetic neuralgia, HIV-neuralgia, post-herpetic neuralgia, trigeminal neuralgia, short-term pain, spinal cord injury pain, thalamic pain, or post-stroke pain.
    [37] The present invention provides a compound represented by the above formula (I) or a salt thereof or a hydrate thereof with sodium channel inhibitors or potassium channel inhibitors, drugs for preventing and treating arrhythmias, anti-arrhythmic drugs of Vaughan Williams class III group, analgesics, and neuralgia. Provided are uses for the preparation of a prophylactic agent.
    [38] In addition, the present invention provides a method for preventing and treating a disease in which sodium channel inhibition or potassium channel inhibition is effective for the prevention and treatment by administering to the patient a pharmacologically effective amount of the compound represented by the formula (I) or a salt thereof or a hydrate thereof. To provide.
    [39] In addition, the present invention provides a method for preventing and treating arrhythmia, Vaughan Williams class III group antiarrhythmia, pain, and neuralgia by administering to the patient a pharmacologically effective amount of the compound represented by the formula (I) or a salt thereof or their hydrate. to provide.
    [40] Hereinafter, the meanings of symbols, terms, and the like described in the present specification will be described, and the present invention will be described in detail.
    [41] In the present specification, the structural formula of the compound is shown in the form of a constant isomer for convenience, but the present invention includes all geometric isomers, optical isomers due to sub-carbons, isomers such as stereoisomers, tautomers and the like, and isomer mixtures. It is not limited to the formula for convenience, but includes both isomers and mixtures thereof. Therefore, the compound of the present invention includes an optically active substance and a racemate having a subsidiary carbon atom in the molecule, but is not limited to the present invention and includes all. In addition, although there exist some crystal polymorphs, they are not limited to the same, Any crystal form may be single or a mixture of crystalline forms, and may be a hydrate other than anhydride. In addition, so-called metabolites resulting from degradation of the compounds according to the present invention are also included in the claims of the present invention.
    [42] In the present specification, "arrhythmia" is a generic term when abnormal coordination among cardiac functions (irritation abnormality and stimulation conduction abnormality), for example, same-sex arrhythmia, extracorporeal contraction, atrial fibrillation paroxysmal loss tachycardia, isotropia, Atrioventricular block and the like. The compound according to the present invention is particularly effective for atrial fibrillation among arrhythmias.
    [43] "Nerve pain" in the present specification refers to pain-induced symptoms (intrinsic and secondary) of neuropathy, which leads to pain occurring in the course or distribution of nerves, for example, diabetic neuralgia, HIV neuralgia, and band herpes. Neuralgia, trigeminal neuralgia, short pain, spinal cord injury pain, hypothalamus, post-stroke pain, and the like. "Analgesic drugs" refer to drugs that relieve or eliminate pain by changing the perception of invasive receptor irritation without causing anesthesia or loss of consciousness.
    [44] In this specification, a "halogen atom" means atoms, such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
    [45] In the present specification, the "C 1-6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec -Butyl group, tert-butyl group, n-pentyl group, 1, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2, 2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1, 1, 2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methyl Butyl 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 And linear or branched alkyl groups such as -methylpentyl group and 3-methylpentyl group.
    [46] As used herein, "C 2-6 alkenyl group" refers to an alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, and 2-methyl. -1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1- Linear or branched alkenyl groups such as pentenyl group, 1-hexenyl group, 1, 3-hexanedienyl group, and 1, 6-hexanedienyl group.
    [47] In the present specification, the "C 2-6 alkynyl group" refers to an alkynyl group having 2 to 6 carbon atoms, for example, an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2 propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1, 3-hexanediynyl group And linear or branched alkynyl groups such as 1,6-hexanediynyl and the like.
    [48] As used herein, the term "C 1-6 alkoxy group" refers to a "C 1-6 alkyloxy group" in which an oxygen atom is bonded to a group having the same meaning as the C 1-6 alkyl group in the above definition. Period, n-propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyl octa Period, n-hexoxy group, iso-hexoxy group, 1, 1-dimethylpropyloxy group, 1, 2-dimethylpropoxy group, 2, 2-dimethylpropyloxy group, 2-ethylpropoxy group, 1- Methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1, 1, 2-trimethylpropoxy group, 1, 1, 2-trimethylpropoxy group, 1, 1-dimethylbutoxy group, 1, 2-dimethylbutoxy group, 2, 2-dimethylbutoxy group, 2, 3-dimethylbutyloxy group, 1, 3-dimethylbutyloxy group, 2-ethylbutoxy group, 1, 3-dimethylbutoxy group, 2- Methyl pentoxy group, 3-methyl pentoxy group, etc. are mentioned.
    [49] In the present specification, "C 1-6 alkenyloxy group" means represents an oxygen atom is bound groups with a C 1-6 alkenyl group as defined in the above definition, preferred groups are, for example vinyl-lock time, allyloxy groups, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyl Oxy group, 3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1, 3-hexane A dienyloxy group, a 1, 6- hexanedienyloxy group, etc. are mentioned.
    [50] In the present specification, "C 1-6 alkylthio group" is, for example, methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, n-butylthio group, iso-butylthio group, sec- Butylthio group, tert-butylthio group, n-pentylthio group, 1, 1-dimethylpropylthio group, 1, 2-dimethylpropylthio group, 2, 2-dimethylpropylthio group, 1-ethylpropylthio group, 2-ethylpropylthio group, n-hexylthio group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio group, 1, 1, 2-trimethylpropylthio group, 1-propylpropyl Thio, 1-methylbutylthio group, 2-methylbutylthio group, 1, 1-dimethylbutylthio group, 1, 2-dimethylbutylthio group, 2, 2-dimethylbutylthio group, 1, 3-dimethylbutyl A thio group, a 2, 3- dimethyl butyl thio group, 2-ethyl butyl thio group, 2-methyl pentyl thio group, 3-methyl pentyl thio group, etc. are mentioned.
    [51] In the present specification, the "C 3-8 cycloalkyl group" refers to a cycloalkyl group in which a ring is formed with 3 to 8 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, Cyclooctyl group etc. are mentioned. In addition, in this specification, a "C 3-8 cycloalkane" represents the ring corresponding to the said C 3-8 cycloalkyl group.
    [52] In the present specification, the "C 3-8 cycloalkenyl group" refers to a C 3-8 cycloalkenyl group in which a ring is formed with 3 to 8 carbon atoms, for example, a formula
    [53]
    [54] The group represented by.
    [55] In the present specification, the "C 6-14 aromatic hydrocarbon ring group" refers to, for example, a phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azurenyl group, heptalenyl group, biphenyl group, indenenyl group, and acenaphthyl group. Monocyclic, bicyclic or tricyclic C 6-14 aromatic hydrocarbon ring groups such as fluorenyl group, penalenyl group, penalenyl group, anthracenyl group, cyclopentacyclooctenyl group and benzocyclooctenyl group.
    [56] As used herein, a "5- to 14-membered aromatic heterocyclic group" means a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic heterocycle including one or more heteroatoms selected from nitrogen, sulfur and oxygen atoms. By, for example, (i) pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group , Benzimidazolyl group, indolyl group, isoindolyl group, indolinyl group, furinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinol group Salyl group, quinazolinyl group, cinnaolinyl group, putridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, Phenanthrolinyl, phenacinyl, imidazopyridinyl groups Nitrogen-containing aromatic heterocycles such as an imidazopyrimidinyl group, a pyrazolopyridinyl group and a pyrazolopyridinyl group; (ii) sulfur-containing aromatic heterocycles such as thienyl group and benzothienyl group; (iii) oxygen-containing aromatic heterocycles such as furyl group, pyranyl group, cyclopentapyranyl group, benzofuranyl group and isobenzofuranyl group; (iv) thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, benzoxazolyl group, It contains two or more different heteroatoms selected from the group consisting of nitrogen atoms, sulfur atoms and oxygen atoms such as oxdiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group and pyridoxazinyl group And aromatic heterocycles to be mentioned.
    [57] As used herein, "a 5 to 14 membered non-aromatic heterocycle" is a monocyclic, bicyclic or tricyclic 5 to 14 membered non-aromatic containing one or more heteroatoms selected from nitrogen, sulfur and oxygen atoms. By extending the heterocycle, for example, pyrrolidine, pyrroline, piperidine, piperazine, imidazoline, pyrazolidine, imidazolidine, morpholine, tetrahydrofuran, tetrahydropyran, aziridine, And condensed rings such as oxirane, oxathiolane, pyridone ring, phthalimide ring, succinimide ring and the like.
    [58] In the present specification, the "hydrocarbon group" specifically refers to a C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, or C 3-8 cycloalkenyl group, respectively. It has the same meaning as above.
    [59] In the compound represented by the formula (I) according to the present invention, preferred groups are as follows.
    [60] The following formula expressing A in the formula (I)
    [61]
    [62]
    [63] In the group represented by [wherein R 1 , R 2 and R 3 each represent the same meaning as defined in Claim 1], preferred atoms in the “halogen atom” of R 1 are a fluorine atom and a chlorine atom. Atom or bromine atom is mentioned, A fluorine atom or a chlorine atom is preferable.
    [64] As the "C 1-6 alkyl group" in the "substituted C 1-6 alkyl group" of R 1 or R 2 , preferably, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group , iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like. In addition, R 1 or roneun "C 2-6 alkenyl group" in R 2 "which may be substituted C 2-6 alkenyl group", preferably a vinyl group, an allyl group, a 1-propenyl group, 2-propenyl Phenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group and the like. Further, R 1, or in the "C 2-6 alkynyl group which may be substituted" for R 2 roneun "C 2-6 alkynyl group", and preferably ethynyl group, 1-propynyl group, 2-propynyl group, 1- Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, and the like.
    [65] Roneun "C 3-8 cycloalkyl group" in the above R 1 or R 2 "which may be substituted with C 3-8 cycloalkyl group", and preferably cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group Etc. In addition, R roneun "cycloalkyl C 3-8 alkenyl group" in the "which may be substituted with C 3-8 cycloalkyl alkenyl group", preferably a cycloalkyl butenyl group, pentenyl group cycloalkyl, cyclohexenyl represented by 1 or 2 R And the like.
    [66] Roneun "C 1-6 alkoxy group" in the "C 1-6 alkoxy group which may be substituted" in the above R 1 or R 3, preferably a methoxy group, an ethoxy group, n- propoxy group, iso- pro Fox group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxyoxy, iso-hex A oxy group and the like. The roneun "C 2-6 alkenyloxy group" in R 3 of the "C 2-6 alkenyloxy group which may be substituted", preferably vinyl rock group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 3-methyl- 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1, 3-hexanedienyloxy group, 1, 6 -Hexanedienyloxy group, and the like.
    [67] Preferable "C 1-6 alkylthio group" in the "substituted C 1-6 alkylthio group" of R 1 is methylthio group, ethylthio group, n-propylthio group, iso-propylthione. A group, n-butylthio group, iso-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, n-hexylthio group, etc. are mentioned.
    [68] Preferable "C 1-6 alkylsulfinyl group" in the "substituted C 1-6 alkylsulfinyl group" of R 1 above is methylmethylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, iso-propyl Sulfinyl group, n-butyl sulfinyl group, iso-butyl sulfinyl group, sec-butyl sulfinyl group, tert-butyl sulfinyl group, n-pentyl sulfinyl group, n-hexyl sulfinyl group, etc. are mentioned.
    [69] As a preferable "C 1-6 alkylsulfonyl group" in the "substituted C 1-6 alkylsulfonyl group" represented by said R <1> , methylmethylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, iso- A propyl sulfonyl group, n-butyl sulfonyl group, iso-butyl sulfonyl group, sec-butyl sulfonyl group, tert- butyl sulfonyl group, n-pentyl sulfonyl group, n-hexyl sulfonyl group, etc. are mentioned.
    [70] Roneun "C 6-14 aromatic hydrocarbon ring group" in the above R 1 or R 2 "are C 6-14 aromatic hydrocarbon ring group which may be substituted" for, the preferably a phenyl group, a naphthyl group or the like. The roneun preferable "5- to 14-membered aromatic heterocyclic group" in the "which may be substituted 5- to 14-membered aromatic heterocyclic group" represented by R 1 or R 2, a pyridyl group, a pyrazolyl chewy flute you group, pyridazinyl The group, thienyl group, thiazolyl group, imidazolyl group, furyl group, etc. are mentioned.
    [71] In "the amino group which may be substituted" of said R <2> , As a preferable substituent of the said amino group, (1) C1-6 alkyl group (for example, the methyl group which may respectively be substituted) may be substituted, for example. , Ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc.), (2) is substituted C 2-6 alkenyl groups which may be present (for example, vinyl groups, allyl groups, 1-propenyl groups, 2-propenyl groups, isopropenyl groups, 1-butenyl groups, 2-butenyl groups, each of which may be substituted each) -Butenyl group, 1-pentenyl group, 1-hexenyl group, etc.), (3) C 2-6 alkynyl group which may be substituted (for example, the ethynyl group, 1-propynyl group, 2 which may be substituted each) -propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group or the like), (4) C 3-8 cycloalkyl which may be substituted alkyl groups (for example G., Each group which may be substituted cyclopropyl, cyclobutyl group, cyclopentyl group, cyclohexyl group etc.), (5) C 3-8 cycloalkyl, for an alkenyl group (for example, which may be substituted with may be substituted respectively, Cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc.), (6) acyl group, (7) substituted carbamoyl group, etc., and the amino group is selected from these groups. You may have arbitrary 1 or 2 groups as a substituent. The amino group is preferably an unsubstituted amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di (n-propyl) amino group, iso-propylamino group, di (iso-propyl) amino group Etc. can be mentioned.
    [72] As a preferable " C3-7 cycloalkyloxy group" in the "substituted C3-7 cycloalkyloxy group" of said R <3> , a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclo Hexyloxy group etc. are mentioned. The roneun Preferred "cycloalkyl C 3-7 alkenyloxy group" in the "C 3-7 cycloalkyl may be substituted with alkenyloxy group" represented by R 3, cycloalkyl butenyl group, pentenyl cycloalkyl group, cyclohexenyl oxide Season, etc. can be mentioned.
    [73] A C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalke, which may be substituted, respectively, represented by R 1 , R 2, or R 3 . group, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 6-14 aromatic hydrocarbon ring group, a 5- to 14-membered aromatic heterocyclic group, C Preferable examples of the "substituent" for a 2-6 alkenyloxy group, a C 3-7 cycloalkyloxy group and a C 3-7 cycloalkenyloxy group include (1) a hydroxyl group and (2) a halogen atom (for example, a fluorine atom). , Chlorine atom, bromine atom, iodine atom), (3) cyano group, (4) nitro group, (5) C 1-6 alkyl group (e.g. methyl group, ethyl group, n-propyl group, iso-propyl group, n -Butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc.), (6) C 2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-part Group, a 1-pentenyl group, 1-hexenyl group and the like), (7) C 2-6 alkynyl group (e.g., ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group , 3-butynyl group, 1-pentynyl group, 1-hexynyl group, etc.), (8) C 3-8 cycloalkyl group (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.), (9) C 1-6 alkoxy group (e.g., methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, etc.), (10) C 1-6 alkylthio group (e.g., methyl thi Ogi, ethylthio group, etc.), (11) 5--14 membered non-aromatic heterocyclic group (for example, piperidyl group, piperazyl group, morpholinyl group, etc.), (12) C 6-14 aromatic hydrocarbon ring group (for example, Phenyl group, naphthyl group, etc.), (13) 5- to 14-membered aromatic heterocyclic group (for example, pyridyl group, thienyl group, furyl group, thiazolyl group, etc.), and (14) amino group which may be substituted (for example, C 1-6 alkyl group, C 1-6 alkenyl group, C 1-6 alkynyl group, C 3 -Amino group which may be substituted with 1 or 2 groups selected from -8 cycloalkyl group, C 3-8 cycloalkenyl group, acyl group, optionally substituted carbamoyl group, C 1-6 alkyl group, sulfonyl group, etc. Unsubstituted amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di (n-propyl) amino group, iso-propylamino group, di (iso-propyl) amino group, etc.), or the substituent Nitrogen ring group formed by bonding together to contain a nitrogen atom together with each other] may be exemplified, and may have one or more groups selected from these groups as a substituent.
    [74] As a more preferable group of said R <1> , a hydrogen atom or a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom etc.) is mentioned. Moreover, as a more preferable group of R <2> , a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group, an aralkyl group (Eg, a benzyl group, a phenethyl group, etc.), a mono (C 1-6 alkyl) amino C 1-6 alkyl group or a di (C 1-6 alkyl) aminoalkyl group can be cited, and a hydrogen atom is most preferred. Moreover, as a more preferable group of R <3> , the C 1-6 alkoxy group which may be substituted is mentioned, and a methoxy group is the most preferable.
    [75] In the compound represented by the formula (I) according to the present invention, a more preferred embodiment of ring A is
    [76]
    [77] [Wherein, R 1 , R 2 and R 3 each represent the same meaning as defined in the above-mentioned claim 1], and in particular, the formula
    [78]
    [79] The ring represented by is preferable.
    [80] In the formula (I), the "substituted C 1-6 alkylene group" of W, "substituted C 2-6 alkenylene group" or "substituted C 2-6 alkynyl expression in group "may be substituted are each -CH 2 -, -CH 2 -CH 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - (CH 2) 5 -, - (CH 2 ) 6- , -CH = CH-, -CH = CH-CH 2- , -CH 2 -CH = CH-, -CH 2 -CH 2 -CH = CH-, -CH 2 -CH = CH-CH And groups represented by 2- , -C≡C-, -CH 2 -C≡C-, -C≡C-CH 2- , and -CH 2 -C≡C-CH 2- . As the "substituent" of the C 1-6 alkylene group, C 2-6 alkenylene group or C 2-6 alkynylene group, for example, a hydroxyl group, a halogen atom, a cyano group, a C 6-14 aromatic hydrocarbon ring group ( For example, a phenyl group), a 5-14 membered aromatic heterocyclic group (for example, pyridyl group, thienyl group, furyl group etc.) etc. are mentioned, Preferably a hydroxyl group, a cyano group, etc. are mentioned.
    [81] The formula (I), a preferred group in W, each of which may be substituted formula -CH 2 -, -CH 2 -CH 2 -, - (CH 2) 3 -, - (CH 2) 4 -, -(CH 2 ) 5 -,-(CH 2 ) 6- , -CH = CH-, -CH = CH-CH 2 -,-CH 2 -CH = CH-, -CH 2 -CH 2 -CH = CH -, -CH 2 -CH = CH-CH 2- , -C≡C-, -CH 2 -C≡C-, -C≡C-CH 2 -or -CH 2 -C≡C-CH 2- Groups that can be represented, or formulas -CH 2 -CO-, -CH 2 -CH 2 -CO-,-(CH 2 ) 3 -CO-, -CH = CH-CO-, -CH = CH-CH 2 -CO-, -C≡C-CO-, -CH 2 -O-, -O-CH 2- , -CH 2 -CH 2 -O-,-(CH 2 ) 3 -O-, -CH = CH -O, -CH = CH-CH 2 -O-, -C≡CO-, -CH 2 -SO 2- , -CH 2 -CH 2 -SO 2 -,-(CH 2 ) 3 -SO 2- , -CH = CH-SO 2- , -CH = CH-CH 2 -SO 2- , -C≡C-SO 2- , -CH 2 -NH-CO-, -CH 2 -CH 2 -NH-CO- ,-(CH 2 ) 3 -NH-CO-, -CH = CH-NH-CO-, -CH = CH-CH 2 -NH-CO-, -C≡C-NH-CO-, -CH 2- NH-SO 2- , -CH 2 -CH 2 -NH-SO 2 -,-(CH 2 ) 3 -NH-SO 2- , -CH = CH-NH-SO 2- , -CH = CH-CH 2 Groups which may be represented by -NH-SO 2 -or -C≡C-NH-SO 2- , and -CH 2 -CH 2- , -CH = CH-, -C≡C-, -CH 2- O- back more Is recommended.
    [82] In said Formula (I), as a preferable example of the "C 6-14 aromatic hydrocarbon ring group" in Z "the C 6-14 aromatic hydrocarbon ring group which may be substituted", a phenyl group, a naphthyl group (for example, 1-naph Tyl group, 2-naphthyl group etc.), an azrenyl group, a heptarenyl group, etc. are mentioned.
    [83] In said Formula (I), as a preferable group in the "substituted 5-14 membered aromatic heterocyclic group" of Z, a pyrrolyl group, a pyridyl group, a thienyl group, a pyridyl group, a pyrimidyl group, a pyrazyl group, an imida A sleepy group, a pyrazolyl group, an indolyl group, a quinolyl group, a quinazolyl group, a thiazolyl group, a benzothienyl group, etc. are mentioned.
    [84] In the above formula (I), when Z is a "substituted C 6-14 aromatic hydrocarbon ring group" or a "substituted 5 to 14 membered aromatic heterocyclic group", as the "substituent", (1) Hydroxyl, (2) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (3) nitrile groups, (4) (i) halogen atoms, (ii) halogen atoms (e.g., fluorine atoms, chlorine atoms) C 6-14 aromatic hydrocarbon ring group (phenyl group, naphthyl group) which may be substituted with (iii) 5-14 membered aromatic heterocyclic group which may be substituted with halogen atom (eg fluorine atom, chlorine atom) For example, a pyridyl group, thienyl group, furyl group, thiazolyl group and the like, iv) C 1-6 alkylsulfonyl group, etc. may be substituted with one or more groups selected from (C 1-6 alkyl group, C 2-6 alkenes) group, C 2-6 alkynyl, C 3-8 cycloalkyl or C 3-8 cyclo alkenyl group), (5) (i) hydroxyl groups, (ii) a halogen atom ( , A fluorine atom, a chlorine atom, ii) C 1-6 alkoxy group, (iv) a hydrocarbon group (C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl group or C A sulfonyl group substituted with a 3-8 cycloalkenyl group), (v) a hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group or C 3-8 C 1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, iso-propoxy group), which may be substituted with one or more groups selected from an amino group which may be substituted with a cycloalkenyl group), (6) (i) hydroxyl group, (ii) halogen atom (e.g., fluorine atom, chlorine atom), (iii) C 1-6 alkoxy group, (iv) hydrocarbon group (C 1-6 alkyl group, C 2-6 alke A sulfonyl group substituted with a alkyl group, a C 2-6 alkynyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkenyl group, (v) a hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group or C 3-8 cycloalkenyl group) A C 3-7 cycloalkyloxy group which may be substituted with a group such as an amino group which may be substituted, (7) a C 6-14 aryloxy group which may be substituted with a halogen atom (eg, a fluorine atom, a chlorine atom) ( (8) Heteroaryloxy groups (e.g., pyridyloxy groups, thienyloxy groups, furyloxy groups), which may be substituted with halogen atoms (e.g., fluorine atoms, chlorine atoms), etc. (i) hydroxyl group, (ii) halogen atom (e.g., fluorine atom, chlorine atom), (iii) C 1-6 alkoxy group, (iv) hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C A sulfonyl group substituted with a 2-6 alkynyl group, a C 3-8 cycloalkyl group or a C 3-8 cycloalkenyl group, and (v) a hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 A hydrocarbonthio group which may be substituted with a group selected from an amino group which may be substituted with an alkynyl group, a C 3-8 cycloalkyl group or a C 3-8 cycloalkenyl group For example, methylthio group, ethylthio group, n-propylthio group, iso-propylthio group), (10) Formula -CO-N (R 6 ) R 7 wherein R 6 and R 7 are the same or Hydrocarbon groups different from (i) hydrogen atoms or (ii) halogen atoms (e.g., fluorine atoms, chlorine atoms) (C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups) , C 3-8 cycloalkyl group or C 3-8 cycloalkenyl group), or R 6 and R 7 join together to include one or two atoms selected from nitrogen atom, oxygen atom and sulfur atom To a seven-membered nitrogen-containing non-aromatic heterocycle (which may form a piperidine, piperazine, morpholine ring, etc.), an acyl group represented by (11) (i) hydroxyl group, (ii) halogen atom (e.g., fluorine atom, chlorine atom, iii) a halogen atom which may be substituted (for example, fluorine atom, chlorine atom), a hydrocarbon group (C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, C 3-8 cycloalkyl or C 3-8 cyclo alkenyl group), (iv) C 1-6 alkoxy group (methoxy group, ethoxy group, n- propoxy group, iso- propoxy group etc.) and (v Hydrocarbon groups (C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups, C 3-8 cycloalkyl groups or C 3 ) which may be substituted with halogen atoms (eg fluorine atoms, chlorine atoms) 5- to 14-membered aromatic group which may be substituted with a group selected from C 1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, etc.) substituted with -8 cycloalkenyl group) (For example, a phenyl group, a naphthyl group, a pyridyl group, a thienyl group, a furyl group, a thiazolyl group, etc.), (12) a 3 to 8 membered ratio containing one or two atoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms Aromatic heterocyclic group (piperidyl group, piperazyl group, morpholinyl group, etc.), (13) hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group Or a sulfonyl group substituted with a C 3-8 cycloalkenyl group), (14) a hydrocarbon group (C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, or C 3 1 selected from groups such as sulfonamide group which may be substituted with -8 cycloalkenyl group), and (15) C 1-4 alkylenedioxy group (for example, methylenedioxy group, ethylenedioxy group, propylenedioxy group) The above group is mentioned. For example, hydroxyl group, nitrile group, halogen atom (fluorine atom, chlorine atom, bromine atom), methyl group, ethyl group, n-butyl group, trifluoromethyl group, methoxy group, ethoxy group, cyclopropylmethoxy group, 2, 2, 2-trifluoroethoxy group, 2-methoxyethoxy group, 2-hydroxyethoxy group, 2- (N, N-dimethylamino) -ethoxy group, phenoxy group, phenyl group, imidazolyl group, pyra Zolyl group, thiazolyl group, methoxyphenyl group, piperidyl group, piperazyl group, morpholinyl group, N-acetylpiperazyl group, methylsulfonyl group, amino group, trifluoroacetylamino group, methylsulfonyl group, ethylsulfonyl group, Alkylenedioxy group etc. are mentioned. Here, the "C 1-6 alkyl group", "C 2-6 alkenyl group", "C 2-6 alkynyl group", "C 3-8 cycloalkyl group", or "C 3-8 " described as the "hydrocarbon group". The cycloalkenyl group "has the same meaning as the above definition, respectively.
    [85] In formula (I), Z is represented by the formula -N (R 4 ) R 5 , wherein R 4 and R 5 each have the same meaning as the definition of claim 1, and R 4 or R As the "C 1-6 alkyl group" of the "substituted C 1-6 alkyl group" represented by 5 , preferably, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso- A butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc. are mentioned, for example, "C 2-6 alkenyl group which may be substituted" is "C 2-6 alkenyl group"", Preferably a vinyl group, an allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl The group etc. are mentioned, As a "C 2-6 alkynyl group" of the "substituted C 2-6 alkynyl group", Preferably an ethynyl group, 1-propynyl group, 2-propynyl group, 1-buty Nyl, 2-butynyl, 3-butynyl, 1-penty Group, and 1-hexynyl group. In addition, R 4 or roneun "C 3-8 cycloalkyl group" in the "which may be substituted with C 3-8 cycloalkyl group" represented by R 5, and preferably cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloalkyl Hexyl group etc. are mentioned, As a "C 3-8 cycloalkenyl group" in the "C 3-8 cycloalkenyl group which may be substituted", Preferably it is a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group Etc. can be mentioned. In addition, there may be mentioned as an example roneun "C 6-14 aromatic hydrocarbon group" in the "which may be substituted with C 6-14 aromatic hydrocarbon group", preferably a phenyl group, a naphthyl group represented by R 4 or R 5, As a preferable 5- to 14-membered aromatic heterocyclic group in the "substituted 5- to 14-membered aromatic heterocyclic group", a pyridyl group, a pyrazyl group, a pyridylyl group, a pyridazinyl group, a thienyl group, a thiazolyl group, An imidazolyl group, a furyl group, etc. are mentioned.
    [86] R 4 or R 5 is the same or different, and each may be substituted C 1-6 alkyl group, C 2-6 alkenyl group which may be substituted, C 2-6 alkynyl group which may be substituted, Substitution is a C 3-8 cycloalkyl group may be or could be C 3-8 cycloalkenyl group substituted in which case, for a preferable example of the "substituent", (1) hydroxyl group, (2) a halogen atom (e.g. For example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), and (3) a C 1-6 alkoxy group which may be substituted (for example, a methoxy group, an ethoxy group and n-propoxy which may each be substituted with a halogen atom). Period, iso-propoxy group, n-butoxy group, tert-butoxy group, etc.) (4) C 6-14 aromatic hydrocarbon ring group which may be substituted (for example, may be substituted with hydroxyl group, halogen atom, halogen atom) Hydrocarbon groups, which may be substituted with halogen atoms It is a C 1-6 alkoxy group and a 55 to 14-membered to 14-membered aromatic group which may be substituted with any one or more selected from the aromatic group, etc.), (5) a 5- to 14-membered aromatic which may be substituted Heterocyclic group (for example, hydroxyl group, halogen atom, hydrocarbon group which may be substituted by halogen atom, C 1-6 alkoxy group which may be substituted by halogen atom, and any one or more groups selected from 5 to 14 member aromatic group) 5-14 membered aromatic group etc. which may be substituted, etc. are mentioned. Specifically, for example, ethyl group, 2-methylpropyl group, iso-propyl group, n-pentyl group, n-octyl group, tert-butyl group, hydroxy-tert-butyl group, cyclohexyl group, cyclopropylmethyl group, 1 -Cyclopropylethyl group, 2-cyclopropylethyl group, 2, 2, 2-trifluoroethyl group, morpholinylethyl group, hydroxyethyl group, hydroxypropyl group, 5-phenylpentyl group, 2-propyn-1-yl group , 1, 2-dimethylpropyl group, 2-ethyl-n-butyl group, benzyl group, phenethyl group, benzyl halide, hydroxybenzyl group, o-phenylbenzyl group, methylsulfonylbenzyl group, methylsulfonylaminobenzyl And 1 or 2 groups selected from group, pyridylmethyl group, furylmethyl group, N-methylpyrrolylethyl group, diphenylmethyl group, methylenedioxyphenylmethyl group, methoxypyridylmethyl group and dimethylaminoethyl group.
    [87] When said R <4> or R <5> is the same or different, and may be substituted, the C 6-14 aromatic hydrocarbon ring group or the 5-14 membered aromatic heterocyclic group which may be substituted, Preferable example of the said "substituent", 1) a hydroxyl group, (2) a halogen atom, (3) a nitrile group, (4) a halogen atom, a 5-14 membered aromatic group which may be substituted with a halogen atom, or a C 1-6 alkyl-sulfonyl group be a hydrocarbon group, (5) a hydroxyl group, a halogen atom, C 1-6 alkoxy group, a hydrocarbon group-substituted sulfonyl group, C 1-6 alkoxy which may be substituted with the amino group and the like which may be substituted with a hydrocarbon group, (6) a C 3-7 cycloalkyl-oxy group which may be substituted with a group such as a hydroxyl group, a halogen atom, a C 1-6 alkoxy group, a sulfonyl group substituted with a hydrocarbon group, an amino group which may be substituted with a hydrocarbon group, (7 Halogen atom (C 6-10 allyl) -oxy group which may be substituted by, etc., (8) (5- to 14-membered heteroaryl) -oxy group which may be substituted by halogen atom, etc., (9) hydroxyl group, halogen atom, C 1 A hydrocarbon-thio group which may be substituted by a group selected from a -6 alkoxy group, a sulfonyl group substituted with a hydrocarbon group, and an amino group which may be substituted with a hydrocarbon group, formula (10) -CO-N (R 12 ) R 13 In which R 12 and R 13 are the same or different and represent a hydrocarbon group which may be substituted with a hydrogen atom or a halogen atom, and in the formula -CO-N (R 12 ) R 13 , R 12 and R 13 are nitrogen atoms and oxygen; May be bonded together with one or two atoms selected from atoms and sulfur atoms to form a 3 to 7 membered nitrogen-containing non-aromatic heterocycle] together with an acyl group represented by (11) a hydroxyl group, a halogen atom, a halogen atom Substituted with hydrocarbon and halogen atoms To be 5 to 14-membered, which may be substituted by a group selected from C 1-6 hydrocarbon group, an alkoxy group an aromatic group, (12) 3 to 7 atoms, which contains one or two selected from a nitrogen atom, an oxygen atom and a sulfur atom And an original non-aromatic heterocyclic group, a sulfonyl group substituted with a (13) hydrocarbon group, a sulfonamide group optionally substituted with a (14) hydrocarbon group, and a (15) C 1-2 alkylenedioxy group.
    [88] The "C 1-6 aliphatic acyl group" of R 4 or R 5 may be a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy-C 1-6 alkyl group, The carbonyl group substituted with groups, such as a C 1-6 alkoxy group, a C 6-14 aryl group, and a 5-14 membered aromatic heterocyclic group, is mentioned, A acetyl group, an ethylcarbonyl group, etc. are mentioned as a preferable example.
    [89] The formula (I) of the, Z is a formula -N (R 4) R R 4 and R 5 in combination with 5 to, and also represents a 3 to 8 hamjil recalled dishes, the group Preferred examples include a piperidyl group , Piperazyl group, morpholinyl group and the like.
    [90] In the formula (I), the symbol l represents an integer of 0, 1, 2, 3, 4, 5 or 6, but is preferably an integer of 1 to 3, more preferably an integer of 1 or 2, More preferably, it is integer 1.
    [91] More preferable aspect of the compound represented by said Formula (I) concerning this invention is a formula.
    [92]
    [93] [In formula, R <1> , R <2> , W, Z, and l represent the same meaning as the said definition, respectively, The compound or its salt, or their hydrate are represented, Especially preferable aspect is a formula
    [94]
    [95] [In formula, R <1> , W and Z show the same meaning as the definition of said Claim 1, respectively, la represents the integer of 1 or 2, The compound or its salt, or their hydrate are represented.
    [96] The term "salt" in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention and is also pharmacologically acceptable, but is preferably a hydrochloride salt (for example, hydrofluoride, hydrochloride, hydrogen bromide). Salts, iodide, etc.), inorganic salts (e.g. sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carbonates (e.g. acetate, trifluoroacetate, oxalate, maleate, Tartarate, fumarate, citrate, etc.), organic sulfonates (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts ( For example, aspartic acid salts, glutamate salts), quaternary amine salts, alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.) may be mentioned. , And the like and more preferably the hydrochloride, oxalate, acetate trifluoroacetate.
    [97] The typical manufacturing method of the compound represented by said Formula (I) which concerns on this invention is shown below.
    [98] Manufacturing method 1
    [99]
    [100] In formula, R <1> , W, Z, and l have the same meaning as the above definition, and L <1> represents a leaving group (for example, halogen atom, tosylate, etc.) or an aldehyde group. Compound (I) -1 according to the present invention can be prepared by condensing piperidine derivative (II) and pyridine derivative (III) in a solvent according to a reduction amination process or in the presence of a base. In the case of reductive amination, the solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, and the like. Halogenated carbons, such as ethers, dichloromethane, chloroform, dichloroethane, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1-methylpyrrolidone, acetonitrile, etc. are preferable. As a reducing agent, metal hydrides, such as sodium borohydride and sodium triacetoxy borohydride, can be used, and can also be performed by the catalytic reduction method normally used. The use amount of reducing agent is 1-5 equivalents with respect to a raw material. The reaction temperature is usually at -50 ° C to the reflux temperature of the solvent, and preferably around 0 to 25 ° C. In condensation in the presence of a base, any organic solvent which does not participate in the reaction can be used. For example, benzene, dichloromethane, acetonitrile, THF, dioxy acid, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone, etc. are mentioned. The base to be used is not particularly limited, but sodium hydride, potassium tert-butoxide, lithium diisopropylamide, potassium carbonate, sodium hydroxide and the like are preferable. The usage-amount of a base is 1-10 equivalent normally with respect to a raw material. As for reaction temperature, 20-80 degreeC is preferable at the reflux temperature of -50 degreeC-a solvent normally.
    [101] Below, the manufacturing method in the case of W being "the hydrocarbon chain which may be substituted" in said Formula (I) is shown.
    [102] Manufacturing method 2
    [103]
    [104] In formula, R <1> and l have the same meaning as the said definition, Z <1> is a 5-14 membered aromatic group which may be substituted, g represents 0, 1 or 2. The pyridylpiperidine derivative (I) -1-1 which is the compound which concerns on this invention can be manufactured by carrying out the Wittig reaction or similar reaction to piperidine aldehyde derivative (IV) in an organic solvent. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxy acid and diethylene glycol dimethyl ether, ethyl acetate and dimethylformamide. , Dimethyl sulfoxide, toluene, benzene and the like are preferred. What is marketed can be purchased easily, and what is not marketed can be easily prepared according to a conventional method. The use amount of the Wittich reagent is 1 to 2 equivalents based on the raw material. As a base to be used, sodium hydride, potassium tert-butoxide, potassium methoxide, sodium ethoxide, lithium diisopropylamide, diazabicyclo undecene, n-butyllithium, sodium hydroxide, etc. are preferable, for example. . The use amount of base is 1-2 equivalents with respect to a raw material. The reaction temperature is usually -70 ° C to reflux temperature of the solvent, and preferably -40 to 60 ° C.
    [105] Manufacturing Method 3
    [106]
    [107] In formula, R <1> and l have the same meaning as the said definition, Z <2> represents the 5-14 aromatic group which may be substituted, and L <2> represents a leaving group (for example, halogen atom, triflate, etc.). Compound (I) -1-2 according to the present invention can be prepared by reacting alkynylpiperidine derivative (V) with (VI) (for example, aryl halide, aryl triplate, etc.) in the presence of a catalyst in a solvent. Can be. The solvent used is not particularly limited as long as the starting material is dissolved to some extent without disturbing the reaction. Examples of the solvent used include ethers such as tetrahydrofuran (THF), dioxyacid and diethylene glycol dimethyl ether, dichloromethane, Halogenated carbons, such as chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, toluene, benzene, 1-methylpyrrolidone, etc. are preferable. The present reaction can be carried out in the presence of a reagent of any one of catalytic amounts of tetrakis (triphenylphosphine) palladium or dichlorobis (triphenylphosphine) palladium (II), copper iodide and tertiary amine. As the tertiary amine to be used, for example, triethylamine, diisopropylethylamine, dimethylaniline, diazabicycloundecene and the like are preferable. The amount of the catalyst used is about 0.001 to 0.1 mol% based on the raw materials. The reaction is carried out in a nitrogen atmosphere, and the reaction temperature is usually -20 ° C to the reflux temperature of the solvent, preferably 80 to 140 ° C.
    [108] Manufacturing method 4
    [109]
    [110] In formula, R <1> , l, g, and Z <1> show the same meaning as the said definition, and h shows the integer of any one of 1-3. Compound (I) -1-3 according to the present invention can be produced by catalytic reduction of pyridylpiperidine derivative (I) -1-1 obtained in reaction 2. The solvent used is not particularly limited as long as the starting material is dissolved to some extent without disturbing the reaction. Examples of the solvent used include ethers such as tetrahydrofuran (THF), dioxyacid and diethylene glycol dimethyl ether, and dichloromethane. And halogenated carbons such as chloroform and dichloroethane, ethyl acetate, dimethylformamide, dimethyl sulfoxide, ethanol, methanol and the like are preferable. In this reaction, even if an appropriate amount of acid is added to the reaction liquid, good results can be obtained. By using the catalyst, such as palladium carbon (Pd-C), Raney nickel (Ranney-Nickel), platinum oxide (PtO 2) is preferred. Reaction temperature is 0-120 degreeC normally, Preferably it is around 25 degreeC. The hydrogen pressure during reduction is 1 to 140 kg / cm 2, but preferably 1 to 3 kg / cm 2.
    [111] Manufacturing Method 5
    [112]
    [113] In formula, R <1> , l and Z <2> show the same meaning as the said definition. The compound (I) -1-4 which concerns on this invention can be manufactured by carrying out the catalytic reduction of the compound (I) -1-2 obtained by "reaction 3". This reaction can be carried out under the same conditions as in "Reaction 4".
    [114] Manufacturing Method 6
    [115]
    [116] In formula, R <1> , l, g, h, and Z <1> show the same meaning as the said definition. Compound (I) -1-3 according to the present invention does not isolate the pyridylpiperidine derivative (I) -1-1 obtained by reacting a piperidine aldehyde derivative (IV) with a Wittig reagent in the presence of a base. It can be prepared by catalytic reduction. The Bitich reaction can be carried out in accordance with the method described in Reaction 2, and the catalytic reduction can be carried out in accordance with the method described in "Reaction 4".
    [117] Manufacturing Method 7
    [118]
    [119] In formula, R <1> , l, i and Z <1> have the same meaning as the above definition, L <3> is a leaving group (for example, halogen atom, a triflate, etc.), Q <1> , Z <3> may be substituted. To a 14-membered aromatic group. Compound (I) -1-5 according to the present invention is a compound (I) -1-1- in which Z 1 is represented by Z 3 -L 3 in compound (I) -1-1 obtained in "Reaction 2". It can be prepared under the palladium catalyst in i. As an aryl metal compound used for reaction, aryl tributyl tin, aryl boronic acid, other commonly used aryl alkoxy borane, aryl alkyl borane, etc. are mentioned, for example. The amount of the aryl metal compound to be used is usually 1 to 5 equivalents, preferably 2 equivalents to the raw material. As a catalyst to be used, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenyl phosphine) palladium (II), etc. are mentioned, for example. The usage-amount of a catalyst is about 0.05 mol% with respect to a raw material. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, toluene, benzene and the like are preferable. In the case of using allyl boronic acid as the aryl metal compound, a mixed solvent system of sodium carbonate water, methanol and an organic solvent is preferable. The reaction temperature is usually room temperature to 150 ° C, and 80 to 130 ° C is preferable. Compound (I) -1-5 obtained by this manufacturing method can be used as a raw material in reaction 4.
    [120] Manufacturing Method 8
    [121]
    [122] In formula, R 1 and l have the same meanings as defined above, j is 1 for any integer of to 3, L 4 is a leaving group (e.g. a halogen atom, tosylate, mesylate, triflate, etc.) , Q 2 represents a substituent (for example, a C 1-6 alkoxy group, an alkylamino group, etc.). Compound (I) -1-8 according to the present invention is also a pyridine derivative (I) having a leaving group L 4 at the 2-position of the aromatic group represented by Z and Z 1 in the compounds obtained in the above reactions 1 and 4 ) -1-7 can also be prepared by reacting with a nucleophilic reagent. As a nucleophilic reagent to be used, for example, alcohols such as methanol, ethanol and dimethylaminoethanol are produced by reacting a base such as sodium hydride, tert-butoxy potassium, metal sodium, metal lithium, sodium diisopropylamide, or the like. Preferred are alkoxides and other primary or secondary amines such as piperidine and morpholine. When amine is used as a nucleophilic agent, good results can be obtained even when bases having weak nucleophilic properties such as potassium carbonate, diisopropylethylamine and triethylamine coexist in the reaction system. The usage-amount of a nucleophile is 1 thru | or very excess with respect to a raw material. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include ethers such as tetrahydrofuran (THF), dioxyacid and diethylene glycol dimethyl ether, and dichloromethane. , Halogenated carbons such as chloroform and dichloroethane, other ethyl acetate, dimethylformamide, dimethylsulfoxide, 1-methylpyrrolidone and the like are preferable. When using an alkoxide as a nucleophilic agent, it is also possible to use an alcohol as a solvent. Do. Although reaction temperature is 0-200 degreeC normally, Preferably it is 100-170 degreeC.
    [123] Manufacturing Method 9
    [124]
    [125] In formula, R <1> , l and g represent the same meaning as the said definition, j represents the integer of any one of 1-3, Z <4> represents the 5-14 membered aromatic group which may be substituted. Compound (I) -1-9 according to the present invention can be prepared by adding 1, 2-addition of metal aryl or metal halide aryl to aldehyde derivative (IV) to form an alcohol intermediate, followed by oxidation. The metal aryl and metal halide aryl used in the 1, 2-addition reaction can be purchased and those not commercially available can be adjusted and used in accordance with conventional methods. The usage-amount of metal aryl and metal halide aryl is 1-5 equivalents with respect to a raw material. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid and diethylene glycol dimethyl ether, and other toluene and benzene Etc. are preferable. The reaction temperature is usually -78 to 0 ° C. As the oxidizing agent used for the oxidation reaction, for example, sulfur trioxide-pyridine complex, pyridinium chlorochromate, manganese dioxide, pyridinium dichromate, swan oxidizing agent adjusted with oxalyl chloride-dimethyl sulfoxide and the like are preferable. The solvent used for the oxidation reaction is not particularly limited as long as it does not interfere with the reaction and dissolves the starting material to some extent, but examples thereof include ethers such as tetrahydrofuran (THF), dioxy acid and diethylene glycol dimethyl ether, and dichloro Halogenated carbons such as methane, chloroform and dichloroethane, other acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone and the like are preferable. The reaction temperature is usually 0 ° C to the reflux temperature of the solvent.
    [126] Manufacturing Method 10
    [127]
    [128] In formula, R <1> , l, and Z <4> have the same meaning as the said definition, and k shows the numerical value of either 0, 1, or 2. Compound (I) -1-9 according to the present invention can be produced by reacting an amide derivative (VII) with a metal aryl or a metal halide aryl. The metal aryl and metal halide aryl used can be purchased and commercially available products can be used after being adjusted in accordance with a conventional method. The use amount of metal aryl and metal halide aryl is about 1 to 2 equivalents relative to the raw material. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, ethers such as tetrahydrofuran (THF), dioxyacid, diethylene glycol dimethyl ether, toluene, benzene and the like This is preferred. The reaction temperature is usually -78 to 0 ° C.
    [129] Manufacturing Method 11
    [130]
    [131] In formula, R <1> , R <4> , R <5> and l have the same meaning as the said definition, m shows the numerical value of any one of 0, 1, or 2. Compound (I) -1-10 according to the present invention can be produced by condensation reaction of a carboxylic acid derivative (VIII) with an amine represented by the formula NH (R 4 ) R 5 in an organic solvent. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, dichloromethane and chloroform And halogenated carbons such as dichloroethane, other ethyl acetate, dimethylformamide, dimethyl sulfoxide, ethanol, methanol and the like are preferable. As a condensation reaction, the reaction normally performed can be used, For example, the DCC method, the DCC-HOBt method, the DCC-HOSu method, and the improvement method based on these (for example, WSC-HOBt method) etc. can be used. The use amount of condensing agent is 1-5 equivalents with respect to raw material (VIII). Moreover, it can also carry out by making a carboxylic acid-piperidine derivative into a reactive derivative normally used, and then reacting with an amine. As the reactive derivative to be used, for example, an acid halide obtained by treatment with thionyl chloride or the like, isobutyloxycarbonyl chloride (IBCF) or 1-ethoxycarbonyl-2-ethoxy-1,2-dihydride Oxyquinoline (EEDQ), ethyl chlorocarbonate and the like are acted on the carboxylic acid derivative (VIII) to induce an acid anhydride, or diphenylphosphoryl azide (DPPA) is used to convert the carboxylic acid derivative (VIII) to acid azide, One or the like is preferable, and it is also possible to induce active esters such as p-nitrophenyl ester (ONp) and N-hydroxysuccinimide (ONSu). By reacting such a reactive derivative with amine NH (R 4 ) R 5 in an organic solvent, compound (I) -1-10 according to the present invention can be obtained.
    [132] Manufacturing Method 12
    [133]
    [134] In formula, R <4> , W, Z, and l show the same meaning as the said definition. The pyridonepiperidine derivative (I) -2 which is the compound which concerns on this invention can be manufactured by hydrolyzing a pyridyl piperidine derivative (I) -1. The present reaction can be carried out by reacting 2 equivalents to a very large amount of a suitable acid in water or in a mixed solvent of water and an organic solvent such as methanol, ethanol, deoxy acid, tetrahydrofuran or the like. As an acid to be used, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid, etc. are preferable, for example, thionyl chloride may be added to an alcohol solvent, and an acid may be generated during reaction. The reaction temperature is usually room temperature to reflux temperature. In addition, the present reaction can be carried out by reacting 2 equivalents to a great excess of trimethylsilane iodide or trimethylsilane-sodium iodide in an organic solvent such as dichloromethane, chloroform, dichloroethane and acetonitrile. The reaction temperature is usually -78 ° C to reflux temperature of the solvent, and preferably -20 ° C to room temperature.
    [135] Manufacturing Method 13
    [136]
    [137] In formula, R <4> , W, Z, and l have the same meaning as the said definition, and L <5> represents a leaving group (for example, halogen atom etc.). The pyridonepiperidine derivative (I) -2 which is the compound which concerns on this invention can also be manufactured by hydrolyzing a bisubstituted pyridine derivative (X). The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, tert-butanol or the like is preferable. Although it does not specifically limit as a base used for a hydrolysis reaction, For example, potassium-tert-butoxide etc. are preferable. The reaction temperature is usually at room temperature to the reflux temperature of the solvent, preferably 100 to 140 ° C.
    [138] Manufacturing Method 14
    [139]
    [140] In formula, R <1> , W, Z, and l show the same meaning as the above definition, and TBSO- in a formula means tert- butyl dimethyl silyl ether. Compound (I) -2 according to the present invention can be produced by condensing piperidine derivative (II) and pyridine derivative (X) in reduction amination in an organic solvent. The solvent used is not particularly limited as long as it does not interfere with the reaction and dissolves the starting material to some extent. For example, ethers such as tetrahydrofuran, dioxy acid, diethylene glycol dimethyl ether, dichloromethane, chloroform, dichloroethane Halogenated carbons such as these, other ethyl acetate, dimethylformamide, dimethyl sulfoxide and the like are preferable. As the reducing agent to be used, for example, metal hydrides such as sodium borohydride and sodium triacetoxy borohydride are preferable, and it is also possible to use a catalytic reduction method usually used. The use amount of metal hydride is 1-5 equivalents with respect to a raw material. In this reaction, the tert-butyldimethylsilyl group is naturally deprotected by the acidity of the silica gel used in the purification step of the product. The reaction temperature is usually at -50 ° C to the reflux temperature of the solvent, and preferably around 0 to 25 ° C.
    [141] Manufacturing Method 15
    [142]
    [143] In formula, R <1> , R <2> , W, Z, and l have the same meaning as the above definition, and L <6> represents a leaving group (for example, a halogen atom, a tosyl group, a mesyl group, etc.). N-substituted pyridone piperidine derivative (I) -3, which is a compound according to the present invention, is prepared by reacting pyridonepiperidine derivative (I) -2 with compound R 2 L 6 in an organic solvent at the same time with a suitable base. can do. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone, tetrahydrofuran (THF), or deoxy Acids, ethers, such as diethylene glycol dimethyl ether, halogenated carbons, such as dichloromethane, chloroform, dichloroethane, other ethyl acetate, ethanol, methanol, etc. are preferable. As a base to be used, sodium hydride, potassium-tert-butoxide, potassium methoxide, lithium diisopropylamide, potassium carbonate, sodium hydroxide, etc. are preferable, for example. The use amount of base is 1-10 equivalent with respect to a raw material. The amount of the compound R 2 L 6 is a great amount of 1 equivalent to excess amount relative to the raw material. The reaction temperature is usually room temperature to reflux temperature.
    [144] Manufacturing Method 16
    [145]
    [146] In formula, R <1> , l and g have the same meaning as the said definition. The piperidine aldehyde derivative (IV) which becomes a raw material in said "reaction 2, 4, 7" can be manufactured by oxidizing an alcohol derivative (XI). The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidone, tetrahydrofuran, dioxy acid, di Ethers such as ethylene glycol dimethyl ether, halogenated carbons such as dichloromethane, chloroform and dichloroethane, other ethyl acetate, acetonitrile, toluene and the like are preferable. As the oxidation method used for the oxidation reaction, for example, an oxidation method using pyridinium chlorochromium, manganese dioxide, pyridinium dichromate as an oxidizing agent, or oxidation methods such as swan oxidation, Jones oxidation, Cohley-Khim oxidation and the like are preferable. The reaction temperature is usually -50 to reflux temperature of the solvent.
    [147] Manufacturing Method 17
    [148]
    [149] In formula, R <1> , l and g have the same meaning as the above definition, and L <7> represents a leaving group (for example, halogen atom, tosylate, etc.) or an aldehyde group. The pyridylpiperidine derivative (XI), which is a raw material for the above-described reaction 17, may be prepared by condensing piperidine derivative (XIII) and pyridine derivative (XII) by reduction amination or in the presence of a base. Can be. This reaction can be carried out under the same conditions as in the above-described "reaction 1". A pyridine derivative (XII) may be used by purchasing a commercial item, and adjusting it according to a conventional method about what is not marketed.
    [150] Manufacturing Method 18
    [151]
    [152] In the formula, R 1 and 1 have the same meaning as in the above definition, and Hal 1 and Hal 2 each represent the same or different halogen atom. The alkynyl piperidine derivative (V) as a raw material of the above-mentioned "reaction 3" can be manufactured by the dehalogenation reaction of an olefin derivative (XIV). The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, toluene and the like are preferable. Do. As a base to be used, n-butyllithium, sec-butyllithium, tert- butyllithium, etc. are preferable, for example. The use amount of base is 1-10 equivalent with respect to a raw material. The reaction temperature is usually -100 to -50 ° C.
    [153] Manufacturing Method 19
    [154]
    [155] In formula, R <1> , l, Hal <1> and Hal <2> show the same meaning as the said definition. The olefin derivative (XIV) which is a raw material of the above-mentioned "reaction 19" can be produced by reacting piperidine aldehyde derivative (IV) -1 and tetrahalogenated carbon in the presence of triphenylphosphine. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, 1-methylpyrrolidone, tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, and the like. Ethers, halogenated carbons such as dichloromethane, chloroform, dichloroethane, other ethyl acetate, acetonitrile, toluene and the like are preferable. As a base to add, tertiary amine, such as triethylamine and diisopropylethylamine, etc. are preferable, for example. The use amount of base can use 2 equivalent thru | or large excess with respect to a raw material. The reaction temperature is usually -50 to 80 ° C, preferably around 0 ° C.
    [156] Manufacturing Method 20
    [157]
    [158] Expression from, R 1 and l have the same meanings as defined above, L 8 is a leaving group (e.g. a halogen atom, tosylate, mesylate, triflate), Q 3 is a substituent (e.g., C 1- 6 alkoxy group, alkylamino group, etc.), n represents the integer of 1-3. In the pyridonepiperidine derivative (I) -2 obtained in said "reaction 13, 14, and 15", the compound (I) -2-1 whose Z is a pyridyl group which has a leaving group in 2nd position is a suitable nucleophilic reagent It can be converted into compound (I) -2-2 according to the present invention by reacting with. This reaction can be carried out under the same conditions as in the above-described "reaction 9".
    [159] Manufacturing Method 21
    [160]
    [161] In formula, R <1> , l, W, Z, and L <5> have the same meaning as the above definition, and L <9> represents a leaving group (for example, halogen atom, tosylate, etc.) or an aldehyde group. The pyridylpiperidine derivative (IX) which is a raw material of "reaction 14" can be prepared by condensing piperidine derivative (II) and pyridine derivative (XV) in a solvent in accordance with reduction amination or in the presence of a base. Can be. This reaction can be carried out under the same conditions as in "reaction 1". The pyridine derivative (XV) to be used can be purchased as a commercial product and can be easily adjusted and used according to a conventional method from known raw materials when it is not commercially available.
    [162] Manufacturing Method 22
    [163]
    [164] In the formula, W and Z represent the same meanings as the above definitions, and Q 4 represents a group usually used for protecting an amino group. Piperidine derivative (II) can be manufactured by deprotection of the piperidine derivative (XVI) which has a protecting group. Deprotection can be performed on the conditions of the deprotection normally used. For example, when Q 4 is a benzyloxycarbonyl group, it can be carried out by a catalytic reduction method using palladium carbon as a catalyst in an organic solvent, and when Q 4 is a tert-butyloxycarbonyl group, in the organic solvent or with water This can be done by reacting a suitable acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like in a mixed solvent of an organic solvent. Moreover, when Q <4> is a benzyl group, it can also carry out by carrying out 1-chloroethyl chloroformate and methanol in a suitable organic solvent (for example, halogen solvents, such as dichloroethane) sequentially.
    [165] Manufacturing Method 23
    [166]
    [167] In formula, Z and Q <4> show the same meaning as the said definition, and p shows the numerical value of either 0 or 1. The piperidine aldehyde derivative (XVIII), which is a raw material for the above-mentioned "reaction 23," can be produced by subjecting the piperidine aldehyde derivative (XVII) to catalytic reduction of an olefin derivative produced by reacting the Witich reagent in the presence of a base. The Wittig reaction can be carried out according to the conditions of the above-described "reaction 2". If it is a commercial item, it will be purchased, and it can be easily adjusted and used according to a conventional method about what is not commercially available. The contact reduction in this reaction can be performed in accordance with the conditions of the above-mentioned "reaction 4".
    [168] Manufacturing Method 24
    [169]
    [170] In formula, R <4> , R <5> and Q <4> represent the same meaning as the said definition, and q shows the integer of 1-2. The amide derivative (XX) as a raw material for the preparation of the compound according to the present invention can be prepared by a common condensation reaction of a carboxylic acid derivative (XIX) and an amine represented by the formula HN (R 4 ) R 5 in an organic solvent. . This reaction can be carried out under the same conditions as in the above "reaction 12".
    [171] Manufacturing Method 25
    [172]
    [173] In formula, Q <4> and q show the same meaning as the said definition. The carboxylic acid derivative (XIX) as a raw material for the "reaction 25" can be produced by protecting the nitrogen atom of the piperidine derivative (XXI) with a suitable group. This reaction can be performed under the conditions normally used for protection of an amino group. For example, in the case of Q 4 being a tert-butoxycarbonyl (Boc) group, di-tert-butyl dicarbonate or the like is preferable as the Bocation reagent, and the amount thereof is 1 to 5 equivalents relative to the raw material. Bocation can be performed in the mixed solvent of water and an organic solvent, such as tert-butanol, in presence of a base, and reaction temperature is 0-80 degreeC normally, Preferably it is 0-25 degreeC.
    [174] Manufacturing Method 26
    [175]
    [176] In formula, R <1> , l, g, h, and Z <4> represent the same meaning as the said definition, and Z <4> represents the 5-14 membered aromatic group which may be substituted. Compound (XXII) according to the present invention can be prepared by adding 1 or 2-metal aryl to the aldehyde derivative (IV) to form an alcohol intermediate, followed by dehydration. The metal aryl used by 1 and 2-addition purchases what is marketed, and can be adjusted and used according to a conventional method about what is not marketed. The usage-amount of a metal aryl is 1-5 equivalents with respect to a raw material. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include ethers such as tetrahydrofuran (THF), dioxy acid, ether, and diethylene glycol dimethyl ether, and the like. Toluene, benzene, etc. are preferable. The reaction temperature is usually -78 to 0 ° C. Examples of the dehydrating agent used in the dehydration reaction include acids such as p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphorus oxychloride. And acid chlorides such as thionyl chloride are preferable. When an acid chloride is used as the dehydrating agent, good results can be obtained even if a base such as pyridine, triethylamine, diisopropylethylamine and the like coexist during the reaction. The reaction can be carried out in a solvent-free or suitable solvent. The solvent to be used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and other toluene and benzene are preferable. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and preferably 0 to 120 ° C.
    [177] Manufacturing Method 27
    [178]
    [179] In formula, R <1> , R <2> , W, Z, and l show the same meaning as the said definition. Compound (I) -2 according to the present invention can be prepared by condensation of piperidine derivative (II) and pyridine derivative (YYYY) in a solvent by reduction amination. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid and diethylene glycol dimethyl ether, dichloromethane and chloroform And halogenated carbons such as dichloroethane, ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1-methylpyrrolidone, acetonitrile and the like are preferable. As a reducing agent, metal hydrides, such as sodium borohydride and sodium triacetoxy borohydride, can be used, and can also be performed by the catalytic reduction method normally used. The usage-amount of a reducing agent is 1-5 equivalents with respect to a raw material. The reaction temperature is usually -50 ° C to reflux temperature of the solvent, and preferably 0 to 25 ° C.
    [180] Manufacturing Method 28
    [181]
    [182] In formula, R <1> and l have the same meaning as the said definition, X is a leaving group (for example, a halogen atom, a triflate, etc.), R <1> -L represents an aryl metal compound or an alkyl metal compound. Examples of the aryl metal compound or alkyl metal compound used in the present reaction include aryl boronic acid, aryl tributyl tin, alkyl boronic acid, alkyl tributyl tin, and other commonly used alkoxy borane derivatives and alkyl borane derivatives. For example. The amount of the aryl metal compound or alkyl metal compound used is usually 1 to 5 equivalents to the raw material, preferably around 2 equivalents. As a catalyst to be used, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenyl phosphine) palladium (II), etc. are mentioned, for example. The amount of the catalyst used is about 0.05 mol% based on the raw materials. The solvent used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. For example, tetrahydrofuran (THF), dioxy acid, diethylene glycol dimethyl ether, toluene, benzene, dimethylformamide ( DMF), 1-methylpyrrolidone and the like are preferred. When aryl boronic acid or alkyl boronic acid is used as an aryl metal compound or an alkyl metal compound, it is preferable to coexist bases, such as potassium carbonate, cesium carbonate, and sodium carbonate, or these aqueous solutions. The reaction temperature is usually at room temperature to the reflux temperature of the solvent, preferably 80 to 130 ° C.
    [183] Manufacturing Method 29
    [184]
    [185] In formula, R <1> and l have the same meaning as the said definition, X represents a leaving group (for example, halogen atom, triflate, etc.). Compound (XXVI) can be manufactured according to the conditions of acetalization normally used from an aldehyde derivative (XXV). For example, trimethyl ortho formate, dimethoxypropane, or the like can be obtained by reacting in an organic solvent in the presence of a catalyst (for example, p-toluenesulfonic acid) or montmorillonite K-10.
    [186] Manufacturing Method 30
    [187]
    [188] In formula, R <1> and l have the same meaning as the said definition, X represents a leaving group (for example, halogen atom, triflate, etc.). Compound (XXVII) is obtained by reacting acetal derivative (XXVI) with a cyanide compound in the presence of copper (I) iodide and a catalyst, followed by hydrolysis of acetal. As a cyan compound used, sodium cyanide, potassium cyanide, zinc cyanide, etc. are mentioned, for example. The amount of the cyan compound used is usually 1 to 5 equivalents based on the raw material, preferably about 2 equivalents. As a catalyst to be used, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenyl phosphine) palladium (II), etc. are mentioned, for example. The amount of the catalyst used is about 0.001 to 0.1 mol% with respect to the raw material. The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without disturbing the reaction. DMF), 1-methylpyrrolidone, acetonitrile, propionitrile and the like are preferred. The reaction temperature is usually at room temperature to the reflux temperature of the solvent, preferably 80 to 140 ° C.
    [189] Hydrolysis reaction can be performed by the conditions of the hydrolysis used normally. For example, it can be performed by reacting a suitable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid in an organic solvent or a mixed solvent of water and an organic solvent.
    [190] Manufacturing Method 31
    [191]
    [192] In the formula, l represents the same meaning as the above definition. The compound (XXIX) according to the present invention can be prepared by reacting acetal derivative (XXVIII) with an organometallic reagent, metallizing it, reacting with a fluorinating agent, and then hydrolyzing the acetal. Metallization can be performed by the conditions of metallization normally used. Examples of the organometallic reagent used for metallization include n-butyllithium, sec-butyllithium, tert-butyllithium and phenyllithium. Examples of the fluorinating agent include N-fluoroimides such as N-fluorobenzenesulfonimide or N-fluoropyridinium derivatives such as N-fluoro-4-methylpyridinium-2-sulfonate. Can be mentioned. The usage-amount of a fluorination agent is 1-2 equivalents with respect to a raw material. The solvent to be used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid, ether, and diethylene glycol dimethyl ether are preferable. Do. The reaction temperature is usually -78 to 0 ° C, preferably -78 to -40 ° C.
    [193] Hydrolysis reaction can be performed by the conditions of the hydrolysis used normally. For example, the reaction can be carried out by reacting a suitable acid such as hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid in an organic solvent or a mixed solvent of water and an organic solvent.
    [194] Manufacturing Method 32
    [195]
    [196] In the formula, l represents the same meaning as the above definition, and R represents an aralkyl group. Compound (XXX) according to the present invention can be prepared by reacting acetal derivative (XXVIII) with an organometallic reagent to metallize it, reacting with an organosulfur compound, oxidizing an aralkylthio group, and then hydrolyzing the acetal. . Metallization can be performed by the conditions of metallization normally used. Examples of the organometallic reagent used for metallization include n-butyllithium, sec-butyllithium, tert-butyllithium and phenyllithium. As an organosulfur compound used for alkylthioation, disulfides, such as dimethyl disulfide and diphenyl disulfide, sulfen chlorides, such as phenyl sulfen chloride, etc. are mentioned, for example. The usage-amount of an organic sulfur compound is 1-2 equivalents with respect to a raw material. The solvent to be used is not particularly limited as long as the starting material is dissolved to some extent without inhibiting the reaction. For example, ethers such as tetrahydrofuran (THF), dioxy acid, ether, and diethylene glycol dimethyl ether are preferable. Do. The reaction temperature is usually -78 to 0 ° C, preferably -78 to -40 ° C.
    [197] The oxidation reaction of the aralkylthio group to the aralkylsulfonyl group can be carried out under the conditions of oxidation which are usually used. For example, it can carry out by making an inorganic peroxide like hydrogen peroxide or an organic peroxide like m-chloroperbenzoic acid react in halogen-type hydrocarbon solvents, such as dichloromethane. In this reaction, it is preferable to coexist bases such as sodium bicarbonate, sodium carbonate and potassium carbonate.
    [198] Subsequent hydrolysis reaction can be performed by the conditions of the hydrolysis used normally. For example, it can be performed by reacting a suitable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid in an organic solvent or a mixed solvent of water and an organic solvent.
    [199] Although the above is a manufacturing method of the compound (I) which concerns on this invention, the raw material compound in manufacture of the compound of this invention may form a salt and a hydrate, and if it does not inhibit a reaction, it will not specifically limit. Moreover, when compound (I) which concerns on this invention is obtained as a vitreous body, it can convert into the state of the salt which the said compound (I) may form according to a conventional method. In addition, when the compound which concerns on this invention is manufactured as a vitreous body, it can convert into the state of a salt by a conventional method. In addition, various isomers (e.g., geometric isomers, optical isomers based on sub-carbons, stereoisomers, tautomers, etc.) obtained with respect to the compound (I) according to the present invention are ordinary separation means (e.g., recrystallization, partial Stereoisomerization, enzymatic fractionation, various chromatography, etc.), can be purified and isolated.
    [200] The compound represented by the formula (I) or a salt thereof or a hydrate thereof according to the present invention can be formulated by a conventional method, and preferred formulations are tablets, powdered medicines, granules, granules, coated tablets and capsules. , Syrups, torokis, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, popsicles, lotions and the like. In formulating, excipients, binders, disintegrating agents, lubricants, coloring agents, colloids, and stabilizing agents, emulsifiers, absorption accelerators, surfactants, pH adjusting agents, preservatives, antioxidants, and the like, which are commonly used, can be used. Generally, the ingredients used as raw materials for pharmaceutical preparations can be blended to be formulated by conventional methods. As these components, For example, animal and vegetable oils, such as soybean oil, tallow, synthetic glycerides; Hydrocarbons such as liquid paraffin, squalane and solid paraffin; Ester oils such as myristic acid octyldodecyl and myristic acid isopropyl; Higher alcohols such as cetostearyl alcohol and behen alcohol; Silicone resin; Silicone oil; Surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene polyoxypropylene block copolymer; Water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methyl cellulose; Lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; Sugars such as glucose and sucrose; Inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate, purified water and the like. Specifically, excipients include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like; As the binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gum tragacanth, gelatin, cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone Polypropylene glycol polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin and the like; As a disintegrating agent, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium and the like; Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, and the like; As a coloring agent, what kind of thing may be used as long as it is authorized to add to a pharmaceutical product; As mating agent, cocoa mal, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder, etc .; As antioxidant, what is permitted to add to pharmaceuticals, such as ascorbic acid and (alpha) -tocopherol, is used, respectively.
    [201] For example, (1) The oral agent is added to the compound or the salt thereof or the hydrate and the excipient according to the present invention and, if necessary, the binder, disintegrant, lubricant, colorant, colloid agent, etc. Powder, granules, granules, tablets, coated tablets, capsules and the like. (2) In the case of tablets and granules, of course, coating of sugar, gelatin, and other necessities is not a problem. (3) In the case of syrups, injectable preparations, eye drops, etc., a pH adjusting agent, a solubilizing agent isotonic agent, and the like, and a dissolution aid, stabilizer, buffer, suspending agent, antioxidant, and the like are added, if necessary, and formulated by a conventional method. do. In the case of the above-mentioned agent, it is also possible to use a lyophilisate, and the injection can be administered intravenously, subcutaneously or intramuscularly. Preferable examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, gum tragacanth powder, carboxymethyl cellulose sodium, polyoxyethylene sorbitan monolaurate and the like; Preferable examples of the dissolution aid include polyoxyethylene hardened castor oil, polysorbate 80, niacinamide, polyoxyethylene sorbitan monolaurate and the like; Preferred examples of the stabilizer include sodium sulfite, sodium metasulfite, ether and the like; Preferred examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like. (4) Moreover, in the case of external preparations, a manufacturing method is not specifically limited, It can manufacture by a normal method. As the base material to be used, it is possible to use various raw materials commonly used in medicine, quasi-drugs, cosmetics, etc., for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants Raw materials such as phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water, and the like, and pH adjusters, antioxidants, chelating agents, preservatives, coloring agents, flavoring agents, and the like may be added as necessary. . If necessary, a component having a differentiation-inducing action, a blood flow promoting agent, a bactericide, an anti-inflammatory agent, a cell-activating agent, a vitamin, an amino acid, a humectant, a keratin soluble agent and the like may be blended. The dosage of the medicament according to the present invention varies depending on the severity of symptoms, age, sex, weight, type of dosage form, salt, difference in sensitivity to drugs, and specific types of diseases. About 30 μg to 1000 mg, preferably 100 μg to 500 mg, more preferably 100 μg to 100 mg, by injection about 1 to 3000 μg / kg, preferably 3 to 1000 μg / kg, each once or Administer in several portions.
    [202] The compound represented by the formula (I) according to the present invention, or a salt thereof or a hydrate thereof has excellent Na + channel inhibitory activity and is useful as a Na + channel inhibitor. Therefore, the compound which concerns on this invention, its salt, or its hydrate, and the pharmaceutical composition containing these can exhibit the outstanding therapeutic and preventive effect with respect to the disease for which Na + channel inhibitory effect is effective for treatment and prevention. For example, arrhythmia (other, symptoms based on atrial fibrillation, for example, palpitations, palpitations, chest discomfort, heart failure, left atrial thrombus, thromboembolism, seizures, etc.), various neuralgias (e.g., For example, diabetic neuralgia, HIV neuralgia, post shingles neuralgia, trigeminal neuralgia, short pain, spinal cord injury pain, hypothalamus, post-stroke pain, etc.
    [203] As the best embodiment in the compound according to the present invention, examples are given below, but these reference examples, examples and pharmacologically acceptable salts thereof, their hydrates, and medicaments and test examples including them are illustrative. In any case, the compound according to the present invention is not limited to the following specific examples. Those skilled in the art can implement the present invention to the maximum by adding various changes to the scope of the claims as well as the examples shown below, and such changes are included in the scope of the claims.
    [204] Reference Example 1
    [205] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinemethanol
    [206] 10 g of 4-piperidinemethanol, 13 g of 3- (chloromethyl) -2-methoxypyridine and 24 g of potassium carbonate were suspended in 80 ml of N, N-dimethylformamide and stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 16.1 g of the title compound as a light brown oil.
    [207] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.38 (2H, m), 1.52 (1H, m), 1.68-1.76 (2H, m), 2.01-2.09 (2H, m), 2.90-2.96 (2H, m), 3.49 (2H, s), 3.50 (2H, d, J = 7.5 Hz), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.65 (1H, dd, J = 7.2, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [208] Reference Example 2
    [209] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde
    [210] 16.1 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinemethanol and 38 ml of triethylamine were suspended in 60 ml of dimethylsulfoxide, 21.7 g of sulfur trioxide-pyridine complex and dimethyl sulfoxide The mixed solution of side 100 ml was dripped, and it stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 10.9 g of the title compound as a pale yellow oil.
    [211] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.66-1.76 (2H, m), 1.87-1.94 (2H, m), 2.15-2.30 (3H, m), 2.82-2.88 (2H, m), 3.50 ( 2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.63 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 5.0, 2.0 Hz), 9.66 (1H, d, J = 1.1 Hz).
    [212] Reference Example 3
    [213] 1-benzyl-4- (2,3-methylenedioxyphenethyl) piperidine
    [214] 20.3 g of 4- (1-benzyl) piperidinecarboxaldehyde and 48.0 g of (2,3-methylenedioxybenzyl) triphenylphosphonium bromide and 12.0 g of potassium t-butoxide were added to N, N-dimethylformamide. It was suspended in 200 ml and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4). The resulting product and 2.03 g of 10% palladium-carbon powder (water) were suspended in 200 ml of ethanol, hydrogenated in the vessel, and then stirred at atmospheric pressure and room temperature for 2 hours. The reaction solution was filtered, and the filtrate was removed under reduced pressure to give 20.3 g of the title compound as a colorless oil.
    [215] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.36 (3H, m), 1.52-1.59 (2H, m), 1.68-1.75 (2H, m), 1.88-1.96 (2H, m), 2.84- 2.91 (2H, m), 3.48 (2H, s), 5.91 (2H, s), 6.63-6.69 (2H, m), 6.74 (1H, dd, J = 7.8, 7.8 Hz), 7.24 (1H, m) , 7.29-7.33 (4H, m).
    [216] Reference Example 4
    [217] 4- (2,3-methylenedioxyphenethyl) piperidine
    [218] 20.3 g of 1-benzyl-4- (2,3-methylenedioxyphenethyl) piperidine is dissolved in 100 ml of 1,2-dichloroethane, 7 ml of 1-chloroethylchloroformate is added under ice-cooling, and 30 minutes It was heated to reflux. The solvent was removed, and the obtained residue was dissolved in 100 ml of methanol and heated to reflux for 1 hour. The solvent was removed, the residue obtained was made alkaline with 5N aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate) to give 13.1 g of the title compound as a pale yellow oil.
    [219] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.08-1.20 (2H, m), 1.39 (1H, m), 1.52-1.59 (2H, m), 1.70-1.78 (2H, m), 2.53-2.62 ( 4H, m), 3.03-3.10 (2H, m), 5.93 (2H, s), 6.64-6.70 (2H, m), 6.76 (1H, dd, J = 7.8, 7.8 Hz).
    [220] Reference Example 5
    [221] 3-methylthio-2-thiophenecarboxaldehyde
    [222] 4.44 g of 3-bromo-2-thiophenecarboxaldehyde and 1.63 g of sodium thiomethoxide were dissolved in 20 ml of N and N-dimethylformamide and stirred for 3 hours under ice-cooling. Ethyl acetate was added to the reaction solution, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give 3.36 g of the title compound as a yellow oil.
    [223] 1 H-NMR (400 MHz, CDCl 3 ) δ 2.59 (3H, s), 7.10 (1H, d, J = 5.1 Hz), 7.73 (1H, dd, J = 5.1, 0.9 Hz), 10.0 (1H, d , J = 0.9 Hz).
    [224] Reference Example 6
    [225] 3-methylthio-2-thiophenmethanol
    [226] 3.36 g of 3-methylthio-2-thiophenecarboxaldehyde and 802 mg of sodium borohydride were suspended in 20 ml of methanol and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain 3.16 g of the title compound as a colorless oil.
    [227] 1 H-NMR (400 MHz, CDCl 3 ) δ 2.05 (1H, t, J = 4.8 Hz), 2.42 (3H, s), 4.87 (1H, d, J = 4.8 Hz), 7.03 (1H, d, J = 5.3 Hz), 7.27 (1H, d, J = 5.3 Hz).
    [228] Reference Example 7
    [229] [(3-methylthio-2-thienyl) methyl] triphenylphosphonium chloride
    [230] 6.26 g of 3-methylthio-2-thiophenmethanol was dissolved in 40 ml of dichloromethane, 2.85 ml of thionyl chloride was added dropwise under ice-cooling, and stirred for 30 minutes under ice-cooling. The reaction solution was washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product and 15.4 g of triphenylphosphine were dissolved in 120 ml of toluene and heated to reflux for 20 hours. The precipitated crystals were filtered, washed with ethyl acetate and air dried to give 14.3 g of the title compound as colorless crystals.
    [231] 1 H-NMR (400 MHz, CDCl 3 ) δ 2.07 (3H, s), 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 (6H, m), 7.72-7.83 (9H, m).
    [232] Reference Example 8
    [233] 1-tert-butoxycarbonyl-4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine
    [234] 14.4 g of [(3-methylthio-2-thienyl) methyl] triphenylphosphonium chloride and 3.67 g of potassium tert-butoxide are dissolved in 120 ml of N, N-dimethylformamide, and 1-tert-butoxy is cooled on ice. A mixed solution of 6.97 g of carbonyl-4-piperidinecarboxaldehyde and 30 ml of N and N-dimethylformamide was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10). The obtained product was dissolved in 40 ml of chloroform, 3.59 g of 3-chloroperbenzoic acid was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated sodium thiosulfate aqueous solution was added to the reaction solution, the organic layer was separated, the organic layer was washed with 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3). The resulting product and 3.0 g of 10% palladium-carbon powder (water) were suspended in 150 ml of ethanol, hydrogenated in the vessel, and then stirred at atmospheric pressure and room temperature for 4 hours. After the reaction solution was filtered, the solvent of the filtrate was removed under reduced pressure to give 11.1 g of the title compound as a pale yellow oil.
    [235] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.10-1.22 (2H, m), 1.46 (9H, s), 1.58-1.64 (2H, m), 1.66-1.77 (3H, m), 2.63-2.75 ( 2H, m), 3.06 (3H, s), 3.18-3.24 (2H, m), 4.10 (2H, br s), 7.19 (1H, dd, J = 5.5, 0.4 Hz), 7.31 (1H, d, J = 5.5 Hz).
    [236] Reference Example 9
    [237] 4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine hydrochloride
    [238] 11.1 g of 1-tert-butoxycarbonyl-4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine was dissolved in 100 ml of ethyl acetate, and 100 ml of 4N ethyl acetate solution was added thereto. It stirred at room temperature for 2 hours. The precipitated crystals were filtered, washed with ethyl acetate and dried naturally to obtain 7.92 g of the title compound as colorless crystals.
    [239] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.42 (2H, m), 1.48-1.65 (3H, m), 1.82-1.88 (2H, m), 2.76-2.88 (2H, m), 3.12-3.18 (2H, m), 3.20 (3H, s), 3.20-3.28 (2H, m), 7.31 (1H, d, J = 5.5 Hz), 7.57 (1H, d, J = 5.5 Hz).
    [240] Reference Example 10
    [241] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2,2-dibromovinyl) piperidine
    [242] 3.0 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidine acetaldehyde, 5.4 ml of triethylamine, 20.1 g of triphenylphosphine and 12.9 g of carbon tetrabromide at 0 ° C. It dissolved in 77 ml and stirred for 1 hour. Dichloromethane was added to the reaction solution, washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 2.9 g of the title compound as a yellow oil.
    [243] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.44-1.60 (2H, m), 1.67-1.78 (2H, m), 2.07-2.20 (2H, m), 2.31 (1H, m), 2.84-2.94 ( 2H, m), 3.52 (2H, s), 3.95 (3H, s), 6.27 (1H, d, J = 9.1 Hz), 6.88 (1H, dd, J = 7.0, 5.0 Hz), 7.65 (1H, dd , J = 7.0, 1.5 Hz), 8.07 (1H, doublet of doublets, J = 5.0, 1,5 Hz).
    [244] Reference Example 11
    [245] 1-[(2-methoxy-3-pyridyl) methyl] -4- (1-ethynyl) piperidine
    [246] 2.9 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- (2,2-dibromovinyl) piperidine was dissolved in 25 ml of tetrahydrofuran and treated at 1.78 M at -78 ° C. 12.3 ml of n-butyllithium hexane solution was dripped. After completion of dropping, the mixture was stirred at -78 ° C for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the title compound was obtained quantitatively as a yellow oil.
    [247] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.66-1.77 (2H, m), 1.83-1.92 (2H, m), 2.07 (1H, d, J = 4.0 Hz), 2.17-2.29 (2H, m) , 2.41 (1H, m), 2.71-2.80 (2H, m), 3.48 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.4, 5.0 Hz), 7.64 (1H, dd , J = 7.4, 1.8 Hz), 8.05 (1H, dd, J = 5.0, 1,8 Hz).
    [248] Reference Example 12
    [249] 1-[(ethoxymethoxy) methyl] -3,4-methylenedioxybenzene
    [250] 4.56 g of piperonyl alcohol and 1.20 g of 60% sodium hydride were suspended in 30 ml of N and N-dimethylformamide, stirred for 30 minutes under ice-cooling, and then 2.28 ml of chloromethylethyl ether was added and stirred at room temperature for 1 hour. . Ethyl acetate was added to the reaction solution, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give 4.98 g of the title compound as a colorless oil.
    [251] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24 (3H, t, J = 7.1 Hz), 3.64 (2H, q, J = 7.1 Hz), 4.50 (2H, s), 4.73 (2H, s), 5.95 (2H, s), 6.78 (1H, d, J = 7.9 Hz), 6.81 (1H, dd, J = 7.9, 1.6 Hz), 6.86 (1H, dd, J = 1.6 Hz).
    [252] Reference Example 13
    [253] 1-[(ethoxymethoxy) methyl] -2- (methylthio) -3,4-methylenedioxybenzene
    [254] 1.05 g of 1-[(ethoxymethoxy) methyl] -3 and 4-methylenedioxybenzene were dissolved in 10 ml of diethyl ether, and 2 ml of 2.52 M n-butyllithium hexane solution was added at 0 ° C, followed by stirring for 2 hours. After that, 471 mg of methyl disulfide was added dropwise to -70 deg. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. An aqueous 1N sodium hydroxide solution was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give 561 mg of the title compound as a colorless oil.
    [255] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 3.66 (2H, q, J = 7.1 Hz), 4.68 (2H, s), 4.76 (2H, s), 6.03 (2H, s), 6.73 (1H, d, J = 7.9 Hz), 6.92 (1H, d, J = 7.9 Hz).
    [256] Reference Example 14
    [257] 1-[(ethoxymethoxy) methyl] -2- (methylsulfonyl) -3,4-methylenedioxybenzene
    [258] Dissolve 1.73 g of 1-[(ethoxymethoxy) methyl] -2- (methylthio) -3 and 4-methylenedioxybenzene in 70 ml of chloroform, add 3.33 g of 3-chloroperbenzoic acid under ice-cooling, and at room temperature Stir for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 1.87 g of the title compound as a colorless oil.
    [259] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25 (3H, t, J = 7.1 Hz), 3.24 (3H, s), 3.64 (2H, q, J = 7.1 Hz), 4.77 (2H, s), 4.94 (2H, s), 6.15 (2H, s), 6.97 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 8.1 Hz).
    [260] Reference Example 15
    [261] [2- (methylsulfonyl) -3,4-methylenedioxyphenyl] methanol
    [262] 571 mg of 1-[(ethoxymethoxy) methyl] -2- (methylsulfonyl) -3 and 4-methylenedioxybenzene were dissolved in 2 ml of dichloromethane, 2 ml of trifluoroacetic acid was added, and 30 minutes at room temperature. Stirred. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 308 mg of the title compound as colorless crystals.
    [263] 1 H-NMR (400 MHz, CDCl 3 ) δ 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).
    [264] Reference Example 16
    [265] [1- (Bromomethyl) -2- (methylsulfonyl) -3,4-methylenedioxybenzene
    [266] 907 mg of [2- (methylsulfonyl) -3, 4-methylenedioxyphenyl] methanol, 1.31 g of carbon tetrabromide and 1.03 g of triphenylphosphine were dissolved in 5 ml of dichloromethane and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 1.10 g of the title compound as colorless crystals.
    [267] 1 H-NMR (400 MHz, CDCl 3 ) δ3.31 (3H, s), 5.04 (2H, s), 6.19 (2H, s), 6.96 (1H, d, J = 8.1 Hz), 6.99 (1H, d, J = 8.1 Hz).
    [268] Reference Example 17
    [269] [2- (methylsulfonyl) -3,4-methylenedioxybenzyl] triphosphonium bromide
    [270] 1- (bromomethyl) -2- (methylsulfonyl) -3, 1.10 g of 4-methylenedioxybenzene, and 1.48 g of triphenylphosphine were dissolved in 20 ml of toluene and heated to reflux for 12 hours. The precipitated crystals were filtered off, washed with ether, and then air dried to yield 1.90 g of the title compound as colorless crystals.
    [271] 1 H-NMR (400 MHz, CDCl 3 ) δ 3.02 (3H, s), 5.90 (2H, d, J = 14.5 Hz), 6.15 (2H, s), 6.96 (1H, dd, J = 8.1, 0.9 Hz) , 7.30 (1H, doublet of doublets, J = 8.1,3.3 Hz), 7.62-7.70 (12H, m), 7.75-7.83 (3H, m).
    [272] Reference Example 18
    [273] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2-[[(trifluoromethyl) sulfonyl] oxy] -3-pyridyl] ethyl] piperidine
    [274] 110 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-oxo-1,2-dihydro-3-pyridinyl) ethyl] piperidine, N-phenyl ( 382 mg of trifluoromethyl) sulfonimide, 311 mg of triethylamine and 13 mg of dimethylaminopyridine were dissolved in 5 ml of tetrahydrofuran and stirred at room temperature for 20 hours. The solvent was removed under reduced pressure, and the residue was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give 151 mg of the title compound as a colorless oil.
    [275] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.40 (3H, m), 1.50-1.62 (2H, m), 1.67-1.76 (2H, m), 1.98-2.08 (2H, m), 2.65- 2.72 (2H, m), 2.87-2.94 (2H, m), 3.48 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.6, 5.2 Hz), 7.29 (1H, dd, J = 7.6, 4.8 Hz), 7.64 (1H, dd, J = 7.6, 2.0 Hz), 7.70 (1H, dd, J = 7.6, 2.0 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz), 8.21 (1H, doublet of doublets, J = 4.8, 2.0 Hz).
    [276] Reference Example 19
    [277] 1-[(6-bromo-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [278] From 457 mg of 4- (2,3-methylenedioxyphenethyl) piperidine and 409 mg of 6-bromo-2-pyridinecarboxaldehyde obtained in Reference Example 4, the title compound 636 mg was obtained as pale yellow oil. Obtained as.
    [279] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.38 (3H, m), 1.52-1.62 (2H, m), 1.70-1.78 (2H, m), 2.02-2.10 (2H, m), 2.56- 2.62 (2H, m), 2.83-2.90 (2H, m), 3.62 (2H, s), 5.92 (2H, s), 6.65 (1H, dd, J = 7.6, 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 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).
    [280] Reference Example 20
    [281] 1-[(2-chloro-3-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [282] 505 mg of 4- (2,3-methylenedioxyphenethyl) piperidine obtained from Reference Example 4 and 464 mg of 2-chloro-3-pyridinecarboxaldehyde as in Example 39 below, the title compound 673 mg was obtained as a colorless oil. Got it.
    [283] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.38 (3H, m), 1.55-1.62 (2H, m), 1.70-1.80 (2H, m), 2.06-2.16 (2H, m), 2.56- 2.62 (2H, m), 2.84-2.91 (2H, m), 3.59 (2H, s), 5.92 (2H, s), 6.66 (1H, dd, J = 7.8, 1.0 Hz), 6.68 (1H, dd, J = 7.8, 1.0 Hz), 6.76 (1H, dd, J = 7.8, 7.8 Hz), 7.23 (1H, dd, J = 7.2, 5.0 Hz), 7.87 (1H, dd, J = 7.2, 2.0 Hz), 8.27 (1H, doublet of doublets, J = 5.0, 2.0 Hz).
    [284] Reference Example 21
    [285] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineethanol
    [286] 8.2 g of 4-piperidine ethanol, 10.0 g of 3- (chloromethyl) -2-methoxypyridine and 17.5 g of potassium carbonate were suspended in 65 ml of N, N-dimethylformamide and stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound quantitatively as a yellow oil.
    [287] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.72 (7H, m), 2.00-2.10 (2H, m), 2.86-2.94 (2H, m), 3.49 (2H, s), 3.70 (2H, t, J = 6.7 Hz), 3.95 (3H, s), 6.87 (1H, dd, J = 7.0, 5.0 Hz), 7.65 (1H, dd, J = 7.0, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [288] Reference Example 22
    [289] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineacetoaldehyde
    [290] 17.4 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineethanol was prepared in the same manner as in Reference Example 6 to obtain 12.0 g of the title compound as a yellow oil.
    [291] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.43 (2H, m), 1.65-1.76 (2H, m), 1.91 (1H, s), 2.02-2.17 (2H, m), 2.83-2.94 ( 2H, m), 3.49 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.63 (1H, dd, J = 7.1, 1.9 Hz), 8.05 (1H , dd, J = 4.9, 1,9 Hz), 9.78 (1H, t, J = 2.0 Hz).
    [292] Reference Example 23
    [293] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidone
    [294] 4.0 g of 4-piperidone hydrochloride, 4.1 g of 3- (chloromethyl) -2-methoxypyridine and 12.6 g of potassium carbonate were suspended in 26 ml of N, N-dimethylformamide and stirred at room temperature for 15 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 5.5 g of the title compound as a yellow oil.
    [295] 1 H-NMR (400 MHz, CDCl 3 ) δ 2.45-2.52 (4H, m), 2.77-2.85 (4H, m), 3.64 (2H, s), 3.96 (3H, s), 6.90 (1H, dd, J = 7.1, 4.9 Hz), 7.70 (1H, dd, J = 7.1, 2.0 Hz), 8.09 (1H, dd, J = 4.9, 2.0 Hz).
    [296] Reference Example 24
    [297] Ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] hexahydro-4-pyridinylidene] acetate
    [298] To a suspension of 0.40 g of 60% sodium hydride (oil suspension) and 18 ml of tetrahydrofuran, a mixed solution of 2.2 ml of triethylphosphonoacetate and 18 ml of tetrahydrofuran was added dropwise under ice cooling, followed by stirring for 5 minutes, followed by 1-[( A mixed solution of 2.0 g of 2-methoxy-3-pyridyl) methyl] -4-piperidone and 9 ml of tetrahydrofuran was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 2.6 g of the title compound as a pale yellow oil.
    [299] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28 (3H, t, J = 6.9 Hz), 2.32-2.38 (2H, m), 2.54-2.62 (4H, m), 2.97-3.05 (2H, m) , 3.53 (2H, s), 3.95 (3H, s), 4.14 (2H, q, J = 6.9 Hz), 5.64 (1H, s), 6.88 (1H, dd, J = 7.2, 4.9 Hz), 7.67 ( 1H, dd, J = 7.2, 2.1 Hz), 8.07 (1H, dd, J = 4.9, 2.1 Hz).
    [300] Reference Example 25
    [301] Ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] acetate
    [302] 2.6 g of ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] hexahydro-4-pyridinylidene] acetate and 380 mg of 10% palladium-carbon powder (water) in 20 ml of ethyl acetate It suspended and hydrogen-substituted the inside of a container, and stirred for 1 hour under normal pressure and normal temperature. The reaction solution was filtered and the filtrate was removed under reduced pressure to give the title compound quantitatively as a yellow oil.
    [303] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25 (3H, t, J = 7.1 Hz), 1.28-1.41 (2H, m), 1.65-1.86 (3H, m), 2.02-2.12 (2H, m) , 2.23 (2H, d, J = 7.0 Hz), 2.84-2.92 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 4.12 (2H, q, J = 7.1 Hz), 6.86 ( 1H, dd, J = 7.2, 5.0 Hz), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 5.0, 2.0 Hz).
    [304] Reference Example 26
    [305] N- (tert-butoxycarbonyl) -4- [2- [2- (methylsulfonyl) phenyl] -2-oxoethyl] piperidine
    [306] 2.2 g of 2-bromothioanisole, 6.9 ml of 1.53 M n-butyllithium hexane solution and 2.0 g of N- (tert-butoxycarbonyl) -4-piperidine acetaldehyde were used in the same manner as in Example 71 below. 2.0 g of (tert-butoxycarbonyl) -4- [2-hydroxy-2- [2- (methylthio) phenyl] ethylethyl] piperidine was obtained as in Reference Example 12, followed by N- ( 2.0 g of tert-butoxycarbonyl) -4- [2- [2- (methylthio) phenyl] ethyl-2-oxoethyl] piperidine was obtained as a pale yellow oil. The resulting product and 2.7 g of 3-chloroperbenzoic acid were dissolved in 15 ml of tetrahydrofuran and stirred at room temperature for 2 hours. An aqueous sodium thiosulfate solution and an aqueous sodium hydroxide solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 1.8 g of the title compound as a yellow oil.
    [307] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.14-1.29 (2H, m), 1.46 (9H, s), 1.78-1.88 (2H, m), 2.22 (1H, m), 2.73-2.86 (2H, m), 2.87 (2H, d, J = 6.6 Hz), 3.25 (3H, s), 3.96-4.24 (2H, s), 7.40 (1H, d, J = 7.5 Hz), 7.62 (1H, dd, J = 7.8, 7.5 Hz), 7.70 (1H, dd, J = 7.5, 7.5 Hz), 8.07 (1H, d, J = 7.8 Hz).
    [308] Reference Example 27
    [309] Methyl 3- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidine] propanoate
    [310] 2.0 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde and 1.6 ml of trimethylphosphonoacetate and 60% sodium hydride obtained in Reference Example 2 were added to 30 ml of tetrahydrofuran. It was suspended and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product and 400 mg of 10% palladium-carbon powder (water) were suspended in 100 ml of ethanol, hydrogenated in the vessel, and then stirred at atmospheric pressure and room temperature for 20 hours. The reaction solution was filtered, the filtrate was removed under reduced pressure, and 2.20 g of the titled compound was obtained as a pale brown oil.
    [311] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.35 (3H, m), 1.55-1.70 (4H, m), 1.96-2.06 (2H, m), 2.33 (2H, t, J = 7.8 Hz) , 2.84-2.93 (2H, m), 3.48 (2H, s), 3.67 (3H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.2, 4.8 Hz), 7.63 (1H, dd , J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz).
    [312] Reference Example 28
    [313] 3- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] propanal
    [314] 2.20 g of methyl 3- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidine] propanoate was reduced by a conventional method using lithium aluminum hydride, and the obtained product was referred to. In the same manner as in Example 43, 1.29 g of the title compound was obtained as a pale yellow oil.
    [315] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.22-1.34 (3H, m), 1.56-1.70 (4H, m), 1.97-2.06 (2H, m), 2.45 (2H, td, J = 7.6, 7.6 , 1.8 Hz), 2.85-2.93 (2H, m), 3.48 (2H, s), 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, 2.0 Hz), 9.77 (1H, t, J = 1.8 Hz).
    [316] Reference Example 29
    [317] 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] -1-ethanol
    [318] 15.6 g of 2-methoxynicotinaldehyde, 14 g of 2-piperidinethanol, 30 g of sodium triacetoxy boron hydride, 6.6 ml of acetic acid, and 200 ml of tetrahydrofuran were stirred at room temperature for 1 hour. Dilute aqueous sodium hydroxide solution was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate followed by ethyl acetate-methanol = 2: 1).
    [319] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35-1.84 (8H, m), 1.93-2.04 (1H, m), 2.05-2.34 (1H, m), 2.76-2.85 (1H, m), 2.95 -3.02 (1H, m), 3.59 (1H, d, J = 16.0 Hz), 3.65-3.73 (1H, m), 3.84-3.92 (1H, m), 3.97 (3H, s), 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), 8.06 (1H, d, J = 6.8 Hz)
    [320] Reference Example 30
    [321] 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetaldehyde
    [322] 3 g of 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] -1-ethanol, triethylamine 7. 3 ml of the solution was dissolved in 15 ml of dimethyl sulfoxide (DMSO). The solution which melt | dissolved 4.2 g of pyridine sulfur- trioxide complexes in DMSO was dripped at internal temperature 20 degrees C or less. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. Sodium bicarbonate water was added, extraction was performed with ethyl acetate, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methanol) to give 2.5 g of reddish brown oil.
    [323] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36-1.83 (6H, m), 2.18-2.26 (1H, m), 2.59-2.69 (2H, m), 2.70-2.79 (1H, m), 2.98 -3.05 (1H, m), 3.37 (1H, d, J = 16.0 Hz), 3.76 (1H, d, J = 16.0 Hz), 3.95 (3H, s), 6.86 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.63 (1H, d, J = 6.8 Hz), 8.05 (1H, d, J = 6.8 Hz), 9.83 (1H, s)
    [324] Reference Example 31
    [325] 1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinecarboxaldehyde
    [326] 2-piperidinemethanol was used instead of 2-piperidineethanol and 1-[(2-methoxy-3-piperidyl) methyl] -2-piperidinecarboxyaldehyde was prepared according to the method of Reference Example 30. It was.
    [327] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.29-1.38 (1H, m), 1.46-1.80 (5H, m), 2.05-2.14 (1H, m), 2.86-2.97 (2H, m), 3.50 (1H, d, J = 16.0 Hz), 3.62 (1H, d, J = 16.0 Hz), 3.94 (3H, s), 6.88 (1H, dd, J = 6.8, 6.8 Hz), 7.64 (1H, dd, J = 6.8, 2.0 Hz), 8.08 (1H, dd, J = 6.8, 2.0 Hz), 9.60 (1H, s)
    [328] Reference Example 32
    [329] Ethyl 2- (2-piperidyl) acetate
    [330] 50 ml of ethyl 2- (2-pyridyl) acetate, 18.7 ml of acetic acid, 5 g of Pd-C (function), and 200 ml of ethanol were placed in an autoclave and stirred at 56 kg / cm 2 and 70 ° C. for 9 hours at a hydrogen pressure. Pd-C was filtered off to remove ethanol under reduced pressure to obtain 72.3 g of white crystals.
    [331] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.12 (3H, t, J = 7.2 Hz), 1.40-1.86 (6H, m), 1.96 (3H, s), 2.54 (1H, dd, J = 16.4 Hz, 7.2 Hz), 2.70-2.89 (2H, m), 3.10-3.20 (1H, m), 3.12-3.30 (1H, m), 4.13 (2H, q, J = 7.2 Hz), 8.39 (2H, s )
    [332] Reference Example 33
    [333] Ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetate
    [334] 25 g of ethyl 2- (2-piperidyl) acetate acetate, 15.6 g of 2-methoxynicotinaldehyde, 30 g of sodium triacetoxyborohydride, 6.6 ml of acetic acid, and 200 ml of THF were stirred overnight at room temperature. A diluted aqueous sodium hydroxide solution was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to give 2.8 g of a colorless oil.
    [335] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.12 (3H, t, J = 7.2 Hz), 1.40-1.80 (6H, m), 2.22-2.32 (1H, m), 2.42 (1H, dd, J = 16.4 Hz, 7.2 Hz), 2.62-2.73 (2H, m), 2.98-3.05 (1H, m), 3.41 (1H, d, J = 15.6 Hz), 3.70 (1H, d, J = 15.6 Hz), 2.95 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 6.86 (1H, dd, J = 7.6 Hz, 4.8 Hz), 7.69 (1H, dd, J = 7.6 Hz, 2.0 Hz), 8.02 (1H, dd, J = 4.8 Hz, 2.0 Hz)
    [336] Reference Example 34
    [337] 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetic acid
    [338] 2.8 g of ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetate, 20 ml of 2N sodium hydroxide aqueous solution and 20 ml of methanol were stirred at 70 ° C. for 1.5 hours. 8 ml of 5N aqueous hydrochloric acid solution was added, and the solvent was removed under reduced pressure. Ethanol was added to the residue and sodium chloride was filtered off. Ethanol was removed under reduced pressure to obtain 2.9 g of a colorless oil.
    [339] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35-1.80 (6H, m), 2.25-2.40 (2H, m), 2.60-2.70 (2H, m), 2.92-3.00 (1H, m), 3.49 (1H, d, J = 15.6 Hz), 3.77 (1H, d, J = 15.6 Hz), 3.90 (3H, s), 7.00 (1H, dd, J = 7.6 Hz, 4.8 Hz), 7.70 (1H, dd , J = 7.6 Hz, 2.0 Hz), 8.08 (1H, d, J = 4.8 Hz, 2.0 Hz)
    [340] Reference Example 35
    [341] 2-[(2R) -1- (tert-butoxycarbonyl) hexahydro-2-pyridyl] acetic acid
    [342] 29.3 g of 2-[(2R) hexahydro-2-pyridinyl] acetic acid, 8 g of sodium hydroxide, 44.7 g of di-tert-butyl dicarbonate, 240 ml of water and 180 ml of tert-butanol were stirred at room temperature overnight. The reaction solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 1.5 with aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure to obtain 18.6 g of the target substance as white crystals.
    [343] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35-1.75 (15H, m), 2.52-2.66 (2H, m), 2.73-2.84 (1H, m), 3.97-4.06 (1H, m), 4.67 -4.75 (1H, m)
    [344] Reference Example 36
    [345] tert-butyl (2R) -2- [2-di (2-propanylamino) -2-oxoethyl] hexahydro-1-pyridinecarboxylate
    [346] 7.4 g of 2-[(2R) -1- (tert-butoxycarbonyl) hexahydro-2-pyridinyl] acetic acid, 2.7 g of dipropargylamine, WSC (1-ethyl-3- (3-dimethylaminopropyl) 7.2 g of) carbodiimide hydrochloride), 2.0 g of HOBt (1-hydroxy-1 H-benzotriazole), and 50 ml of DMF were stirred at room temperature for 2 hours. Saturated brine was added, extraction was performed with ethyl acetate and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1 then 2: 1). 7.7 g of the target product was obtained as a yellow oil.
    [347] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.36-1.75 (15H, m), 2.22 (1H, s), 2.30 (1H, s), 2.50-2.60 (1H, m), 2.73-2.85 (2H , m), 3.93-4.05 (1H, m), 4.18-4.30 (2H, m), 4.30-4.45 (2H, m), 4.58-4.65 (1H, m)
    [348] Reference Example 37
    [349] N1, N1-di (2-propanyl) -2-[(2R) hexahydro-2-pyridyl] acetamide
    [350] 7.7 g of tert-butyl (2R) -2- [2- (di2-propynylamino) -2-oxoethyl] hexahydro-1-pyridinecarboxylate, 100 ml of 5N hydrochloric acid solution, 50 ml of methyl alcohol at room temperature for 1 hour Stirred. 110 ml of 5N aqueous sodium hydroxide solution was added, extracted with ethyl acetate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate, 4.4 g of the target substance which removed the organic solvent under reduced pressure was obtained as an oil.
    [351] [a] D = -23.4 ° (C = 0.74, MeOH, 28 ° C)
    [352] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.15-1.50 (3H, m), 1.56-1.63 (2H, m), 1.72-1.80 (1H, m), 2.21 (1H, s), 2.28 (1H , s), 2.40-2.48 (2H, m), 2.63-2.72 (1H, m), 2.93-3.03 (2H, m), 4.10-4.39 (4H, m)
    [353] Reference Example 38
    [354] 1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinecarboaldehyde
    [355] To a reaction solution of 8.7 g of 2-methoxynicotinaldehyde, 5.8 g of 2-piperidinmethanol, 3 ml of acetic acid, and 100 ml of THF, 17 g of sodium triacetoxyboron hydride was added at room temperature and stirred overnight. Diluted aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1, then ethyl acetate, then ethyl acetate: methanol = 4: 1) to obtain 5.4 g of an oil. The solution obtained by dissolving 5.4 g of the oily substance thus obtained, 14 ml of triethylamine, and 20 ml of DMSO, in which 8.0 g of pyridine sulfur-trioxide complex was dissolved in DMSO was added at an internal temperature of 20 ° C. or lower. After stirring at room temperature for 3 hours, cold sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane-ethyl acetate = 4: 1 then 3: 2, then 2: 1) to give 2.7 g of a yellow oil.
    [356] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28-1.80 (6H, m), 2.05-2.14 (1H, m), 2.85-2.96 (2H, m), 3.50 (1H, d, J = 14.8 Hz ), 3.62 (1H, d, J = 14.8 Hz), 3.94 (3H, s), 6.85 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.65 (1H, d, J = 6.8 Hz), 8.07 ( 1H, d, J = 6.8 Hz), 9.60 (1H, s)
    [357] Reference Example 39
    [358] Ethyl (E) -3- [1- (2-methoxy-3-pyridyl) methyl] -2-piperidyl] -2-propanoate
    [359] To a solution of 4.2 ml of triethylphosphonoacetate dissolved in 40 ml of THF, 2.4 g of tert-butoxy potassium was added under room temperature stirring. After 10 minutes a solution of 5 g of 1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinecarboaldehyde in THF was added under room temperature stirring. After stirring for 1 hour as it was, water was added and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1 then 2: 1) to obtain 3.4 g of an oil.
    [360] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.28-1.80 (6H, m), 1.94-2.02 (1H, m), 2.82-2.97 (2H, m ), 3.19 (1H, d, J = 14.8 Hz), 3.70 (1H, d, J = 14.8 Hz), 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 Hz, 6.8 Hz), 6.96 (1H, dd, J = 16.0 Hz, 7.0 Hz), 7.67 (1H, d, J = 6.8 Hz), 8.02 (1H, d, J = 6.8 Hz)
    [361] Reference Example 40
    [362] Ethyl 3- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] propanoate
    [363] 3.4 g of ethyl- (E) -3- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] -2-propenoate was dissolved in ethanol to give Pd-C (function 1 g of water) was added and catalytically reduced overnight under atmospheric pressure. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the remainder was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to give 1.58 g of a colorless oil.
    [364] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.03 (3H, t, J = 7.2 Hz), 1.30-1.73 (6H, m), 1.88-1.95 (2H, m), 2.09-2.17 (1H, m ), 2.23-2.45 (3H, m), 2.75-2.80 (1H, m), 3.26 (1H, d, J = 14.8 Hz), 3.83 (1H, d, J = 14.8 Hz), 3.95 (3H, s) , 4.10 (2H, q, J = 7.2 Hz), 6.84 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.67 (1H, d, J = 6.8 Hz), 8.02 (1H, d, J = 6.8 Hz )
    [365] Reference Example 41
    [366] (2-methoxy-3-pyridyl) methyl cyanide
    [367] 4 g of (2-methoxy-3-pyridyl) methyl chloride, 2.5 g of sodium cyanate, and 10 ml of DMF were heated and stirred at 100 ° C for 10 minutes. Water was added, extraction was performed with ethyl acetate and dried over magnesium sulfate. The desiccant was removed and the solvent was removed under reduced pressure. The remainder was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to give 2.5 g of a colorless oil.
    [368] 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.65 (2H, s), 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)
    [369] Reference Example 42
    [370] 2- (2-methoxy-3-pyridyl) acetic acid
    [371] 2.2 g of (2-methoxy-3-pyridyl) methyl cyanide, 35 ml of 5N sodium hydroxide aqueous solution and 35 ml of methanol were heated and stirred at 100 ° C for 1.5 hours. Returning to room temperature, 35 ml of 5N aqueous hydrochloric acid solution was added, and the solvent was removed under reduced pressure. Ethanol was added to the residue and the solids were filtered off. Ethanol was removed under reduced pressure, ethanol was added to the residue again and the solids were filtered off. Ethanol was removed under reduced pressure to obtain 2.4 g of white crystals.
    [372] 1 H-NMR (400 Hz, DMSO-d6) δ: 3.53 (2H, s), 3.86 (3H, s), 6.95 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.60 (1H, d, J = 6.8 Hz), 8.07 (1H, d, J = 6.8 Hz)
    [373] Reference Example 43
    [374] 2- (2-methoxy-3-pyridyl) ethanol
    [375] 2.4 g of 2- (2-methoxy-3-pyridyl) acetic acid, 550 mg of lithium aluminum hydride, and 20 ml of THF were stirred at room temperature for 0.5 hour. 0.27 ml of water, 3.9 ml of 3.8 N sodium hydroxide aqueous solution and 0.78 ml of water were processed sequentially, and the precipitated solid was filtered off. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 2: 1 then 1: 1) to obtain 1.2 g of a yellow oil.
    [376] 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.83 (3H, t, J = 7.2 Hz), 3.84 (2H, q, J = 7.2 Hz), 3.97 (3H, s), 6.83 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.42 (1H, d, J = 6.8 Hz), 8.03 (1H, d, J = 6.8 Hz)
    [377] Reference Example 44
    [378] 2- (2-methoxy-3-pyridyl) acetaldehyde
    [379] To a solution of 1.2 g of 2- (2-methoxy-3-pyridyl) ethanol and 4.8 ml of triethylamine in DMSO was added dropwise a solution of 2.7 g of pyridinesulfur-trioxide complex dissolved in DMSO at 20 ° C. or lower. After stirring for 0.5 hour, cold sodium bicarbonate water was added and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated under reduced pressure, and the remainder was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1) to give 200 mg of a yellow oil.
    [380] 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.60 (2H, s), 3.95 (3H, s), 6.85 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.40 (1H, d, J = 6.8 Hz), 8.10 (1H, d, J = 6.8 Hz)
    [381] Reference Example 45
    [382] [[(2- (cyclohexylmethyloxy) phenyl] methyl] triphenylphosphonium chloride
    [383]
    [384] 3.06 g of 2- (cyclohexylmethyloxy) benzyl alcohol was dissolved in 30 ml of toluene, 1.52 ml of thionyl chloride, 5 drops of N, N-dimethylformamide were added, and stirred for 70 minutes under ice-cooling. An aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Filtration with alumina removed the solvent under reduced pressure to give a pale yellow oil. The oil was dissolved in 3 ml of acetonitrile, 3.65 g of triphenylphosphine was added and stirred at 110 ° C. for 1 hour 45 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was collected by filtration to give 6.51 g of the title compound as a white powder.
    [385] 1 H-NMR (400 MHz, CDCl 3 ) δ0.75-0.89 (2H, m), 1.06-1.38 (4H, m), 1.51-1.58 (2H, m), 1.64-1.84 (3H, m), 3.21 ( 2H, d, J = 6.4 Hz), 5.34 (2H, d, J = 14.0 Hz), 6.59 (1H, d, J = 8.0 Hz), 6.80 (1H, dt, J = 8.0, 0.8 Hz), 7.22 ( 1H, m), 7.32 (1H, m), 7.58-7.68 (12H, m), 7.73-7.81 (3H, m)
    [386] Reference Example 46
    [387] Methyl 5-methyl-2-methoxy-3-pyridinecarboxylate
    [388]
    [389] 1.2 g of methyl 5-bromo-2-methoxy-3-pyridinecarboxylate is dissolved in 20 ml of N and N-dimethylformamide, 440 mg of methyl boronic acid, 4.79 g of cesium carbonate anhydride, and tetrakis (triphenylphosphine) Palladium 564 mg was added, and it stirred at 120 degreeC under nitrogen atmosphere for 2 hours. Ice water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 461 mg of the title compound as a colorless oil.
    [390] 1 H-NMR (400 MHz, CDCl 3 ) δ2.29 (3H, s), 3.90 (3H, s), 4.02 (3H, s), 7.99 (1H, d, J = 2.4 Hz), 8.12 (1H, d , J = 2.4 Hz)
    [391] Reference Example 47
    [392] Methyl 5-phenyl-2-methoxy-3-pyridinecarboxylate
    [393]
    [394] The title compound was obtained from the raw material according to the method of Reference Example 46.
    [395] 1 H-NMR (400 MHz, CDCl 3 ) δ3.94 (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)
    [396] Reference Example 48
    [397] Methyl 5- (3-pyridyl) -2-methoxy-3-pyridinecarboxylate
    [398]
    [399] The title compound was obtained from the raw material according to the method of Reference Example 46.
    [400] 1 H-NMR (400 MHz, CDCl 3 ) δ3.95 (3H, s), 4.11 (3H, s), 7.41 (1H, ddd, J = 8.0, 4.8, 1.2 Hz), 7.86 (1H, ddd, J = 8.0, 2.4, 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, 1.6 Hz), 8.83 (1H, dd, J = 2.4, 1.2 Hz)
    [401] Reference Example 49
    [402] Methyl 5- (4-pyridyl) -2-methoxy-3-pyridinecarboxylate
    [403]
    [404] The title compound was obtained from the raw material according to the method of Reference Example 46.
    [405] 1 H-NMR (400 MHz, CDCl 3 ) δ 3.95 (3H, s), 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)
    [406] Reference Example 50
    [407] 6-methyl-2-methoxy-3-pyridinemethanol
    [408]
    [409] 0.9 g of lithium aluminum hydride was suspended in 60 ml of tetrahydrofuran, and a solution in which 4.41 g of methyl 6-methyl-2-methoxy-3-pyridinecarboxylate was dissolved in 20 ml of tetrahydrofuran was added dropwise while stirring under ice cooling. After stirring for 30 minutes, 0.9 ml of water, 0.9 ml of 15% aqueous sodium hydroxide solution, and 2.7 ml of water were sequentially processed, celite and anhydrous magnesium sulfate were added and stirred at room temperature. After the reaction solution was filtered, the solvent was removed under reduced pressure, and 3.78 g of the title compound was obtained as a white solid.
    [410] 1 H-NMR (400 MHz, CDCl 3 ) δ2.26 (1H, m), 2.44 (3H, s), 3.98 (3H, s), 4.60 (2H, d, J = 5.2 Hz), 6.71 (1H, d , J = 7.2 Hz), 7.42 (1H, d, J = 7.2 Hz)
    [411] Reference Example 51
    [412] 5-chloro-2-methoxy-3-pyridinmethanol
    [413]
    [414] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [415] 1 H-NMR (400 MHz, CDCl 3 ) δ3.97 (3H, s), 4.63 (2H, s), 7.59-7.65 (1H, m), 8.03 (1H, d, J = 2.4 Hz)
    [416] Reference Example 52
    [417] 5-bromo-2-methoxy-3-pyridinmethanol
    [418]
    [419] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [420] 1 H-NMR (400 MHz, CDCl 3 ) δ3.96 (3H, s), 4.63 (2H, s), 7.73 (1H, d, J = 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz)
    [421] Reference Example 53
    [422] 5-methyl-2-methoxy-3-pyridinmethanol
    [423]
    [424] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [425] 1 H-NMR (400 MHz, CDCl 3 ) δ2.25 (3H, s), 3.97 (3H, s), 4.26 (2H, s), 7.40 (1H, d, J = 2.4 Hz), 7.89 (1H, d , J = 2.4 Hz)
    [426] Reference Example 54
    [427] 5-phenyl-2-methoxy-3-pyridinmethanol
    [428]
    [429] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [430] 1 H-NMR (400 MHz, CDCl 3 ) δ4.04 (3H, s), 4.72 (2H, s), 7.36 (1H, m), 7.42-7.48 (2H, m), 7.52-7.56 (2H, m) , 7.82 (1H, d, J = 2.4 Hz), 8.32 (1H, d, J = 2.4 Hz)
    [431] Reference Example 55
    [432] 5- (3-pyridyl) -2-methoxy-3-pyridinmethanol
    [433]
    [434] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [435] 1 H-NMR (400 MHz, CDCl 3 ) δ4.05 (3H, s), 4.74 (2H, s), 7.39 (1H, ddd, J = 8.0, 4.8, 0.4 Hz), 7.85-7.88 (2H, m) , 8.32 (1H, d, J = 2.4 Hz), 8.61 (1H, dd, J = 4.8, 1.6 Hz), 8.11 (1H, dd, J = 2.4, 0.4 Hz)
    [436] Reference Example 56
    [437] 5- (4-pyridyl) -2-methoxy-3-pyridinmethanol
    [438]
    [439] The title compound was obtained from the raw material according to the method of Reference Example 50.
    [440] 1 H-NMR (400 MHz, CDCl 3 ) δ2.38 (1H, s), 4.06 (3H, s), 4.75 (2H, s), 7.47-7.50 (2H, m), 7.91 (1H, m), 8.40 (1H, d, J = 2.4 Hz), 8.64-8.68 (2H, m)
    [441] Reference Example 57
    [442] 6-methyl-2-methoxy-3- (chloromethyl) pyridine
    [443]
    [444] 3.78 g of 6-methyl-2-methoxy-3-pyridinemethanol was dissolved in 60 ml of carbon tetrachloride, and 6.48 g of triphenylphosphine was added and heated to reflux for 6 hours 30 minutes. The solvent was removed under reduced pressure, n-hexane was added to the residue and the insolubles were filtered off. The filtrate was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 1) to give 2.29 g of the title compound as a colorless oil.
    [445] 1 H-NMR (400 MHz, CDCl 3 ) δ 2.45 (3H, s), 3.98 (3H, s), 4.58 (2H, s), 6.72 (1H, d, J = 7.2 Hz), 7.50 (1H, d , J = 7.2 Hz)
    [446] Reference Example 58
    [447] 5-chloro-2-methoxy-3- (chloromethyl) pyridine
    [448]
    [449] The title compound was obtained from the raw material according to the method of Reference Example 57.
    [450] 1 H-NMR (400 MHz, CDCl 3 ) δ3.98 (3H, s), 4.55 (2H, s), 7.63-7.68 (1H, m), 8.07 (1H, d, J = 2.4 Hz)
    [451] Reference Example 59
    [452] 5-bromo-2-methoxy-3- (chloromethyl) pyridine
    [453]
    [454] The title compound was obtained from the raw material according to the method of Reference Example 57.
    [455] 1 H-NMR (400 MHz, CDCl 3 ) δ3.98 (3H, s), 4.54 (2H, s), 7.78 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz)
    [456] Reference Example 60
    [457] 5-methyl-2-methoxy-3- (chloromethyl) pyridine
    [458]
    [459] The title compound was obtained from the raw material according to the method of Reference Example 57.
    [460] 1 H-NMR (400 MHz, CDCl 3 ) δ2.26 (3H, s), 3.97 (3H, s), 4.58 (2H, s), 7.48 (1H, d, J = 2.0 Hz), 7.93 (1H, d , J = 2.0 Hz)
    [461] Reference Example 61
    [462] 5-phenyl-2-methoxy-3- (chloromethyl) pyridine
    [463]
    [464] The title compound was obtained from the raw material according to the method of Reference Example 57.
    [465] 1 H-NMR (400 MHz, CDCl 3 ) δ4.05 (3H, s), 4.66 (2H, s), 7.37 (1H, m), 7.43-7.48 (2H, m), 7.52-7.56 (2H, m) , 7.88 (1H, d, J = 2.4 Hz), 8.36 (1H, d, J = 2.4 Hz)
    [466] Reference Example 62
    [467] 5- (4-pyridyl) -2-methoxy-3-pyridinecarboxaldehyde
    [468]
    [469] 321 mg of 5- (4-pyridinyl) -2-methoxy-3-pyridinmethanol was dissolved in 10 ml of chloroform, 1.6 g of manganese dioxide was added and stirred at room temperature for 14 hours. After filtration through celite, the filtrate was removed under reduced pressure and the crude product was purified by silica gel column chromatography (toluene: ethyl acetate = 3: 1) to give 329 mg of the title compound as a white powder.
    [470] 1 H-NMR (400 MHz, CDCl 3 ) δ4.17 (3H, s), 7.48-7.56 (2H, m), 8.40 (1H, d, J = 2.8 Hz), 8.66-8.76 (3H, m), 10.45 (1H, s)
    [471] Reference Example 63
    [472] 5- (3-pyridyl) -2-methoxy-3-pyridinecarboxaldehyde
    [473]
    [474] The title compound was obtained from the raw material according to the method of Reference Example 62.
    [475] 1 H-NMR (400 MHz, CDCl 3 ) δ4.15 (3H, s), 7.41 (1H, ddd, J = 0.8, 4.8, 8.0 Hz), 7.87 (1H, ddd, J = 8.0, 2.4, 1.6 Hz) , 8.33 (1H, d, J = 2.4 Hz), 8.63 (1H, d, J = 2.4 Hz), 8.65 (1H, dd, J = 4.8,1.6 Hz), 8.84 (1H, dd, J = 2.4, 0.8 Hz), 10.44 (1H, s)
    [476] Reference Example 64
    [477] 5-Bromo-2-methoxy-3-pyridinecarboxaldehyde dimethylacetal
    [478]
    [479] 2.58 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde was dissolved in 30 ml of dichloromethane, a mixture of 9 ml of trimethyl ortho formate and montmorillonite K-10 (3 g) was added, and the mixture was stirred at room temperature for 2 hours. . After the reaction solution was filtered, the filtrate was removed under reduced pressure, and ethyl acetate was added to the residue, followed by filtration with alumina. The filtrate was removed under reduced pressure to give 3.09 g of the title compound as a yellow oil.
    [480] 1 H-NMR (400 MHz, CDCl 3 ) δ3.36 (6H, s), 3.96 (3H, s), 5.51 (1H, s), 7.90 (1H, dd, J = 2.4, 0.4 Hz), 8.18 (1H , d, J = 2.4 Hz)
    [481] Reference Example 65
    [482] 5- (methylsulfonyl) -2-methoxy-3-pyridinecarboxaldehyde dimethylacetal
    [483]
    [484] 20 ml of tetrahydrofuran was cooled to -78 deg. C, 4.17 ml of n-butyllithium (1.6 M, hexane solution) was added and stirred. A solution of 1.59 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde dimethylacetal dissolved in 5 ml of tetrahydrofuran was added dropwise. After 30 minutes, 0.66 ml of dimethyl disulfide was added dropwise and stirred for 1 hour and 30 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a pale yellow oil. The oil was dissolved in 30 ml of dichloromethane, 5.12 g of sodium bicarbonate and 2.32 g of m-chloroperbenzoic acid were added and stirred for 30 minutes under ice-cooling. An aqueous sodium thiosulfate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, 1N-sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 0.81 g of the title compound as a white solid.
    [485] 1 H-NMR (400 MHz, CDCl 3 ) δ3.08 (3H, s), 3.38 (6H, s), 4.08 (3H, s), 5.51 (1H, s), 8.29 (1H, dd, J = 2.8, 0.8 Hz), 8.71 (1H, d, J = 2.8 Hz)
    [486] Reference Example 66
    [487] 5- (methylsulfonyl) -2-methoxy-3-pyridinecarboxaldehyde
    [488]
    [489] 0.81 g of 5- (methylsulfonyl) -2-methoxy-3-pyridinecarboxaldehyde dimethylacetal was dissolved in 8 ml of acetone, 2 ml of 5N-hydrochloric acid was added, and stirred at room temperature for 30 minutes. An aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was filtered through addition of n-hexane to give 0.62 g of the title compound as a white powder.
    [490] 1 H-NMR (400 MHz, CDCl 3 ) δ3.11 (3H, s), 4.12 (3H, s), 8.58 (1H, d, J = 2.8 Hz), 8.93 (1H, d, J = 2.8 Hz), 10.38 (1H, s)
    [491] Reference Example 67
    [492] 5-fluoro-2-methoxy-3-pyridinecarboxaldehyde
    [493]
    [494] 20 ml of tetrahydrofuran was cooled to -78 deg. C, 2.41 ml of n-butyllithium (2.6 M, hexane solution) was added and stirred. A solution of 1.50 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde dimethylacetal dissolved in 5 ml of tetrahydrofuran was added dropwise. For 25 minutes, a solution in which 2.16 g of N-fluorobenzenesulfonimide was dissolved in 20 ml of tetrahydrofuran was added dropwise over 20 minutes, followed by stirring for 55 minutes. 20 ml of saturated sodium chloride aqueous solution and 2N hydrochloric acid were added to the reaction solution, and the mixture was stirred at room temperature. For 40 minutes, diluted ammonia water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a yellow oil. The oil was dissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was added and left at room temperature for 30 minutes. An aqueous potassium carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 15: 1) to give 234 mg of the title compound as a pale yellow solid.
    [495] 1 H-NMR (400 MHz, CDCl 3 ) δ4.07 (3H, s), 7.84 (1H, dd, J = 3.2, 7.6 Hz), 8.24 (1H, d, J = 3.2 Hz), 10.33 (1H, d , J = 2.8 Hz)
    [496] Reference Example 68
    [497] 5-cyano-2-methoxy-3-pyridinecarboxaldehyde
    [498]
    [499] 2.00 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde dimethylacetal is dissolved in 25 ml of propionitrile, 449 mg of sodium cyanide, 152 mg of copper iodide, and 462 mg of tetrakis (triphenylphosphine) palladium Was added and stirred at 100 ° C. for 45 minutes under nitrogen atmosphere. Dilute aqueous ammonia was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain an oily substance. The oil was dissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was added and left at room temperature for 30 minutes. An aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (toluene: ethyl acetate = 1: 1) to give 843 mg of the title compound as white crystals.
    [500] 1 H-NMR (400 MHz, CDCl 3 ) δ4.17 (3H, s), 8.34 (1H, d, J = 2.4 Hz), 8.67 (1H, d, J = 2.4 Hz), 10.33 (1H, s)
    [501] Reference Example 69
    [502] 1- (benzyloxycarbonyl) -4-[(E) -2- [2- (cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [503]
    [504] 1.75 g of [[2- (cyclohexylmethyloxy) phenyl] methyl] triphenylphosphonium chloride was dissolved in 10 ml of dimethylsulfoxide, 144 mg of 60% sodium hydride was added and stirred at 70 ° C. After cooling to room temperature, a solution obtained by dissolving 800 mg of 1- (benzyloxycarbonyl) -4-piperidinecarboxaldehyde in 3 ml of tetrahydrofuran was added dropwise and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 554 mg of the title compound as a colorless oil.
    [505] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.98-1.50 (7H, m), 1.63-1.92 (8H, m), 2.34 (3 / 4H, m), 2.66 (1 / 4H, m), 2.73- 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, s), 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), 6.81-6.94 (2H, m), 7.14-7.41 (7H, m)
    [506] Reference Example 70
    [507] (2-cyclohexylmethyloxy) bromobenzene
    [508]
    [509] 5.00 ml of 2-bromophenol was dissolved in 90 ml of N and N-dimethylformamide, 7.21 ml of (bromomethyl) cyclohexane and 7.15 g of potassium carbonate were added and stirred at 100 ° C. for 5 hours. Water was added to the reaction mixture, extraction was performed with n-hexane, and the organic layer was washed with water, 5N-sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. Filtration with alumina and removal of the solvent under reduced pressure gave 10.47 g of the title compound as a pale yellow oil.
    [510] 1 H-NMR (400 MHz, CDCl 3 ) δ1.04-1.38 (5H, m), 1.67-1.95 (6H, m), 3.81 (2H, d, J = 6.0 Hz), 6.80 (1H, dt, J = 7.6, 1.2 Hz), 6.87 (1H, dd, J = 8.0, 1.2 Hz), 7.23 (1H, ddd, J = 8.0, 7.6, 2.0 Hz), 7.52 (1H, d, J = 7.6, 2.0 Hz)
    [511] Reference Example 71
    [512] 1-benzyl-4- [2-hydroxy-2-[(2-cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [513]
    [514] 10 ml of tetrahydrofuran was cooled to -78 deg. C, and 5.11 ml of n-butyllithium (1.6 M, hexane solution) was added and stirred. A solution in which 2.000 g of (2-cyclohexylmethyloxy) bromobenzene was dissolved in 5 ml of tetrahydrofuran was added dropwise. After 1 hour, a solution of 1.93 g of 1-benzyl-4-piperidine acetaldehyde in 5 ml of tetrahydrofuran was added dropwise, followed by stirring for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH-foam silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 2.986 g of the title compound as a colorless oil.
    [515] 1 H-NMR (400 MHz, CDCl 3 ) δ1.03-1.44 (7H, m), 1.47-1.90 (11H, m), 1.92-2.02 (2H, m), 2.83-2.92 (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, 7.6, Hz), 6.84 ( 1H, dd, J = 8.0, 0.8 Hz), 6.93 (1H, dt, J = 7.6, 1.2 Hz), 7.18-7.34 (7H, m)
    [516] Reference Example 72
    [517] 1-benzyl-4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [518]
    [519] Dissolve 2.986 g of 1-benzyl-4- [2-hydroxy-2-[(2-cyclohexylmethyloxy) phenyl] ethyl] piperidine in 70 ml of toluene, add 1.38 g of p-toluenesulfonic acid, and add 1 It was heated to reflux for time. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2.848 g of the title compound as a pale yellow oil.
    [520] 1 H-NMR (400 MHz, CDCl 3 ) δ1.02-1.42 (5H, m), 1.48-1.92 (10H, m), 2.01-2.10 (2H, m), 2.16 (1H, m), 2.89-2.96 ( 2H, m), 3.53 (2H, s), 3.76 (2H, d, J = 6.4 Hz), 6.19 (1H, dd, J = 16.0, 7.2 Hz), 6.70 (1H, d, J = 16.0 Hz), 6.82 (1H, dd, J = 8.8, 0.8 Hz), 6.87 (1H, dt, J = 8.8, 0.8 Hz), 7.14 (1H, dt, J = 8.8, 0.8 Hz), 7.22-7.36 (5H, m) , 7.40 (1H, doublet of doublets, J = 8.8, 0.8 Hz)
    [521] Reference Example 73
    [522] 1-benzyl-4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine
    [523]
    [524] 1.19 g of 1-benzyl-4-ethynylpiperidine is dissolved in 20 ml of N, N-dimethylformamide, 1.774 g of (2-cyclohexylmethyloxy) bromobenzene, 114 mg of copper (I) iodide, triethyl 0.92 ml of amine and 347 mg of tetrakis (triphenylphosphine) palladium were added and stirred at 100 ° C. for 3 hours 30 minutes under a nitrogen atmosphere. Ice water and diluted ammonia water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration with alumina and silica gel, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 316 mg of the title compound as a pale yellow oil.
    [525] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.36 (5H, m), 1.64-1.98 (10H, m), 2.22-2.34 (2H, m), 2.64-2.81 (3H, m), 3.52 ( 2H, s), 3.80 (2H, d, J = 6.0 Hz), 6.82 (1H, dd, J = 8.4, 1.2 Hz), 6.84 (1H, dt, J = 8.4, 1.2 Hz), 7.18-7.36 (7H , m)
    [526] Reference Example 74
    [527] 1- (vinyloxycarbonyl) -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [528]
    [529] 2.848 g of 1-benzyl-4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine was dissolved in 15 ml of 1,2-dichloroethane and chloroformic acid 0.93 ml of vinyl was added, stirred at room temperature for 50 minutes and then heated to reflux for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 1) to give 2.026 g of the title compound as a colorless oil.
    [530] 1 H-NMR (400 MHz, CDCl 3 ) δ1.03-1.52 (7H, m), 1.67-1.92 (8H, m), 2.37 (1H, m), 2.84-3.03 (2H, m), 3.78 (2H, d, J = 6.4 Hz), 4.16-4.27 (2H, m), 4.45 (1H, dd, J = 6.4, 1.6 Hz), 4.78 (1H, dd, J = 13.2, 1.6 Hz), 6.15 (1H, dd , J = 16.0, 6.8 Hz), 6.73 (1H, d, J = 16.0 Hz), 6.84 (1H, dd, J = 8.4, 1.2 Hz), 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)
    [531] Reference Example 75
    [532] 1- (vinyloxycarbonyl) -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine
    [533]
    [534] Indeed, depending on the method goye 74 to obtain the title compound from the raw material.
    [535] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.39-1.52 (2H, m), 1.83 (2H, br d, J = 15.6 Hz), 2.37 (1H, m), 2.83-3.01 (2H, m), 4.09-4.29 (2H, m), 4.46 (1H, dd, J = 6.4, 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, 8.4, 1.2 Hz), 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)
    [536] Reference Example 76
    [537] 1- (vinyloxycarbonyl) -4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine
    [538]
    [539] The title compound was obtained from the raw material according to the method of Reference Example 74.
    [540] 1 H-NMR (400 MHz, CDCl 3 ) δ1.03-1.35 (5H, m), 1.65-1.93 (10H, m), 2.98 (1H, m), 3.56-3.64 (2H, m), 3.67-3.79 ( 2H, m), 3.79 (2H, d, J = 6.4 Hz), 4.45 (1H, dd, J = 6.4, 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)
    [541] Reference Example 77
    [542] 1- (vinyloxycarbonyl) -4-[(E) -2- (2-chlorophenyl) -1-ethenyl] piperidine
    [543]
    [544] The title compound was obtained from the raw material according to the method of Reference Example 74.
    [545] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.40-1.54 (2H, m), 1.85 (2H, br d, J = 13.2 Hz), 2.41 (1H, m), 2.83-3.02 (2H, m), 4.19-4.29 (2H, m), 4.46 (1H, dd, J = 6.0, 1.6 Hz), 4.79 (1H, dd, J = 14.4, 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), 7.50 (1H, dd, J = 7.6, 2.0 Hz )
    [546] Reference Example 78
    [547] 1- (vinyloxycarbonyl) -4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine
    [548]
    [549] The title compound was obtained from the raw material according to the method of Reference Example 74.
    [550] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.39-1.53 (2H, m), 1.84 (2H, br d, J = 12.8 Hz), 2.33 (3H, s), 2.36 (1H, m), 2.83- 3.02 (2H, m), 4.19-4.29 (2H, m), 4.45 (1H, dd, J = 6.4, 1.6 Hz), 4.78 (1H, dd, J = 14.0, 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)
    [551] Reference Example 79
    [552] 4- [2-[(cyclohexylmethyloxy) phenyl] piperidine
    [553]
    [554] 398 mg of 1-benzyl-4- [2- (cyclohexylmethyloxy) phenyl] -3,4-dehydropiperidine is dissolved in 10 ml of ethanol, 150 mg of 20% palladium hydroxide-carbon powder (water) Was added and stirred overnight at atmospheric pressure and room temperature under hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the filtrate was removed under reduced pressure to give 315 mg of the title compound as a pale yellow oil.
    [555] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.38 (5H, m), 1.54-1.92 (10H, m), 2.74-2.82 (2H, m), 3.10 (1H, tt, J = 12.0, 3.2 Hz), 3.16-3.23 (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 ), 7.15 (1H, dt, J = 8.0, 1.2 Hz), 7.19 (1H, dd, J = 8.0, 1.2 Hz)
    [556] Reference Example 80
    [557] 4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [558]
    [559] Dissolve 554 mg of 1- (benzyloxycarbonyl) -4-[(E) -2- [2- (cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine in 10 ml of ethanol, 10% 250 mg of palladium-carbon powder (water) was added, and the mixture was stirred overnight at atmospheric pressure and room temperature under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was removed under reduced pressure to give 379 mg of the title compound as a colorless oil.
    [560] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.76 (8H, m), 1.67-1.96 (10H, m), 2.56-2.67 (4H, m), 3.06-3.13 (2H, m), 3.75 ( 2H, d, J = 5.6 Hz), 6.81 (1H, d, J = 8.0 Hz), 6.85 (1H, dt, J = 8.0, 1.2 Hz), 7.09-7.16 (2H, m)
    [561] Reference Example 81
    [562] 4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine
    [563]
    [564] The title compound was obtained from the raw material according to the method of Reference Example 80.
    [565] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05 (6H, d, J = 6.8 Hz), 1.12-1.24 (2H, m), 1.42 (1H, m), 1.48-1.56 (2H, m), 1.73 -1.81 (2H, m), 2.10 (1H, m), 2.56-2.67 (4H, m), 3.06-3.14 (2H, m), 3.72 (2H, d, J = 6.4 Hz), 6.80 (1H, d , J = 8.0 Hz), 6.86 (1H, dt, J = 1.2, 7.6 Hz), 7.09-7.17 (2H, m)
    [566] Reference Example 82
    [567] 4-[[2- (2-phenylethyl) phenyl] ethyl] piperidine
    [568]
    [569] The title compound was obtained from the raw material according to the method of Reference Example 80.
    [570] 1 H-NMR (400 MHz, CDCl 3 ) δ1.13-1.26 (2H, m), 1.39-1.55 (3H, m), 1.72-1.79 (2H, m), 2.56-2.66 (4H, m), 2.84- 2.94 (4H, m), 3.06-3.14 (2H, m), 7.12-7.33 (9H, m)
    [571] Reference Example 83
    [572] [2- [2-[(cyclohexylmethyl) amino] phenyl] ethyl] piperidine
    [573]
    [574] The title compound was obtained from the raw material according to the method of Reference Example 80.
    [575] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.95-1.08 (2H, m), 1.12-1.34 (5H, m), 1.40-1.86 (7H, m), 1.87-2.04 (4H, m), 2.43- 2.50 (2H, m), 2.62 (2H, dt, J = 12.0, 2.4 Hz), 2.98 (2H, d, J = 6.8 Hz), 3.08-3.14 (2H, m), 3.61 (1H, m), 4.22 (2H, m), 6.61 (1H, dd, J = 1.2, 7.6 Hz), 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)
    [576] Reference Example 84
    [577] [2- [2- [N- (cyclohexylmethyl) -N-methylamino] phenyl] ethyl] piperidine
    [578]
    [579] The title compound was obtained from the raw material according to the method of Reference Example 80.
    [580] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.95-1.08 (2H, m), 1.12-1.34 (5H, m), 1.40-1.86 (8H, m), 1.87-2.04 (4H, m), 2.43- 2.50 (2H, m), 2.62 (2H, dt, J = 12.0, 2.4 Hz), 2.98 (2H, d, J = 6.8 Hz), 3.08-3.14 (2H, m), 3.61 (1H, m), 6.61 (1H, dd, J = 1.2, 7.6 Hz), 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)
    [581] Reference Example 85
    [582] 4-[[2- (cyclohexylethyl) phenoxy] methyl] piperidine
    [583]
    [584] 1.138 g of 1- (tert-butoxycarbonyl) -4-[[2- (cyclohexylethyl) phenoxy] methyl] piperidine is dissolved in 3 ml of dichloromethane, and 3 ml of trifluoroacetic acid is added It was left at room temperature for 1 hour 30 minutes. An aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, n-hexane was added to the residue and the residue was filtered to give 899 mg of the title compound as a white powder.
    [585] 1 H-NMR (400 MHz, CDCl 3 ) δ0.86-0.97 (2H, m), 1.09-1.22 (4H, m), 1.40-1.48 (2H, m), 1.61-1.80 (7H, m), 2.05- 2.20 (3H, m), 2.56-2.63 (2H, m), 2.96 (2H, dt, J = 12.8, 2.4 Hz), 3.50 (2H, br d, J = 11.6 Hz), 3.84 (2H, d, J = 6.4 Hz), 6.78 (1H, d, J = 8.0 Hz), 6.89 (1H, dt, J = 7.6, 0.8 Hz), 7.16 (1H, d, J = 7.6 Hz), 7.15 (1H, dd, J = 7.6, 0.8 Hz)
    [586] Reference Example 86
    [587] 4-[(E) -2- [2- (cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [588]
    [589] 2.0 ml of 1- (vinyloxycarbonyl) -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine 20 ml of 10% -hydrogen chloride-methanol solution It was suspended in and stirred for 20 minutes under ice-cooling. After stirring for 15 minutes at room temperature, the mixture was heated to reflux for 1 hour 10 minutes. The solvent was removed under reduced pressure, an aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, n-heptane was added to the residue and the insolubles were filtered off. The filtrate was removed under reduced pressure to give 1.556 g of the title compound as a colorless oil.
    [590] 1 H-NMR (400 MHz, CDCl 3 ) δ1.03-1.46 (6H, m), 1.66-1.93 (9H, m), 2.28 (1H, m), 2.68 (2H, dt, J = 2.4, 12.0 Hz) , 3.12 (2H, dt, J = 12.0, 3.2 Hz), 3.77 (2H, d, J = 6.0 Hz), 6.18 (1H, dd, J = 16.0 Hz), 6.70 (1H, d, J = 16.0 Hz) , 6.82 (1H, dd, J = 7.6, 0.8 Hz), 6.88 (1H, dt, J = 7.6, 0.8 Hz), 7.15 (1H, dt, J = 7.6, 0.8 Hz), 7.41 (1H, dd, J = 7.6, 0.8 Hz)
    [591] Reference Example 87
    [592] 4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine
    [593]
    [594] 904 mg of 1- (vinyloxycarbonyl) -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine is suspended in 5 ml of 10% hydrogen chloride-methanol solution, The mixture was stirred at room temperature for 15 minutes and then heated at 70 ° C. for 1 hour. The solvent was removed under reduced pressure, water and ethyl acetate were added to the residue, and the aqueous layer was separated. The aqueous layer was made alkaline with dilute ammonia water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 660 g of the title compound as a colorless oil.
    [595] 1 H-NMR (400 MHz, CDCl 3 ) δ1.34-1.47 (2H, m), 1.75-1.84 (2H, m), 2.29 (1H, m), 2.64-2.73 (2H, m), 3.13 (2H, br d, J = 12.4 Hz), 6.24 (1H, dd, J = 16.0,6.4 Hz), 6.54 (1H, d, J = 16.0 Hz), 6.97-7.11 (2H, m), 7.16 (1H, m) , 7.44 (1H, m)
    [596] Reference Example 88
    [597] 4-[(E) -2- (2-chlorophenyl) -1-ethenyl] piperidine
    [598]
    [599] The title compound was obtained from the raw material according to the method of Reference Example 87.
    [600] 1 H-NMR (400 MHz, CDCl 3 ) δ1.34-1.46 (2H, m), 1.75-1.86 (2H, m), 2.31 (1H, m), 2.68 (2H, dt, J = 8.4, 2.8 Hz) , 3.12 (2H, dt, J = 11.6, 3.2 Hz), 6.15 (1H, dd, J = 16.0, 6.8 Hz), 6.75 (1H, dd, J = 16.0, 0.8 Hz), 7.13 (1H, dt, J = 8.0, 2.0 Hz), 7.20 (1H, dd, J = 8.0, 1.6 Hz), 7.33 (1H, dd, J = 8.0, 1.6 Hz), 7.51 (1H, dd, J = 8.0, 2.0 Hz)
    [601] Reference Example 89
    [602] 4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine
    [603]
    [604] The title compound was obtained from the raw material according to the method of Reference Example 87.
    [605] 1 H-NMR (400 MHz, CDCl 3 ) δ1.34-1.47 (2H, m), 1.75-1.84 (4H, m), 2.29 (1H, m), 2.64-2.73 (2H, m), 3.13 (2H, br d, J = 12.4 Hz), 6.24 (1H, dd, J = 16.0, 6.4 Hz), 6.54 (1H, d, J = 16.0 Hz), 6.97-7.11 (2H, m), 7.16 (1H, m) , 7.41-7.48 (2H, m)
    [606] Reference Example 90
    [607] 4- [2- (2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine
    [608]
    [609] The title compound was obtained from the raw material according to the method of Reference Example 87.
    [610] Example 1
    [611] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (methylsulfonyl) phenethyl] piperidine
    [612] 3.90 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde and 8.92 g of (2-methylsulfonylbenzyl) triphenylphosphonium chloride and 1.96 of potassium t-butoxide g was suspended in 80 ml of N, N-dimethylformamide and stirred at room temperature for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4). The obtained product and 440 mg of 10% palladium-carbon powder (water) were suspended in 80 ml of ethanol, and the container was hydrogen-substituted, followed by stirring at atmospheric pressure and room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was removed under reduced pressure to give 4.05 g of the title compound as a colorless oil.
    [613] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.61-1.68 (2H, m), 1.74-1.81 (2H, m), 2.02-2.10 (2H, m), 2.88- 2.96 (2H, m), 3.00-3.08 (2H, m), 3.08 (3H, s), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.1, 5.0 Hz) , 7.33-7.42 (2H, m), 7.55 (1H, double doublet of doublets, J = 7.7, 7.7, 1.3 Hz), 7.65 (1H, doubled, J = 7.1, 1.8 Hz), 8.00-8.08 (2H, m).
    [614] Example 2
    [615] 1-[(2-methoxy-3-pyridyl) methyl] -4- (3,4- (methylenedioxyphenethyl) piperidine
    [616] The title compound was obtained from the raw material according to the method of Example 1.
    [617] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.22-1.37 (3H, m), 1.47-1.58 (2H, m), 1.64-1.77 (2H, m), 1.96-2.07 (2H, m), 2.50- 2.59 (2H, m), 2.84-2.94 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 5.91 (2H, s), 6.61 (1H, dd, J = 7.8, 1.6 Hz) , 6.67 (1H, d, J = 1.6 Hz), 6.72 (1H, d, J = 7.8 Hz), 6.87 (1H, dd, J = 7.2, 5.2 Hz), 7.64 (1H, dd, J = 7.2, 1.8 Hz), 8.05 (1H, doublet of doublets, J = 5.2, 1.8 Hz).
    [618] Example 3
    [619] 1-[(2-methoxy-3-pyridyl) methyl] -4-phenethylpiperidine
    [620] The title compound was obtained from the raw material according to the method of Example 1.
    [621] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.39 (3H, m), 1.52-1.61 (2H, m), 1.68-1.77 (2H, m), 1.96-2.07 (2H, m), 2.58- 2.66 (2H, m), 2.85-2.93 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.14-7.21 (3H, m), 7.23-7.31 (2H, m), 7.65 (1H, doublet of doublets, J = 7.1, 1.8 Hz), 8.05 (1H, doublet of doublets, J = 4.9, 1.8 Hz).
    [622] Example 4
    [623] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-hydroxyphenethyl) piperidine
    [624] The title compound was obtained from the raw material according to the method of Example 1.
    [625] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.42 (3H, m), 1.46-1.54 (2H, m), 1.69-1.77 (2H, m), 2.00-2.10 (2H, m), 2.57- 2.63 (2H, m), 2.73-3.00 (2H, m), 3.55 (2H, s), 3.90 (3H, s), 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, 7.5, 1.6 Hz), 7.07 (1H, dd, J = 7.5, 1.6 Hz), 7.62 (1H, dd, J = 7.2, 1.9 Hz), 8.07 (1H, dd, J = 5.1, 1.9 Hz).
    [626] Example 5
    [627] 1-[(2-methoxy-3-pyridyl) methyl] -4- (3-fluorophenethyl) piperidine
    [628] The title compound was obtained from the raw material according to the method of Example 1.
    [629] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.21-1.40 (3H, m), 1.51-1.61 (2H, m), 1.65-1.77 (2H, m), 1.95-2.08 (2H, m), 2.57- 2.66 (2H, m), 2.85-2.94 (2H, m), 3.48 (2H, s), 3.95 (3H, s), 6.83-6.91 (2H, m), 6.87 (1H, dd, J = 7.1, 4.9 Hz), 6.94 (1H, m), 7.18-7.26 (1H, m), 7.64 (1H, dd, J = 7.1, 2.0 Hz), 8.05 (1H, dd, J = 4.9, 2.0 Hz).
    [630] Example 6
    [631] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-trifluoromethylphenethyl) piperidine
    [632] The title compound was obtained from the raw material according to the method of Example 1.
    [633] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.42 (3H, m), 1.51-1.61 (2H, m), 1.69-1.80 (2H, m), 1.99-2.11 (2H, m), 2.73- 2.82 (2H, m), 2.87-2.95 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (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), 7.45 (1H, dd, J = 7.6, 7.5 Hz), 7.60 (1H, d, J = 7.7 Hz), 7.65 (1H, dd, J = 7.1, 1.9 Hz), 8.05 (1H, dd, J = 4.9, 1.9 Hz).
    [634] Example 7
    [635] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (1-pyrazolo) phenethyl] piperidine
    [636] The title compound was obtained from the raw material according to the method of Example 1.
    [637] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.10-1.23 (3H, m), 1.32-1.39 (2H, m), 1.49-1.57 (2H, m), 1.90-1.99 (2H, m), 2.52- 2.59 (2H, m), 2.78-2.85 (2H, m), 3.44 (2H, s), 3.93 (3H, s), 6.42 (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), 7.61 (1H, dd, J = 7.2, 2.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 8.04 (1H, doublet of doublets, J = 4.8, 2.0 Hz).
    [638] Example 8
    [639] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (4-acetylpiperazino) phenethyl] piperidine
    [640] The title compound was obtained from the raw material according to the method of Example 1.
    [641] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.39 (3H, m), 1.52-1.61 (2H, m), 1.71-1.79 (2H, m), 1.97-2.07 (2H, m), 2.14 ( 3H, s), 2.65-2.72 (2H, m), 2.81-2.94 (6H, m), 3.48 (2H, s), 3.55-3.61 (2H, m), 3.70-3.78 (2H, m), 3.95 ( 3H, s), 6.87 (1H, dd, J = 7.2, 4.8 Hz), 7.04 (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), 7.64 (1H, dd, J = 7.2, 1.6 Hz), 8.05 (1H, dd, J = 4.8, 1.6 Hz).
    [642] Example 9
    [643] 1-[(2-methoxy-3-pyridyl) methyl] -4- [6- (methylsulfonyl) -2,3-methylenedioxyphenethyl] piperidine
    [644] The title compound was obtained from the raw material according to the method of Example 1.
    [645] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.56-1.66 (2H, m), 1.73-1.81 (2H, m), 2.02-2.10 (2H, m), 2.88- 2.99 (4H, m), 3.04 (3H, s), 3.49 (2H, s), 3.95 (3H, s), 6.08 (2H, s), 6.78 (1H, d, J = 8.3 Hz), 6.87 (1H , dd, J = 7.2, 5.0 Hz), 7.62 (1H, d, J = 8.3 Hz), 7.66 (1H, dd, J = 7.2, 1.8 Hz), 8.05 (1H, dd, J = 5.0, 1.8 Hz) .
    [646] Example 10
    [647] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-thienyl) ethyl] piperidine
    [648] The title compound was obtained from the raw material according to the method of Example 1.
    [649] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.59-1.75 (4H, m), 1.95-2.06 (2H, m), 2.80-2.93 (4H, m), 3.47 ( 2H, s), 3.94 (3H, s), 6.77 (1H, d, J = 3.5 Hz), 6.85 (1H, dd, J = 7.1, 4.9 Hz), 6.90 (1H, dd, J = 5.1, 3.5 Hz ), 7.09 (1H, d, J = 5.1 Hz), 7.64 (1H, dd, J = 7.1, 1.8 Hz), 8.04 (1H, dd, J = 4.9, 1.8 Hz).
    [650] Example 11
    [651] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-methoxy-2-thienyl) ethyl] piperidine
    [652] The title compound was obtained from the raw material according to the method of Example 1.
    [653] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.37 (3H, m), 1.52-1.59 (2H, m), 1.67-1.77 (2H, m), 1.96-2.07 (2H, m), 2.67- 2.74 (2H, m), 2.85-2.92 (2H, m), 3.47 (2H, s), 3.80 (3H, s), 3.94 (3H, s), 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), 7.64 (1H, dd, J = 7.1, 1.8 Hz), 8.04 (1H, dd, J = 4.9,1.8 Hz).
    [654] Example 12
    [655] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-cyano-2-thienyl) ethyl] piperidine
    [656] The title compound was obtained from the raw material according to the method of Example 1.
    [657] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.40 (3H, m), 1.62-1.77 (4H, m), 1.98-2.09 (2H, m), 2.87-2.95 (2H, m), 2.99- 3.06 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.1, 4.9 Hz), 7.11 (1H, d, J = 5.3 Hz), 7.17 (1H , d, J = 5.3 Hz), 7.64 (1H, dd, J = 7.1, 1.8 Hz), 8.05 (1H, dd, J = 4.9, 1.8 Hz).
    [658] Example 13
    [659] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-phenyl-2-thienyl) ethyl] piperidine
    [660] The title compound was obtained from the raw material according to the method of Example 1.
    [661] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.21-1.31 (3H, m), 1.55-1.69 (4H, m), 1.91-2.01 (2H, m), 2.80-2.92 (4H, m), 3.46 ( 2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.00 (1H, d, J = 5.2 Hz), 7.15 (1H, d, J = 5.2 Hz), 7.27-7.43 (5H, m), 7.62 (1H, doublet of doublets, J = 7.1, 2.0 Hz), 8.04 (1H, doubled, J = 4.9, 2.0 Hz).
    [662] Example 14
    [663] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-thienyl) ethyl] piperidine
    [664] The title compound was obtained from the raw material according to the method of Example 1.
    [665] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.38 (3H, m), 1.54-1.64 (2H, m), 1.66-1.76 (2H, m), 1.96-2.07 (2H, m), 2.62- 2.68 (2H, m), 2.85-2.94 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.87 (1H, dd, J = 7.2, 5.2 Hz), 6.90-6.95 (2H, m), 7.24 (1H, doublet of doublets, J = 5.2, 3.0 Hz), 7.64 (1H, doublet of doublets, J = 7.2, 2.0 Hz), 8.05 (1H, doubled, J = 5.2, 2.0 Hz).
    [666] Example 15
    [667] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methanesulfonyl-3-thienyl) ethyl] piperidine
    [668] The title compound was obtained from the raw material according to the method of Example 1.
    [669] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.41 (3H, m), 1.56-1.66 (2H, m), 1.68-1.80 (2H, m), 1.97-2.10 (2H, m), 2.85- 2.99 (4H, m), 3.14 (3H, s), 3.48 (2H, s), 3.95 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.01 (1H, d, J = 5.0 Hz), 7.56 (1H, d, J = 5.0 Hz), 7.64 (1H, dd, J = 7.1, 1.8 Hz), 8.05 (1H, dd, J = 4.9, 1.8 Hz).
    [670] Example 16
    [671] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (benzo [b] thiophen-2-yl) ethyl] piperidine
    [672] The title compound was obtained from the raw material according to the method of Example 1.
    [673] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.41 (3H, m), 1.65-1.78 (4H, m), 1.96-2.07 (2H, m), 2.85-2.97 (4H, m), 3.48 ( 2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.3, 5.1 Hz), 6.99 (1H, s), 7.24 (1H, dd, J = 7.5, 7.1 Hz), 7.30 (1H , dd, J = 7.9, 7.1 Hz), 7.64 (1H, dd, J = 7.3, 2.0 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.75 (1H, d, J = 7.9 Hz), 8.05 (1H, doublet of doublets, J = 5.1, 2.0 Hz).
    [674] Example 17
    [675] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methylsulfonyl-3-pyridyl) ethyl] piperidine
    [676] The title compound was obtained from the raw material according to the method of Example 1.
    [677] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.40 (3H, m), 1.60-1.68 (2H, m), 2.02-2.10 (2H, m), 2.88-2.95 (2H, m), 3.08- 3.14 (2H, m), 3.37 (3H, m), 3.50 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 4.8 Hz), 7.43 (1H, dd, J = 7.8, 4.8 Hz), 7.66 (1H, dd, J = 7.2, 1.8 Hz), 7.71 (1H, dd, J = 7.8, 1.8 Hz), 8.05 (1H, dd, J = 4.8, 1.8 Hz), 8.41 ( 1H, dd, J = 4.8, 1.8 Hz).
    [678] Example 18
    [679] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-n-butyl-3-pyridyl) ethyl] piperidine
    [680] The title compound was obtained from the raw material according to the method of Example 1.
    [681] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.96 (3H, t, J = 7.3 Hz), 1.30-1.48 (5H, m), 1.48-1.56 (2H, m), 1.63-1.80 (4H, m) , 2.00-2.11 (2H, m), 2.57-2.66 (2H, m), 2.77 (2H, t, J = 8.1 Hz), 2.88-2.97 (2H, m), 3.50 (2H, s), 3.95 (3H , s), 6.87 (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), 7.65 (1H, dd, J = 7.6, 1.8 Hz), 8.06 (1H, dd, J = 5.0, 1.8 Hz), 8.37 (1H, dd, J = 4.8, 1.8 Hz).
    [682] Example 19
    [683] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-pyridyl) ethyl] piperidine
    [684] The title compound was obtained from the raw material according to the method of Example 1.
    [685] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.40 (3H, m), 1.54-1.62 (2H, m), 1.67-1.76 (2H, m), 1.98-2.08 (2H, m), 2.60- 2.66 (2H, m), 2.87-2.96 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 8.0, 5.0 Hz), 7.20 (1H, dd, J = 8.0, 5.0 Hz), 7.49 (1H, ddd, J = 8.0, 2.0, 2.0 Hz), 7.65 (1H, d, J = 8.0 Hz), 8.06 (1H, dd, J = 5.0, 2.0 Hz), 8.42-8.46 (2H, m).
    [686] Example 20
    [687] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-phenoxy-3-pyridyl) ethyl] piperidine
    [688] The title compound was obtained from the raw material according to the method of Example 1.
    [689] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.40 (3H, m), 1.55-1.68 (2H, m), 1.70-1.80 (2H, m), 1.98-2.08 (2H, m), 2.70- 2.77 (2H, m), 2.86-2.94 (2H, m), 3.48 (2H, s), 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), 7.36-7.42 (2H, m), 7.52 (1H, dd, J = 7.1, 2.0 Hz), 7.64 (1H , dd, J = 7.1, 2.0 Hz), 8.00 (1H, dd, J = 5.0, 2.0 Hz), 8.05 (1H, dd, J = 5.0, 2.0 Hz).
    [690] Example 21
    [691] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (5-methoxy-2-pyridyl) ethyl] piperidine
    [692] 300 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and [(5-methoxy-2-pyridyl) methyl] triphenylforce 310 mg of the title compound was obtained as a colorless oil by the same procedure as in Example 1 with 592 mg of phonyl chloride.
    [693] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.41 (3H, m), 1.59-1.68 (2H, m), 1.71-1.83 (2H, m), 1.97-2.08 (2H, m), 2.79- 2.94 (4H, m), 3.49 (2H, s), 3.82 (3H, m), 3.95 (3H, s), 6.87 (1H, dd, J = 7.1, 4.9 Hz), 7.09 (1H, d, J = 2.9 Hz), 7.09 (1H, d, J = 2.9 Hz), 7.65 (1H, dd, J = 7.1, 1.8 Hz), 8.05 (1H, dd, J = 4.9, 1.8 Hz), 8.11 (1H, dd, J = 2.9, 2.9 Hz).
    [694] Example 22
    [695] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (4-methoxyphenyl) -3-pyridyl) ethyl] piperidine
    [696] The title compound was obtained from the raw material according to the method of Example 1.
    [697] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.11-1.23 (3H, m), 1.41-1.49 (2H, m), 1.51-1.59 (2H, m), 1.90-1.99 (2H, m), 2.62- 2.69 (2H, m), 2.78-2.88 (2H, m), 3.44 (2H, s), 3.85 (3H, s), 3.93 (3H, s), 6.85 (1H, dd, J = 7.2, 4.8 Hz) , 6.96 (2H, d, J = 8.4 Hz), 7.17 (1H, dd, J = 8.0, 4.8 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.57 (1H, dd, J = 8.0, 1.6 Hz), 7.61 (1H, dd, J = 7.2, 2.0 Hz), 8.04 (1H, dd, J = 4.8, 2.0 Hz), 8.49 (1H, dd, J = 4.8, 1.6 Hz).
    [698] Example 23
    [699] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (1,3-thiazol-2-yl) ethyl] piperidine
    [700] The title compound was obtained from the raw material according to the method of Example 1.
    [701] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.40 (3H, m), 1.69-1.81 (4H, m), 1.97-2.07 (2H, m), 2.85-2.93 (2H, m), 3.01- 3.08 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.3, 5.1 Hz), 7.18 (1H, d, J = 3.5 Hz), 7.64 (1H , dd, J = 7.3, 2.0 Hz), 7.66 (1H, d, J = 3.5 Hz), 8.05 (1H, dd, J = 5.1, 2.0 Hz).
    [702] Example 24
    [703] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2- (1-morpholino) -3-pyridyl) ethyl] piperidine
    [704] The title compound was obtained from the raw material according to the method of Example 1.
    [705] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.39 (3H, m), 1.56-1.64 (2H, m), 1.70-1.78 (2H, m), 1.99-2.07 (2H, m), 2.60- 2.66 (2H, m), 2.86-2.94 (2H, m), 3.10 (4H, t, J = 4.7 Hz), 3.49 (2H, s), 3.85 (4H, J = 4.7 Hz), 3.95 (3H, s ), 6.87 (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), 7.64 (1H, dd, J = 7.4, 1.9 Hz), 8.06 (1H, dd, J = 4.8, 1.9 Hz), 8.18 (1H, dd, J = 4.8, 1.9 Hz).
    [706] Example 25
    [707] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-aminophenethyl) piperidine
    [708] Example by 310 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and 767 mg of (2-nitrobenzyl) triphenylphosphonium bromide As in 1, 255 mg of the title compound were obtained as colorless crystals.
    [709] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.40 (3H, m), 1.52-1.66 (2H, m), 1.72-1.82 (2H, m), 2.00-2.10 (2H, m), 2.46- 2.54 (2H, m), 2.87-2.96 (2H, m), 3.49 (2H, s), 3.59 (2H, br s), 3.95 (3H, s), 6.68 (1H, dd, J = 8.3, 1.1 Hz ), 6.73 (1H, dd, J = 7.4, 1.1 Hz), 6.87 (1H, dd, J = 7.1, 4.9 Hz), 7.01-7.06 (2H, m), 7.65 (1H, dd, J = 7.1, 1.8 Hz), 8.05 (1H, doublet of doublets, J = 4.9, 1.8 Hz).
    [710] Example 26
    [711] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(2-methylsulfonylamino) phenethyl] piperidine
    [712] 255 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-aminophenethyl) piperidine and 110 mg of methylsulfonylchloride and 0.13 ml of pyridine are dissolved in 5 ml of tetrahydrofuran And it stirred at room temperature for 3 hours. An aqueous 1N sodium hydroxide solution was added to the reaction solution, made alkaline, extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 286 mg of the title compound as a colorless oil.
    [713] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.41 (3H, m), 1.50-1.60 (2H, m), 1.68-1.78 (2H, m), 2.00-2.09 (2H, m), 2.61- 2.68 (2H, m), 2.88-2.95 (2H, m), 3.03 (3H, s), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.3, 5.0 Hz) , 7.15-7.26 (3H, m), 7.45 (1H, m), 7.65 (1H, dd, J = 7.3, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [714] Example 27
    [715] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-6-methyl-3-pyridyl) ethyl] piperidine
    [716] 500 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and [(2-chloro-6-methyl-3-pyridyl) methyl] 1.01 g of triphenylphosphonium chloride was obtained by following the method of Example 1 to obtain 445 mg of the title compound as a colorless oil.
    [717] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.39 (3H, m), 1.50-1.59 (2H, m), 1.70-1.78 (2H, m), 1.98-2.07 (2H, m), 2.49 ( 3H, s), 2.63-2.71 (2H, m), 2.86-2.95 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.1, 4.9 Hz) , 7.01 (1H, d, J = 7.9 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.65 (1H, dd, J = 7.1,2.0 Hz), 8.05 (1H, dd, J = 4.9,2.0 Hz).
    [718] Example 28
    [719] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (6-chloro-3-pyridyl) ethyl] piperidine
    [720] 504 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and [(6-chloro-3-pyridyl) methyl] triphenylphosphonium 600 mg of the title compound were obtained as a colorless oil by 1.01 g of chloride according to the method of Example 1.
    [721] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.38 (3H, m), 1.50-1.59 (2H, m), 1.66-1.74 (2H, m), 1.96-2.06 (2H, m), 2.57- 2.65 (2H, m), 2.85-2.94 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 5.0 Hz), 7.24 (1H, d, J = 8.3 Hz), 7.46 (1H, dd, J = 8.3, 2.4 Hz), 7.63 (1H, dd, J = 7.1, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz), 8.20 ( 1H, d, J = 2.4 Hz.
    [722] Example 29
    [723] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-pyridyl) -1-ethenyl] piperidine
    [724] 488 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and 1.07 g of (2-pyridylmethyl) triphenylphosphonium chloride hydrochloride and potassium 561 mg of tert-butoxide was suspended in 10 ml of N, N-dimethylformamide and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give 453 mg of the title compound as a colorless oil.
    [725] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.55-1.70 (3H, m), 1.75-1.85 (2H, m), 2.08-2.20 (2H, m), 2.91-3.00 (2H, m), 3.53 ( 2H, s), 3.96 (3H, s), 6.48 (1H, dd, J = 15.8, 1.3 Hz), 6.71 (1H, dd, J = 15.8, 6.9 Hz), 6.88 (1H, dd, J = 7.2, 5.0 Hz), 7.10 (1H, ddd, J = 7.6, 4.8, 1.1 Hz), 7.25 (1H, m), 7.60 (1H, ddd, J = 7.6, 7.6, 1.8 Hz), 7.67 (1H, dd, J = 7.2, 1.9 Hz), 8.06 (1H, dd, J = 5.0, 1.9 Hz), 8.53 (1H, m).
    [726] Example 30
    [727] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-pyridyl) ethyl] piperidine
    [728] 332 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-pyridyl) -1-ethenyl] piperidine obtained in Example 29 and 10 79 mg of palladium-carbon powder (water) was suspended in 5 ml of ethanol, and the container was hydrogen-substituted, followed by stirring for 30 minutes at normal pressure and room temperature. The reaction solution was filtered and the filtrate was removed under reduced pressure to give 234 mg of the title compound as a colorless oil.
    [729] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.41 (3H, m), 1.62-1.78 (4H, m), 1.98-2.09 (2H, m), 2.76-2.84 (2H, m), 2.86- 2.95 (2H, m), 3.49 (2H, s), 3.94 (3H, s), 6.87 (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), 7.65 (1H, dd, J = 7.5, 2.0 Hz), 8.05 (1H, dd, J = 5.0, 2.0 Hz), 8.52 (1H, m).
    [730] Example 31
    [731] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E)-(2,3-methylenedioxyphenyl) -1-ethenyl] piperidine
    [732] 784 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and 1.76 g of (3,4-methylenedioxybenzyl) triphenylphosphonium bromide In the same manner as in Example 29, 324 mg of the title compound were obtained as a colorless oil.
    [733] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.62 (3H, m), 1.70-1.79 (2H, m), 2.06-2.18 (2H, m), 2.90-2.99 (2H, m), 3.52 ( 2H, s), 3.96 (3H, s), 5.94 (2H, s), 6.00 (1H, dd, J = 15.8, 7.2 Hz), 6.29 (1H, d, J = 15.8 Hz), 6.70-6.79 (2H m), 6.83-6.92 (2H, m), 7.67 (1H, doublet of doublets, J = 7.0, 1.8 Hz), 8.06 (1H, doubled, J = 5.2, 1.8 Hz).
    [734] Example 32
    [735] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) ethyl] piperidine
    [736] 2.35 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and [(2-chloro-3-pyridyl) methyl] triphenylphosphonium 4.68 g of chloride and 1.24 g of potassium tert-butoxide were suspended in 50 ml of N, N-dimethylformamide and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1:19). The obtained product and 330 mg of platinum oxide were suspended in a mixed solvent of 20 ml of ethanol and 40 ml of tetrahydrofuran, and hydrogen-substituted in the vessel, followed by stirring at atmospheric pressure and room temperature for 20 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1:19) to obtain 1.89 g of the title compound as a colorless oil.
    [737] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.44 (3H, m), 1.54-1.62 (2H, m), 1.70-1.81 (2H, m), 2.00-2.12 (2H, m), 2.70 -2.77 (2H, m), 2.88-2.98 (2H, m), 3.51 (2H, s), 3.95 (3H, s), 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), 8.06 (1H, dd, J = 5.2, 2.0 Hz) , 8.24 (1H, doublet of doublets, J = 5.0, 2.0 Hz).
    [738] Example 33
    [739] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [4- (methylsulfonyl) -3- (1,3-thiazol-2-yl) -2-thienyl ] Ethyl] piperidine
    [740] 250 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2, [[4- (methylsulfonyl) -3-bromo-2- 680 mg of thienyl] methyl] triphenylphosphonium bromide and 258 mg of potassium tert-butoxide were suspended in 5 ml of N, N-dimethylformamide and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4). The obtained product, 408 mg of 2- (tributylstannyl) thiazole and 39 mg of tetrakis (triphenylphosphine) palladium were suspended in 5 ml of toluene and heated to reflux for 8 hours under a nitrogen stream. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate). The obtained product and 300 mg of 10% palladium-carbon powder (water) were suspended in 10 ml of ethanol, and hydrogen-substituted in the vessel, followed by stirring at atmospheric pressure and room temperature for 3 hours. The reaction solution was filtered, the filtrate was removed under reduced pressure to give 230 mg of the title compound as a colorless oil.
    [741] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.32 (3H, m), 1.54-1.65 (4H, m), 1.92-2.02 (2H, m), 2.76-2.90 (4H, m), 3.24 ( 3H, s), 3.44 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.4, 5.0 Hz), 7.55 (1H, d, J = 3.4 Hz), 7.65 (1H, dd , J = 7.4, 2.0 Hz), 7.94 (1H, d, J = 3.4 Hz), 8.05 (1H, dd, J = 5.0, 2.0 Hz), 8.10 (1H, s).
    [742] Example 34
    [743] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (1,3-thiazol-2-yl) -2-thienyl] ethyl] piperidine
    [744] 400 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and [(3-bromo-2-thienyl) methyl] triphenylphosph 230 mg of the title compound was obtained as a colorless oil by 974 mg of ponium bromide.
    [745] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.43 (3H, m), 1.65-1.78 (4H, m), 1.98-2.09 (2H, m), 2.87-2.95 (2H, m), 3.21- 3.27 (2H, m), 3.50 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.5, 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), 8.05 (1H , dd, J = 4.9, 2.0 Hz).
    [746] Example 35
    [747] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (1,3-thiazol-2-yl) phenethyl] piperidine
    [748] 293 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and (2-bromobenzyl) triphenylphosphonium bromide of Example 33 According to the method, 233 mg of the title compound were obtained as a colorless oil.
    [749] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.15-1.28 (3H, m), 1.42-1.50 (2H, m), 1.56-1.66 (2H, m), 1.93-2.02 (2H, m), 2.80- 2.89 (2H, m), 2.91-2.98 (2H, m), 3.45 (2H, s), 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), 7.57 (1H, d, J = 7.6 Hz), 7.62 (1H, dd, J = 6.8, 2.0 Hz), 7.88 (1H, d, J = 3.2 Hz), 8.04 (1H, dd, J = 4.8, 2.0 Hz).
    [750] Example 36
    [751] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [752] 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 it stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give 809 mg of the title compound as a pale yellow oil.
    [753] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.53-1.61 (2H, m), 1.68-1.78 (2H, m), 1.97-2.06 (2H, m), 2.56- 2.62 (2H, m), 2.85-2.92 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 5.92 (2H, s), 6.63-6.70 (2H, m), 6.75 (1H, dd, J = 7.7, 7.7 Hz), 6.86 (1H, dd, J = 7.1, 5.0 Hz), 7.64 (1H, dd, J = 7.1, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz ).
    [754] Example 37
    [755] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-cyanophenethyl) piperidine
    [756] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.57-1.65 (2H, m), 1.72-1.80 (2H, m), 1.98-2.09 (2H, m), 2.81- 2.95 (4H, m), 3.48 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.3, 5.1 Hz), 7.27 (1H, ddd, J = 7.7, 7.7, 0.9 Hz) , 7.31 (1H, dd, J = 7.7, 1.5 Hz), 7.50 (1H, ddd, J = 7.7, 7.7, 1.5 Hz), 7.60 (1H, dd, J = 7.7, 0.9 Hz), 7.65 (1H, dd , J = 7.3, 2.0 Hz), 8.05 (1H, dd, J = 5.1, 2.0 Hz).
    [757] Example 38
    [758] 1-[(2-methoxy-3-pyridyl) methyl] -4- (3-cyanophenethyl) piperidine
    [759] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.39 (3H, m), 1.52-1.61 (2H, m), 1.66-1.78 (2H, m), 1.97-2.07 (2H, m), 2.61- 2.70 (2H, m), 2.86-2.94 (2H, m), 3.48 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.3, 5.1 Hz), 7.33-7.50 (4H, m), 7.64 (1H, doublet of doublets, J = 7.3, 1.8 Hz), 8.05 (1H, doublet of doublets, J = 5.1, 1.8 Hz).
    [760] Example 39
    [761] 1-[(2-methoxy-3-pyridyl) methyl] -4- (4-phenylphenethyl) piperidine
    [762] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.40 (3H, m), 1.57-1.64 (2H, m), 1.70-1.80 (2H, m), 2.00-2.08 (2H, m), 2.64- 2.70 (2H, m), 2.86-2.94 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.22-7.27 (2H, m), 7.32 (1H, m), 7.40-7.45 (2H, m), 7.49-7.53 (2H, m), 7.56-7.60 (2H, m), 7.65 (1H, dd, J = 7.2, 1.8 Hz) , 8.05 (1H, doublet of doublets, J = 5.0, 1.8 Hz).
    [763] Example 40
    [764] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-phenylphenethyl) piperidine
    [765] 181 mg of 4- (2-phenylphenethyl) piperidine and 150 mg of 2-methoxy-3-pyridinecarboxaldehyde and 226 mg of sodium triacetoxyborohydride synthesized by the corresponding starting materials in the same manner as described above It was suspended in 5 ml of tetrahydrofuran and stirred at room temperature for 20 hours. An aqueous 1 N sodium hydroxide solution was added to the reaction solution, made alkaline, extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1:19) to give 213 mg of the title compound as a colorless oil.
    [766] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.07-1.20 (3H, m), 1.37-1.45 (2H, m), 1.45-1.53 (2H, m), 1.87-1.97 (2H, m), 2.55- 2.62 (2H, m), 2.75-2.83 (2H, m), 3.43 (2H, s), 3.93 (3H, s), 6.85 (1H, dd, J = 7.6, 5.0 Hz), 7.18-7.42 (9H, m), 7.60 (1H, doublet of doublets, J = 7.6, 2.0 Hz), 8.04 (1H, doublet of doublets, J = 5.0, 2.0 Hz).
    [767] Example 41
    [768] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-methylthiophenethyl) piperidine
    [769] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.52-1.62 (2H, m), 1.71-1.82 (2H, m), 2.02-2.13 (2H, m), 2.46 ( 3H, s), 2.68-2.74 (2H, m), 2.87-2.97 (2H, m), 3.51 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.2 Hz) , 7.04-7.14 (2H, m), 7.16-7.21 (2H, m), 7.66 (1H, doublet of doublets, J = 7.2, 2.0 Hz), 8.05 (1H, doubled, J = 5.2, 2.0 Hz).
    [770] Example 42
    [771] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-methoxyphenethyl) piperidine
    [772] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.38 (3H, m), 1.48-1.57 (2H, m), 1.70-1.79 (2H, m), 1.97-2.07 (2H, m), 2.57- 2.65 (2H, m), 2.85-2.93 (2H, m), 3.48 (2H, s), 3.81 (3H, s), 3.94 (3H, s), 6.84 (1H, dd, J = 8.0, 1.2 Hz) , 6.86 (1H, dd, J = 7.2, 5.0 Hz), 6.88 (1H, ddd, J = 7.6, 7.6, 1.2 Hz), 7.12 (1H, dd, J = 7.6, 1.6 Hz), 7.17 (1H, ddd , J = 8.0, 7.6, 1.6 Hz), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 5.0, 2.0 Hz).
    [773] Example 43
    [774] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine
    [775] 4.41 g of 4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine hydrochloride, 2.36 g of 3- (chloromethyl) -2-methoxypyridine and 5.90 g of potassium carbonate were added N, N- It was suspended in 30 ml of dimethylformamide and stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 809 mg of the title compound as a colorless oil.
    [776] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.42 (3H, m), 1.66-1.78 (4H, m), 2.00-2.09 (2H, m), 2.88-2.94 (2H, m), 3.06 ( 3H, s), 3.17-3.23 (2H, m), 3.49 (2H, s), 3.94 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.18 (1H, d, J = 5.4 Hz), 7.30 (1H, d, J = 5.4 Hz), 7.64 (1H, dd, J = 7.2, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [777] Example 44
    [778] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (methylsulfonyl) -2-thienyl] -1-ethynyl] piperidine
    [779] 500 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- (1-ethynyl) piperidine, 530 mg of 2-bromo-3- (methylsulfonyl) thiophene, iodide anhydrous 21 mg of copper and 127 mg of tetrakis (triphenylphosphine) palladium were suspended in a mixed solvent of 2.2 ml of triethylamine and 2.2 ml of N and N-dimethylformamide and stirred at 100 ° C. for 2 hours under a nitrogen stream. Ethyl acetate was added to the reaction solution, and the precipitate was filtered off, and then water was added to the filtrate and extracted with ethyl acetate. After removing the solvent under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate) to give 450 mg of the title compound as a colorless oil.
    [780] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.77-1.89 (2H, m), 1.93-2.03 (2H, m), 2.25-2.37 (2H, m), 2.70-2.84 (3H, m), 3.19 ( 3H, m), 3.51 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.21 (1H, d, J = 7.1 Hz), 7.38 (1H, d , J = 7.1 Hz), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 5.0, 2.0 Hz).
    [781] Example 45
    [782] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (methylsulfonyl) -2-thienyl] ethyl] piperidine
    [783] 450 mg and 10% 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (methylsulfonyl) -2-thienyl] -1-ethynyl] piperidine 250 mg of palladium-carbon powder (water) was suspended in 10 ml of ethanol, and the inside of the vessel was hydrogen-substituted, followed by stirring at normal pressure and room temperature for 8 hours. The reaction solution was filtered and the filtrate was removed under reduced pressure to give the title compound quantitatively as a yellow oil.
    [784] The NMR spectral data of this Example compound were consistent with the Example 42 compound.
    [785] Example 46
    [786] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (methylsulfonyl) -3,4-methylenedioxyphenethyl] piperidine
    [787] 800 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde and [2- (methylsulfonyl) -3,4-methylenedioxybenzyl] triphenylphosphonium 1.90 g of bromide and 384 mg of potassium tert-butoxide were suspended in 10 ml of N, N-dimethylformamide and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4). The obtained product and 400 mg of 10% palladium-carbon powder (water) were suspended in 40 ml of ethanol, hydrogenated in the vessel, and then stirred at atmospheric pressure and room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was removed under reduced pressure to quantitatively obtain the title compound as a colorless oil.
    [788] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.40 (3H, m), 1.52-1.60 (2H, m), 1.68-1.78 (2H, m), 2.00-2.09 (2H, m), 2.86- 2.93 (2H, m), 2.96-3.02 (2H, m), 3.21 (3H, s), 3.49 (2H, s), 3.95 (3H, s), 6.12 (2H, s), 6.75 (1H, d, J = 8.1 Hz), 6.86 (1H, dd, J = 7.1, 5.0 Hz), 6.93 (1H, d, J = 8.1 Hz), 7.64 (1H, dd, J = 7.1, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [789] Example 47
    [790] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-oxo-1,2-dihydro-3-pyridyl) ethyl] piperidine
    [791] 500 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2, [(2-chloro-3-pyridyl) methyl] triphenylphosphonium 905 mg chloride and 340 mg potassium tert-butoxide were suspended in 15 ml of N, N-methylformamide and stirred at room temperature for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1:19). The obtained product was dissolved in 5 ml of N and N-dimethylformamide in 116 mg of benzyl alcohol and 35 mg of 60% sodium hydride oil suspension, and added to a stirred solution at room temperature for 1 hour, followed by stirring at 120 ° C. for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1:19). The obtained product and 50 mg of 5% palladium-carbon (water) were suspended in 20 ml of methanol, hydrogenated in the vessel, and then stirred at atmospheric pressure and room temperature for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, washed with ethyl acetate to give 130 mg of the title compound as colorless crystals.
    [792] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.39 (3H, m), 1.49-1.59 (2H, m), 1.70-1.80 (2H, m), 1.97-2.09 (2H, m), 2.50- 2.58 (2H, m), 2.84-2.93 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 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), 7.64 (1H, dd, J = 4.8, 2.0 Hz), 8.04 (1H, doublet of doublets, J = 4.8, 2.0 Hz).
    [793] Example 48
    [794] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (1,3-thiazol-2-yl) -3-pyridyl] ethyl] piperidine
    [795] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2-[[(trifluoromethyl) sulfonyl] oxy] -3-pyridyl] ethyl] piperidine 150 180 mg, 2- (tributylstannyl) thiazole and 20 mg of tetrakis (triphenylphosphine) palladium were suspended in 4 ml of toluene and heated to reflux for 2 hours under a nitrogen stream. After the solvent was removed under reduced pressure, the residue was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 39 mg of the title compound as a colorless oil.
    [796] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.41 (3H, m), 1.52-1.62 (2H, m), 1.72-1.78 (2H, m), 1.99-2.09 (2H, m), 2.86- 2.94 (2H, m), 3.27-3.34 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.23 (1H, dd, J = 8.0, 4.8 Hz), 7.40 (1H, d, J = 3.4 Hz), 7.61 (1H, dd, J = 8.0, 1.6 Hz), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 7.91 ( 1H, d, J = 3.4 Hz), 8.05 (1H, dd, J = 5.0, 2.0 Hz), 8.47 (1H, dd, J = 4.8, 1.6 Hz).
    [797] Example 49
    [798] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [1- (4-hydroxy) piperidino] -3-pyridyl) ethyl] piperidine
    [799] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2-[[(trifluoromethyl) sulfonyl] oxy] -3-pyridyl] ethyl obtained in Reference Example 18. ] 269 mg of piperidine and 178 mg of 4-hydroxypiperidine and 243 mg of potassium carbonate were suspended in 5 ml of N, N-dimethylformamide and stirred at 130 ° C. for 3 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 70 mg of the title compound as a colorless oil.
    [800] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (3H, m), 1.54-1.80 (6H, m), 1.98-2.08 (4H, m), 2.58-2.64 (2H, m), 2.84- 2.95 (4H, m), 3.25-3.33 (2H, m), 3.49 (2H, s), 3.84 (1H, m), 3.95 (3H, s), 6.85-6.92 (2H, m), 7.44 (1H, dd, J = 7.2, 1.9 Hz), 7.64 (1H, d, J = 7.2 Hz), 8.06 (1H, dd, J = 4.9, 1.9 Hz), 8.15 (1H, dd, J = 4.9, 1.9 Hz).
    [801] Example 50
    [802] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (3-cyanopropoxy) -3-pyridyl] ethyl] piperidine
    [803] 200 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-oxo-1,2-dihydro-3-pyridinyl) ethyl] piperidine in Example 47 , 95 mg of γ-bromobutyronitrile and 169 mg of potassium carbonate were suspended in 5 ml of N and N-dimethylformamide, and stirred at 60 ° C. for 4 hours. Ethyl acetate was added, the resulting salt was filtered off and the solvent was removed under reduced pressure. The crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give 77 mg of the title compound as a colorless oil.
    [804] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.39 (3H, m), 1.47-1.56 (2H, m), 1.68-1.77 (2H, m), 1.97-2.07 (2H, m), 2.11- 2.21 (2H, m), 2.51-2.61 (4H, m), 2.86-2.93 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 4.40-4.45 (2H, m), 6.82 ( 1H, dd, J = 7.2, 5.0 Hz), 6.87 (1H, dd, J = 7.2, 4.8 Hz), 7.38 (1H, dd, J = 7.2, 2.0 Hz), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 7.97 (1H, dd, J = 5.0, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz).
    [805] Example 51
    [806] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [1- (2-fluorobenzyl) -2-oxo-1,2-dihydro-3-pyridyl] ethyl ] Piperidine
    [807] 100 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-oxo-1,2-dihydro-3-pyridinyl) ethyl] piperidine in Example 47 And 61 mg of 2-fluorobenzylbromide in the same manner as in Example 49 to obtain 87 mg of the title compound as a colorless oil.
    [808] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.36 (3H, m), 1.47-1.56 (2H, m), 1.68-1.78 (2H, m), 1.97-2.06 (2H, m), 2.51- 2.58 (2H, m), 2.84-2.92 (2H, m), 3.47 (2H, s), 3.94 (3H, s), 5.17 (2H, s), 6.08-6.13 (1H, m), 6.86 (1H, dd, J = 7.2, 5.2 Hz), 7.03-7.16 (3H, m), 7.24-7.31 (2H, m), 7.40-7.46 (1H, m), 7.64 (1H, dd, J = 7.2, 2.0 Hz) , 8.04 (1H, doublet of doublets, J = 5.2, 2.0 Hz).
    [809] Example 52
    [810] 1-[(2-benzyloxy-3-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [811] 478 mg of 1-[(2-chloro-3-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine in the same manner as in Example 120 below, 369 mg of the title compound was obtained as a colorless oily form. Obtained as water.
    [812] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.36 (3H, m), 1.54-1.62 (2H, m), 1.69-1.77 (2H, m), 1.98-2.07 (2H, m), 2.56- 2.63 (2H, m), 2.86-2.92 (2H, m), 3.53 (2H, s), 5.41 (2H, s), 5.92 (2H, s), 6.66 (1H, dd, J = 7.8, 1.0 Hz) , 6.68 (1H, dd, J = 7.8, 1.0 Hz), 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), 7.45-7.50 (2H, m), 7.68 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 5.0, 2.0 Hz).
    [813] Example 53
    [814] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-hydroxy-2- (2-thienyl) ethyl] piperidine
    [815] 48.4 ml of 1.0 M (2-thienyl) lithium tetrahydrofuran solution was dissolved in 40 ml of tetrahydrofuran at −78 ° C. to give 1-[(2-methoxy-3-pyridyl) methyl] in Example 24. A mixed solution of 10.0 g of 4-piperidine acetaldehyde and 40 ml of tetrahydrofuran was added dropwise. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 20 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 12.1 g of the title compound as a yellow oil.
    [816] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.55 (3H, m), 1.65-2.08 (6H, m), 2.83-2.90 (2H, m), 3.47 (2H, s), 3.94 (3H, s), 5.03 (1H, dd, 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), 8.04 (1H, dd, J = 4.9, 2.0 Hz).
    [817] Example 54
    [818] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-thienyl) ethyl] piperidine
    [819] 12.0 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-hydroxy-2- (2-thienyl) ethyl] piperidine and 30.2 ml of triethylamine were added to dimethylsulfoxide. It was dissolved in 72 ml, and a mixed solution of 17.2 g of sulfur trioxide-pyridine complex and 90 ml of dimethyl sulfoxide was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Sodium bicarbonate water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 9.6 g of the title compound as a pale yellow oil.
    [820] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.48 (2H, m), 1.69-1.80 (2H, m), 1.94-2.15 (3H, m), 2.82 (2H, d, J = 7.0 Hz) , 2.84-2.93 (2H, m), 3.49 (2H, s), 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), 7.64 (1H, dd, J = 7.3, 1.9 Hz), 7.70 (1H, dd, J = 3.9, 1.3 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [821] Example 55
    [822] N1-methoxy, N1-methyl-2- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] acetamide
    [823] 2.6 g of ethyl 2- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] acetate and 1.3 g of N, O-dimethylhydroxyamine hydrochloride are suspended in 18 ml of tetrahydrofuran. And 13.2 ml of 2M chloroisopropylmagnesium diethyl ether solutions were dripped at -23 degreeC. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Aqueous solution of saturated ammonia chloride was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 2.3 g of the title compound as a yellow oil.
    [824] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.42 (2H, m), 1.69-1.78 (2H, m), 1.88 (1H, m), 2.05-2.15 (2H, m), 2.32-2.40 ( 2H, m), 2.85-2.94 (2H, m), 3.18 (3H, s), 3.49 (2H, s), 3.67 (3H, s), 3.95 (3H, s), 6.86 (1H, dd, J = 7.2, 5.0 Hz), 7.64 (1H, dd, J = 7.2, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [825] Example 56
    [826] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-thienyl) ethyl] piperidine
    [827] 0.50 g of N 1 -methoxy, N 1 -methyl-2- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] acetamide obtained in Example 55 was added to tetrahydrofuran. It dissolved in 3 ml, and 1.8 ml of 1.0 M (2- thienyl) lithium tetrahydrofuran solutions were dripped at -78 degreeC. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 1 hour. Aqueous solution of saturated ammonia chloride was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 0.22 g of the title compound as a pale yellow oil. The NMR spectral data of the present compound corresponded to that of Example 54.
    [828] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.48 (2H, m), 1.69-1.80 (2H, m), 1.94-2.15 (3H, m), 2.82 (2H, d, J = 7.0 Hz) , 2.84-2.93 (2H, m), 3.49 (2H, s), 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), 7.64 (1H, dd, J = 7.3, 1.9 Hz), 7.70 (1H, dd, J = 3.9, 1.3 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz).
    [829] Example 57
    [830] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-hydroxy-2-phenylethyl) piperidine
    [831] Example 53 and 2.0 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineacetaldehyde obtained in Reference Example 2 and 10.0 ml of 0.97 M phenyllithiumcyclohexane / diethyl ether solution In the same manner, 2.2 g of the title compound was obtained as a yellow oil.
    [832] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.60 (4H, m), 1.64-1.82 (3H, m), 1.96-2.07 (2H, m), 2.82-2.91 (2H, m), 3.46 ( 2H, s), 3.92 (3H, s), 4.71-4.78 (1H, m), 6.84 (1H, dd, J = 7.1, 4.9 Hz), 7.23-7.37 (5H, m), 7.62 (1H, dd, J = 7.1, 2.0 Hz), 8.03 (1H, dd, J = 4.9, 2.0 Hz).
    [833] Example 58
    [834] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2-oxo-2-phenylethyl) piperidine
    [835] 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 heated for 2 hours. It was refluxed. The reaction solution was filtered, the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1.54 g of the title compound as a pale yellow oil.
    [836] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.47 (2H, m), 1.70-1.80 (2H, m), 1.92-2.17 (3H, m), 2.83-2.94 (4H, m), 3.49 ( 2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.3, 5.1 Hz), 7.42-7.49 (3H, m), 7.52-7.59 (1H, m), 7.64 (1H, dd, J = 7.3, 2.0 Hz), 7.92-7.98 (2H, m), 8.05 (1H, doublet of doublets, J = 5.1, 2.0 Hz).
    [837] Example 59
    [838] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chlorophenyl) -2-hydroxyethyl] piperidine
    [839] 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 heated for 2 hours. It was refluxed. The reaction solution was filtered, the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1.54 g of the title compound as a pale yellow oil.
    [840] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.45 (2H, m), 1.52-1.95 (5H, m), 2.83-2.97 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 5.19-5.27 (1H, m), 6.86 (1H, dd, J = 7.2, 5.0 Hz), 7.19 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.28 (1H, dd, J = 7.6, 1.6 Hz), 7.31 (1H, ddd, J = 7.6, 7.6, 1.6 Hz), 7.57 (1H, dd, J = 7.6, 1.6 Hz), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 8.04 (1H, doublet of doublets, J = 5.0, 2.0 Hz).
    [841] Example 60
    [842] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chlorophenyl) -2-oxoethyl] piperidine
    [843] Using 900 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chlorophenyl) -2-hydroxyethyl] piperidine and titled as in Example 54 720 mg of compound were obtained as a pale yellow oil.
    [844] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.46 (2H, m), 1.71-1.80 (2H, m), 1.93-2.16 (3H, m), 2.84-2.93 (4H, m), 3.50 ( 2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.2, 5.0 Hz), 7.26-7.44 (4H, m), 7.64 (1H, d, J = 7.2, 1.8 Hz), 8.05 (1H, doublet, J = 5.0, 1.8 Hz).
    [845] Example 61
    [846] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) -2-hydroxyethyl] piperidine
    [847] 0.26 ml of 2-chloropyridine, 2.9 ml of 0.97M phenyllithium cyclohexane / diethyl ether solution, and 0.039 ml of diisopropylamine were dissolved in 9 ml of tetrahydrofuran and stirred at -45 ° C for 1 hour. A mixed solution of 500 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidine acetaldehyde and 2 ml of tetrahydrofuran obtained in Reference Example 22 was added dropwise, Stirred for a minute. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 420 mg of the title compound as a yellow oil.
    [848] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.55-1.95 (5H, m), 2.01-2.14 (2H, m), 2.83-2.97 (2H, m), 3.49 ( 2H, s), 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), 7.65 (1H, dd, J = 7.3, 2.0 Hz), 7.94 (1H, dd, J = 7.7, 1.9 Hz), 8.05 (1H, dd, J = 5.0, 1.9 Hz), 8.29 (1H, dd, J = 5.0 , 2.0 Hz).
    [849] Example 62
    [850] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) -2-oxoethyl) piperidine
    [851] The method of Example 54 at 610 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) -2-hydroxyethyl] piperidine 463 mg of the title compound were obtained as a pale yellow oil.
    [852] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.70-1.79 (2H, m), 1.93-2.17 (3H, m), 2.84-2.97 (4H, m), 3.50 ( 2H, s), 3.95 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.33 (1H, dd, J = 7.7, 4.9 Hz), 7.63 (1H, dd, J = 7.1, 1.8 Hz), 7.77 (1H, dd, J = 7.7, 1.9 Hz), 8.05 (1H, d, J = 4.9, 1.9 Hz), 8.48 (1H, dd, J = 4.9, 1.8 Hz).
    [853] Example 63
    [854] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-trifluoroacetylaminophenyl) ethyl] piperidine
    [855] 482 mg of 2-bromo-N- (trifluoroacetyl) aniline was dissolved in a mixed solvent of 1.8 ml of tetrahydrofuran and 1.8 ml of diethyl ether, and 1.8 ml of 1.14M methyllithium diethyl ether solution was added dropwise at 0 ° C. It was. After stirring for 10 minutes, a solution of 2.4 ml of 1.51 M tert-butyllithium pentane solution and 4 ml of diethyl ether, cooled to -78 ° C, was slowly transferred by cannula and stirred for 1 hour. Then 500 mg of N 1 -methoxy, N 1-methyl-2- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] acetamide obtained in Example 54 and tetra A mixture solution of 2 ml of hydrofuran was added dropwise and stirred for 20 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 150 mg of the title compound as a yellow oil.
    [856] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.35-1.48 (2H, m), 1.70-1.80 (2H, m), 1.94-2.18 (3H, m), 2.87-2.95 (2H, m), 2.98 ( 2H, d, J = 6.4 Hz), 3.51 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 4.9 Hz), 7.29 (1H, dd, J = 8.6, 7.7 Hz ), 7.62 (1H, dd, J = 7.2, 1.9 Hz), 7.64 (1H, dd, J = 8.1, 7.7 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.06 (1H, dd, J = 4.9, 1.9 Hz), 8.70 (1H, d, J = 8.6 Hz).
    [857] Example 64
    [858] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-aminophenyl) -2-oxoethyl] piperidine
    [859] 150 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-trifluoroacetylaminophenyl) ethyl] piperidine obtained in Example 63, carbonic acid 141 mg of potassium was suspended in a mixed solvent of 3 ml of methanol and 3 ml of water, and stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the title compound was obtained quantitatively as a yellow oil.
    [860] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.70-1.79 (2H, m), 1.90-2.03 (1H, m), 2.06-2.17 (2H, m), 2.82- 2.94 (4H, m), 3.50 (2H, s), 3.94 (3H, s), 6.64 (1H, dd, J = 8.0, 7.0 Hz), 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, 7.2, 1.5 Hz), 7.64 (1H, dd, J = 7.2, 1.8 Hz), 7.73 (1H, dd, J = 7.0 , 1.5 Hz), 8.05 (1H, doublet of doublets, J = 5.0, 1.8 Hz).
    [861] Example 65
    [862] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methylsulfonylaminophenyl) -2-oxoethyl] piperidine
    [863] 120 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-aminophenyl) -2-oxoethyl] piperidine obtained in Example 64, 0.1 ml of triethylamine And 0.041 ml of methanesulfonyl chloride were dissolved in 2 ml of dichloromethane and stirred for 2 hours under ice-cooling. Sodium bicarbonate water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to yield 90 mg of the title compound as a pale yellow oil.
    [864] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.47 (2H, m), 1.76-1.85 (2H, m), 1.99-2.22 (3H, m), 2.83-2.96 (4H, m), 3.50 ( 3H, s), 3.52 (2H, s), 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), 7.65 (1H, dd, J = 7.3, 1.9 Hz), 7.67 (1H, dd, J = 5.9, 3.4 Hz), 8.05 (1H, doublet of doublets, J = 5.0, 1.9 Hz).
    [865] Example 66
    [866] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (methylsulfonyl) phenyl] -2-oxoethyl] piperidine
    [867] 953 mg of N- (tert-butoxycarbonyl) -4- [2- (2-methylsulfonylphenyl) -2-oxoethyl] piperidine and 19.2 ml of 4 M ethyl chloride acetate solution in 15 ml of ethyl acetate It dissolved and stirred at room temperature for 4 hours. After removal of the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to obtain 800 mg of 4- [2- (2-methylsulfonylphenyl) -2-oxoethyl] piperidine hydrochloride, followed by 3- (chloromethyl)- It was suspended in 400 mg of 2-methoxypyridine, 1.0 g of potassium carbonate and 15 ml of N, N-dimethylformamide and stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 1.07 g of the title compound as a pale yellow oil.
    [868] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.80-1.89 (2H, m), 2.02-2.20 (3H, m), 2.85-2.95 (4H, m), 3.25 ( 3H, s), 3.50 (2H, s), 3.95 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 7.41 (1H, d, J = 7.5 Hz), 7.61 (1H, dd , J = 7.9, 7.5 Hz), 7.64 (1H, d, J = 7.1, 1.8 Hz), 7.69 (1H, dd, J = 7.5, 7.5 Hz), 8.05 (1H, dd, J = 4.9, 1.8 Hz) , 8.07 (1H, doublet, J = 7.9 Hz).
    [869] Example 67
    [870] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methoxyphenyl) -2-oxoethyl] piperidine
    [871] 2.1 g of 2-bromoanisole, 7.4 ml of 1.54 Mn-butyllithium hexane solution and 2.0 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineacetaldehyde obtained in Reference Example 22 2.4 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-hydroxy-2- (2-methoxyphenyl) ethyl] piperidine was prepared according to the method of Example 59. Then, the title compound was obtained in the same manner as in Example 54, and 0.93 g of the title compound was obtained as a pale yellow oil.
    [872] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.43 (2H, m), 1.65-1.77 (2H, m), 1.89-2.15 (3H, m), 2.81-2.95 (4H, m), 3.48 ( 2H, s), 3.89 (3H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.99 (1H, dd , J = 7.5, 7.5 Hz), 7.44 (1H, ddd, J = 8.4, 7.5, 1.5 Hz), 7.61 (1H, dd, J = 7.5, 1.5 Hz), 7.63 (1H, dd, J = 7.1, 1.8 Hz), 8.04 (1H, doublet of doublets, J = 4.9, 1.8 Hz).
    [873] Example 68
    [874] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-cyclopropylmethoxyphenyl) -2-oxoethyl] piperidine
    [875] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.32-0.39 (2H, m), 0.62-0.70 (2H, m), 1.22-1.47 (3H, m), 1.69-1.80 (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), 3.94 (3H , s), 6.86 (1H, dd, J = 7.1, 4.9 Hz), 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, 7.4, 1.8 Hz), 7.64 (1H, dd, J = 7.5, 1.8 Hz), 7.65 (1H, dd, J = 7.1, 1.8 Hz), 8.05 (1H, dd, J = 4.9, 1.8 Hz ).
    [876] Example 69
    [877] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-trifluoro methylphenyl) ethyl] piperidine
    [878] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.43 (2H, m), 1.73-1.83 (2H, m), 1.96-2.18 (3H, m), 2.79 (2H, d, J = 6.6 Hz) , 2.85-2.94 (2H, m), 3.50 (2H, s), 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 = 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), 8.05 (1H, doublet of doublets, J = 4.9, 1.8 Hz).
    [879] Example 70
    [880] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (3-thienyl) ethyl] piperidine
    [881] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.46 (2H, m), 1.68-1.80 (2H, m), 1.92-2.15 (3H, m), 2.78-2.94 (4H, m), 3.49 ( 2H, s), 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), 8.05 (1H, dd, J = 4.9, 1.8 Hz).
    [882] Example 71
    [883] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (1,3-thiazol-2-yl) ethyl] piperidine
    [884] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.37-1.51 (2H, m), 1.71-1.80 (2H, m), 1.97-2.16 (3H, m), 2.85-2.93 (2H, m), 3.10 ( 2H, d, J = 6.8 Hz), 3.49 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.1, 5.0 Hz), 7.64 (1H, dd, J = 7.1, 1.8 Hz ), 7.67 (1H, d, J = 3.0 Hz), 8.00 (1H, dd, J = 3.0 Hz), 8.05 (1H, dd, J = 5.0, 1.8 Hz).
    [885] Example 72
    [886] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3,4-methylenedioxyphenyl) -2-oxoethyl] piperidine
    [887] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.38-1.43 (2H, m), 1.68-1.76 (2H, m), 2.09 (1H, m) 2.80 (2H, d, J = 6.8 Hz), 2.84- 2.92 (2H, m), 3.48 (2H, s), 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), 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), 8.05 (1H, dd, J = 4.9, 1.8 Hz).
    [888] Example 73
    [889] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-bromo-2-thienyl) -2-oxoethyl] piperidine
    [890] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.48 (2H, m), 1.72-1.82 (2H, m), 1.95-2.17 (3H, m), 2.84-2.99 (4H, m), 3.49 ( 2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.3, 5.1 Hz), 7.11 (1H, d, J = 5.1 Hz), 7.50 (1H, d, J = 5.1 Hz), 7.64 (1H, doublet, J = 7.3, 2.0 Hz), 8.05 (1H, doublet, J = 5.1, 2.0 Hz).
    [891] Example 74
    [892] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- [3- (1,3-thiazol-2-yl) -2-thienyl] ethyl] pi Ferridine
    [893] 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- (tributylstannyl) thiazole and 42 mg of tetrakis (triphenylphosphine) palladium were suspended in 4 ml of toluene and heated to reflux for 2 hours under a nitrogen stream. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to give 300 mg of the title compound as a colorless oil.
    [894] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.43 (2H, m), 1.66-1.96 (2H, m), 1.94-2.14 (3H, m), 2.76-2.91 (4H, m), 3.48 ( 2H, s), 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), 7.62 (1H, dd, J = 7.3, 2.0 Hz), 7.82 (1H, d, J = 5.2 Hz), 7.93 (1H, d, J = 3.3 Hz), 8.05 (1H, dd, J = 5.1, 2.0 Hz ).
    [895] Example 75
    [896] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (3-phenyl-2-thienyl) ethyl] piperidine
    [897] 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 phenylboronic acid and 42 mg of tetrakis (triphenylphosphine) palladium were suspended in 5.6 ml of toluene, 1.4 ml of methanol and 2.8 ml of 2M sodium carbonate, and heated to reflux for 3 hours under a nitrogen stream. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate) to give 290 mg of the title compound as a yellow oil.
    [898] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.09-1.24 (2H, m), 1.48-1.59 (2H, m), 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), 7.48 (1H, d, J = 7.5 Hz), 7.54 (1H, d, J = 4.9 Hz).
    [899] Example 76
    [900] 1-[(2-methoxy-3-pyridyl) methyl] -4- (3-phenylpropyl) piperidine
    [901] 332 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineacetaldehyde obtained in Reference Example 22 and 491 mg of benzyltriphenylphosphonium chloride according to the method of Example 46 according to the title compound. 214 mg were obtained as a colorless oil.
    [902] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (5H, m), 1.57-1.70 (4H, m), 1.76-2.06 (2H, m), 2.59 (2H, t, J = 7.7 Hz) , 2.84-2.91 (2H, m), 3.47 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.2, 5.0 Hz), 7.14-7.20 (3H, m), 7.24-7.30 (2H, m), 7.64 (1H, doublet of doublets, J = 7.2, 1.9 Hz), 8.04 (1H, doubled, J = 5.0, 1.9 Hz).
    [903] Example 77
    [904] 1-[(2-methoxy-3-pyridyl) methyl] -4- (3- (2-thienyl) propyl) piperidine
    [905] 261 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidineacetaldehyde obtained in Reference Example 22 and 499 mg of (2-thienylmethyl) triphenylphosphonium chloride as the title compound 206 mg was obtained as a light brown oil.
    [906] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.35 (5H, m), 1.62-1.74 (4H, m), 1.76-2.06 (2H, m), 2.81 (2H, t, J = 7.6 Hz) , 2.84-2.92 (2H, m), 3.48 (2H, s), 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), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 8.04 (1H, dd, J = 5.0, 2.0 Hz).
    [907] Example 78
    [908] 1-[(2-methoxy-3-pyridyl) methyl] -4-benzylpiperidine
    [909] 292 mg of 4-benzylpiperidine were obtained as light yellow oil as 472 mg of the title compound according to the method of Example 43.
    [910] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.40 (2H, m), 1.53 (1H, m), 1.58-1.68 (2H, m), 1.95-2.04 (2H, m), 2.54 (2H, d, J = 7.0 Hz), 2.84-2.91 (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), 7.24-7.30 (2H, m), 7.63 (1H, doublet of doublets, J = 7.2, 2.0 Hz), 8.04 (1H, doubled, J = 5.0, 2.0 Hz).
    [911] Example 79
    [912] 1-[(2-methoxy-3-pyridyl) methyl] -4- (4-phenylbutyl) piperidine
    [913] The method of Example 46 with 220 mg of 3- [1-[(2-methoxy-3-pyridyl) methyl] -4-piperidyl] propanal obtained from Reference Example 30 and 407 mg of benzyltriphenylphosphonium chloride 150 mg of the title compound were obtained as a colorless oil.
    [914] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.38 (7H, m), 1.55-1.70 (4H, m), 1.96-2.06 (2H, m), 2.60 (2H, t, J = 7.7 Hz) , 2.84-2.93 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.86 (1H, dd, J = 7.2, 5.0 Hz), 7.14-7.20 (3H, m), 7.24-7.30 (2H, m), 7.64 (1H, doublet of doublets, J = 7.2, 1.8 Hz), 8.05 (1H, doubled, J = 5.0, 1.8 Hz).
    [915] Example 80
    [916] 1-[(2-methoxy-3-pyridyl) methyl] -4- [oxo (2-thienyl) methyl) piperidine
    [917] 210 mg of the title compound were obtained as colorless crystals using 210 mg of 4- [oxo (2-thienyl) methyl] piperidine according to the method of Example 43.
    [918] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.82-1.98 (4H, m), 2.14-2.23 (2H, m), 2.94-3.03 (2H, m), 3.09 (1H, m), 3.52 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.12 (1H, dd, J = 5.0, 3.8 Hz), 7.62 (1H, dd, J = 5.0, 1.0 Hz ), 7.07 (1H, dd, J = 7.2, 1.8 Hz), 7.72 (1H, dd, J = 3.8, 1.0 Hz), 8.05 (1H, dd, J = 5.0, 1.8 Hz).
    [919] Example 81
    [920] 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxamide
    [921] 496 mg of isonifecotamide was obtained as colorless crystals according to the method of Example 43.
    [922] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.73-1.91 (4H, m), 2.04-2.22 (3H, m), 2.90-2.98 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 5.35 (1H, br s), 5.47 (1H, br s), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.65 (1H, dd, J = 7.2, 1.9 Hz), 8.06 (1H , dd, J = 5.0, 1.9 Hz).
    [923] Example 82
    [924] N4-[(2-phenyl) benzyl-1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxamide
    [925] 212 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxamide and 0.16 ml of 2- (bromomethyl) biphenyl and 46 mg of 60% sodium hydride were added N, N It was suspended in 5 ml of dimethylformamide and stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give 92 mg of the title compound as colorless crystals.
    [926] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.60-1.78 (4H, m), 1.96-2.08 (3H, m), 2.86-2.94 (2H, m), 3.47 (2H, s), 3.94 (3H, s), 4.43 (2H, d, J = 5.5 Hz), 5.48 (1H, t, J = 5.5 Hz), 6.87 (1H, dd, J = 7.2, 5.0 Hz), 7.24-7.45 (9H, m), 7.63 (1H, doublet of doublets, J = 7.2, 1.9 Hz), 8.05 (1H, doublet of doublets, J = 5.0, 1.9 Hz).
    [927] Example 83
    [928] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[(2-bromo-3-pyridyl) oxy] methyl] piperidine
    [929] 1.18 g of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinemethanol and 0.87 g of 2-bromo-3-hydroxypyridine obtained in Reference Example 1 were added to 50 ml of tetrahydrofuran. It melt | dissolved, 1.12 g of diisopropyl azo dicarboxylates and 1.44 g of triphenylphosphines were added under 10 degreeC cooling, and it stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 550 mg of the title compound as a colorless oil.
    [930] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.40-1.52 (2H, m), 1.84-1.98 (3H, m), 2.08-2.17 (2H, m), 2.92-3.01 (2H, m), 3.53 ( 2H, s), 3.87 (2H, d, J = 6.4 Hz), 3.96 (3H, s), 6.88 (1H, dd, J = 6.8, 4.8 Hz), 7.11 (1H, dd, J = 8.0, 1.6 Hz ), 7.19 (1H, dd, J = 8.0, 4.8 Hz), 7.65 (1H, dd, J = 6.8, 2.0 Hz), 7.97 (1H, dd, J = 4.8, 1.6 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz).
    [931] Example 84
    [932] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[[2- (1,3-thiazol-2-yl) -3-pyridyl] oxy] methyl] piperidine
    [933] 250 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-[[(2-bromo-3-pyridyl) oxy] methyl] piperidine titled according to the method of Example 33 238 mg of compound were obtained as a colorless oil.
    [934] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.44-1.59 (2H, m), 1.92-2.20 (5H, m), 2.93-3.02 (2H, m), 3.54 (2H, s), 3.96 (3H, s), 4.04 (2H, d, J = 6.4 Hz), 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), 7.48 (1H, d, J = 3.2 Hz), 7.66 (1H, dd, J = 7.2, 1.6 Hz), 8.04 (1H, d, J = 3.2 Hz), 8.06 (1H, dd , J = 4.8, 1.6 Hz), 8.39 (1H, dd, J = 4.4, 1.2 Hz).
    [935] Example 85
    [936] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-cyano-2- (3,4-methylenedioxyphenyl) ethyl] piperidine
    [937] 200 mg of 4- [2-cyano-2- (3,4-methylenedioxyphenyl) ethyl] piperidine were subjected to the method of Example 33 to yield 227 mg of the title compound as a colorless oil.
    [938] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (2H, m), 1.43-1.56 (1H, m), 1.63-1.80 (3H, m), 1.86-1.96 (1H, m), 2.00- 2.10 (2H, m), 2.84-2.93 (2H, m), 3.48 (2H, s), 3.71-3.77 (1H, m), 3.94 (3H, s), 5.98 (2H, s), 6.73-6.80 ( 3H, m), 6.86 (1H, dd, J = 7.2, 4.8 Hz), 7.62 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz).
    [939] Example 86
    [940] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-cyano-2- (2-methoxyphenyl) ethyl] piperidine
    [941] 244 mg of 4- [2-cyano-2- (2-methoxyphenyl) ethyl] piperidine were prepared in the same manner as in Example 80 to obtain 191 mg of the title compound as a colorless oil.
    [942] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (2H, m), 1.52-1.74 (3H, m), 1.80-1.91 (2H, m), 2.01-2.12 (2H, m), 2.83- 2.95 (2H, m), 3.48 (2H, s), 3.84 (3H, s), 3.95 (3H, s), 4.22-4.28 (1H, m), 6.86 (1H, dd, J = 7.2, 5.2 Hz) , 6.88 (1H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 8.0, 7.6 Hz), 7.29 (1H, dd, J = 8.0, 7.6 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.62 (1H, doublet of doublets, J = 7.2, 2.0 Hz), 8.05 (1H, doublet of doublets, J = 5.2, 2.0 Hz).
    [943] Example 87
    [944] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (methylsulfonyl) phenethyl] piperidine
    [945] 479 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (methylsulfonyl) phenethyl] piperidine obtained in Reference Example 1 and 2 ml of thionyl chloride were 50 ml of ethanol. It dissolved in and heated to reflux for 2 hours. An aqueous 1N sodium hydroxide solution was added to the reaction solution, made alkaline, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product obtained was purified by NH foam silica gel column chromatography (ethyl acetate) to give 368 mg of the title compound as colorless crystals.
    [946] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.48 (3H, m), 1.62-1.68 (2H, m), 1.75-1.82 (2H, m), 2.06-2.16 (2H, m), 2.91- 2.99 (2H, m), 3.02-3.07 (2H, m), 3.08 (3H, s), 3.48 (2H, s), 6.33 (1H, dd, J = 6.5, 6.5 Hz), 7.35-7.40 (3H, m), 7.53-7.58 (2H, m), 8.03 (1H, doublet of doublets, J = 8.3, 1.4 Hz).
    [947] Example 88
    [948] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (3,4-methylenedioxyphenethyl) piperidine
    [949] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.38 (3H, m), 1.49-1.57 (2H, m), 1.68-1.77 (2H, m), 2.02-2.12 (2H, m), 2.52- 2.58 (2H, m), 2.88-2.96 (2H, m), 3.47 (2H, s), 5.92 (2H, s), 6.34 (1H, dd, J = 6.6, 6.6 Hz), 6.61 (1H, dd, J = 7.9, 1.7 Hz), 6.67 (1H, d, J = 1.7 Hz), 6.72 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.53 (1H, d, J = 6.6 Hz).
    [950] Example 89
    [951] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-phenethylpiperidine
    [952] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (3H, m), 1.53-1.62 (2H, m), 1.69-1.79 (2H, m), 2.01-2.13 (2H, m), 2.58- 2.67 (2H, m), 2.88-2.97 (2H, m), 3.47 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.14-7.21 (3H, s), 7.24-7.31 ( 2H, s), 7.36 (1H, d, J = 6.6 Hz), 7.54 (1H, d, J = 6.6 Hz).
    [953] Example 90
    [954] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-hydroxyphenethyl) piperidine
    [955] 1 H-NMR (400 MHz, DMSO-d6) δ 1.12-1.24 (3H, m), 1.40-1.48 (2H, m), 1.64-1.71 (2H, m), 1.87-1.96 (2H, m), 2.48 -2.55 (2H, m), 2.75-2.82 (2H, m), 3.22 (2H, s), 6.16 (1H, dd, J = 6.6, 6.6 Hz), 6.69 (1H, ddd, J = 7.5, 7.5, 1.2 Hz), 6.75 (1H, dd, J = 7.5, 1.2 Hz), 6.96 (1H, ddd, J = 7.5, 7.5, 1.7 Hz), 7.02 (1H, dd, J = 7.5, 1.7 Hz), 7.24 ( 1H, dd, J = 6.6, 2.2 Hz), 7.37 (1H, dd, J = 6.6, 2.2 Hz).
    [956] Example 91
    [957] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (3-fluorophenethyl) piperidine
    [958] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.40 (3H, m), 1.52-1.61 (2H, m), 1.68-1.77 (2H, m), 2.02-2.12 (2H, m), 2.58- 2.66 (2H, m), 2.88-2.97 (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), 7.36 (1H, d, J = 6.8 Hz), 7.54 (1H, d, J = 6.8 Hz).
    [959] Example 92
    [960] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-trifluoromethylphenethyl) piperidine
    [961] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.45 (3H, m), 1.51-1.61 (2H, m), 1.70-1.81 (2H, m), 2.04-2.16 (2H, m), 2.73- 2.82 (2H, m), 2.89-2.99 (2H, m), 3.49 (2H, s), 6.34 (1H, dd, J = 6.8, 6.8 Hz), 7.26 (1H, dd, J = 7.7, 7.6 Hz) , 7.31 (1H, d, J = 7.5 Hz), 7.36 (1H, d, J = 6.8 Hz), 7.45 (1H, dd, J = 7.6, 7.5 Hz), 7.54 (1H, d, J = 6.8 Hz) , 7.60 (1H, doublet, J = 7.7 Hz).
    [962] Example 93
    [963] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (1-pyrazolo) phenethyl] piperidine
    [964] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.12-1.24 (3H, m), 1.31-1.40 (2H, m), 1.50-1.59 (2H, m), 1.94-2.04 (2H, m), 2.51- 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 (1H, dd, J = 2.4, 2.0 Hz) , 7.23-7.38 (5H, m), 7.52 (1H, d, J = 6.4 Hz), 7.56 (1H, d, J = 2.4 Hz), 7.70 (1H, d, J = 2.0 Hz).
    [965] Example 94
    [966] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (4-acetylpiperazino) phenethyl] piperidine
    [967] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.40 (3H, m), 1.53-1.61 (2H, m), 1.73-1.81 (2H, m), 2.03-2.12 (2H, m), 2.13 ( 3H, s), 2.65-2.72 (2H, m), 2.81-2.97 (6H, m), 3.46 (2H, s), 3.55-3.61 (2H, m), 3.68-3.77 (2H, m), 6.34 ( 1H, dd, J = 6.4, 6.4 Hz), 7.04 (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), 7.36 (1H, d, J = 6.4 Hz), 7.51 (1H, d, J = 6.4 Hz).
    [968] Example 95
    [969] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [6- (methylsulfonyl) -2,3-methylenedioxyphenethyl] piperidine
    [970] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.44 (3H, m), 1.58-1.67 (2H, m), 1.74-1.84 (2H, m), 2.06-2.15 (2H, m), 2.90- 2.98 (4H, m), 3.05 (3H, s), 3.49 (2H, s), 6.09 (2H, s), 6.34 (1H, dd, J = 6.5, 6.5 Hz), 6.78 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 6.5 Hz), 7.54 (1H, d, J = 6.5 Hz), 7.62 (1H, d, J = 8.4 Hz).
    [971] Example 96
    [972] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-thienyl) ethyl] piperidine
    [973] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.40 (3H, m), 1.60-1.77 (4H, m), 2.02-2.12 (2H, m), 2.81-2.97 (4H, m), 3.47 ( 2H, s), 6.33 (1H, dd, J = 6.9, 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), 7.36 (1H, d, J = 6.9 Hz), 7.52 (1H, d, J = 6.9 Hz).
    [974] Example 97
    [975] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-methoxy-2-thienyl) ethyl] piperidine
    [976] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.38 (3H, m), 1.52-1.61 (2H, m), 1.70-1.79 (2H, m), 2.01-2.12 (2H, m), 2.67- 2.75 (2H, m), 2.87-2.96 (2H, m), 3.46 (2H, s), 3.81 (3H, s), 6.33 (1H, dd, J = 6.4, 6.4 Hz), 6.81 (1H, d, J = 5.2 Hz), 6.99 (1H, d, J = 5.2 Hz), 7.36 (1H, d, J = 6.4 Hz), 7.54 (1H, d, J = 6.4 Hz).
    [977] Example 98
    [978] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-cyano-2-thienyl) ethyl] piperidine
    [979] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.31-1.42 (3H, m), 1.63-1.81 (4H, m), 2.03-2.15 (2H, m), 2.90-2.99 (2H, m), 3.00- 3.07 (2H, m), 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).
    [980] Example 99
    [981] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-phenyl-2-thienyl) ethyl] piperidine
    [982] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.33 (3H, m), 1.56-1.66 (4H, m), 1.96-2.07 (2H, m), 2.83-2.92 (4H, m), 3.44 ( 2H, s), 6.32 (1H, dd, J = 6.4, 6.4 Hz), 7.00 (1H, d, J = 5.2 Hz), 7.15 (1H, d, J = 5.2 Hz), 7.27-7.43 (6H, m ), 7.52 (1H, d, J = 6.4 Hz).
    [983] Example 100
    [984] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-thienyl) ethyl] piperidine
    [985] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.38 (3H, m), 1.55-1.62 (2H, m), 1.66-1.78 (2H, m), 2.01-2.12 (2H, m), 2.62- 2.68 (2H, m), 2.88-2.96 (2H, m), 3.47 (2H, s), 6.34 (1H, dd, J = 6.4 Hz), 6.91-6.95 (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).
    [986] Example 101
    [987] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (methylsulfonyl) -3-thienyl] ethyl] piperidine
    [988] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.46 (3H, m), 1.57-1.66 (2H, m), 1.73-1.82 (2H, m), 2.10-2.22 (2H, m), 2.92- 3.03 (4H, m), 3.14 (3H, s), 3.54 (2H, s), 6.34 (1H, dd, J = 6.6, 6.6 Hz), 7.01 (1H, d, J = 5.0 Hz), 7.36 (1H , d, J = 6.6 Hz), 7.54 (1H, d, J = 6.6 Hz), 7.57 (1H, d, J = 5.0 Hz).
    [989] Example 102
    [990] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (benzo [b] thiophen-2-yl) ethyl] piperidine
    [991] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.43 (3H, m), 1.66-1.80 (4H, m), 2.02-2.13 (2H, m), 2.89-2.97 (4H, m), 3.47 ( 2H, s), 6.33 (1H, dd, J = 6.4, 6.4 Hz), 7.00 (1H, s), 7.24 (1H, dd, J = 7.2, 7.1 Hz), 7.30 (1H, dd, J = 7.6, 7.1 Hz), 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 ).
    [992] Example 103
    [993] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (methylsulfonyl) -3-pyridyl] ethyl] piperidine
    [994] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.46 (3H, m), 1.62-1.70 (2H, m), 1.74-1.83 (2H, m), 2.06-2.17 (2H, m), 2.91- 2.99 (2H, m), 3.07-3.15 (2H, m), 3.37 (3H, s), 3.49 (2H, s), 6.34 (1H, dd, J = 6.6, 6.6 Hz), 7.37 (1H, d, J = 6.6 Hz), 7.43 (1H, dd, J = 7.8, 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).
    [995] Example 104
    [996] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-n-butyl-3-pyridyl) ethyl] piperidine
    [997] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.96 (3H, t, J = 7.3 Hz), 1.34-1.49 (5H, m), 1.49-1.60 (2H, m), 1.63-1.80 (4H, m) , 2.06-2.17 (2H, m), 2.59-2.66 (2H, m), 2.77 (2H, t, J = 8.1 Hz), 2.92-3.00 (2H, m), 3.50 (2H, s), 6.34 (1H , dd, J = 6.4, 6.4 Hz), 7.04 (1H, dd, J = 7.6, 4.8 Hz), 7.33-7.42 (2H, m), 7.53 (1H, d, J = 6.4 Hz), 8.37 (1H, dd, J = 4.8, 1.8 Hz).
    [998] Example 105
    [999] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-pyridyl) ethyl] piperidine
    [1000] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.40 (3H, m), 1.56-1.62 (2H, m), 1.70-1.78 (2H, m), 2.04-2.12 (2H, m), 2.60- 2.66 (2H, m), 2.90-2.97 (2H, m), 3.47 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.21 (1H, dd, J = 7.8, 4.8 Hz) , 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).
    [1001] Example 106
    [1002] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-phenoxy-3-pyridyl) ethyl] piperidine
    [1003] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.40 (3H, m), 1.60-1.68 (2H, m), 1.72-1.82 (2H, m), 2.04-2.12 (2H, m), 2.70- 2.77 (2H, m), 2.90-2.97 (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) , 7.07-7.12 (2H, m), 7.17 (1H, m), 7.33-7.42 (3H, m), 7.50-7.55 (2H, m), 8.00 (1H, dd, J = 5.0, 1.8 Hz).
    [1004] Example 107
    [1005] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (5-methoxy-2-pyridyl) ethyl] piperidine
    [1006] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.61-1.70 (2H, m), 1.74-1.84 (2H, m), 2.05-2.16 (2H, m), 2.80- 2.87 (2H, m), 2.91-2.99 (2H, m), 3.49 (2H, s), 3.83 (3H, m), 6.34 (1H, dd, J = 6.4, 6.4 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.37 (1H, d, J = 6.4 Hz), 7.57 (1H, d, J = 6.4 Hz), 8.11 (1H, dd, J = 2.8, 2.8 Hz).
    [1007] Example 108
    [1008] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[2- (4-methoxyphenyl) -3-pyridyl] ethyl] piperidine
    [1009] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.13-1.29 (3H, m), 1.41-1.50 (2H, m), 1.52-1.62 (2H, m), 1.96-2.09 (2H, m), 2.62- 2.70 (2H, m), 2.81-2.93 (2H, m), 3.45 (2H, s), 3.85 (3H, s), 6.31 (1H, dd, J = 6.4, 6.4 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.18 (1H, dd, J = 7.8, 4.8 Hz), 7.33 (1H, d, J = 6.4 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 6.4 Hz), 7.57 (1H, dd, J = 7.8, 1.6 Hz), 8.50 (1H, dd, J = 4.8, 1.6 Hz).
    [1010] Example 109
    [1011] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (1,3-thiazol-2-yl) ethyl] piperidine
    [1012] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.29-1.42 (3H, m), 1.69-1.83 (4H, m), 2.03-2.13 (2H, m), 2.89-2.97 (2H, m), 3.02- 3.10 (2H, m), 3.47 (2H, s), 6.33 (1H, dd, J = 6.6, 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), 7.67 (1H, d, J = 3.3 Hz).
    [1013] Example 110
    [1014] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (1-morpholino) -3-pyridyl] ethyl] piperidine
    [1015] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.56-1.64 (2H, m), 1.72-1.80 (2H, m), 2.04-2.12 (2H, m), 2.60- 2.66 (2H, m), 2.72-2.78 (2H, m), 3.10 (4H, t, J = 4.7 Hz), 3.48 (2H, s), 3.85 (4H, t, J = 4.7 Hz), 6.34 (1H , dd, J = 6.6, 6.6 Hz), 6.93 (1H, dd, J = 7.4, 4.8 Hz), 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, doublet of doublets, J = 4.8, 1.9 Hz).
    [1016] Example 111
    [1017] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-[(methylsulfonyl) amino] phenethyl] piperidine
    [1018] 286 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-[(methylsulfonyl) amino] phenethyl] piperidine obtained in Example 26 was prepared as in Example 87. 155 mg of the title compound were obtained as colorless crystals.
    [1019] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.31-1.40 (3H, m), 1.52-1.60 (2H, m), 1.72-1.80 (2H, m), 2.04-2.13 (2H, m), 2.64- 2.71 (2H, m), 2.90-2.97 (2H, m), 3.03 (3H, s), 3.47 (2H, s), 6.33 (1H, dd, J = 6.6, 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).
    [1020] Example 112
    [1021] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methoxy-6-methyl-3-pyridyl) ethyl] piperidine
    [1022] 275 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-6-methyl-3-pyridyl) ethyl] piperidine obtained in Example 27 Example 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- (2-chloro-6-methyl-3-pyridyl) ethyl] After piperidine was obtained, it was dissolved in 5 ml of 28% sodium methoxide methanol solution and heated to reflux for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 80 mg of the title compound as colorless crystals.
    [1023] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.21-1.39 (3H, m), 1.45-1.55 (2H, m), 1.68-1.78 (2H, m), 1.97-2.08 (2H, m), 2.41 ( 3H, s), 2.48-2.56 (2H, m), 2.85-2.95 (2H, m), 3.49 (2H, s), 3.92 (3H, s), 3.95 (3H, s), 6.35 (1H, dd, J = 6.6, 6.6 Hz), 6.63 (1H, d, J = 7.3 Hz), 7.23 (1H, d, J = 7.3 Hz), 7.37 (1H, d, J = 6.6 Hz), 7.53 (1H, d, J = 6.6 Hz).
    [1024] Example 113
    [1025] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (6-methoxy-3-pyridyl) ethyl] piperidine
    [1026] The method of Example 112 at 300 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (6-chloro-3-pyridyl) ethyl] piperidine obtained in Example 28. 86 mg of the title compound were obtained as colorless crystals.
    [1027] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.44 (3H, m), 1.47-1.59 (2H, m), 1.67-1.78 (2H, m), 2.04-2.17 (2H, m), 2.51- 2.58 (2H, m), 2.90-3.01 (2H, m), 3.51 (2H, s), 3.92 (3H, m), 6.35 (1H, dd, J = 6.6,6.6 Hz), 6.68 (1H, d, J = 8.3 Hz), 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).
    [1028] Example 114
    [1029] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-pyridyl) -1-ethenyl] piperidine
    [1030] 121 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-pyridyl) -1-ethenyl] piperidine obtained in Example 29 110 mg of the title compound were obtained as colorless crystals according to the method of Example 87.
    [1031] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.57-1.72 (3H, m), 1.77-1.88 (2H, m), 2.15-2.28 (2H, m), 2.95-3.05 (2H, m), 3.52 ( 2H, s), 6.35 (1H, dd, J = 6.6, 6.6 Hz), 6.49 (1H, d, J = 15.9 Hz), 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), 7.56-7.65 (2H, m), 8.54 (1H, m).
    [1032] Example 115
    [1033] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-pyridyl) ethyl] piperidine
    [1034] 150 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-pyridyl) ethyl] piperidine obtained in Example 30 according to the method of Example 114 according to the title compound 128 mg were obtained as colorless crystals.
    [1035] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.42 (3H, m), 1.64-1.82 (4H, m), 2.03-2.15 (2H, m), 2.77-2.85 (2H, m), 2.90- 2.99 (2H, m), 3.48 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.10 (1H, ddd, J = 7.8, 4.4, 1.2 Hz), 7.14 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.53-7.62 (2H, m), 7.52 (1H, dd, J = 4.4, 1.2 Hz).
    [1036] Example 116
    [1037] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2,3-methylenedioxyphenyl) -1-ethenyl] piperi Dean
    [1038] 99 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E)-(2,3-methylenedioxyphenyl) -1-ethenyl] piperidine obtained in Example 31 By the method of Example 114, 64 mg of the title compound was obtained as colorless crystals.
    [1039] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.50-1.64 (3H, m), 1.70-1.83 (2H, m), 2.12-2.24 (2H, m), 2.94-3.02 (2H, m), 3.51 ( 2H, s), 5.94 (2H, s), 6.01 (1H, dd, J = 15.8, 7.0 Hz), 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 (1H, d, J = 1.4 Hz), 7.35 (1H, d, J = 6.8 Hz ), 7.56 (1H, doublet, J = 6.8 Hz).
    [1040] Example 117
    [1041] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) ethyl] piperidine
    [1042] The method of Example 1 with 1.37 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) ethyl] piperidine obtained in Example 32. According to the obtained 1.15 g of the title compound as colorless crystals.
    [1043] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.44 (3H, m), 1.54-1.64 (2H, m), 1.72-1.84 (2H, m), 2.07-2.18 (2H, m), 2.69- 2.78 (2H, m), 2.92-3.01 (2H, m), 3.51 (2H, s), 6.34 (1H, dd, J = 6.6, 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), 7.57 (1H, d, J = 6.4 Hz), 8.25 (1H, dd, J = 4.8, 1.8 Hz).
    [1044] Example 118
    [1045] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methoxy-3-pyridyl) ethyl] piperidine
    [1046] 220 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- (2-chloro-3-pyridyl) ethyl] piperidine obtained in Example 117 According to the method of Example 112, 192 mg of the title compound was obtained as colorless crystals.
    [1047] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.40 (3H, m), 1.49-1.57 (2H, m), 1.72-1.80 (2H, m), 2.03-2.13 (2H, m), 2.54- 2.60 (2H, m), 2.89-2.98 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 6.33 (1H, dd, J = 6.6 Hz), 6.80 (1H, dd, J = 7.2, 5.0 Hz), 7.34-7.39 (2H, m), 7.57 (1H, d, J = 6.6 Hz), 8.01 (1H, dd, J = 5.2, 1.8 Hz).
    [1048] Example 119
    [1049] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methylthio-3-pyridyl) ethyl] piperidine
    [1050] 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 sodium thiomethoxide were suspended in 5 ml of 1-methyl-2-pyrrolidinone and stirred at 150 ° C. for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (methanol: ethyl acetate = 1:19) to obtain 20 mg of the title compound as colorless crystals.
    [1051] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.54-1.64 (2H, m), 1.72-1.83 (2H, m), 2.05-2.16 (2H, m), 2.57 ( 3H, s), 2.57-2.66 (2H, m), 2.90-3.00 (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), 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).
    [1052] Example 120
    [1053] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-[(2-methoxyethoxy) -3-pyridyl] ethyl] piperidine
    [1054] 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 of 60% sodium hydride oil suspension in 3 ml of 2-methoxyethanol and stirred at 150 ° C. for 2 hours. Water was added to the reaction solution, extraction was performed with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (methanol: ethyl acetate = 1:19) to give 135 mg of the title compound as colorless crystals.
    [1055] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.42 (3H, m), 1.50-1.60 (2H, m), 1.72-1.82 (2H, m), 2.03-2.15 (2H, m), 2.56- 2.65 (2H, m), 2.89-3.00 (2H, m), 3.43 (3H, s), 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), 6.80 (1H, dd, J = 7.2, 4.8 Hz), 7.34-7.41 (2H, m), 7.56 (1H, d, J = 6.6 Hz) , 7.97 (1H, doublet of doublets, J = 4.8, 1.8 Hz).
    [1056] Example 121
    [1057] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-cyclopropylmethoxy) -3-pyridyl] ethyl] piperidine
    [1058] 179 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- (2-chloro-3-pyridyl) ethyl] piperidine obtained in Example 117 And 0.44 ml of cyclopropanemethanol and 246 mg of 60% sodium hydride oil suspension were suspended in 5 ml of 1-methyl-2-pyrrolidinone and stirred at 150 ° C. for 1 hour. Water was added to the reaction solution, extraction was performed with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (methanol: ethyl acetate = 1:19) to obtain 147 mg of the title compound as colorless crystals.
    [1059] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.31-0.70 (2H, m), 0.54-0.60 (2H, m), 1.22-1.42 (4H, m), 1.52-1.60 (2H, m), 1.74- 1.82 (2H, m), 2.05-2.14 (2H, m), 2.56-2.64 (2H, m), 2.90-2.99 (2H, m), 3.48 (2H, s), 4.14 (2H, d, J = 7.0 Hz), 6.34 (1H, dd, J = 6.6, 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 ), 7.96 (1H, doublet of doublets, J = 5.0, 1.9 Hz).
    [1060] Example 122
    [1061] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-trifluoroethoxy) -3-pyridyl] ethyl] piperidine
    [1062] 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 trifluoroethanol, according to the method of Example 120, 373 mg of the title compound was obtained as colorless crystals.
    [1063] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.40 (3H, m), 1.50-1.58 (2H, m), 1.70-1.80 (2H, m), 2.02-2.14 (2H, m), 2.56- 2.64 (2H, m), 2.89-2.98 (2H, m), 3.48 (2H, s), 4.76 (2H, q, J = 8.4 Hz), 6.34 (1H, dd, J = 6.6, 6.6 Hz), 6.90 (1H, dd, J = 7.2, 5.0 Hz), 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, doublet of doublets, J = 5.0, 2.0 Hz).
    [1064] Example 123
    [1065] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-hydroxyethoxy) -3-pyridyl] ethyl] piperidine
    [1066] 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 were obtained 72 mg of the title compound as colorless crystals according to the method of Example 121.
    [1067] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.41 (3H, m), 1.50-1.59 (2H, m), 1.70-1.79 (2H, m), 2.03-2.13 (2H, m), 2.56- 2.63 (2H, m), 2.90-2.97 (2H, m), 3.47 (2H, s), 3.92-3.97 (2H, m), 4.47-4.52 (2H, m), 6.33 (1H, dd, J = 6.6 , 6.6 Hz), 6.85 (1H, dd, J = 7.2, 5.0 Hz), 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, doublet of doublets, J = 5.0, 1.8 Hz).
    [1068] Example 124
    [1069] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (N, N-dimethylamino) ethoxy-3-pyridyl] ethyl] py Ferridine
    [1070] 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 0.77 ml of N, N-dimethylaminoethanol, according to the method of Example 121, 220 mg of the title compound were obtained as colorless crystals.
    [1071] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.40 (3H, m), 1.50-1.58 (2H, m), 1.72-1.80 (2H, m), 2.04-2.13 (2H, m), 2.36 ( 6H, s), 2.53-2.61 (2H, m), 2.76 (2H, t, J = 5.8 Hz), 2.90-2.98 (2H, m), 3.48 (2H, s), 4.44 (2H, t, J = 5.8 Hz), 6.35 (1H, dd, J = 6.4, 6.4 Hz), 6.80 (1H, dd, J = 7.2, 5.2 Hz), 7.34-7.40 (2H, m), 7.54 (1H, d, J = 6.4 Hz), 7.99 (1H, doublet of doublets, J = 5.0, 2.0 Hz).
    [1072] Example 125
    [1073] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [4- (methylsulfonyl) -3- (1,3-thiazol-2-yl ) -2-thienyl] ethyl] piperidine
    [1074] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [4- (methylsulfonyl) -3- (1,3-thiazol-2-yl) obtained in Example 33 230 mg of 2-thienyl] ethyl] piperidine were obtained as colorless crystals according to the method of Example 87, as a colorless crystal.
    [1075] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.33 (3H, m), 1.54-1.65 (4H, m), 1.97-2.09 (2H, m), 2.76-2.94 (4H, m), 3.24 ( 3H, s), 3.44 (2H, s), 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).
    [1076] Example 126
    [1077] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [3- (1,3-thiazol-2-yll) -2-thienyl] Ethyl] piperidine
    [1078] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (1,3-thiazol-2-yl) -2-thienyl] ethyl] obtained in Example 34. 230 mg of piperidine was obtained according to the method of Example 87. 156 mg of the title compound were obtained as colorless crystals.
    [1079] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.45 (3H, m), 1.65-1.81 (4H, m), 2.05-2.16 (2H, m), 2.90-2.99 (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 ), 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).
    [1080] Example 127
    [1081] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (1,3-thiazol-2-yl) phenethyl] piperidine
    [1082] Example 233 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (1,3-thiazol-2-yl) phenethyl] piperidine obtained in Example 35 According to the method of 87, 171 mg of the title compound were obtained as colorless crystals.
    [1083] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.33 (3H, m), 1.43-1.52 (2H, m), 1.58-1.69 (2H, m), 1.98-2.09 (2H, m), 2.82- 2.98 (4H, m), 3.45 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.26 (1H, dd, J = 7.6, 7.6 Hz), 7.30 (1H, d, J = 7.6 Hz), 7.36 (1H, dd, J = 7.6, 7.6 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.39 (1H, d, J = 3.2 Hz), 7.51 (1H, d, J = 6.6 Hz), 7.57 (1H, d, J = 7.6 Hz), 7.89 (1H, d, J = 3.2 Hz).
    [1084] Example 128
    [1085] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [1086] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.40 (3H, m), 1.54-1.62 (2H, m), 1.70-1.80 (2H, m), 2.02-2.12 (2H, m), 2.56- 2.63 (2H, m), 2.88-2.96 (2H, m), 3.46 (2H, s), 5.92 (2H, s), 6.33 (1H, dd, J = 6.5 Hz), 6.64-6.70 (2H, m) , 6.75 (1H, doublet, J = 7.8, 7.8 Hz), 7.36 (1H, d, J = 6.5 Hz), 7.54 (1H, d, J = 6.5 Hz).
    [1087] Example 129
    [1088] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-cyanophenethyl) piperidine
    [1089] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.31-1.45 (3H, m), 1.57-1.67 (2H, m), 1.72-1.82 (2H, m), 2.03-2.15 (2H, m), 2.81- 2.99 (4H, m), 3.47 (2H, s), 6.32 (1H, dd, J = 6.9, 6.3 Hz), 7.27 (1H, dd, J = 7.6, 7.6 Hz), 7.32 (1H, d, J = 7.6 Hz), 7.36 (1H, d, J = 6.3 Hz), 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).
    [1090] Example 130
    [1091] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (3-cyanophenethyl) piperidine
    [1092] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.41 (3H, m), 1.52-1.62 (2H, m), 1.68-1.77 (2H, m), 2.01-2.13 (2H, m), 2.62- 2.71 (2H, m), 2.89-2.99 (2H, m), 3.47 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.36-7.50 (4H, m), 7.36 (1H, d, J = 6.6 Hz), 7.57 (1H, d, J = 6.6 Hz).
    [1093] Example 131
    [1094] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (4-phenylphenethyl) piperidine
    [1095] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.42 (3H, m), 1.58-1.65 (2H, m), 1.73-1.81 (2H, m), 2.05-2.14 (2H, m), 2.64- 2.70 (2H, m), 2.91-2.98 (2H, m), 3.48 (2H, s), 6.34 (1H, dd, J = 6.4, 6.4 Hz), 7.23-7.28 (2H, m), 7.32 (1H, m), 7.37 (1H, d, J = 6.4 Hz), 7.40-7.45 (2H, m), 7.49-7.60 (5H, m).
    [1096] Example 132
    [1097] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-phenylphenethyl) piperidine
    [1098] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.10-1.20 (3H, m), 1.37-1.45 (2H, m), 1.46-1.54 (2H, m), 1.94-2.03 (2H, m), 2.56- 2.62 (2H, m), 2.79-2.86 (2H, m), 3.43 (2H, s), 6.32 (1H, dd, J = 6.4, 6.4 Hz), 7.18-7.42 (10H, m), 7.48 (1H, d, J = 6.4 Hz).
    [1099] Example 133
    [1100] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-methylphenethyl) piperidine
    [1101] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.43 (3H, m), 1.53-1.62 (2H, m), 1.73-1.84 (2H, m), 2.06-2.17 (2H, m), 2.46 ( 3H, s), 2.67-2.75 (2H, m), 2.90-3.00 (2H, m), 3.49 (2H, s), 6.34 (1H, dd, J = 6.6 Hz), 7.06-7.16 (2H, m) , 7.18-7.21 (2H, m), 7.37 (1H, d, J = 6.6 Hz), 7.57 (1H, d, J = 6.6 Hz).
    [1102] Example 134
    [1103] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-methoxyphenethyl) piperidine
    [1104] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.40 (3H, m), 1.48-1.57 (2H, m), 1.72-1.82 (2H, m), 2.02-2.14 (2H, m), 2.58- 2.66 (2H, m), 2.88-2.97 (2H, m), 3.48 (2H, s), 3.81 (3H, s), 6.35 (1H, dd, J = 6.6, 6.6 Hz), 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, doublet, J = 6.6 Hz), 7.53 (1H, doublet, J = 6.6 Hz).
    [1105] Example 135
    [1106] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine
    [1107] 6.09 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3-methylsulfonyl-2-thienyl) ethyl] piperidine obtained in Example 43 and thionyl chloride 2 ml were dissolved in 50 ml of ethanol and heated to reflux for 2 hours. An aqueous 1N sodium hydroxide solution was added to the reaction solution, made alkaline, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was purified by NH foam silica gel column chromatography (ethyl acetate) to give 4.89 g of the title compound as colorless crystals.
    [1108] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.67-1.80 (4H, m), 2.04-2.13 (2H, m), 2.90-2.97 (2H, m), 3.06 ( 3H, s), 3.18-3.24 (2H, m), 3.46 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.18 (1H, d, J = 5.5 Hz), 7.31 (1H , d, J = 5.5 Hz), 7.36 (1H, dd, J = 6.6, 2.0 Hz), 7.56 (1H, dd, J = 6.6, 2.0 Hz).
    [1109] Example 136
    [1110] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (methylsulfonyl) -3,4-methylenedioxyphenethyl] piperidine
    [1111] 1.45 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (methylsulfonyl) -3,4-methylenedioxyphenethyl] piperidine obtained in Reference Example 1 According to the method of Example 135, 875 mg of the title compound were obtained as colorless crystals.
    [1112] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.52-1.60 (2H, m), 1.72-1.80 (2H, m), 2.07-2.16 (2H, m), 2.90- 2.96 (2H, m), 2.96-3.02 (2H, m), 3.21 (3H, s), 3.48 (2H, s), 6.12 (2H, s), 6.34 (1H, dd, J = 6.5, 6.5 Hz) , 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).
    [1113] Example 137
    [1114] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (1,3-thiazol-2-yl) -3-pyridyl] ethyl ] Piperidine
    [1115] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.46 (3H, m), 1.54-1.63 (2H, m), 1.73-1.82 (2H, m), 2.06-2.16 (2H, m), 2.90- 2.98 (2H, m), 3.27-3.34 (2H, m), 3.49 (2H, s), 6.34 (1H, dd, J = 6.4, 6.4 Hz), 7.23 (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), 7.61 (1H, dd, J = 7.6, 1.6 Hz) , 7.91 (1H, doublet, J = 3.6 Hz), 8.47 (1H, doublet, J = 4.4, 1.6 Hz).
    [1116] Example 138
    [1117] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [1- (4-hydroxy) piperidino] -3-pyridyl] ethyl] pipe Ferridine
    [1118] 1- [2-methoxy-3-pyridyl) methyl] -4- [2- [1- (4-hydroxy) piperidino] -3-pyridyl] ethyl] piperidine obtained in Example 49 At 70 mg, 49 mg of the title compound were obtained as a colorless oil, following the method of Example 135.
    [1119] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.42 (3H, m), 1.54-1.62 (2H, m), 1.64-1.82 (4H, m), 1.96-2.14 (4H, m), 2.58- 2.65 (2H, m), 2.84-2.99 (4H, m), 3.25-3.34 (2H, m), 3.48 (2H, s), 3.84 (1H, m), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 6.90 (1H, dd, J = 7.4, 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, doublet of doublets, J = 4.9, 1.9 Hz).
    [1120] Example 139
    [1121] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (3-cyanopropoxy) -3-pyridyl] ethyl] piperidine
    [1122] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.40 (3H, m), 1.48-1.57 (2H, m), 1.70-1.81 (2H, m), 2.03-2.20 (4H, m), 2.51- 2.61 (4H, m), 2.89-2.97 (2H, m), 3.47 (2H, s), 4.40-4.47 (2H, m), 6.33 (1H, dd, J = 6.4, 6.4 Hz), 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), 7.97 ( 1H, dd, J = 5.2, 2.0 Hz).
    [1123] Example 140
    [1124] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [1- (2-fluorobenzyl) -2-oxo-1,2-dihydro- 3-pyridyl] ethyl] piperidine
    [1125] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.41 (3H, m), 1.48-1.57 (2H, m), 1.71-1.82 (2H, m), 2.01-2.15 (2H, m), 2.52- 2.58 (2H, m), 2.88-2.98 (2H, m), 3.49 (2H, s), 5.17 (2H, s), 6.08-6.13 (1H, m), 6.34 (1H, dd, J = 6.4, 6.4 Hz), 7.03-7.17 (3H, m), 7.24-7.31 (2H, m), 7.36 (1H, d, J = 6.4 Hz), 7.40-7.46 (1H, m), 7.55 (1H, d, J = 6.4 Hz).
    [1126] Example 141
    [1127] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- (2-thienyl) ethyl] piperidine
    [1128] 9.6 g of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-oxo-2- (2-thienyl) ethyl] piperidine and 8.5 ml thionyl chloride obtained in Example 54 Was dissolved in 60 ml of ethanol and heated to reflux for 3 hours. After the solvent was removed under reduced pressure, the residue was dissolved in chloroform and 1 N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from ethanol to give 9.0 g of the title compound as colorless crystals.
    [1129] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.49 (2H, m), 1.72-1.81 (2H, m), 2.03 (1H, m), 2.09-2.20 (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 = 6.6,6.6 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), 7.70 (1H, dd, J = 3.9, 1.1 Hz).
    [1130] Example 142
    [1131] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-oxo-2-phenylethyl) piperidine
    [1132] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.35-1.49 (2H, m), 1.72-1.82 (2H, m), 1.97-2.22 (3H, m), 2.87-2.97 (3H, m), 3.48 ( 2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 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).
    [1133] Example 143
    [1134] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-chlorophenyl) -2-ox / U> U> ethyl] piperidine
    [1135] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.72-1.82 (2H, m), 2.01 (1H, m), 2.09-2.21 (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, doublet, J = 6.8 Hz).
    [1136] Example 144
    [1137] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methoxyphenyl) -2-oxoethyl] piperidine
    [1138] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.32-1.46 (2H, m), 1.69-1.79 (2H, m), 1.99 (1H, m), 2.09-2.20 (2H, m), 2.86-2.96 ( 3H, m), 3.48 (2H, s), 3.89 (3H, s), 6.33 (1H, dd, J = 7.0, 5.8 Hz), 6.99 (1H, dd, J = 7.5, 7.2 Hz), 6.95 (1H , d, J = 8.4 Hz), 7.37 (1H, d, J = 5.8 Hz), 7.44 (1H, ddd, J = 8.4, 7.2, 1.8 Hz), 7.53 (1H, d, J = 7.0 Hz), 7.62 (1H, doublet of doublets, J = 7.5, 1.8 Hz).
    [1139] Example 145
    [1140] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methylsulfonylphenyl) -2-oxoethyl] piperidine
    [1141] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.35-1.49 (2H, m), 1.81-1.91 (2H, m), 2.05-2.25 (3H, m), 2.85-2.99 (4H, m), 3.25 ( 3H, s), 3.49 (2H, s), 6.32 (1H, dd, J = 6.6, 6.2 Hz), 7.36 (1H, d, J = 6.2 Hz), 7.41 (1H, d, J = 7.5 Hz), 7.55 (1H, d, J = 6.6 Hz), 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 ).
    [1142] Example 146
    [1143] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-cyclopropylmethoxyphenyl) -2-oxoethyl] piperidine
    [1144] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.32-0.38 (2H, m), 0.63-0.70 (2H, m), 1.24-1.46 (3H, m), 1.70-1.80 (2H, m), 2.02 ( 1H, m), 2.08-2.19 (2H, m), 2.86-2.94 (2H, m), 3.02 (2H, d, J = 6.8 Hz), 3.47 (2H, s), 3.89 (2H, d, J = 7.2 Hz), 6.32 (1H, dd, J = 6.9, 5.9 Hz), 6.88 (1H, d, J = 8.2 Hz), 6.97 (1H, dd, J = 7.7, 7.4 Hz), 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), 7.65 (1H, d, J = 7.7 Hz).
    [1145] Example 147
    [1146] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- (2-trifluoromethylphenyl) ethyl] piperidine
    [1147] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.31-1.45 (2H, m), 1.75-1.85 (2H, m), 1.95-2.24 (3H, m), 2.80 (2H, d, J = 6.6 Hz) , 2.88-2.98 (2H, m), 3.48 (2H, s), 6.32 (1H, dd, J = 7.1, 6.2 Hz), 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, 7.1, Hz), 7.60 (1H, dd, J = 7.8, 7.3 Hz), 7.71 (1H, d, J = 7.1 Hz).
    [1148] Example 148
    [1149] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- (3-thienyl) ethyl] piperidine
    [1150] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.48 (2H, m), 1.71-1.81 (2H, m), 2.02 (1H, m), 2.09-2.21 (2H, m), 2.80 (2H, d, J = 6.8 Hz), 2.88-2.97 (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 ), 7.36 (1H, d, J = 6.8 Hz), 7.54 (1H, d, J = 6.8 Hz), 7.545 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 2.9 Hz).
    [1151] Example 149
    [1152] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- (1,3-thiazol-2-yl) ethyl] piperidine
    [1153] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.39-1.52 (2H, m), 1.73-1.82 (2H, m), 2.01-2.21 (3H, m), 2.87-2.96 (2H, m), 3.11 ( 2H, d, J = 6.8 Hz), 3.47 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.34 (1H, d, J = 6.6 Hz), 7.54 (1H, d, J = 6.6 Hz), 7.67 (1H, d, J = 3.1 Hz), 8.00 (1H, dd, J = 3.1 Hz).
    [1154] Example 150
    [1155] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3,4-methylenedioxyphenyl) -2-oxoethyl] piperidine
    [1156] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.45 (2H, m), 1.71-1.80 (2H, m), 2.01 (1H, m), 2.10-2.20 (2H, m), 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), 7.36 (1H, d, J = 6.5 Hz), 7.43 (1H, d, J = 1.7 Hz), 7.52 (1H, d, J = 6.5 Hz), 7.55 (1H, dd, J = 8.2, 1.7 Hz).
    [1157] Example 151
    [1158] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- [3- (1,3-thiazol-2-yl) -2- Thienyl] ethyl] piperidine
    [1159] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.31-1.45 (2H, m), 1.69-1.78 (2H, m), 1.96-2.19 (3H, m), 2.80 (2H, d, J = 6.8 Hz) , 2.85-2.94 (2H, m), 3.46 (2H, s), 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), 7.93 (1H, d, J = 3.3 Hz).
    [1160] Example 152
    [1161] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-oxo-2- (3-phenyl-2-thienyl) ethyl] piperidine
    [1162] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.09-1.24 (2H, m), 1.48-1.59 (2H, m), 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), 7.48 (1H, d, J = 7.5 Hz), 7.54 (1H, d, J = 4.9 Hz).
    [1163] Example 153
    [1164] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) -2-oxoethyl] piperidine
    [1165] 100 mg and 4 of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-chloro-3-pyridyl) -2-oxoethyl] piperidine obtained in Example 62 0.35 ml of M ethyl chloride acetate solution was dissolved in 4 ml of acetonitrile and heated to reflux for 1 hour. After the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from ethanol to give 46 mg of the title compound as colorless crystals.
    [1166] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.34-1.48 (2H, m), 1.71-1.81 (2H, m), 2.02 (1H, m), 2.09-2.21 (2H, m), 2.87-2.98 ( 4H, m), 3.47 (2H, s), 6.31 (1H, dd, J = 6.6, 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), 7.77 (1H, dd, J = 7.5, 1.9 Hz), 8.48 (1H, dd, J = 4.8, 1.9 Hz).
    [1167] Example 154
    [1168] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methylsulfonylaminophenyl) -2-oxoethyl] piperidine
    [1169] 90 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methanesulfonylaminophenyl) -2-oxoethyl] piperidine obtained in Example 65 and concentrated hydrochloric acid 0.30 ml was dissolved in 4 ml of acetonitrile and heated to reflux for 5 hours. After the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from ethanol to give 45 mg of the title compound as colorless crystals.
    [1170] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.33-1.47 (2H, m), 1.75-1.89 (2H, m), 2.01-2.25 (3H, m), 2.83-2.98 (4H, m), 3.50 ( 5H, m), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.40 (1H, dd, J = 5.6, 3.2 Hz), 7.52 (1H, d , J = 6.6 Hz), 7.55 (1H, d, J = 3.2 Hz), 7.57 (1H, dd, J = 3.4 Hz), 7.67 (1H, dd, J = 5.6, 3.4 Hz).
    [1171] Example 155
    [1172] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (3-phenylpropyl) piperidine
    [1173] 214 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- (3-phenylpropyl) piperidine obtained in Example 76, colorless of 161 mg of the title compound according to the method of Example 141 Obtained as a crystal.
    [1174] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.22-1.34 (5H, m), 1.58-1.72 (4H, m), 2.00-2.10 (2H, m), 2.59 (2H, t, J = 7.8 Hz) , 2.86-2.94 (2H, m), 3.45 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.14-7.20 (3H, m), 7.24-7.30 (2H, m), 7.36 (1H, doublet, J = 6.6 Hz), 7.53 (1H, m).
    [1175] Example 156
    [1176] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-benzylpiperidine
    [1177] 472 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-benzylpiperidine obtained in Example 78 was followed by the method of Example 141 to obtain 365 mg of the title compound as colorless crystals.
    [1178] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (2H, m), 1.56 (1H, m), 1.60-1.68 (2H, m), 2.02-2.10 (2H, m), 2.55 (2H, d, J = 7.0 Hz), 2.89-2.96 (2H, m), 3.46 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.12-7.21 (3H, m), 7.24-7.30 (2H, m), 7.35 (1H, d, J = 6.6 Hz), 7.54 (1H, d, J = 6.6 Hz).
    [1179] Example 157
    [1180] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (4-phenylbutyl) piperidine
    [1181] 150 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- (4-phenylbutyl) piperidine obtained in Example 79 was colorless crystals of 105 mg of the title compound according to the method of Example 141. Obtained as.
    [1182] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.40 (7H, m), 1.56-1.70 (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), 7.24-7.30 (2H, m), 7.37 (1H, d, J = 6.5 Hz), 7.54 (1H, d, J = 6.5 Hz).
    [1183] Example 158
    [1184] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [oxo (2-thienyl) methyl] piperidine
    [1185] 273 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [oxo (2-thienyl) methyl] piperidine obtained in Example 80 according to the method of Example 172 below 101 mg were obtained as colorless crystals.
    [1186] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.86-2.02 (4H, m), 2.20-2.30 (2H, m), 3.00-3.07 (2H, m), 3.13 (1H, m), 3.52 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 7.14 (1H, dd, J = 5.0, 4.0 Hz), 7.33 (1H, dd, J = 6.6, 2.0 Hz), 7.61 (1H, m ), 7.64 (1H, doublet of doublets, J = 5.0, 1.0 Hz), 7.74 (1H, doublet of doublets, J = 4.0, 1.0 Hz).
    [1187] Example 159
    [1188] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (3-oxo-3-phenylpropyl) piperidine
    [1189] 414 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxaldehyde obtained in Reference Example 2 and 0.46 ml of diethyl (2-oxo-2-phenylethyl) phosphonate And 78 mg of 60% sodium hydride oil suspension were suspended in 8 ml of tetrahydrofuran and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product and 160 mg of 10% palladium-carbon powder (water) were suspended in 10 ml of ethanol, and hydrogen-substituted in the vessel, followed by stirring at atmospheric pressure and room temperature for 4 hours. The reaction solution was filtered, and the filtrate was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 9). The resulting product and 0.15 ml of thionyl chloride were dissolved in 2 ml of ethanol and heated to reflux for 2 hours. 1N aqueous sodium hydroxide solution was added, made alkaline and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product obtained was purified by NH foam silica gel column chromatography (ethyl acetate) to obtain 104 mg of the title compound as colorless crystals.
    [1190] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.67-1.78 (4H, m), 2.04-2.14 (2H, m), 2.90-2.97 (2H, m), 3.00 ( 2H, t, J = 7.5 Hz), 3.46 (2H, s), 6.32 (1H, dd, J = 6.6, 6.6 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.44-7.49 (2H, m ), 7.53-7.59 (2H, m), 7.96-7.99 (2H, m).
    [1191] Example 160
    [1192] N4- (2-phenyl) benzyl-1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-piperidinecarboxamide
    [1193] 92 mg of N 4- (2-phenyl) benzyl-1-[(2-methoxy-3-pyridyl) methyl] -4-piperidinecarboxamide obtained in Reference Example 82 according to the method of Example 141 47 mg of the title compound were obtained as colorless crystals.
    [1194] 1 H-NMR (400 MHz, DMSO-d6) δ 1.52-1.68 (4H, m), 1.90-1.98 (2H, m), 2.14 (1H, m), 2.78-2.85 (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).
    [1195] Example 161
    [1196] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[[2- (1,3-thiazol-2-yl) -3-pyridyl] oxy] Methyl] piperidine
    [1197] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[[2- (1,3-thiazol-2-yl) -3-pyridyl] oxy] methyl obtained in Example 84 ] 200 mg of the title compound was obtained as colorless crystals according to the method of Example 141 at 238 mg of piperidine.
    [1198] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.47-1.61 (2H, m), 1.93-2.26 (5H, m), 2.97-3.06 (2H, m), 3.52 (2H, s), 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), 7.36 ( 1H, dd, J = 8.4, 1.2 Hz), 7.48 (1H, d, J = 3.0 Hz), 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).
    [1199] Example 162
    [1200] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-cyano-2- (3,4-methylenedioxyphenyl) ethyl] piperidine
    [1201] 227 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-cyano-2- (3,4-methylenedioxyphenyl) ethyl] piperidine obtained in Example 85 According to the method of Example 141, 183 mg of the title compound was obtained as colorless crystals.
    [1202] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27-1.42 (2H, m), 1.45-1.58 (1H, m), 1.63-1.79 (3H, m), 1.85-1.95 (1H, m), 2.04- 2.15 (2H, m), 2.88-2.97 (2H, m), 3.47 (2H, s), 3.70-3.77 (1H, m), 5.97 (2H, s), 6.30 (1H, dd, J = 6.4, 6.4 Hz), 6.72-6.81 (3H, m), 7.34 (1H, d, J = 6.4 Hz), 7.54 (1H, d, J = 6.4 Hz).
    [1203] Example 163
    [1204] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-cyano-2- (2-methoxyphenyl) ethyl] piperidine dihydrochloride
    [1205] 1 ml of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-cyano-2- (2-methoxyphenyl) ethyl] piperidine obtained in Example 86 was dissolved in 2 ml of ethanol. It dissolved in, 0.3 ml of 4N ethyl acetate solution was added, and it heated and refluxed for 2 hours. The solvent was removed under reduced pressure to give 199 mg of the title compound as colorless crystals.
    [1206] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.43-1.67 (4H, m), 1.80-1.96 (3H, m), 2.87-2.99 (2H, m), 3.28-3.37 (2H, m), 3.81 (3H, s), 4.00 (2H, s), 4.27-4.33 (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, 7.6 Hz), 7.51 (1H, d, J = 6.4 Hz) , 7.77 (1H, doublet, J = 7.6 Hz).
    [1207] Example 164
    [1208] 1-[(6-methoxy-2-pyridyl) methyl] -4- (3,4-methylenedioxyphenethyl) piperidine
    [1209] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.47-1.56 (2H, m), 1.66-1.74 (2H, m), 2.01-2.10 (2H, m), 2.50- 2.57 (2H, m), 2.90-2.98 (2H, m), 3.56 (2H, s), 3.91 (3H, s), 5.91 (2H, s), 6.58 (1H, d, J = 8.2 Hz), 6.61 (1H, dd, J = 7.9, 1.6 Hz), 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, doublet of doublets, J = 8.2, 7.2 Hz).
    [1210] Example 165
    [1211] 1-[(6-methoxy-2-pyridyl) methyl] -4- [2- (3-thienyl) ethyl] piperidine
    [1212] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.39 (3H, m), 1.54-1.63 (2H, m), 1.68-1.77 (2H, m), 2.01-2.11 (2H, m), 2.61- 2.69 (2H, m), 2.71-2.79 (2H, m), 3.57 (2H, s), 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 (1H, dd, J = 7.7, 2.9 Hz), 7.52 (1H, dd, J = 8.2, 7.3 Hz).
    [1213] Example 166
    [1214] 1-[(6-methoxy-2-pyridyl) methyl] -4- [2- (2-methoxy-3-pyridyl) ethyl] piperidine
    [1215] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.40 (3H, m), 1.48-1.56 (2H, m), 1.70-1.78 (2H, m), 2.02-2.12 (2H, m), 2.53- 2.60 (2H, m), 2.92-2.99 (2H, m), 3.57 (2H, s), 3.92 (3H, s), 3.94 (3H, s), 6.59 (1H, d, J = 8.2 Hz), 6.80 (1H, dd, J = 7.1, 5.1 Hz), 6.99 (1H, d, J = 7.1 Hz), 7.36 (1H, dd, J = 7.1, 1.8 Hz), 7.52 (1H, dd, J = 8.2, 7.1 Hz), 8.00 (1H, doublet of doublets, J = 5.1, 1.8 Hz).
    [1216] Example 167
    [1217] 1-[(6-methoxy-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [1218] 218 mg of 1-[(6-bromo-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine obtained in Reference Example 19, 2 ml of 28% sodium methoxymethanol solution It melt | dissolved in and heated and refluxed for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 144 mg of the title compound as a colorless oil.
    [1219] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.54-1.60 (2H, m), 1.70-1.77 (2H, m), 2.02-2.10 (2H, m), 2.56- 2.62 (2H, m), 2.92-2.98 (2H, m), 3.56 (2H, s), 3.91 (3H, s), 5.92 (2H, s), 6.58 (1H, d, J = 8.2 Hz), 6.66 (1H, dd, J = 7.8, 1.2 Hz), 6.68 (1H, dd, J = 7.8, 1.2 Hz), 6.75 (1H, dd, J = 7.8, 7.8 Hz), 6.98 (1H, d, J = 7.4 Hz), 7.52 (1H, doublet of doublets, J = 8.2, 7.4 Hz).
    [1220] Example 168
    [1221] 1-[[6- (2-hydroxyethoxy) -2-pyridyl] methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [1222] Subject compound according to the method of Example 123 with 320 mg of 1-[(3-bromo-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine obtained in Reference Example 19 226 mg were obtained as a colorless oil.
    [1223] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.38 (3H, m), 1.54-1.61 (2H, m), 1.62-1.75 (2H, m), 1.98-2.06 (2H, m), 2.55- 2.62 (2H, m), 2.85-2.92 (2H, m), 3.52 (2H, s), 3.90-3.94 (2H, m), 4.45-4.50 (2H, m), 5.92 (2H, s), 6.64- 6.69 (3H, m), 6.75 (1H, doublet of doublets, J = 7.8, 7.8 Hz), 6.97 (1H, doublet, J = 7.2 Hz), 7.56 (1H, doubled, J = 7.8, 7.2 Hz).
    [1224] Example 169
    [1225] 1-[(6-oxo-1,6-dihydro-2-pyridyl) methyl] -4- (3,4-methylenedioxyphenethyl) piperidine
    [1226] 186 mg of 4- (3,4-methylenedioxyphenethyl) piperidine obtained in Reference Example 4, 228 mg of 6-tert-butyldimethylsilyloxy-2-pyridinecarboxaldehyde and 203 mg of sodium triacetoxyborohydride Was suspended in 2 ml of tetrahydrofuran and stirred at room temperature for 20 hours. Saturated sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate) to give 160 mg of the title compound as colorless crystals.
    [1227] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.36 (3H, m), 1.48-1.61 (2H, m), 1.66-1.75 (2H, m), 2.03-2.13 (2H, m), 2.51- 2.58 (2H, m), 2.73-2.81 (2H, m), 3.34 (2H, s), 5.92 (2H, s), 5.99 (1H, d, J = 6.8 Hz), 6.43 (1H, d, J = 9.3 Hz), 6.62 (1H, dd, J = 7.9, 1.6 Hz), 6.67 (1H, d, J = 1.6 Hz), 6.73 (1H, d, J = 7.9 Hz), 7.31 (1H, dd, J = 9.3, 6.8 Hz).
    [1228] Example 170
    [1229] 1-[(6-oxo-1,6-dihydro-2-pyridyl) methyl] -4- [2- (3-thienyl) ethyl] piperidine
    [1230] The title compound was obtained according to the method of Example 169.
    [1231] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.22-1.37 (3H, m), 1.53-1.63 (2H, m), 1.67-1.76 (2H, m), 2.03-2.13 (2H, m), 2.61- 2.69 (2H, m), 2.74-2.82 (2H, m), 3.35 (2H, s), 5.95 (1H, d, J = 6.8 Hz), 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).
    [1232] Example 171
    [1233] 1-[(6-oxo-1,6-dihydro-2-pyridyl) methyl] -4- [2- (2-methoxy-3-pyridyl) ethyl] piperidine
    [1234] The title compound was obtained according to the method of Example 169.
    [1235] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.23-1.38 (3H, m), 1.49-1.58 (2H, m), 1.71-1.79 (2H, m), 2.04-2.14 (2H, m), 2.53- 2.61 (2H, m), 2.75-2.83 (2H, m), 3.36 (2H, s), 3.95 (2H, s), 5.95 (1H, d, J = 6.8 Hz), 6.43 (1H, d, J = 9.3 Hz), 6.81 (1H, dd, J = 7.1, 5.1 Hz), 7.32 (1H, dd, J = 9.3, 6.8 Hz), 7.36 (1H, dd, J = 7.1, 1.8 Hz), 8.01 (1H, dd, J = 5.1, 1.8 Hz).
    [1236] Example 172
    [1237] 1-[(6-oxo-1,6-dihydro-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine
    [1238] Tert 1-[(6-bromo-2-pyridyl) methyl] -4- (2,3-methylenedioxyphenethyl) piperidine obtained in Reference Example 19 and 880 mg of potassium tert-butoxide It was suspended in 5 ml of butanol and heated to reflux for 8 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH foam silica gel column chromatography (ethyl acetate) to give 96 mg of the title compound as colorless crystals.
    [1239] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.36 (3H, m), 1.54-1.64 (2H, m), 1.71-1.78 (2H, m), 2.04-2.12 (2H, m), 2.56- 2.62 (2H, m), 2.75-2.82 (2H, m), 3.35 (2H, s), 5.93 (2H, s), 5.99 (1H, d, J = 6.8 Hz), 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).
    [1240] Example 173
    [1241] N1-benzyl-2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinyl] acetamide
    [1242] 1.0 g of 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetic acid, 0.41 ml of benzylamine, 950 mg of WSC, and 260 mg of HOBt were suspended in DMF, followed by 2 hours at room temperature. Stirred. Water was added, extraction was performed with ethyl acetate and dried over sodium sulfate. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the remainder was purified by silica gel chromatography (ethyl acetate-methanol = 10: 1 followed by 5: 1) to obtain 500 mg of white crystals.
    [1243] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.30-1.42 (2H, m), 1.52-1.85 (4H, m), 2.03-2.10 (1H, m), 2.47 (1H, dd, J = 16.4, 4.8 Hz), 2.66-2.73 (1H, m), 2.76-2.85 (2H, m), 3.33 (1H, d, J = 13.6 Hz), 3.86 (3H, s), 3.94 (1H, d, J = 13.6 Hz), 4.30 (1H, dd, J = 14.8, 5.2 Hz), 4.54 (1H, dd, J = 14.8, 6.4 Hz), 6.67 (1H, dd, J = 7.2, 4.8 Hz), 7.17 (1H, dd) , J = 7.2, 2 Hz), 7.24-7.34 (5H, m), 8.02 (1H, dd, J = 4.8, 2 Hz), 8.70 (1H, bs)
    [1244] Example 174
    [1245] N1- (3-fluorobenzyl) -2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinyl] acetamide
    [1246] The title compound was obtained from the raw material according to the method of Example 173.
    [1247] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.30-1.45 (2H, m), 1.52-1.65 (2H, m), 1.67-1.84 (2H, m), 2.08-2.17 (1H, m), 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), 3.97 (1H, d, J = 13.6 Hz), 4.28 (1H, dd, J = 14.8, 5.2 Hz), 4.52 (1H, dd, J = 14.8, 6.4 Hz), 6.72 (1H, dd, J = 7.2, 4.8 Hz), 6.90-7.08 (3H , m), 7.22-7.32 (2H, m), 8.04 (1H, dd, J = 4.8,2.0 Hz), 8.03 (1H, bs)
    [1248] Example 175
    [1249] N1, N1-di (2-propynyl) -2-[(R) -1-[(2-methoxy-3-pyridyl) methyl] -2-pyreridyl] acetamide
    [1250] 4.4 g of N1, N 1-di (2-propynyl) -2-[(2R) hexahydro-2-pyridinyl] acetamide, 3.8 g of 3- (chloromethyl) -2-methoxypyridine, potassium carbonate 16.6 g, 50 ml of DMF was stirred overnight at room temperature. Water was added, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, the organic solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 to 1: 1, ethyl acetate followed by ethyl acetate: methanol = 9: 1) to obtain an oily substance 640. mg was obtained.
    [1251] [α] D = + 31.8 ° (C = 0.99, MeOH, 28 ° C)
    [1252] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.40-1.70 (5H, m), 1.75-1.85 (1H, m), 2.23 (1H, m), 2.26 (1H, m), 2.47-2.84 (1H , m), 2.51 (1H, dd, J = 15.6 Hz, 8.4 Hz), 2.69-2.75 (1H, m), 2.83 (1H, dd, J = 15.6 Hz, 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), 3.94 (3H, s), 4.21 (2H, s), 4.33 (2H, s), 6.86 (1H , dd, J = 6.8 Hz, 6.8 Hz), 7.70 (1H, dd, J = 6.8 Hz, 2.0 Hz), 8.04 (1H, dd, J = 6.8 Hz, 2.0 Hz)
    [1253] Example 176
    [1254] N1, N1-di (2-propynyl) -3- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] propanamide
    [1255] 500 mg of ethyl 3- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] propanoate, 2 ml of 2N-sodium hydroxide aqueous solution, 2 ml of methanol at 60 ° C. for 2 hours Stirred. After returning to room temperature, 4 ml of 1N hydrochloride was added and the solvent was removed under reduced pressure. Ethanol was added to the residue, the insolubles were filtered off, and the solvent was removed under reduced pressure. 500 mg of the obtained oil, 170 mg of dipropargylamine, 450 mg of WSC, and 240 mg of HOBt were dissolved in DMF, and stirred at room temperature for 3 hours. Water was added, extraction was performed with ethyl acetate, dried over sodium sulfate, and the solvent was removed under reduced pressure. Purification by silica gel chromatography (hexane-ethyl acetate = 2: 1 then 1: 1 then ethyl acetate) gave 300 mg of an oil.
    [1256] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.32-1.52 (4H, m), 1.60-1.75 (2H, m), 1.91-2.02 (2H, m), 2.10-2.25 (3H, m), 2.44 -2.53 (3H, m), 2.76-2.83 (1H, m), 3.29 (1H, d, J = 14.8 Hz), 3.83 (1H, d, J = 14.8 Hz), 3.94 (3H, s), 4.99 ( 2H, s), 4.30 (2H, s), 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)
    [1257] Example 177
    [1258] N1- (3-fluorobenzyl) -2- [1- [2- (2-methoxy-3-pyridyl) ethyl] -2-piperidyl] acetamide
    [1259] 200 mg of 2- (2-methoxy-3-pyridyl) acetaldehyde, 400 mg of N 1- (3-fluorobenzyl) -2- (2-piperidyl) acetamide, sodium triacetoxynergide 440 mg of ride and 0.12 ml of acetic acid were suspended in THF and stirred at room temperature for 1 hour. Sodium bicarbonate water was added, extracted with ethyl acetate, and dried over sodium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, and the remainder was purified by silica gel chromatography (ethyl acetate-methanol = 8: 1 then 4: 1) to give 370 mg of a yellow oil.
    [1260] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.28-1.75 (6H, m), 2.26-2.34 (1H, m), 2.37 (1H, dd, J = 16.8 Hz, 4.4 Hz), 2.57-2.80 ( 5H, m), 2.93-3.00 (1H, m), 3.06-3.13 (1H, m), 3.91 (3H, s), 4.20 (1H, dd, J = 15.2 Hz, 5.2 Hz), 4.46 (1H, dd , J = 15.2 Hz, 6.4 Hz), 6.77 (1H, dd, J = 7.2 Hz, 5.2 Hz), 6.88-6.98 (2H, m), 7.01 (1H, dd, J = 7.6 Hz, 1.0 Hz) 7.22- 7.30 (2H, m), 8.01 (1H, dd, J = 5.2 Hz, 2.0 Hz), 8.81 (1H, bs)
    [1261] Example 178
    [1262] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -2- [3- (2-pyridyl) propyl] piperidine
    [1263] 2.1 g of triphenyl (2-pyridylmethyl) phosphonium dihydrochloride was dissolved in DMF and 1.4 g of tert-butoxy potassium was added at room temperature with stirring. After 15 minutes, a solution of 1.25 g of 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetaldehyde in DMF was added dropwise into the solution under room temperature stirring, It was left overnight. Water was added, extraction was performed with ethyl acetate, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1 then ethyl acetate followed by ethyl acetate-methanol = 4: 1). 760 mg of the brown oil obtained, 0.56 ml of thionyl chloride, and 10 ml of ethanol were stirred at reflux for 30 minutes. The reaction solution was returned to room temperature, 2N-sodium hydroxide aqueous solution was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated under reduced pressure, and the remainder was purified by NH-silica gel chromatography (hexane-ethyl acetate = 2: 1 followed by ethyl acetate followed by ethyl acetate-methanol = 4: 1). The obtained 350 mg of yellow oil was dissolved in 10 ml of ethanol, and Pd-C (water) was subjected to catalytic reduction for 1.5 hours under 100 mg processing and atmospheric stirring. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the remainder was purified by NH silica gel chromatography (ethyl acetate followed by ethyl acetate-methanol = 4: 1) to obtain 310 mg of an oil.
    [1264] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.28-1.86 (10H, m), 2.16-2.24 (1H, m), 2.40-2.48 (1H, m), 2.73-2.82 (3H, m), 3.30 (1H, d, J = 16.0 Hz), 3.77 (1H, d, J = 16.0 Hz), 6.33 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.05-7.13 (2H, m), 7.35 (1H) , d, J = 6.8 Hz), 7.55 (1H, ddd, J = 7.0 Hz, 7.0 Hz, 2.0 Hz), 7.63 (1H, d, J = 6.8 Hz), 8.50 (1H, d, J = 5 Hz)
    [1265] Example 179
    [1266] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -2- (2-phenylethyl] piperidine
    [1267] The title compound was obtained using the compound obtained in Reference Example 31 according to the method of Example 163.
    [1268] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.36-1.46 (1H, m), 1.48-1.64 (3H, m), 1.66-1.98 (4H, m), 2.20-2.28 (1H, m), 2.48 -2.77 (3H, m), 2.78-2.86 (1H, m), 3.34 (1H, d, J = 16 Hz), 3.85 (1H, d, J = 16.0 Hz), 6.32 (1H, dd, J = 6.8, 6.8 Hz), 7.13-7.34 (6H, m), 7.63 (1H, d, J = 6.8 Hz)
    [1269] Example 180
    [1270] 1-[(2-oxo-1-cyclopropylmethyl-1,2-dihydro-3-pyridyl) methyl] -2-[(3-pyridyl) propyl] piperidine
    [1271] 300 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -2- [3- (2-pyridyl) propyl] piperidine obtained in Example 178, (bromo 0.2 ml of methyl) cyclopropane and 610 mg of potassium carbonate were suspended in 5 ml of N and N-dimethylformamide (DMF) and stirred at 80 ° C. for 4 hours. Water was added, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and 150 mg of the oily substance of the target was purified by NH-silica gel chromatography (hexane-ethyl acetate = 2: 1 followed by 1: 1 ethyl acetate).
    [1272] 1 H-NMR (400 MHz, CDCl 3 ) δ; 0.36-0.42 (2H, m), 0.57-0.64 (2H, m), 1.20-1.90 (11H, m), 2.15-2.23 (1H, m), 2.39 -2.47 (1H, m), 2.72-2.82 (3H, m), 3.29 (1H, d, J = 16.4 Hz), 3.75 (1H, d, J = 16.4 Hz), 3.81 (2H, d, J = 7.2 Hz), 6.19 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.05-7.14 (2H, m), 7.27 (1H, dd, J = 6.8 Hz, 2 Hz), 7.50-7.58 (2H, m), 8.48-8.52 (1H, m)
    [1273] Example 181
    [1274] N1-benzyl-2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1275] 250 mg of N 1 -benzyl-2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidinyl] acetamide obtained in Example 173, 0.11 ml of thionyl chloride, and 5 ml of ethanol To this was added and stirred at 100 ° C. for 1.5 hours. The solvent was removed under reduced pressure, and diluted aqueous sodium hydroxide solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then 180 mg of an oily substance of the target product to be removed under reduced pressure was obtained.
    [1276] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.30-1.43 (2H, m), 1.50-1.82 (4H, m), 2.07-2.16 (1H, m), 2.50-2.60 (1H, m), 2.67 -2.80 (2H, m), 2.83-2.90 (1H, m), 3.30 (1H, d, J = 14.4 Hz), 3.89 (1H, d, J = 14.4 Hz), 4.33 (1H, dd, J = 14.8 Hz, 2.8 Hz), 4.51 (1H, dd, J = 14.8 Hz, 2.0 Hz), 6.05 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.06 (1H, dd, J = 6.8 Hz, 2.0 Hz) , 7.11 (1H, dd, J = 6.8 Hz, 2.0 Hz), 7.18-7.32 (5H, m), 8.67-8.74 (1H, m)
    [1277] Example 182
    [1278] N1- (2-cyclopropylethyl) -2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-pyridinyl] acetamide
    [1279] 500 mg of N 1- (3-fluorobenzyl) -2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetamide obtained in Example 174 and 2N hydrochloric acid The aqueous solution was stirred at 90 ° C. for 3.5 hours. Back to room temperature, 2N aqueous sodium hydroxide solution was added and made basic, extracted with ethyl acetate, and dried over sodium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, and the remainder was purified by NH foam silica gel chromatography (hexane-ethyl acetate = 1: 1, then ethyl acetate, then ethyl acetate: methanol = 4: 1) to give 270 mg of a colorless oil. Got.
    [1280] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.32-1.88 (6H, m), 2.10-2.21 (1H, m), 2.52-2.63 (1H, m), 2.69-2.80 (2H, m), 2.87 -2.95 (1H, m), 3.29 (1H, d, J = 13.6 Hz), 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), 8.86-8.94 (1H, m)
    [1281] Example 183
    [1282] N1- (2-cyclopropylethyl) -2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1283] 400 mg of 2- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetic acid obtained in Reference Example 34, 200 mg of 2-cyclopropylethylamine, 370 mg of WSC, 100 mg of HOBt, 0.42 ml of triethylamine and 10 ml of DMF were stirred overnight at room temperature. Water was added, extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 310 mg of the obtained oil was added to 0.23 ml of thionyl chloride and 5 ml of ethanol and stirred for 1 hour under reflux. Diluted aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by NH foam silica gel column chromatography (hexane-ethyl acetate = 2: 1, followed by ethyl acetate, then ethyl acetate: methanol = 10: 1, then 4: 1) to yellow. 290 mg of oil was obtained.
    [1284] 1 H-NMR (400 MHz, CDCl 3 ) δ; -0.08-0.08 (2H, m), 0.35-0.40 (2H, m), 0.58-0.68 (1H, m), 1.30-1.80 (8H, m), 2.10-2.20 (1H, m), 2.45-2.53 (1H, s), 2.65-2.74 (2H, m), 2.88-2.95 (1H, m), 3.13-3.22 (1H, m), 3.33 (1H, d , J = 14.4 Hz), 3.35-3.45 (1H, m), 3.91 (1H, d, J = 14.4 Hz), 6.30 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.33 (1H, dd, J = 6.8 Hz, 2.0 Hz), 7.44 (1H, dd, J = 6.8 Hz, 2.0 Hz)
    [1285] Example 184
    [1286] N1-cyclopropylmethyl-2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1287] The title compound was obtained using the compound according to the method of Example 183.
    [1288] 1 H-NMR (400 MHz, CDCl 3 ) δ; 0.25-0.30 (2H, m), 0.40-0.47 (2H, m), 0.88-1.00 (1H, m), 1.30-1.80 (6H, m), 2.10 -2.20 (1H, m), 2.42-2.50 (1H, m), 2.67-2.78 (2H, m), 2.90-3.02 (2H, m), 3.19-3.27 (1H, m), 3.34 (1H, d, J = 14.4 Hz), 3.94 (1H, d, J = 14.4 Hz), 6.30 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.35 (1H, dd, J = 6.8 Hz, 2 Hz), 7.49 (1H , dd, J = 6.8 Hz, 2.0 Hz), 8.20 (1H, m)
    [1289] Example 185
    [1290] N1- (4-fluorophenyl) -2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1291] The title compound was obtained using the compound according to the method of Example 183.
    [1292] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.30-1.84 (6H, m), 2.49 (1H, dd, J = 16.4 Hz, 4.4 Hz), 2.57-2.65 (1H, m), 2.97-3.06 ( 2H, m), 3.11 (1H, dd, J = 16.4 Hz, 4 Hz), 4.22 (1H, d, J = 12.8 Hz), 6.09 (1H, dd, J = 6.8 Hz, 6.8 Hz), 6.64 (1H, dd, 6.8 Hz, 2.0 Hz), 6.81-6.89 (2H, m), 7.35 (1H, dd, J = 6.8 Hz, 2.0 Hz), 7.50-7.58 (2H, m), 10.68 (1H, s)
    [1293] Example 186
    [1294] N1- (2-pyridylmethyl) -2- [1- (2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1295] The title compound was obtained using the compound according to the method of Example 183.
    [1296] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.30-1.80 (6H, m), 2.13-2.22 (1H, m), 2.05-2.63 (1H, m), 2.70-2.82 (2H, m), 2.88 -2.95 (1H, m), 3.35 (1H, d, J = 14.8 Hz, 2.0 Hz), 3.92 (1H, d, J = 14.8 Hz, 2.0 Hz), 4.49 (1H, dd, J = 16.0 Hz, 5.2 Hz), 4.64 (1H, dd, J = 16.0 Hz, 2.0 Hz), 6.16 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.12-7.17 (1H, m), 7.22 (1H, dd, 6.8 Hz , 2.0 Hz), 7.25-7.32 (1H, m), 7.45 (1H, dd, J = 6.8 Hz, 2.0 Hz), 7.58-7.64 (1H, m), 8.47-8.52 (1H, m), 8.86-8.93 (1H, m)
    [1297] Example 187
    [1298] N1- (2-cyclopropylethyl) -2- [1-[[1- (cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl] methyl] -2-piperidyl] Acetamide
    [1299] N 1- (2-cyclopropylethyl) -2- [1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -2-pyridinyl] acetamide 300 obtained in Example 183 mg, (bromomethyl) cyclopropane and 470 mg of potassium carbonate were suspended in 5 ml of N, N-dimethylformamide (DMF) and stirred at 80 ° C. for 4 hours. Water was added, extracted with ethyl acetate and dried over sodium sulfate. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the remainder was purified by NH-silica gel chromatography (hexane-ethyl acetate = 2: 1 then 1: 1, followed by ethyl acetate) to obtain 150 mg of the oily substance of the target product.
    [1300] 1 H-NMR (400 MHz, CDCl 3 ) δ; 0.02-0.08 (2H, m), 0.37-0.45 (4H, m), 0.58-0.74 (3H, m), 1.20-1.84 (9H, m), 2.02 -2.21 (1H, m), 2.49-2.73 (3H, m), 2.87-2.96 (1H, m), 3.17-3.27 (1H, m), 3.33 (1H, d, J = 14.4 Hz), 3.32-3.43 (1H, m), 3.81 (1H, d, J = 6.8 Hz), 3.90 (1H, d, J = 14.4 Hz), 6.19 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.31 (1H, dd , J = 6.8 Hz, 2 Hz), 7.36 (1 H, dd, J = 6.8 Hz, 2 Hz), 8.14-8.20 (1 H, m)
    [1301] Example 188
    [1302] N1- (3-fluorobenzyl) -2- [1-[[1- (cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl] methyl] -2-piperidyl] Acetamide
    [1303] The title compound was obtained using the compound according to the method of Example 187.
    [1304] 1 H-NMR (400 MHz, CDCl 3 ) δ; 0.27-0.33 (2H, m), 0.50-0.58 (2H, m), 1.05-1.16 (1H, m), 1.30-1.85 (6H, m), 2.09 -2.18 (1H, m), 2.55-2.78 (3H, m), 2.87-2.96 (1H, m), 3.27 (1H, d, J = 14.6 Hz), 3.56-3.70 (2H, m), 3.98 (1H , d, J = 14.6 Hz), 4.38 (1H, dd, J = 15.2, 5.2 Hz), 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)
    [1305] Example 189
    [1306] N1- (4-fluorophenyl) -2- [1-[[1- (cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] Acetamide
    [1307] The title compound was obtained using the compound according to the method of Example 187.
    [1308] 1 H-NMR (400 MHz, CDCl 3 ) δ; 0.30-0.40 (2H, m), 0.56-0.63 (2H, m), 1.15-1.25 (1H, m), 1.30-1.87 (6h, m), 2.16 -2.24 (1H, m), 2.60-2.73 (2H, m), 2.89 (1H, dd, J = 15.2, 4.0 Hz), 2.99-3.06 (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), 7.36 (1H, dd, J = 6.8, 2.0 Hz) 7.55-7.63 (2H, m), 10.49 (1H, s)
    [1309] Example 190
    [1310] N1- (2-pyridylmethyl) -2- [1-[(1-benzyl-2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1311] The title compound was obtained using the compound according to the method of Example 187.
    [1312] 1 H-NMR (400 MHz, CDCl 3 ) δ; 1.33-1.80 (6H, m), 2.17-2.24 (1H, m), 2.60-2.75 (2H, m), 2.76 (1H, m), 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 Hz, 5.2 Hz), 4.64 (1H, dd, J = 16.0 Hz, 6.0 Hz), 5.00 (1H, d, J = 14.4 Hz), 5.07 (1H, d, J = 14.4 Hz), 6.06 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.10-7.35 (9H, m), 7.55 (1H, ddd, J = 7.6 Hz, 7.6 Hz, 1.6 Hz), 8.48-8.52 (1H, m), 8.87-8.93 (1H, m)
    [1313] Example 191
    [1314] N1, N1-di (2-propynyl) -2-[(2R) -1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1315] N1, N1-di (2-propynyl) -2-[(R) -1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] acetamide 640 obtained in Example 175 Mg and 0.45 ml of thionyl chloride were dissolved in 20 ml of ethanol and heated to reflux for 1.5 hours. After returning to room temperature, 2N aqueous sodium hydroxide solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off and ethyl acetate was removed under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: methanol = 9: 1) to obtain 530 mg of an oil of interest.
    [1316] [α] D = + 37.9 ° (C = 0.23, MeOH, 26 ° C.)
    [1317] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.40-1.70 (5H, m), 1.81 (1H, m), 2.22 (1H, s), 2.28 (1H, s), 2.37 (1H, m), 2.53 (1H, dd, J = 15.6 Hz, 8.4 Hz), 2.75 (1H, m), 2.88 (1H, dd, J = 15.6 Hz, 4.0 Hz), 3.19 (1H, m), 3.40 (1H, d, J = 16.0 Hz), 3.68 (1H, d, J = 16.0 Hz), 4.16-4.40 (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)
    [1318] Example 192
    [1319] N1, N1-di (2-propynyl) -2-[(2R) -1-[(1-cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl) methyl] hexahydro -2-pyridyl] acetamide
    [1320] N1, N1-di (2-propynyl) -2-[(2R) -1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -2-pi obtained in Example 95 200 mg of ferridyl] acetamide, 0.09 ml of (bromomethyl) cyclopropane and 510 mg of potassium carbonate were suspended in 10 ml of DMF and stirred at 80 ° C. for 1.5 hours. Water was added, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off and ethyl acetate was removed under reduced pressure. The residue was purified by NH foam silica gel chromatography (hexane-ethyl acetate = 2: 1 then 1: 1) to give 100 mg of the target substance as an oil.
    [1321] 1 H-NMR (400 MHz, CDCl 3 ) δ: 0.35-0.42 (2H, m), 0.57-0.64 (2H, m), 1.19-1.30 (1H, m), 1.40-1.85 (6H, m), 2.21 (1H, s), 2.28 (1H, s), 2.34-2.43 (1H, m), 2.50-2.60 (1H, m), 2.69-2.76 (1H, m), 2.85-2.93 (1H, m), 3.19 (1H, bs), 3.40 (1H, d, J = 14.8 Hz), 3.68 (1H, d, J = 14.8 Hz), 3.75-3.86 (2H, m), 4.18-4.40 (4H, m), 6.20 ( 1H, t, J = 6.8 Hz), 7.29 (1H, d, J = 6.8 Hz), 7.50 (1H, d, J = 6.8 Hz)
    [1322] Example 193
    [1323] N1, N1-di (2-propynyl) -2-[(2R) -1-[[1- (2-methoxyethyl) -2-oxo-1,2-dihydro-3-pyridyl] methyl ] Hexahydro-2-pyridyl] acetamide
    [1324] The title compound was obtained using the compound according to the method of Example 192.
    [1325] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40-1.83 (6H, m), 2.21 (1H, s), 2.28 (1H, s), 2.33-2.42 (1H, m), 2.49-2.58 (1H , m), 2.69-2.76 (1H, m), 2.83-2.90 (1H, m), 3.17 (1H, bs), 3.32 (3H, s), 3.39 (1H, d, J = 15.5 Hz), 3.64- 3.71 (3H, m), 4.06-4.17 (2H, m), 4.20-4.35 (4H, m), 6.16 (1H, dd, J = 6.8 Hz, 6.8 Hz), 7.23 (1H, dd, J = 6.8 Hz , 2 Hz), 7.49 (1H, dd, J = 6.8 Hz, 2 Hz)
    [1326] Example 194
    [1327] N1, N1-di (2-propynyl) -2-[(2R) -1-[[2-oxo-1- (2,2,2-trifluoroethyl) -1,2-dihydro-3 -Pyridyl] methyl] hexahydro-2-pyridyl] acetamide
    [1328] The title compound was obtained using the compound according to the method of Example 192.
    [1329] 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40-1.70 (5H, m), 1.75-1.85 (1H, m), 2.21 (1H, s), 2.28 (1H, s), 2.32-2.42 (1H , m), 2.52 (1H, dd, J = 15.2, 8.4 Hz), 2.68-2.76 (1H, m), 2.83 (1H, dd, J = 15.2, 4.0 Hz), 3.20 (1H, bs), 3.38 ( 1H, d, J = 16.4Hz), 3.66 (1H, d, J = 16.4Hz), 4.17-4.40 (4H, m), 4.62 (2H, q, J = 8.8Hz) 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)
    [1330] Example 195
    [1331] N1, N1-di (2-propynyl) -2-[(2R) -1- [1- [2- (diisopropylamino) ethyl] -2-oxo-1,2-dihydro-3-pyri Dill] methyl] hexahydro-2-pyridyl] acetamide
    [1332] The title compound was obtained using the compound according to the method of Example 192.
    [1333] 1 H-NMR (400 MHz, CDCl 3 ) δ0.93 (6H, d, J = 6.8 Hz), 1.40-1.65 (5H, m), 1.74-1.83 (1H, m) 2.20 (1H, s), 2.27 (1H, s), 2.30-2.38 (1H, m), 2.53 (1H, dd, J = 15.2, 9.2 Hz), 2.65-2.76 (3H, m), 2.83-2.90 (1H, m), 2.92-3.02 (2H, m), 3.13-3.20 (1H, m), 3.38 (1H, d, J = 15.6 Hz), 3.67 (1H, d, J = 15.6 Hz), 3.80-3.92 (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)
    [1334] Example 196
    [1335] N1, N1-di (2-propynyl) -3- [1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -2-piperidyl] acetamide
    [1336] 300 mg of N1, N1-di (2-propynyl) -3- [1-[(2-methoxy-3-pyridyl) methyl] -2-piperidyl] propanamide obtained in Example 176, thi chloride 0.4 ml of O'Neill and 5 ml of ethanol were stirred for 1 hour under reflux agitation and left overnight. Dilute aqueous sodium hydroxide solution was added, extracted with ethyl acetate, and dried over sodium sulfate. Sodium sulfate was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1, followed by ethyl acetate and ethyl acetate: methanol = 9: 1) to obtain 300 mg of a yellow oil. .
    [1337] 1 H-NMR (400 MHz, CDCl 3 ) δ1.33-1.57 (4H, m), 1.62-1.75 (2H, m), 1.87-2.00 (2H, m), 2.17-2.27 (2H, m), 2.30 -2.59 (4H, m), 2.80-2.88 (1H, m), 3.31 (1H, d, J = 16.0 Hz), 3.82 (1H, d, J = 16.0 Hz), 4.20 (2H, s), 4.31 ( 2H, s), 6.31 (1H, dd, J = 6.8 Hz), 7.33 (1H, d, J = 6.8 Hz), 7.59 (1H, d, J = 6.8 Hz)
    [1338] Example 197
    [1339] N1, N1-di (2-propynyl) -3- [1-[(1-cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl] methyl] -2-piperidyl ] Propanamide
    [1340] N1, N1-di (2-propynyl) -3- [1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -2-piperidyl] propanamide 300 mg, cyclo 0.1 ml of propylmethylbromide, 620 mg of potassium carbonate, and 5 ml of DMF were heated and stirred at 60 ° C for 1 hour and 80 ° C for 1 hour. Water was added, extraction was performed with ethyl acetate and dried over magnesium sulfate. The desiccant was filtered off and the solvent was removed under reduced pressure. The residue was purified by NH foam silica gel chromatography (hexane-ethyl acetate = 4: 1 then 2: 1 then ethyl acetate) to give 150 mg of an oil.
    [1341] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.35-0.75 (2H, m), 0.57-0.71 (2H, m), 1.20-1.30 (1H, m), 1.30-1.55 (4H, m), 1.61 -1.75 (2H, m), 1.90-1.97 (2H, m), 2.15-2.28 (3H, m), 2.43-2.58 (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 Hz, 6.8 Hz), 7.28 (1H, dd, J = 6.8 Hz, 2.0 Hz), 7.48 (1H, dd, J = 6.8 Hz, 2.0 Hz)
    [1342] Example 198
    [1343] N1- (3-fluorobenzyl) -2- [1- [2- (2-oxo-1,2-dihydro-3-pyridyl) ethyl] -2-piperidyl] acetamide
    [1344] 370 mg N 1- (3-fluorobenzyl) -2- [1- [2- (2-methoxy-3-pyridyl) ethyl] -2-piperidyl] acetamide obtained in Example 177, chloride 0.44 ml of thionyl and 5 ml of ethanol were stirred at 100 ° C. for 2 hours. The solvent was evaporated under reduced pressure, sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. After drying over sodium sulfate, the drying agent was filtered off, and the solvent was removed under reduced pressure to obtain 330 mg of white crystals.
    [1345] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.77 (6H, m), 2.30-2.58 (3H, m), 2.69-2.80 (4H, m), 2.88-2.97 (1H, m), 3.00 -3.06 (1H, m), 4.32 (1H, dd, J = 15.2 Hz, 5.6 Hz), 4.48 (1H, dd, J = 15.2 Hz, 6.0 Hz), 6.16 (1H, dd, J = 6.8 Hz, 6.8 Hz), 6.86-6.93 (1H, m), 6.97-7.03 (1H, m), 7.04 (1H, d, J = 7.6 Hz), 7.16-7.26 (3H, m), 8.80-8.86 (1H, m)
    [1346] Example 199
    [1347] N1- (3-fluorobenzyl) -2- [1- [2- [1- (cyclopropylmethyl) -2-oxo-1,2-dihydro-3-pyridyl] ethyl] -2-piperi Dill] acetamide
    [1348] N1- (3-fluorobenzyl) -2- [1- [2- (2-oxo-1,2-dihydro-3-pyridinyl) ethyl] -2-piperidyl] acet obtained in Example 102 230 mg of amide, 0.08 ml of cyclopropylmethylchloride, 450 mg of potassium carbonate and 5 ml of DMF were stirred at 60 ° C for 1 hour. Water was added, extraction was performed with ethyl acetate and dried over sodium sulfate. The drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was purified by NH foam silica gel chromatography (hexane-ethyl acetate = 1: 1, ethyl acetate) to obtain 180 mg of a colorless oil.
    [1349] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.30-0.35 (2H, m), 0.54-0.60 (2H, m), 1.12-1.22 (1H, m), 1.28-1.48 (6H, m), 2.32 -2.40 (1H, m), 2.45-2.63 (3H, m), 2.67-2.91 (4H, m), 2.95-3.02 (1H, m), 3.65-3.77 (2H, m), 4.29 (1H, dd, J = 15.2 Hz, 5.2 Hz), 4.49 (1H, dd, J = 15.2 Hz, 5.6 Hz), 6.08 (1H, dd, J = 6.8 Hz, 6.8 Hz), 6.87-7.11 (4H, m), 7.20- 7.27 (1 H, m), 8.86 (1 H, bs)
    [1350] Example 200
    [1351] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [3- (2-thienyl) propyl] piperidine
    [1352] 206 mg of 1-[(2-methoxy-3-pyridyl) methyl] -4- [3- (2-thienyl) propyl] piperidine obtained in Example 77 to give 159 mg of the title compound as colorless crystals .
    [1353] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.36 (5H, m), 1.62-1.76 (4H, m), 2.02-2.10 (2H, m), 2.81 (2H, t, J = 7.6 Hz) , 2.87-2.94 (2H, m), 3.46 (2H, s), 6.33 (1H, dd, J = 6.6, 6.6 Hz), 6.77 (1H, dd, J = 3.3, 1.1 Hz), 6.91 (1H, dd , J = 5.1, 3.3 Hz), 7.10 (1H, dd, J = 5.1, 1.1 Hz), 7.36 (1H, d, J = 6.6 Hz), 7.52 (1H, m).
    [1354] Example 201
    [1355] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(2-methoxyphenoxy) methyl] piperidine
    [1356] 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 3 at room temperature Stir for 15 minutes. After the reaction solution was filtered, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2) to obtain 359 mg of the title compound as a colorless oil.
    [1357] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.48 (2H, m), 1.84-1.97 (3H, m), 2.05-2.14 (2H, m), 2.94 (2H, br d, J = 11.6 Hz ), 3.51 (2H s), 3.86 (3H, s), 3.87 (2H, s), 3.95 (3H, s), 6.85-6.94 (5H, m), 7.66 (1H, dd, J = 7.2, 2.0 Hz ), 8.06 (1H, doublet of doublets, J = 5.2, 2.0 Hz)
    [1358] Example 202
    [1359] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(2-fluorophenoxy) methyl] piperidine
    [1360] The title compound was obtained using the compound according to the method of Example 201.
    [1361] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.52 (2H, m), 1.86 (3H, br d, J = 8.8 Hz), 2.10 (2H, brt, J = 12.0 Hz), 2.94 (2H , br d, J = 8.4 Hz), 3.51 (2H, s), 3.87 (2H, d, J = 6.0 Hz), 3.95 (3H, s), 6.84-6.93 (2H, m), 6.90-7.00 (1H , m), 7.04 (1H, t, J = 7.6 Hz), 7.00-7.14 (1H, m), 7.66 (1H, dd, J = 7.6, 2.0 Hz), 8.06 (1H, dd, J = 5.2,2.0 Hz)
    [1362] Example 203
    [1363] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[(2-fluorophenoxy) methyl] piperidine
    [1364] The title compound was obtained using the compound according to the method of Example 201.
    [1365] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.36-1.52 (2H, m), 1.87 (3H, br d, J = 8.8 Hz), 2.12 (2H, brt, J = 10.8 Hz), 2.92 (2H , br d, J = 11.6 Hz), 3.46 (2H, s), 3.88 (2H, d, J = 6.0 Hz), 3.93 (3H, s), 6.84-6.93 (1H, m), 6.95 (1H, t , J = 8.0 Hz), 7.00-7.14 (2H, m), 7.64-7.70 (1H, m), 7.98 (1H, d, J = 2.0 Hz)
    [1366] Example 204
    [1367] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(2- (cyclohexylmethyloxy) phenoxymethyl) piperidine
    [1368] The title compound was obtained using the compound according to the method of Example 201.
    [1369] 1 H-NMR (400 MHz, CDCl 3 ) δ1.01-1.12 (2H, m), 1.13-1.36 (3H, m), 1.38-1.50 (2H, m), 1.64-1.94 (9H, m), 2.06- 2.15 (2H, m), 2.94 (2H, br d, J = 11.6 Hz), 3.51 (2H, s), 3.78 (2H, d, J = 6.0 Hz), 3.84 (2H, d, J = 6.0 Hz) , 3.95 (3H, s), 6.84-6.92 (5H, m), 7.67 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1370] Example 205
    [1371] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[[2- (2-cyclohexylethyl) phenoxy] methyl] piperidine
    [1372] The title compound was obtained using the compound according to the method of Example 201.
    [1373] 1 H-NMR (400 MHz, CDCl 3 ) δ0.87-0.99 (2H, m), 1.009-1.34 (4H, m), 1.42-1.54 (4H, m), 1.60-1.90 (8H, m), 2.08- 2.16 (2H, m), 2.58-2.64 (2H, m), 2.96 (2H, br d, J = 11.2 Hz), 3.52 (2H, s), 3.80 (2H, d, J = 5.6 Hz), 3.96 ( 3H, s), 6.80 (1H, d, J = 7.6 Hz), 6.83-6.90 (2H, m), 7.10-7.16 (2H, m), 7.68 (1H, dd, J = 4.8, 2.0 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1374] Example 206
    [1375] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4- [2- (cyclohexylmethyloxy) phenoxymethyl] piperidine
    [1376] 150 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde, 291 mg of 4- [2- (cyclohexylmethyloxy) phenoxymethyl] piperidine are dissolved in 5 ml of 1,2-dichloroethane, Then, 0.06 ml of acetic acid and 214 mg of sodium triacetoxy borohydride were added and stirred overnight at room temperature. Aqueous solution of saturated sodium carbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 285 mg of the title compound as a pale yellow oil.
    [1377] 1 H-NMR (400 MHz, CDCl 3 ) δ1.01-1.36 (5H, m), 1.39-1.52 (2H, m), 1.65-1.94 (9H, m), 2.08-2.16 (2H, m), 2.92 ( 2H, br d, J = 11.6 Hz), 3.46 (2H, s), 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), 7.67 (1H, d, J = 2.4 Hz), 7.98 (1H, d, J = 2.4 Hz)
    [1378] Example 207
    [1379] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-etheny] piperidine
    [1380] 500 mg of 2-methoxy-3- (chloromethyl) pyridine, 1.04 g of 4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine, 531 mg was added to 10 ml of acetonitrile and stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, filtered through alumina-silica gel, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to give 961 mg of the title compound. Obtained as a pale yellow oil.
    [1381] 1 H-NMR (400 MHz, CDCl 3 ) δ1.02-1.38 (5H, m), 1.52-1.92 (10H, m), 2.10-2.23 (3H, m), 2.92-2.98 (2H, m), 3.53 ( 2H, s), 3.77 (2H, d, J = 6.0 Hz), 3.96 (3H, s), 6.19 (1H, dd, J = 16.0, 7.2 Hz), 6.71 (1H, d, J = 16.0 Hz), 6.80-6.92 (3H, m), 7.15 (1H, dt, J = 7.2, 1.2 Hz), 7.41 (1H, dd, J = 7.2, 1.6 Hz), 7.67 (1H, dd, J = 7.6, 2.0 Hz) , 8.06 (1H, doublet of doublets, J = 4.8, 2.0 Hz)
    [1382] Example 208
    [1383] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine
    [1384] 200 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde, 263 mg of 4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine 1,2- It was dissolved in 5 ml of dichloroethane, 0.09 ml of acetic acid and 339 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 2 hours 30 minutes. The reaction solution was filtered through NH-foam silica gel, and the filtrate was removed under reduced pressure. Ethyl acetate was added to the residue, and the filtrate was removed under reduced pressure after filtration with alumina. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 245 mg of the title compound as a colorless oil.
    [1385] 1 H-NMR (400 MHz, CDCl 3 ) δ1.53-1.69 (2H, m), 1.75-1.83 (2H, m), 2.10-2.24 (3H, m), 2.85-2.96 (2H, m), 3.47 ( 2H, s), 3.93 (3H, s), 6.25 (1H, dd, J = 16.0, 6.8 Hz), 6.55 (1H, d, J = 16.0 Hz), 7.01 (1H, ddd, J = 10.8, 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), 7.68 (1H, d, J = 2.4 Hz) , 7.99 (1H, d, J = 2.4 Hz)
    [1386] Example 209
    [1387] 1-[(5-cyano-2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine
    [1388] The title compound was obtained using the compound according to the method of Example 206.
    [1389] 1 H-NMR (400 MHz, CDCl 3 ) δ1.53-1.66 (2H, m), 1.76-1.84 (2H, m), 2.12-2.26 (3H, m), 2.85-2.92 (2H, m), 3.48 ( 2H, s), 4.01 (3H, s), 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, 8.4, 1.2 Hz), 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) , 8.37 (1H, doublet, J = 2.4 Hz)
    [1390] Example 210
    [1391] 1-[(5-fluoro-2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine
    [1392] 117 mg of 5-fluoro-2-methoxy-3-pyridinecarboxaldehyde, 201 mg of 4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine 1,2 It was dissolved in 3 ml of dichloroethane, 0.06 ml of acetic acid and 238 mg of sodium triacetoxyborohydride were added, and the mixture was stirred overnight at room temperature. Aqueous solution of saturated sodium carbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to give 221 mg of the title compound as a colorless oil.
    [1393] 1 H-NMR (400 MHz, CDCl 3 ) δ1.53-1.69 (2H, m), 1.75-1.83 (2H, m), 2.11-2.25 (3H, m), 2.89-2.96 (2H, m), 3.48 ( 2H, s), 3.93 (3H, s), 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, 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, 3.2 Hz), 7.87 (1H, d, J = 3.2 Hz)
    [1394] Example 211
    [1395] 1-[(5-fluoro-2-methoxy-3-pyridyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperi Dean
    [1396] The title compound was obtained using the compound according to the method of Example 206.
    [1397] 1 H-NMR (400 MHz, CDCl 3 ) δ1.03-1.38 (5H, m), 1.52-1.93 (10H, m), 2.12-2.24 (3H, m), 2.89-2.96 (2H, m), 3.48 ( 2H, s), 3.78 (2H, d, J = 6.0 Hz), 3.93 (3H, s), 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), 6.88 (1H, dt, J = 7.6, 1.6 Hz), 7.15 (1H, dt, J = 7.6, 2.0 Hz), 7.41 (1H, dd, J = 7.6, 1.6 Hz), 7.53 (1H, dd, J = 8.4, 2.8 Hz), 7.87 (1H, d, J = 2.8 Hz)
    [1398] Example 212
    [1399] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-chlorophenyl) -1-ethenyl] piperidine
    [1400] The title compound was obtained using the compound according to the method of Example 206.
    [1401] 1 H-NMR (400 MHz, CDCl 3 ) δ1.54-1.66 (2H, m), 1.76-1.84 (2H, m), 2.15 (2H, dt, J = 2.4, 12.0 Hz), 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 = 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), 7.68 (1H, d, J = 2.8 Hz)
    [1402] Example 213
    [1403] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine
    [1404] The title compound was obtained using the compound according to the method of Example 206.
    [1405] 1 H-NMR (400 MHz, CDCl 3 ) δ1.53-1.67 (2H, m), 1.75-1.83 (2H, m), 2.10-2.24 (3H, m), 2.33 (3H, s), 2.89-2.96 ( 2H, m), 3.47 (2H, s), 3.93 (3H, s), 6.06 (1H, dd, J = 16.0, 7.2 Hz), 6.48 (1H, dd, J = 16.0, 0.8 Hz), 7.08-7.18 (3H, m), 7.41 (1H, d, J = 6.8 Hz), 7.68 (1H, d, J = 2.8 Hz), 7.98 (1H, d, J = 2.8 Hz)
    [1406] Example 214
    [1407] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine
    [1408] 1.15 g of [(2-methylphenyl) methyl] triphenylphosphonium bromide was suspended in 10 ml of N, N-dimethylformamide, 288 mg of potassium tert-butoxide was added and stirred for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4-piperidinecarboxaldehyde in 3 ml of N and N-dimethylformamide was added dropwise and stirred overnight at room temperature. Ice water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give 473 mg of the title compound as a pale yellow oil.
    [1409] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.68 (2H, m), 1.74-1.83 (2H, m), 1.96-2.22 (3H, m), 2.19 (3 / 4H s), 2.32 (9 / 4H, s), 2.86 (1 / 2H, br d, J = 7.6 Hz), 2.99 (3 / 2H, br d, J = 12 Hz), 3.47 (1 / 2H s), 3.52 (3 / 2H, s ), 3.93 (3 / 4H s), 3.96 (9 / 4H, s), 5.55 (1 / 4H, dd, J = 11.6, 10.0 Hz), 6.05 (3 / 4H, dd, J = 15.6, 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), 7.67 (3 / 4H, dd, J = 6.8, 2.0 Hz), 8.03-8.09 (1H, m)
    [1410] Example 215
    [1411] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [3- (benzyloxy) phenyl] -1-ethenyl] piperidine
    [1412] The title compound was obtained using the compound according to the method of Example 214.
    [1413] 1 H-NMR (400 MHz, CDCl 3 ) δ1.50-1.80 (4H, m), 2.02-2.20 (11 / 5H, m), 2.56 (4 / 5H, m), 2.85-2.98 (2H, m), 3.49 (2 / 5H, s), 3.52 (8 / 5H, s), 3.94 (3 / 5H, s), 3.96 (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), 6.35 (4 / 5H, d, J = 16.0 Hz), 6.80-6.90 (3H, m), 6.93-7.00 (2H, m), 7.18-7.25 (1H, m), 7.20-7.46 (4H, m), 7.65 (1 / 5H, br d, J = 6.4 Hz), 7.67 (4 / 5H, br d, J = 6.4 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1414] Example 216
    [1415] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[(E) -2- (2-phenylmethyl) phenyl] -1-ethenyl] piperidine
    [1416] The title compound was obtained using the compound according to the method of Example 214.
    [1417] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.52-1.66 (2H, m), 1.74-1.83 (11 / 6H, m), 2.01 (1 / 6H, m), 2.10-2.24 (17 / 6H, m ), 2.36 (1 / 6H, m), 2.78-3.00 (6H, m), 3.47 (1 / 3H, s), 3.53 (5 / 3H, s), 3.53 (1 / 2H, s), 3.96 (5 / 2H, s), 5.91 (1 / 6H, dd, J = 11.2, 10.0 Hz), 6.07 (5 / 6H, dd, J = 15.6, 6.8 Hz), 6.46 (1 / 6H, d, J = 11.2 Hz ), 6.64 (5 / 6H, d, J = 15.6 Hz), 6.84-6.92 (1H, m), 7.09-7.24 (6H, m), 7.25-7.33 (2H, m), 7.43 (1H, dd, J) = 6.8, 2.0 Hz), 7.63 (1 / 5H, br d, J = 6.8 Hz), 7.68 (5 / 6H, br d, J = 6.8 Hz), 8.05 (1 / 5H, dd, J = 5.2, 2.0 Hz), 8.06 (5 / 6H, dd, J = 5.2, 2.0 Hz)
    [1418] Example 217
    [1419] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (isobutyloxy) phenyl] -1-ethenyl] piperidine
    [1420] The title compound was obtained using the compound according to the method of Example 214.
    [1421] 1 H-NMR (400 MHz, CDCl 3 ) δ1.02 (6 / 5H, d, J = 6.8 Hz), 1.05 (24 / 5H, d, J = 6.8 Hz), 1.48-1.64 (2H, m), 1.74 -1.83 (2H, m), 2.00-2.22 (19 / 5H, m), 2.51 (1 / 5H, m), 2.84-2.98 (2H, m), 3.48 (2 / 5H, s), 3.52 (8 / 5H, m), 3.72 (2 / 5H, d, J = 6.4 Hz), 3.74 (8 / 5H, d, J = 6.4 Hz), 3.94 (3 / 5H, s), 3.96 (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 (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, 1.6 Hz), 7.65 (1 / 5H, dd , J = 6.8, 2.0 Hz), 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)
    [1422] Example 218
    [1423] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [3- (cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [1424] The title compound was obtained using the compound according to the method of Example 214.
    [1425] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.98-1.38 (5H, m), 1.49-1.92 (10H, m), 2.03-2.20 (11 / 4H, m), 2.60 (1 / 4H, m), 2.86-2.98 (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 (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), 7.57 (3 / 4H, dd, J = 7.2, 2.0 Hz), 8.07 (1H, dd, J = 5.6, 2.0 Hz)
    [1426] Example 219
    [1427] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (2-phenylethoxy) phenyl] -1-ethenyl] piperidine
    [1428] The title compound was obtained using the compound according to the method of Example 214.
    [1429] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.81 (4H, m), 2.00-2.20 (17 / 6H, m), 2.48 (1 / 6H, m), 2.85-3.00 (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 (5 / 2H, s), 4.179 (1 / 3H, t, J = 6.8 Hz), 4.19 (5 / 3H, t, J = 6.8 Hz), 5.52 (1 / 6H, dd, J = 11.6, 10.0 Hz), 6.15 (5 / 6H, dd, J = 16.0, 7.2 Hz), 6.44 (1 / 6H, d, J = 11.6 Hz), 6.67 (5 / 6H, d, J = 16.0 Hz ), 6.80-6.94 (3H, m), 7.11-7.37 (6H, m), 7.40 (1H, dd, J = 8.0, 1.6 Hz), 7.65 (1 / 6H, br d, J = 6.8 Hz), 7.69 (5 / 6H, br d, J = 6.8 Hz), 8.05 (1 / 6H, dd, J = 4.8, 2.0 Hz), 8.06 (5 / 6H, dd, J = 4.8, 2.0 Hz)
    [1430] Example 220
    [1431] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (phenoxymethyl) phenyl] -1-ethenyl] piperidine
    [1432] The title compound was obtained using the compound according to the method of Example 214.
    [1433] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.46-1.78 (4H, m), 1.95-2.20 (17 / 6H, m), 2.31 (1 / 6H, m), 2.82-2.96 (2H, m), 3.43 (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 / 6H, dd, J = 11.6,10.0 Hz), 6.11 (5 / 6H, dd, J = 16.0, 6.8 Hz), 6.48 (1 / 6H, dd, J = 11.6 Hz), 6.62 (5 / 6H, dd, J = 16.0 Hz), 6.85-6.90 (1H, m), 6.92-7.02 (2H, m), 7.17-7.36 (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 / 6H, br d, J = 7.2 Hz), 7.65 (5 / 6H, br d, J = 7.2 Hz), 8.06 (1H, doublet of doublets, J = 5.2, 2.0 Hz)
    [1434] Example 221
    [1435] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclopentylmethyloxy) phenyl] -1-ethenyl] piperidine
    [1436] The title compound was obtained using the compound according to the method of Example 214.
    [1437] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (2H, m), 1.50-1.73 (8H, m), 1.74-1.91 (11 / 4H, m), 2.00-2.22 (9 / 4H, m ), 2.39 (3 / 4H, m), 2.51 (1 / 4H, m), 2.98 (1 / 2H, br d, J = 11.6 Hz), 2.95 (3 / 2H, br d, 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 (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), 7.12-7.23 (1H, m), 7.40 (1H , dd, J = 7.6, 1.2 Hz), 7.65 (1 / 4H, dd, J = 7.2, 2.0 Hz), 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)
    [1438] Example 222
    [1439] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E)-[2- (2-cyclohexylethyl) phenyl] -1-ethenyl] piperidine
    [1440] The title compound was obtained using the compound according to the method of Example 214.
    [1441] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.85-1.00 (2H, m), 1.10-1.83 (15H, m), 1.65-2.04 (3 / 4H, m), 2.10-2.23 (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), 2.91-2.99 (3 / 2H, m), 3.46 (1 / 2H, s), 3.53 (3 / 2H, s), 3.93 (3 / 4H, s), 3.96 (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), 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)
    [1442] Example 223
    [1443] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclohexylmethyloxy) -5-fluorophenyl] -1-ethenyl] piperi Dean
    [1444] The title compound was obtained using the compound according to the method of Example 214.
    [1445] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.97-1.38 (5H, m), 1.48-1.92 (10H, m), 2.01-2.23 (8 / 3H, m), 2.48 (1 / 3H, m), 2.85-2.98 (2H, m), 3.48 (2 / 3H, s), 3.52 (4 / 3H, s), 3.71 (2 / 3H, d, J = 6.4 Hz), 3.72 (4 / 3H, d, J = 6.4 Hz), 3.94 (1H, s), 3.96 (2H, s), 5.55 (1 / 3H, t, J = 11.6 Hz), 6.20 (2 / 3H, dd, J = 16.0, 6.8 Hz), 6.43 (1 / 3H, d, J = 11.6 Hz), 6.67 (2 / 3H, d, J = 16.0 Hz), 6.71-6.93 (3H, m), 7.11 (1H, dd, J = 9.6, 3.2 Hz), 7.62-7.70 (1H, m), 8.06 (1H, m)
    [1446] Example 224
    [1447] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2- (cyclohexylmethyloxy) -4-fluorophenyl) -1-ethenyl] piperi Dean
    [1448] The title compound was obtained using the compound according to the method of Example 214.
    [1449] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.97-1.38 (5H, m), 1.47-1.81 (10H, m), 1.99-2.21 (8 / 3H, m), 2.43 (1 / 3H, m), 2.85-2.97 (2H, m), 3.47 (2 / 3H, s), 3.51 (4 / 3H, s), 3.72 (2 / 3H, d, J = 6.8 Hz), 3.73 (4 / 3H, d, J = 6.0 Hz), 3.94 (1H, s), 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), 7.62-7.70 (1H, m), 78.03-8.11 (1H, m)
    [1450] Example 225
    [1451] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2- (cyclohexylmethyloxy) -6-fluorophenyl) -1-ethenyl] piperi Dean
    [1452] The title compound was obtained using the compound according to the method of Example 214.
    [1453] 1 H-NMR (400 MHz, CDCl 3 ) δ1.04-1.38 (6H, m), 1.44 (1H, m), 1.52-1.65 (2H, m), 1.68-1.91 (6H, m), 2.10-2.22 ( 3H, m), 2.90-2.98 (2H, m), 3.52 (2H, s), 3.78 (2H, d, J = 6.0 Hz), 3.96 (3H, s), 6.48-6.68 (4H, m), 6.88 (1H, dd, J = 7.6, 5.2 Hz), 7.05 (1H, dt, J = 8.0, 6.4 Hz), 7.67 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 5.2 , 2.0 Hz)
    [1454] Example 226
    [1455] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-methoxy-5-methylphenyl) -1-ethenyl] piperidine oxalate
    [1456] According to the method of Example 214, the vitreous was obtained from the corresponding raw material, and the title compound was obtained as oxalate according to a conventional method.
    [1457] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.54-1.72 (2H, m), 1.89 (2H, br d, J = 11.6 Hz), 2.23 (3H, s), 2.30-2.54 (1H, m), 2.90-3.06 (2H, m), 3.35 (2H, br d, J = 10.8 Hz), 3.75 (3H, s), 3.94 (3H, s), 4.20 (2H, s), 6.10-6.26 (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, 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)
    [1458] Example 227
    [1459] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (3-bromophenyl) -1-ethenyl] piperidineoxalate
    [1460] The title compound was obtained using the compound according to the method of Example 226.
    [1461] 1 H-NMR (400 MHz, CDCl 3 ) δ1.56-1.74 (2H, m), 1.91 (2H, br d, J = 12.8 Hz), 2.36-2.50 (1H, m), 2.90-3.06 (2H, m ), 3.35 (2H, br d, J = 11.2 Hz), 3.94 (3H, s) 4.19 (2H, s), 6.30-6.48 (2H, m), 7.06-7.14 (1H, m), 7.24-7.38 ( 1H, m), 7.38-7.50 (2H, m), 7.65 (1H, s), 7.88 (1H, d, J = 7.6 Hz), 8.27 (1H, d, J = 4.4 Hz)
    [1462] Example 228
    [1463] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclopentyloxy) phenyl] -1-ethenyl] piperidine
    [1464] 786 mg of 2- (cyclopentyloxy) benzylphosphonic acid diethyl was dissolved in 10 ml of tetrahydrofuran, 281 mg of potassium tert-butoxide was added and stirred for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4-piperidinecarboxaldehyde in 3 ml of tetrahydrofuran was added dropwise and stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give 473 mg of the title compound as a pale yellow oil.
    [1465] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.94 (12H, m), 2.00-2.22 (11 / 4H, m), 2.50 (1 / 4H, m), 2.85-3.00 (2H, m), 3.48 (1 / 2H s), 3.52 (3 / 2H, s), 3.94 (3 / 4H s), 3.96 (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
    [1466] .03-8.09 (1H, m)
    [1467] Example 229
    [1468] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2-phenoxyphenyl) -1-ethenyl] piperidine
    [1469] The title compound was obtained using the compound according to the method of Example 228.
    [1470] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.44-1.74 (4H, m), 1.98-2.16 (2H, m), 2.40-2.55 (1H, m), 2.84-2.94 (2H, m), 3.48 ( 2H, s), 3.94 (3H, s), 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), 8.02-8.06 (1H, m)
    [1471] Example 230
    [1472] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [3- (cyclopentyloxy) phenylphenyl] -1-ethenyl] piperidine
    [1473] The title compound was obtained using the compound according to the method of Example 228.
    [1474] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.96 (12H, m), 2.04-2.18 (14 / 5H, m), 2.61 (1 / 5H, m), 2.86-2.99 (2H, m), 3.50 (2 / 5H s), 3.52 (8 / 5H, s), 3.94 (3 / 5H s), 3.96 (12 / 5H, s), 4.72-4.80 (1H, m), 5.49 (1 / 5H, dd , J = 11.6, 10.0 Hz), 6.16 (4 / 5H, dd, J = 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), 7.15-7.25 (1H, m), 7.63-7.70 (1H, m), 8.04-8.08 (1H, m)
    [1475] Example 231
    [1476] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- [2- (benzyloxy) phenyl] -1-ethenyl] piperidine
    [1477] The title compound was obtained using the compound according to the method of Example 228.
    [1478] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.48-1.82 (4H, m), 2.00-2.23 (14 / 5H, m), 2.50 (1 / 5H, m), 2.85-2.98 (2H, m), 3.48 (2 / 5H s), 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), 7.28-7.48 (5H, m), 7.64 (1 / 5H, br d, J = 6.8 Hz), 7.66 (4 / 5H, br d, J = 6.8 Hz), 8.05 (1 / 5H, dd, J = 4.8,2.4 Hz), 8.06 (4 / 5H, dd, J = 4.8,2.4 Hz)
    [1479] Example 232
    [1480] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (2,5-dimethylphenyl) -1-ethenyl] piperidine oxalate
    [1481] According to the method of Example 228, a vitreous body was obtained from a corresponding raw material, and the title compound was obtained as oxalate according to a conventional method.
    [1482] 1 H-NMR (400 MHz, CDCl 3 ) δ1.54-1.74 (2H, m), 1.88 (2H, br d, J = 13.2 Hz), 2.22 (3H, s), 2.25 (3H, s), 2.30- 2.50 (1H, m), 2.64-2.90 (2H, m), 3.26 (2H, br d, J = 10.8 Hz), 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), 7.08 (1H, dd, J = 7.6, 5.2 Hz), 7.26 (1H, s), 7.85 (1H, dd, J = 7.6, 1.2 Hz), 8.23 (1H, dd, J = 5.2, 1.2 Hz)
    [1483] Example 233
    [1484] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(E) -2- (3,5-dimethylphenyl) -1-ethenyl] piperidine oxalate
    [1485] The title compound was obtained using the compound according to the method of Example 232.
    [1486] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.56-1.74 (2H, m), 1.90 (2H, br d, J = 12.0 Hz), 2.24 (6H, s), 2.30-2.50 (1H, m), 2.90-3.08 (2H, m), 3.35 (2H, br d, J = 11.2 Hz), 3.93 (3H, s), 4.20 (2H, s), 6.10-6.26 (1H, m), 6.30-6.40 (1H , m), 6.86 (1H, s), 7.01 (2H, s), 7.06-7.14 (1H, m), 7.89 (1H, d, J = 7.2 Hz), 8.27 (1H, d, J = 4.8 Hz)
    [1487] Example 234 1-[(2-methoxy-3-pyridyl) methyl] -4-[(Z) -4- [2,3- (methylenedioxy) phenyl] -1-butenyl] piperidine
    [1488] The title compound was obtained using the compound according to the method of Example 214.
    [1489] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.46 (4H, m), 1.98-2.08 (2H, m), 2.19 (1H m), 2.26-2.42 (2H, m), 2.63 (2H, t , J = 8.0 Hz), 2.84 (2H, br d, J = 11.6 Hz), 3.47 (2H s), 3.95 (3H, s), 5.24 (1H, dd, J = 10.4, 9.6 Hz), 5.34 (1H , m), 5.93 (2H, s), 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 (1H, dd, J = 7.2, 4.8 Hz), 7.63 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1490] Example 235
    [1491] 1-[(2-methoxy-3-pyridyl) methyl] -4-[(Z) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine
    [1492] 2.355 g of [[2- (cyclohexylmethyloxy) phenyl] methyl] triphenylphosphonium chloride, 650 mg of potassium carbonate, 18-crown-6 (11 mg) are added to 5 ml of dichloromethane and under reflux, 1 A solution of 1.000 g of-[(2-methoxy-3-pyridinyl) methyl] -4-piperidinecarboxaldehyde in 10 ml of dichloromethane was added dropwise over 20 minutes. After heating under reflux for 6 hours, ethyl acetate was added to the reaction solution, and the mixture was filtered through NH-foam silica gel. The filtrate was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 1.047 g of a pale yellow oil. The oily substance was dissolved in 20 ml of ethyl acetate, 944 mg of di-O-benzoyl D-tartrate was added, and the precipitated crystals were filtered off. A saturated sodium carbonate aqueous solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Filtration was carried out with alumina, and the filtrate was removed under reduced pressure to give 374 mg of the title compound as a pale yellow oil.
    [1493] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.98-1.36 (5H, m), 1.52-1.92 (10H, m), 2.00-2.10 (2H, m), 2.51 (1H, m), 2.84-2.92 (2H , m), 3.48 (2H, s), 3.75 (2H, d, J = 6.4 Hz), 3.94 (3H, s), 5.52 (1H, dd, J = 11.6, 10.4 Hz), 6.49 (1H, d, J = 11.6 Hz), 6.80-6.94 (3H, m), 7.15-7.25 (2H, m), 7.65 (1H, br d, J = 7.2 Hz), 8.05 (1H, dd, J = 5.2,2.0 Hz)
    [1494] Example 236
    [1495] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2,2-diphenyl-1-ethenyl) piperidine
    [1496] The title compound was obtained using the compound according to the method of Example 214.
    [1497] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.52-1.68 (4H, m), 1.90-2.02 (2H, m), 2.14 (1H, m), 2.86 (2H, br d, J = 10.8 Hz), 3.46 (2H s), 3.93 (3H s), 5.92 (1H, d, J = 10.0 Hz), 6.87 (1H, dd, J = 7.2, 4.8 Hz), 7.14-7.40 (10H, m), 7.64 (1H , br d, J = 6.8 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1498] Example 237
    [1499] 1-[(2-methoxy-3-pyridyl) methyl] -4- [3- [2,3- (methylenedioxy) phenyl] propyl] piperidine
    [1500] The title compound was obtained using the compound according to the method of Example 201.
    [1501] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.34 (4H, m), 1.58-1.62 (5H, m), 2.01 (2H, br t, J = 10.8 Hz), 2.55 (2H, t, J = 7.6 Hz), 2.89 (2H, br d, J = 11.2 Hz), 3.48 (2H s), 3.94 (3H, s), 5.92 (2H, s), 6.66 (1H, dd, J = 7.6, 2.0 Hz ), 6.68 (1H, dd, J = 7.6, 2.0 Hz), 6.75 (1H, t, J = 7.6 Hz), 6.86 (1H, dd, J = 7.2, 4.8 Hz), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1502] Example 238
    [1503] 1-[(2-methoxy-3-pyridyl) methyl] -4- [5- [2,3- (methylenedioxy) phenyl] pentyl] piperidine
    [1504] The title compound was obtained using the compound according to the method of Example 201.
    [1505] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.16-1.38 (8H, m), 1.55-1.70 (5H, m), 2.01 (2H, br t, J = 11.6 Hz), 2.56 (2H, t, J = 8.0 Hz), 2.89 (2H, br d, J = 11.6 Hz), 3.48 (2H s), 3.93 (3H, s), 5.92 (2H, s), 6.66 (1H, dd, J = 8.0, 1.2 Hz ), 6.68 (1H, dd, J = 8.0, 1.2 Hz), 6.75 (1H, t, J = 8.0 Hz), 6.86 (1H, dd, J = 7.2, 4.8 Hz), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1506] Example 239
    [1507] 1-[(6-methyl-2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1508] The title compound was obtained using the compound according to the method of Example 201.
    [1509] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.52-1.59 (2H, m), 1.67-1.76 (2H, m), 1.99 (2H, m), 2.42 (3H, s), 2.55-2.62 (2H, m), 2.88 (2H, br d, J = 11.6 Hz), 3.45 (2H s), 3.92 (3H, s), 5.92 (2H, s), 6.07 (1H, br d, J = 6.8 Hz), 6.65 (1H, dd, J = 7.6, 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.49 ( 1H, d, J = 7.2 Hz)
    [1510] Example 240
    [1511] 1-[(2-methoxy-3-pyridyl) methyl] -4- (2,2-diphenylethyl) piperidine
    [1512] The title compound was obtained using the compound according to the method of Example 256.
    [1513] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.17 (1H, m), 1.24-1.40 (2H, m), 1.67-1.75 (2H, m), 1.87-2.02 (4H, m), 2.84 (2H, br d, J = 11.6 Hz), 3.44 (2H, s), 3.92 (3H, s), 4.04 (1H, t, J = 7.6 Hz), 6.85 (1H, dd, J = 6.8, 4.8 Hz), 7.14 -7.30 (10H, m), 7.62 (1H, broad doublet, J = 6.8 Hz), 8.04 (1H, dd, J = 5.2, 2.0 Hz)
    [1514] Example 241
    [1515] 1-[(5-bromo-2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1516] The title compound was obtained using the compound according to the method of Example 201.
    [1517] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.40 (3H, m), 1.54-1.65 (2H, m), 1.68-1.79 (2H, m), 1.98-2.09 (2H, m), 2.56- 2.64 (2H, m), 2.86 (2H, br d, J = 11.6 Hz), 3.43 (2H, s), 3.91 (3H, s), 5.93 (2H, s), 6.66 (1H, dd, J = 7.6 , 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 6.76 (1H, t, J = 7.6 Hz), 7.78 (1H, br d, J = 1.2 Hz), 8.07 (1H, d, J = 2.8 Hz)
    [1518] Example 242
    [1519] 1-[(5-methyl-2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1520] The title compound was obtained using the compound according to the method of Example 201.
    [1521] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.40 (3H, m), 1.54-1.62 (2H, m), 1.68-1.79 (2H, m), 2.01 (2H, br t, J = 11.2 Hz ), 2.24 (3H, s), 2.59 (2H, brt, J = 8.0 Hz), 2.89 (2H, br d, J = 11.6 Hz), 3.45 (2H s), 3.91 (3H, s), 5.92 ( 2H, s), 6.66 (1H, dd, J = 7.6, 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.47 (1H, br s), 7.84 (1H, br s)
    [1522] Example 243
    [1523] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (benzyloxy) phenyl] ethyl] piperidine
    [1524] The title compound was obtained using the compound according to the method of Example 201.
    [1525] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.39 (3H, m), 1.52-1.60 (2H, m), 1.66-1.77 (2H, m), 1.96-2.08 (2H, m), 2.65- 2.72 (2H, m), 2.87 (2H, br d, J = 10.8 Hz), 3.48 (2H, s), 3.95 (3H, s), 5.08 (2H, s), 6.85-6.93 (3H, m), 7.12-7.18 (2H, m), 7.28-7.46 (5H, m), 7.66 (1H, br d, J = 6.8 Hz), 8.06 (1H, dd, J = 5.2, 2.0 Hz)
    [1526] Example 244
    [1527] 1-[(5-phenyl-2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1528] The title compound was obtained using the compound according to the method of Example 201.
    [1529] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.40 (3H, m), 1.52-1.78 (4H, m), 2.00-2.10 (2H, m), 2.55-2.62 (2H, m), 2.90- 2.96 (2H, m), 3.54 (2H, s), 3.99 (3H, s), 5.92 (2H, s), 6.65 (1H, dd, J = 7.6, 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.35 (1H, m), 7.42-7.48 (2H, m), 7.53-7.58 (2H, m), 7.89 (1H, d, J = 2.4 Hz), 8.28 (1H, d, J = 2.4 Hz)
    [1530] Example 245
    [1531] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[2- (2-piperidino-2-oxoethoxy) phenyl] ethyl] piperidine
    [1532] The title compound was obtained using the compound according to the method of Example 201.
    [1533] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.38 (2H, m), 1.51-1.78 (11H, m), 1.98-2.08 (2H, m), 2.62-2.68 (2H, m), 2.90 ( 2H, br d, J = 10.8 Hz), 3.45-3.60 (6H, m), 3.95 (3H, s), 4.67 (2H, s), 6.84-6.95 (3H, m), 7.12-7.18 (2H, m ), 7.66 (1H, broad doublet, J = 6.8 Hz), 8.05 (1H, doublet, J = 5.2, 2.0 Hz)
    [1534] Example 246
    [1535] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[2- (4-pyridyloxy) phenyl] ethyl] piperidine
    [1536] The title compound was obtained using the compound according to the method of Example 201.
    [1537] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.15-1.32 (3H, m), 1.45-1.54 (2H, m), 1.57-1.68 (2H, m), 1.99 (2H, br d, J = 10.4 Hz ), 2.48-2.55 (2H, m), 2.87 (2H, br d, J = 10.4 Hz), 3.48 (2H, s), 3.94 (3H, s), 6.74-6.79 (2H, m), 6.86 (1H , dd, J = 7.2, 5.2 Hz), 7.00 (1H, dd, J = 7.6, 1.6 Hz), 7.17-7.34 (3H, m), 7.64 (1H, br d, J = 6.8 Hz), 8.05 (1H , dd, J = 4.8, 2.0 Hz), 8.41-8.46 (2H, m)
    [1538] Example 247
    [1539] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (1- (dimethylcarbamoyl) cyclopentyloxy) phenyl] ethyl] piperidine
    [1540] The title compound was obtained using the compound according to the method of Example 201.
    [1541] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.41 (3H, m), 1.47-1.58 (2H, m), 1.68-1.82 (6H, m), 1.98-2.10 (2H, m), 2.11- 2.20 (2H, m), 2.38-2.40 (2H, m), 2.56-2.64 (2H, m), 2.91 (2H, m), 2.92 (3H, s), 3.09 (3H, s), 3.51 (2H, s), 3.95 (3H, s), 6.67 (1H, dd, J = 7.6, 1.2 Hz), 6.82-6.91 (2H, m), 7.04 (1H, dd, J = 7.6, 1.6 Hz), 7.11 (1H , dd, J = 7.6, 1.6 Hz), 7.66 (1H, br d, J = 6.0 Hz), 8.06 (1H, dd, J = 5.2, 2.0 Hz)
    [1542] Example 248
    [1543] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (benzyloxy) phenyl] ethyl] piperidine
    [1544] The title compound was obtained using the compound according to the method of Example 201.
    [1545] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.39 (3H, m), 1.52-1.60 (2H, m), 1.66-1.77 (2H, m), 1.96-2.08 (2H, m), 2.65- 2.72 (2H, m), 2.87 (2H, br d, J = 10.8 Hz), 3.48 (2H, s), 3.95 (3H, s), 5.08 (2H, s), 6.87-6.94 (2H, m), 7.13-7.20 (2H, m), 7.29-7.46 (5H, m), 7.66 (1H, br s), 7.98 (1H, d, J = 2.0 Hz)
    [1546] Example 249
    [1547] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4- [2- [2- (2-methoxyethoxy) phenyl] ethyl] piperidine
    [1548] The title compound was obtained using the compound according to the method of Example 201.
    [1549] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.40 (3H, m), 1.50-1.60 (2H, m), 1.70-1.80 (2H, m), 2.00-2.10 (2H, m), 2.65 ( 2H, t, J = 8.0 Hz), 2.87 (2H, br d, J = 10.8 Hz), 3.44 (2H, s), 3.46 (3H, s), 3.76 (2H, t, J = 4.8 Hz), 3.92 (3H, s), 4.12 (2H, t, J = 4.8 Hz), 6.84 (1H, d, J = 8.0 Hz), 6.89 (1H, t, J = 7.6 Hz), 7.10-7.18 (2H, m) , 7.66 (1H, d, J = 2.8 Hz), 7.97 (1H, d, J = 2.4 Hz)
    [1550] Example 250
    [1551] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (benzylamino) phenyl] ethyl] piperidine
    [1552] The title compound was obtained using the compound according to the method of Example 201.
    [1553] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.39 (3H, m), 1.55-1.80 (4H, m), 1.98-2.08 (2H, m), 2.46-2.54 (2H, m), 2.89 ( 2H, br d, J = 11.2 Hz), 3.49 (2H, s), 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), 7.24-7.42 (5H, m), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1554] Example 251
    [1555] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (N-benzyl-N-methylamino) phenyl] ethyl] piperidine
    [1556] The title compound was obtained using the compound according to the method of Example 201.
    [1557] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (3H, m), 1.47-1.65 (2H, m), 1.71-1.78 (2H, m), 1.98-2.08 (2H, m), 2.56 ( 3H, s), 2.75-2.81 (2H, m), 2.89 (2H, br d, J = 11.2 Hz), 3.49 (2H, s), 3.95 (3H, s), 4.00 (2H, s), 6.87 ( 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), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1558] Example 252
    [1559] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2-[(cyclohexylmethyl) amino] phenyl] ethyl] piperidine
    [1560] The title compound was obtained using the compound according to the method of Example 201.
    [1561] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.95-1.08 (2H, m), 1.12-1.42 (5H, m), 1.52-1.86 (11H, m), 2.00-2.12 (2H, m), 2.43- 2.49 (2H, m), 2.92 (2H, br d, J = 7.2 Hz), 2.98 (2H, d, J = 6.4 Hz), 3.50 (2H, s), 3.95 (3H, s), 6.60 (1H, dd, J = 1.2, 7.6 Hz), 6.65 (1H, dt, J = 7.6, 1.2 Hz), 6.87 (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), 7.65 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1562] Example 253
    [1563] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- [N- (cyclohexylmethyl) N-methylamino] phenyl] ethyl] piperidine
    [1564] The title compound was obtained using the compound according to the method of Example 201.
    [1565] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.81-0.93 (2H, m), 1.08-1.40 (6H, m), 1.44-1.60 (3H, m), 1.61-1.78 (6H, m), 1.79- 1.87 (2H, m), 1.99-2.08 (2H, m), 2.56 (3H, s), 2.65 (2H, d, J = 7.2 Hz), 2.68-2.74 (2H, m), 2.90 (2H, br d , J = 11.2 Hz), 3.49 (2H, s), 3.95 (3H, s), 6.87 (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), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1566] Example 254
    [1567] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-cyclohexylmethyloxy) phenyl] piperidine
    [1568] The title compound was obtained using the compound according to the method of Example 201.
    [1569] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.38 (5H, m), 1.60-1.90 (10H, m), 2.18-2.26 (2H, m), 2.97 (1H, m), 3.01-3.07 ( 2H, m), 3.56 (2H, s), 3.76 (2H, d, J = 6.0 Hz), 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), 7.71 (1H, dd, J = 7.2, 2.0 Hz), 8.07 (1H, dd, J = 7.2, 2.0 Hz)
    [1570] Example 255
    [1571] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-phenoxyphenyl) ethyl] piperidine oxalate
    [1572] According to the method of Example 201, a vitreous was obtained from the corresponding starting material, and the title compound was obtained as oxalate according to a conventional method.
    [1573] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.20-1.50 (3H, m), 1.40-1.55 (2H, m), 1.75 (2H, br d, J = 12.8 Hz), 2.56 (2H, t , J = 8.0 Hz), 2.60-2.80 (2H, m), 3.18 (2H, br d, J = 11.2 Hz), 3.90 (3H, s), 4.04 (2H, s), 6.89 (3H, d, J = 8.4 Hz), 7.04-7.18 (3H, m), 7.23 (1H, dt, J = 1.4, 7.6 Hz), 7.35 (3H, d, J = 8.0 Hz), 7.81 (1H, dd, J = 7.6, 1.6 Hz), 8.22 (1H, dd, J = 5.2, 1.6 Hz)
    [1574] Example 256
    [1575] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methylphenyl) ethyl] piperidine
    [1576] 473 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine is dissolved in 10 ml of ethanol, 100 mg of 10% palladium-carbon powder (water) was added thereto, and the mixture was stirred for 1 hour and 30 minutes at atmospheric pressure under hydrogen atmosphere. The reaction solution was filtered and the filtrate was removed under reduced pressure to give 465 mg of the title compound as a colorless oil.
    [1577] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.42 (2H, m), 1.47-1.55 (2H, m), 1.66-1.84 (3H, m), 2.06 (2H, m), 2.29 (3H, s), 2.56-2.64 (2H, m), 2.92 (2H, br d, J = 11.2 Hz), 3.50 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 8.8, 4.2 Hz), 7.06-7.16 (4H, m), 7.66 (1H, dd, J = 8.8, 2.0 Hz), 8.06 (1H, dd, J = 4.2, 2.0 Hz)
    [1578] Example 257
    [1579] 1-[(2-methoxy-3-pyridyl) methyl] -4- [4- [2,3- (methylenedioxy) phenyl] butyl] piperidine
    [1580] The title compound was obtained using the compound according to the method of Example 256.
    [1581] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.16-1.39 (6H, m), 1.55-1.68 (4H, m), 1.72 (1H, m), 2.00 (2H, t, J = 11.2 Hz), 2.57 (2H, t, J = 8.0 Hz), 2.88 (2H, br d, J = 11.2 Hz), 3.48 (2H, s), 3.94 (3H, s), 5.92 (2H, s), 6.65 (1H, dd , J = 8.0, 2.0 Hz), 6.68 (1H, dd, J = 8.0, 2.0 Hz), 6.75 (1H, d, J = 8.0 Hz), 6.86 (1H, dd, J = 7.2, 4.8 Hz), 7.64 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1582] Example 258
    [1583] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (trifluoro methoxy) phenyl] ethyl] piperidine
    [1584] The title compound was obtained using the compound according to the method of Example 256.
    [1585] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.45 (3H, m), 1.48-1.60 (2H, m), 1.73 (2H, br d, J = 9.6 Hz), 2.04 (2H, br d, J = 10.8 Hz), 2.66 (2H, t, J = 8.4 Hz), 2.91 (2H, br d, J = 11.2 Hz), 3.50 (2H, s), 3.94 (3H, s), 6.87 (1H, dd , J = 7.2, 5.2 Hz), 7.14-7.32 (3H, m), 7.66 (1H, dd, J = 7.2, 1.2 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1586] Example 259
    [1587] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (cyclopentyloxy) phenyl] ethyl] piperidine
    [1588] The title compound was obtained using the compound according to the method of Example 256.
    [1589] 1 H-NMR (400 MHz, CDCl 3 ) δ1.22-1.38 (3H, m), 1.46-1.54 (2H, m), 1.55-1.94 (10H, m), 1.98-2.10 (2H, m), 2.54- 2.62 (2H, m), 2.90 (2H, br d, J = 11.2 Hz), 3.50 (2H, s), 3.95 (3H, s), 4.77 (1H, m), 6.78-6.90 (3H, m), 7.08-7.16 (2H, m), 7.06 (1H, broad, J = 6.8 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1590] Example 260
    [1591] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (cyclopentyloxy) phenyl] ethyl] piperidine
    [1592] The title compound was obtained using the compound according to the method of Example 256.
    [1593] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.52-1.95 (12H, m), 1.96-2.08 (2H, m), 2.54-2.62 (2H, m), 2.90 ( 2H, br d, J = 11.2 Hz), 3.49 (2H, s), 3.94 (3H, s), 4.75 (1H, m), 6.66-6.76 (3H, m), 6.84 (1H, dd, J = 7.2 , 4.8 Hz), 7.16 (1 H, m), 7.66 (1 H, br d, J = 6.8 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1594] Example 261
    [1595] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (3-pyridyl) phenyl] ethyl] piperidine
    [1596] 0.3 g of 1-[(2-methoxy-3-pyridinyl) methyl] -4-[(E) -2- (3-bromophenyl) -1-ethenyl] piperidine and 3-pyridineboronic acid 0.3 g was dissolved in 50 ml of methanol, 0.3 ml of an aqueous sodium carbonate solution and 0.1 g of tetrakis (triphenylphosphine) palladium were added, and the mixture was heated to reflux for 3 hours under a nitrogen stream. The reaction liquid was returned to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.3 g of a yellow oil. The oil was obtained according to the method of Example 256 to yield 0.3 g of the title compound as a yellow oil.
    [1597] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.44 (3H, m), 1.44-1.80 (2H, m), 1.60-1.84 (2H, m), 1.96-2.10 (2H, m), 2.64- 2.74 (2H, m), 2.86-2.96 (2H, m), 3.49 (2H, s) 3.94 (3H, s), 6.84-6.90 (1H, m), 7.18-7.30 (1H, m), 7.32-7.44 (4H, m), 7.65 (1H, d, J = 6.8 Hz), 7.87 (1H, d, J = 7.6 Hz), 8.05 (1H, d, J = 5.2 Hz), 8.58 (1H, d, J = 4.4 Hz), 8.84 (1H, d, J = 2.0 Hz)
    [1598] Example 262
    [1599] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3-[(tetrahydropyran-2-yl) methyloxy] phenyl] ethyl] piperidine
    [1600] The title compound was obtained using the compound according to the method of Example 256.
    [1601] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.10-2.00 (15H, 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), 3.96 (3H, s), 6.70-6.80 (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)
    [1602] Example 263
    [1603] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2-[(tetrahydropyran-2-yl) methyloxy] phenyl] ethyl] piperidine
    [1604] The title compound was obtained using the compound according to the method of Example 256.
    [1605] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.40 (3H, m), 1.40-2.00 (10H, m), 1.97-2.10 (2H, m), 2.57-2.68 (2H, m), 2.90 ( 2H, br d, J = 11.2 Hz), 3.49 (2H, s) 3.45-3.55 (1H, m), 3.65-3.75 (1H, m), 3.80-3.90 (1H, m), 3.95 (3H, s) , 3.93-4.10 (2H, m), 6.78-6.92 (3H, m), 7.08-7.18 (2H, m), 7.66 (1H, dd, J = 7.6, 2.0 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1606] Example 264:
    [1607] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3-[(benzyloxy) phenyl] ethyl] piperidine
    [1608] The title compound was obtained using the compound according to the method of Example 256.
    [1609] 1 H-NMR (400 MHz, CDCl 3 ) δ1.22-1.38 (3H, m), 1.52-1.76 (4H, m), 1.96-2.08 (2H, m), 2.56-2.64 (2H, m), 2.85- 2.94 (2H, m), 3.49 (2H, s), 3.95 (3H, s), 5.05 (2H, s), 6.76-6.83 (3H, m), 6.87 (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, br d, J = 6.8 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1610] Example 265
    [1611] 1-[(2-methoxy-3-pyridyl) methyl] -4-[[2- (2-phenylethyl) phenyl] ethyl] piperidine
    [1612] The title compound was obtained using the compound according to the method of Example 256.
    [1613] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.40 (3H, m), 1.48-1.56 (2H, m), 1.70-1.78 (2H, m), 2.00-2.10 (2H, m), 2.58- 2.64 (2H, m), 2.84-2.94 (6H, m), 3.50 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 7.2, 5.2 Hz), 7.11-7.33 (9H, m), 7.66 (1H, broad doublet, J = 7.2 Hz), 8.05 (1H, doublet, J = 4.8, 1.6 Hz)
    [1614] Example 266
    [1615] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1616] The title compound was obtained using the compound according to the method of Example 256.
    [1617] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.40 (8H, m), 1.49-1.58 (2H, m), 1.65-1.90 (8H, m), 1.99-2.10 (2H, m), 2.58- 2.66 (2H, m), 2.86-2.95 (2H, m), 3.50 (2H, s), 3.74 (2H, d, J = 6.0 Hz), 3.95 (3H, s), 6.78-6.90 (3H, m) , 7.08-7.16 (2H, m), 7.66 (1H, broad doublet, J = 7.6 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1618] Example 267
    [1619] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine
    [1620] The title compound was obtained using the compound according to the method of Example 256.
    [1621] 1 H-NMR (400 MHz, CDCl 3 ) δ1.04 (6H, d, J = 6.8 Hz), 1.26-1.38 (3H, m), 1.50-1.58 (2H, m), 1.70-1.78 (2H, m) , 1.99-2.15 (3H, m), 2.60-2.67 (2H, m), 2.86-2.94 (2H, m), 3.49 (2H, s), 3.72 (2H, d, J = 6.4 Hz), 3.95 (3H , s), 6.80 (1H, d, J = 8.0 Hz), 6.82-6.90 (2H, m), 7.08-7.16 (2H, m), 7.66 (1H, br dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1622] Example 268
    [1623] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [3- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1624] The title compound was obtained using the compound according to the method of Example 256.
    [1625] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.98-1.11 (2H, m), 1.14-1.38 (6H, m), 1.52-1.60 (2H, m), 1.62-1.91 (8H, m), 1.97- 2.08 (2H, m), 2.54-2.62 (2H, m), 2.85-2.93 (2H, m), 3.48 (2H, s), 3.73 (2H, d, J = 6.4 Hz), 3.94 (3H, s) , 6.68-6.76 (3H, m), 6.87 (1H, dd, J = 5.2, 7.6 Hz), 7.17 (1H, m), 7.65 (1H, br dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1626] Example 269
    [1627] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (2-methoxyethoxy) phenyl] ethyl] piperidine
    [1628] The title compound was obtained using the compound according to the method of Example 256.
    [1629] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.45-1.70 (5H, m), 1.60-1.80 (2H, m), 1.95-2.10 (2H, m), 2.64 (2H, t, J = 8.0 Hz) , 2.90 (2H, br d, J = 10.4 Hz), 3.45 (3H, t), 3.48 (2H, s), 3.64-3.80 (2H, m), 3.95 (3H, s), 4.11 (2H, t, J = 4.8 Hz), 6.80-6.92 (2H, m), 7.10-7.18 (1H, m), 7.42-7.74 (3H, m), 8.02-8.08 (1H, m)
    [1630] Example 270
    [1631] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (2-phenylethoxy) phenyl] ethyl] piperidine
    [1632] The title compound was obtained using the compound according to the method of Example 256.
    [1633] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.36 (3H, m), 1.43-1.51 (2H, m), 1.62-1.75 (2H, m), 1.99-2.08 (2H, m), 2.54- 2.26 (2H, m), 2.86-2.94 (2H, m), 3.10 (2H, t, J = 6.8 Hz), 3.50 (2H, s), 3.95 (3H, s), 4.17 (2H, t, J = 6.8 Hz), 6.78-6.90 (3H, m), 7.07-7.16 (2H, m), 7.19-7.36 (5H, m), 7.67 (1H, br d, J = 7.2 Hz), 8.06 (1H, dd, J = 5.2, 2.0 Hz)
    [1634] Example 271
    [1635] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (phenoxymethyl) phenyl] ethyl] piperidine
    [1636] The title compound was obtained using the compound according to the method of Example 256.
    [1637] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.39 (3H, m), 1.54-1.78 (4H, m), 1.96-2.08 (2H, m), 2.65-2.73 (2H, m), 2.84- 2.93 (2H, m), 3.48 (2H, s), 3.94 (3H, s), 5.04 (2H, s), 6.87 (1H, dd, J = 7.6, 5.2 Hz), 6.95-7.01 (2H, m) , 7.18-7.34 (6H, m), 7.42 (1H, d, J = 7.6 Hz), 7.64 (1H, br d, J = 6.4 Hz), 8.05 (1H, dd, J = 4.8, 2.0 Hz)
    [1638] Example 272
    [1639] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- [2- (cyclopentylmethyloxy) phenyl] ethyl] piperidine
    [1640] The title compound was obtained using the compound according to the method of Example 256.
    [1641] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.45 (5H, m), 1.49-1.88 (10H, m), 1.98-2.10 (2H, m), 2.37 (1H, septet, J = 7.4 Hz) , 2.58-2.66 (2H, m), 2.86-2.96 (2H, m), 3.50 (2H, s), 3.82 (2H, d, J = 6.8 Hz), 3.95 (3H, s), 6.78-6.90 (3H , m), 7.09-7.17 (2H, m), 7.66 (1H, dd, J = 7.2, 2.0 Hz), 8.05 (1H, dd, J = 5.2, 2.0 Hz)
    [1642] Example 273
    [1643] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2-[(2-cyclohexylethyl) phenyl] ethyl] piperidine
    [1644] The title compound was obtained using the compound according to the method of Example 256.
    [1645] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.99-1.01 (2H, m), 1.10-1.56 (10H, m), 1.62-1.83 (8H, m), 2.02-2.11 (2H, m), 2.56- 2.63 (4H, m), 2.89-2.96 (2H, m), 3.51 (2H, s), 3.95 (3H, s), 6.87 (1H, dd, J = 6.8, 4.8 Hz), 7.08-7.16 (4H, m), 7.66 (1H, dd, J = 7.2, 2.0 Hz), 8.06 (1H, dd, J = 4.8, 2.0 Hz)
    [1646] Example 274
    [1647] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2,5-dimethylphenyl) ethyl] piperidine oxalate
    [1648] The title compound was obtained using the compound according to the method of Example 256.
    [1649] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.55 (5H, m), 1.80-1.90 (2H, m), 2.19 (3H, s), 2.22 (3H, s), 2.45-2.55 ( 2H, m), 2.65-2.85 (2H, m), 3.15-3.25 (2H, m), 3.91 (3H, s), 4.04 (2H, s), 6.87 (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), 7.80-7.85 (1H, m), 8.20-8.25 (1H, m)
    [1650] Example 275
    [1651] 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (3,5-dimethylphenyl) ethyl] piperidine oxalate
    [1652] The title compound was obtained using the compound according to the method of Example 274.
    [1653] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.55 (5H, m), 1.84 (2H, br d, J = 12.8 Hz), 2.22 (3H, s), 2.50 (3H, s), 2.45-2.55 (2H, m), 2.75-2.90 (2H, m), 3.26 (2H, br d, J = 10.8 Hz), 3.92 (3H, s), 4.12 (2H, s), 6.69 (3H, s ), 7.08 (1H, dd, J = 7.6, 5.2 Hz), 7.82-7.86 (1H, m), 8.25 (1H, dd, J = 5.2, 2.0 Hz)
    [1654] Example 276
    [1655] Oxalate of 1-[(2-methoxy-3-pyridyl) methyl] -4- [2- (2-methoxy-5-methylphenyl) ethyl] piperidine
    [1656] The title compound was obtained using the compound according to the method of Example 274.
    [1657] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.55 (5H, m), 1.87 (2H, br d, J = 11.2 Hz), 2.20 (3H, s), 2.40-2.60 (2H, m ), 2.80-3.00 (2H, m), 3.25-3.35 (2H, m), 3.72 (3H, s), 3.93 (3H, s), 4.10-4.20 (2H, m), 6.81 (1H, d, J = 8.4 Hz), 6.90-7.00 (2H, m), 7.10 (1H, dd, J = 7.6, 5.6 Hz), 7.85 (1H, d, J = 7.6 Hz), 8.24-8.30 (1H, m)
    [1658] Example 277
    [1659] 1-[[5- (3-pyridyl) -2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1660] The title compound was obtained using the compound according to the method of Example 206.
    [1661] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.41 (3H, m), 1.54-1.62 (2H, m), 1.70-1.80 (2H, m), 2.07 (2H, br t, J = 10.4 Hz ), 2.56-2.64 (2H, m), 2.93 (2H, br d, J = 11.2 Hz), 3.15 (2H, s), 4.00 (3H, s), 5.92 (2H, s), 6.66 (1H, dd) , J = 7.6, 1.6 Hz), 6.68 (1H, dd, J = 7.6, 1.6 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.38 (1H, ddd, J = 8.0, 4.8, 1.2 Hz) , 7.85 (1H, ddd, J = 8.0, 2.4, 1.6 Hz), 7.92 (1H, br s), 8.27 (1H, d, J = 2.4 Hz), 8.59 (1H, dd, J = 4.8, 1.6 Hz) , 8.82 (1H, doublet of doublets, J = 2.4, 1.2 Hz)
    [1662] Example 278
    [1663] 1-[[5- (4-pyridyl) -2-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1664] The title compound was obtained using the compound according to the method of Example 206.
    [1665] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.41 (3H, m), 1.55-1.63 (2H, m), 1.68-1.82 (2H, m), 2.07 (2H, br t, J = 11.2 Hz ), 2.56-2.64 (2H, m), 2.92 (2H, br d, J = 11.2 Hz), 3.54 (2H, s), 4.01 (3H, s), 5.92 (2H, s), 6.66 (1H, dd) , J = 8.0, 1.2 Hz), 6.68 (1H, dd, J = 8.0, 1.2 Hz), 6.75 (1H, t, J = 8.0 Hz), 7.46-7.52 (2H, m), 7.97 (1H, br s ), 8.35 (1H, d, J = 2.4 Hz), 8.63-8.69 (2H, m)
    [1666] Example 279
    [1667] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4- [2- (2-fluorophenyl) ethyl] piperidine
    [1668] The title compound was obtained using the compound according to the method of Example 206.
    [1669] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.40 (3H, m), 1.50-1.65 (2H, m), 1.70-1.80 (2H, m), 2.04 (2H, br t, J = 10.8 Hz ), 2.66 (2H, d, J = 7.6 Hz), 2.87 (2H, br d, J = 11.6 Hz), 3.43 (2H, s), 3.92 (3H, s), 6.96-7.08 (2H, m), 7.12-7.22 (2H, m), 7.66 (1H, d, J = 2.8 Hz), 7.97 (1H, d, J = 2.8 Hz)
    [1670] Example 280
    [1671] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1672] The title compound was obtained using the compound according to the method of Example 206.
    [1673] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.40 (7H, m), 1.49-1.60 (2H, m), 1.62-1.91 (9H, m), 1.99-2.11 (2H, m), 2.58- 2.66 (2H, m), 2.83-2.92 (2H, m), 3.44 (2H, s), 3.75 (2H, d, J = 6.0 Hz), 3.92 (3H, s), 6.80 (1H, d, J = 8.0 Hz), 6.85 (1H, dt, J = 7.2, 1.2 Hz), 7.09-7.20 (2H, m), 7.67 (1H, d, J = 2.4 Hz), 7.97 (1H, d, J = 2.4 Hz)
    [1674] Example 281
    [1675] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine
    [1676] The title compound was obtained using the compound according to the method of Example 206.
    [1677] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05 (6H, d, J = 6.8 Hz), 1.24-1.40 (3H, m), 1.51-1.59 (2H, m), 1.72-1.80 (2H, m) , 2.00-2.19 (3H, m), 2.61-2.68 (2H, m), 2.84-2.92 (2H, m), 3.44 (2H, s), 3.72 (2H, d, J = 6.4 Hz), 3.92 (3H , s), 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)
    [1678] Example 282
    [1679] 1-[(5-chloro-2-methoxy-3-pyridyl) methyl] -4-[[2- (2-phenylethyl) phenyl] ethyl] piperidine
    [1680] The title compound was obtained using the compound according to the method of Example 206.
    [1681] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.42 (3H, m), 1.39-1.56 (2H, m), 1.70-1.80 (2H, m), 2.02-2.11 (2H, m), 2.58- 2.65 (2H, m), 2.84-2.95 (6H, m), 3.44 (2H, s), 3.92 (3H, s), 7.12-7.34 (9H, m), 7.66 (1H, d, J = 2.4 Hz) , 7.98 (1H, d, J = 2.4 Hz)
    [1682] Example 283
    [1683] 1-[(5- (methylsulfonyl) -2-methoxy-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1684] The title compound was obtained using the compound according to the method of Example 206.
    [1685] 1 H-NMR (400 MHz, CDCl 3 ) δ1.04-1.40 (8H, m), 1.51-1.58 (2H, m), 1.64-1.90 (8H, m), 2.04-2.12 (2H, m), 2.60- 2.68 (2H, m), 2.82-2.91 (2H, m), 3.08 (3H, s), 3.49 (2H, s), 3.75 (2H, d, J = 6.0 Hz), 4.04 (3H, s), 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), 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)
    [1686] Example 284
    [1687] 1-[(4-methoxy-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1688] The title compound was obtained using the compound according to the method of Example 201.
    [1689] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20-1.39 (3H, m), 1.52-1.62 (2H, m), 1.66-1.76 (2H, m), 2.00 (2H, br t, J = 11.2 Hz ), 2.54-2.64 (2H, m), 2.92 (2H, br d, J = 12.0 Hz), 3.53 (2H, s), 3.86 (3H, s), 5.92 (2H, s), 6.65 (1H, dd) , J = 7.6, 1.2 Hz), 6.67 (1H, dd, J = 7.6, 1.2 Hz), 6.75 (1H, t, J = 7.6 Hz), 6.77 (1H, d, J = 5.6 Hz), 8.40 (1H , d, J = 5.6 Hz), 8.41 (1H, s)
    [1690] Example 285
    [1691] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methylphenyl) ethyl] piperidine
    [1692] 465 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4- [2- (2-methylphenyl) ethyl] piperidine was dissolved in 10 ml of ethanol, and 4 N-hydrogen chloride-methanol solution 1.75 ml was added and heated to reflux for 3 hours. The solvent was removed under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with chloroform. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 344 mg of the title compound as white needle crystals.
    [1693] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.42 (3H, m), 1.47-1.56 (2H, m), 1.72-1.83 (2H, br d, J = 9.2 Hz), 2.10 (2H, br t, J = 10.4 Hz), 2.30 (3H, s), 2.56-2.64 (2H, m), 2.95 (2H, br d, J = 11.2 Hz), 3.48 (2H, s), 6.33 (1H, t, J = 6.4 Hz), 7.06-7.18 (4H, m), 7.37 (1H, br d, J = 5.2 Hz), 7.57 (1H, br d, J = 6.0 Hz)
    [1694] Example 286
    [1695] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [4- [2,3- (methylenedioxy) phenyl] butyl] piperidine
    [1696] The title compound was obtained using the compound according to the method of Example 285.
    [1697] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.40 (7H, m), 1.55-1.70 (4H, m), 2.06 (2H, t, J = 10.4 Hz), 2.57 (2H, t, J = 7.6 Hz), 2.92 (2H, br d, J = 11.2 Hz), 3.47 (2H, s), 5.93 (2H, s), 6.34 (1H, t, J = 6.8 Hz), 6.66 (1H, dd, J = 8.0, 2.0 Hz), 6.80 (1H, dd, J = 8.0, 2.0 Hz), 6.75 (1H, t, J = 8.0 Hz), 7.38 (1H, m), 7.53 (1H, br d, J = 6.8 Hz)
    [1698] Example 287
    [1699] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [3- [2,3- (methylenedioxy) phenyl] propyl] piperidine
    [1700] The title compound was obtained using the compound according to the method of Example 285.
    [1701] 1 H-NMR (400 MHz, CDCl 3 ) δ1.22-1.35 (4H, m), 1.48-1.53 (5H, m), 2.08 (2H, brt, J = 10.4 Hz), 2.56 (2H, t, J = 8.0 Hz), 2.92 (2H, br d, J = 11.2 Hz), 3.48 (2H, s), 5.92 (2H, s), 6.34 (1H, t, J = 6.8 Hz), 6.66 (1H, dd, J = 7.6,1.2 Hz), 6.68 (1H, dd, J = 7.6,1.2 Hz), 6.75 (1H, t, J = 7.2 Hz), 7.37 (1H, m), 7.54 (1H, br d, J = 6.4 Hz)
    [1702] Example 288
    [1703] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [5- [2,3- (methylenedioxy) phenyl] pentyl] piperidine
    [1704] The title compound was obtained using the compound according to the method of Example 285.
    [1705] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.16-1.36 (8H, m), 1.56-1.90 (5H, m), 2.07 (2H, brt, J = 10.0 Hz), 2.57 (2H, t, J = 7.6 Hz), 2.92 (2H, br d, J = 10.8 Hz), 3.48 (2H, s), 3.93 (3H, s), 5.92 (2H, s), 6.66 (1H, dd, J = 7.6, 1.2 Hz), 6.68 (1H, dd, J = 7.6, 1.2 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.38 (1H, m), 7.54 (1H, br d, J = 6.0 Hz)
    [1706] Example 289
    [1707] 1-[(6-methyl-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1708] The title compound was obtained using the compound according to the method of Example 285.
    [1709] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.38 (3H, m), 1.53-1.60 (2H, m), 1.68-1.77 (2H, m), 2.06 (2H, m), 2.31 (3H, s), 2.55-2.62 (2H, m), 2.93 (2H, br d, J = 11.6 Hz), 3.45 (2H s), 5.92 (2H, s), 6.07 (1H, br d, J = 6.8 Hz) , 6.66 (1H, dd, J = 7.6, 1.6 Hz), 6.68 (1H, dd, J = 7.6, 1.6 Hz), 6.75 (1H, t, J = 7.6 Hz), 7.41 (1H, br d, J = 6.8 Hz)
    [1710] Example 290
    [1711] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2,2-diphenylethyl) piperidine
    [1712] The title compound was obtained using the compound according to the method of Example 285.
    [1713] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.20 (1H, m), 1.30-1.42 (2H, m), 1.69-1.76 (2H, m), 1.94-2.04 (4H, m), 2.88 (2H, br d, J = 11.6 Hz), 3.43 (2H, s), 4.04 (1H, t, J = 8.0 Hz), 6.31 (1H, t, J = 6.4 Hz), 7.14-7.19 (2H, m), 7.21 -7.30 (8H, m), 7.34 (1H, broad, J = 5.2 Hz), 7.54 (1H, broad, J = 6.4 Hz)
    [1714] Example 291
    [1715] 1-[(5-bromo-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1716] The title compound was obtained using the compound according to the method of Example 285.
    [1717] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.56-1.64 (2H, m), 1.76-1.86 (2H, m), 2.09-2.20 (2H, m), 2.56- 2.64 (2H, m), 2.95 (2H, br d, J = 11.6 Hz), 3.57 (2H, s), 5.93 (2H, s), 6.65 (1H, dd, J = 7.6, 1.2 Hz), 6.68 ( 1H, dd, J = 7.6, 1.2 Hz), 6.76 (1H, t, J = 7.6 Hz), 7.48 (1H, br s), 7.94 (1H, br s)
    [1718] Example 292
    [1719] 1-[(5-methyl-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1720] The title compound was obtained using the compound according to the method of Example 285.
    [1721] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.41 (3H, m), 1.54-1.62 (2H, m), 1.72-1.80 (2H, m), 2.08 (2H, br t, J = 11.2 Hz ), 2.11 (3H, s), 2.56-2.64 (2H, m), 2.94 (2H, br d, J = 11.2 Hz), 3.46 (2H, s), 5.92 (2H, s), 6.66 (1H, dd) , J = 8.0, 1.6 Hz), 6.68 (1H, dd, J = 8.0, 1.6 Hz), 6.76 (1H, t, J = 8.0 Hz), 7.17 (1H, br s), 7.39 (1H, br s)
    [1722] Example 293
    [1723] 1-[(5-phenyl-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [1724] The title compound was obtained using the compound according to the method of Example 285.
    [1725] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.25-1.44 (3H, m), 1.54-1.63 (2H, m), 1.74-1.82 (2H, m), 2.14 (2H, br t, J = 10.8 Hz ), 2.56-2.64 (2H, m), 3.00 (2H, br d, J = 11.2 Hz), 3.58 (2H, s), 5.92 (2H, s), 6.65 (1H, dd, J = 8.0,1.2 Hz ), 6.68 (1H, dd, J = 8.0,1.2 Hz), 6.75 (1H, t, J = 8.0 Hz), 7.33 (1H, m), 7.40-7.50 (5H, m), 7.70 (1H, br s ), 7.87 (1H, broad singlet)
    [1726] Example 294
    [1727] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-piperidino-2-oxoethoxy) phenyl] ethyl] piperidine
    [1728] The title compound was obtained using the compound according to the method of Example 285.
    [1729] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.40 (2H, m), 1.46-1.81 (11H, m), 2.02-2.14 (2H, m), 2.62-2.68 (2H, m), 2.90- 2.99 (2H, m), 3.43-3.60 (6H, m), 4.68 (2H, s), 6.35 (1H, m), 6.83-6.95 (2H, m), 7.11-7.20 (2H, m), 7.38 ( 1H, m), 7.58 (1H, m)
    [1730] Example 295
    [1731] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[2- (4-pyridyloxy) phenyl] ethyl] piperidine
    [1732] The title compound was obtained using the compound according to the method of Example 285.
    [1733] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.32 (3H, m), 1.46-1.54 (2H, m), 1.58-1.68 (2H, m), 2.02 (2H, br d, J = 10.4 Hz ), 2.48-2.56 (2H, m), 2.88 (2H, br d, J = 11.2 Hz), 3.44 (2H, s), 6.32 (1H, t, J = 6.4 Hz), 6.74-6.80 (2H, m ), 7.00 (1H, dd, J = 1.2, 8.0 Hz), 7.18-7.32 (3H, m), 7.35 (1H, br d, J = 6.0 Hz), 7.52 (1H, br d, J = 6.0 Hz) , 8.42-8.46 (2H, m)
    [1734] Example 296
    [1735] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- [1- (dimethylcarbamoyl) cyclopentyloxy] phenyl] ethyl] piperidine
    [1736] The title compound was obtained using the compound according to the method of Example 285.
    [1737] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.43 (3H, m), 1.47-1.56 (2H, m), 1.70-1.82 (6H, m), 2.06-2.21 (4H, m), 2.38- 2.50 (2H, m), 2.57-2.64 (2H, m), 2.93 (3H, s), 2.96 (2H, br d, J = 11.2 Hz), 3.09 (3H, s), 3.50 (2H, s), 6.34 (1H, t, J = 6.4 Hz), 6.68 (1H, dd, J = 8.4, 1.2 Hz), 6.86 (1H, dd, J = 7.6, 1.2 Hz), 7.04 (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, broad, J = 5.6 Hz)
    [1738] Example 297
    [1739] 1-[[5- (3-pyridyl) -2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl ] Piperidine
    [1740] The title compound was obtained using the compound according to the method of Example 285.
    [1741] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.28-1.43 (3H, m), 1.56-1.64 (2H, m), 1.74-1.83 (2H, m), 2.14 (2H, br t, J = 10.8 Hz ), 2.56-2.64 (2H, m), 2.88 (2H, br d, J = 10.8 Hz), 3.58 (2H, s), 5.93 (2H, s), 6.66 (1H, dd, J = 7.6, 1.6 Hz ), 6.69 (1H, dd, J = 7.6, 1.6 Hz), 6.76 (1H, t, J = 7.6 Hz), 7.37 (1H, ddd, J = 8.0, 5.2, 0.8 Hz), 7.74 (1H, br s ), 7.78 (1H, ddd, J = 8.0, 2.4, 1.6 Hz), 8.84 (1H, br s), 8.58 (1H, dd, J = 5.2, 1.6 Hz), 8.76 (1H, dd, J = 2.4, 0.8 Hz)
    [1742] Example 298
    [1743] 1-[[5- (4-pyridyl) -2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl ] Piperidine
    [1744] The title compound was obtained using the compound according to the method of Example 285.
    [1745] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.30-1.44 (3H, m), 1.56-1.64 (2H, m), 1.75-1.84 (2H, m), 2.15 (2H, br t, J = 10.0 Hz ), 2.57-2.64 (2H, m), 2.99 (2H, br d, J = 11.2 Hz), 3.58 (2H, s), 5.93 (2H, s), 6.66 (1H, dd, J = 7.6, 1.2 Hz ), 6.69 (1H, dd, J = 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)
    [1746] Example 299
    [1747] 1- [5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (benzyloxy) phenyl] ethyl] piperidine
    [1748] The title compound was obtained using the compound according to the method of Example 285.
    [1749] 1 H-NMR (400 MHz, CDCl 3 ) δ1.23-1.39 (3H, m), 1.53-1.62 (2H, m), 1.72-1.80 (2H, m), 2.09 (2H, br t, J = 10.8 Hz ), 2.65-2.72 (2H, m), 2.88 (2H, br d, J = 11.6 Hz), 3.51 (2H, s), 5.08 (2H, s), 6.88-6.93 (2H, m), 7.13-7.20 (2H, m), 7.29-7.46 (6H, m), 7.77 (1H, br s)
    [1750] Example 300
    [1751] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [3- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1752] The title compound was obtained using the compound according to the method of Example 285.
    [1753] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.98-1.11 (2H, m), 1.14-1.42 (6H, m), 1.53-1.62 (2H, m), 1.65-1.92 (8H, m), 2.05- 2.16 (2H, m), 2.55-2.63 (2H, m), 2.90-2.99 (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), 7.36 (1H, br d, J = 6.0 Hz), 7.58 (1H, br d, J = 6.4 Hz)
    [1754] Example 301
    [1755] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine
    [1756] The title compound was obtained using the compound according to the method of Example 285.
    [1757] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.43 (9H, m), 1.52-1.60 (2H, m), 1.66-1.90 (7H, m), 2.10-2.20 (2H, m), 2.59- 2.66 (2H, m), 2.94 (2H, br d, J = 10.4 Hz), 3.56 (2H, s), 3.75 (2H, d, J = 5.6 Hz), 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, 1.6 Hz), 7.14 (1H, dt, J = 8.0, 1.6 Hz), 7.35 (1H, d, J = 2.4 Hz), 7.87 (1H, broad singlet)
    [1758] Example 302
    [1759] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine oxalate
    [1760] 226 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine was dissolved in 4 ml of ethanol and 4N 1 ml of hydrogen chloride-methanol solution was added and heated to reflux for 1 hour 30 minutes. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The resulting oil was dissolved in ethanol, 49 mg of oxalic acid and ethyl acetate were added, and the precipitate was filtered to give 229 mg of the title compound as a white powder.
    [1761] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.05-1.35 (6H, m), 1.35-1.55 (4H, m), 1.62-1.90 (8H, m), 2.56 (2H, m), 2.88 ( 2H, m), 3.23-3.36 (2H, m), 3.77 (2H, d, J = 5.6 Hz), 4.00 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.83 (1H, t , J = 7.2 Hz), 6.89 (1H, d, J = 8.0 Hz), 7.09-7.17 (2H, m), 7.52 (1H, br d, J = 6.4 Hz), 7.68 (1H, br d, J = 6.0 Hz)
    [1762] Example 303
    [1763] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [3- (cyclopentyloxy) phenyl] ethyl] piperidine oxalate
    [1764] The title compound was obtained using the compound according to the method of Example 302.
    [1765] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.20-1.38 (3H, m), 1.44-1.80 (10H, m), 1.82-1.94 (2H, m), 2.48-2.58 (2H, m), 3.05 (2H, m), 3.49 (2H, br s), 3.64 (2H, br s), 4.78 (1H, br t, J = 6.0 Hz), 6.23 (1H, t, J = 6.8 Hz), 6.66- 6.75 (3H, m), 7.15 (1H, t, J = 7.6 Hz), 7.39 (1H, br d, J = 5.2 Hz), 7.53 (1H, br d, J = 5.2 Hz)
    [1766] Example 304
    [1767] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (benzyloxy) phenyl] ethyl] piperidine oxalate
    [1768] The title compound was obtained using the compound according to the method of Example 302.
    [1769] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.44 (5H, m), 1.76-1.86 (2H, m), 2.60 (2H, brt, J = 7.6 Hz), 2.83 (2H, m ), 3.24 (2H, br d, J = 8.8 Hz), 3.98 (2H, s), 5.11 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.87 (1H, t, J = 7.2 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.12-7.18 (2H, m), 7.29-7.37 (1H, m), 7.38-7.48 (5H, m), 7.52 (1H, dd, J = 6.4, 1.2 Hz), 7.67 (1H, dd, J = 6.4, 1.2 Hz)
    [1770] Example 305
    [1771] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [3- (benzyloxy) phenyl] ethyl] piperidine oxalate
    [1772] The title compound was obtained using the compound according to the method of Example 302.
    [1773] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.32-1.58 (5H, m), 1.76-1.88 (2H, m), 2.55 (2H, m), 2.84 (1H, m), 3.28 (2H, m), 3.56 (2H, m), 3.98 (2H, br s), 5.08 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.76-6.88 (3H, m), 7.19 (1H, t, J = 7.6 Hz), 7.24-7.46 (5H, m), 7.52 (1H, br d, J = 6.4 Hz), 7.67 (1H, br d, J = 6.4 Hz)
    [1774] Example 306
    [1775] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[2- (2-phenylethyl) phenyl] ethyl] piperidine oxalate
    [1776] The title compound was obtained using the compound according to the method of Example 302.
    [1777] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.34-1.58 (3H, m), 1.80-1.90 (2H, m), 2.57 (2H, brt, J = 8.0 Hz), 2.74-2.92 (6H , m), 3.26 (2H, m), 3.62 (2H, m), 3.94 (2H, br s), 6.29 (1H, d, J = 6.4 Hz), 7.08-7.33 (9H, m), 7.50 (1H) , br d, J = 2.4 Hz), 7.66 (1H, br d, J = 6.4 Hz)
    [1778] Example 307
    [1779] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (cyclopentyloxy) phenyl] ethyl] piperidine oxalate
    [1780] The title compound was obtained using the compound according to the method of Example 302.
    [1781] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.32-1.50 (5H, m), 1.55-1.76 (6H, m), 1.78-1.93 (4H, m), 2.54-2.62 (2H, m), 2.82 (2H, br s), 3.26 (2H m), 3.95 (2H, br s), 4.83 (1H, br t, J = 5.6 Hz), 6.28 (1H, t, J = 6.8 Hz), 6.81 (1H , t, J = 8.0 Hz), 6.90 (1H, d, J = 8.0 Hz), 7.08-7.16 (2H, m), 7.50 (1H, dd, J = 6.4,2.0 Hz), 7.66 (1H, br d , J = 6.4Hz)
    [1782] Example 308
    [1783] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine oxalate
    [1784] The title compound was obtained using the compound according to the method of Example 302.
    [1785] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.01 (6H, d, J = 6.4 Hz), 1.26-1.40 (3H, m), 1.42-1.51 (2H, m), 1.72-1.81 (2H, m), 2.03 (1H, m), 2.46 (2H, m), 2.53-2.60 (2H, m), 3.06 (2H, br d, J = 11.2 Hz), 3.64 (2H, br s), 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 (1H, d, J = 8.0 Hz), 7.09-7.16 (2H , m), 7.40 (1H, broad doublet, J = 6.4, 2.0 Hz), 7.54 (1H, d, J = 5.2 Hz)
    [1786] Example 309
    [1787] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (2-phenylethoxy) phenyl] ethyl] piperidine oxalate
    [1788] The title compound was obtained using the compound according to the method of Example 302.
    [1789] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.28-1.44 (5H, m), 1.72-1.81 (2H, m), 2.43-2.50 (2H, m), 2.86 (2H, m), 3.03 ( 2H, t, J = 6.4 Hz), 3.28 (2H, m), 4.00 (2H, br s), 4.18 (2H, t, J = 5.2 Hz), 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), 7.18-7.25 (1H, m), 7.28-7.36 (3H, m), 7.53 (1H, doublet of doublets, J = 6.0, 2.0 Hz), 7.68 (1H, high d, J = 5.6 Hz)
    [1790] Example 310
    [1791] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (phenoxymethyl) phenyl] ethyl] piperidine oxalate
    [1792] The title compound was obtained using the compound according to the method of Example 302.
    [1793] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.32-1.58 (5H, m), 1.78-1.86 (2H, m), 2.62-2.68 (2H, m), 2.85 (2H, m), 3.58 ( 2H, m), 3.98 (2H, br s), 5.08 (2H, s), 6.29 (1H, t, J = 6.8 Hz), 6.95 (1H, t, J = 7.2 Hz), 6.99-7.04 (2H, m), 7.18-7.24 (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, br d, J = 6.8 Hz)
    [1794] Example 311
    [1795] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (cyclopentylmethyloxy) phenyl] ethyl] piperidine oxalate
    [1796] The title compound was obtained using the compound according to the method of Example 302.
    [1797] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.28-1.67 (11H, m), 1.73-1.86 (4H, m), 2.31 (1H, septet, J = 7.3 Hz), 2.52-2.58 (2H, m), 2.67 (2H, m), 3.15-3.24 (2H, m), 3.83 (2H, d, J = 6.4 Hz), 3.84 (2H, br s), 6.26 (1H, t, J = 6.4 Hz) , 6.82 (1H, dt, J = 6.8, 1.2 Hz), 6.90 (1H, d, J = 8.0 Hz), 7.09-7.16 (2H, m), 7.46 (1H, dd, J = 6.4, 1.2 Hz), 7.61 (1H, broad doublet, J = 5.6 Hz)
    [1798] Example 312
    [1799] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-[(2-cyclohexylethyl) phenyl] ethyl] piperidine oxalate
    [1800] The title compound was obtained using the compound according to the method of Example 302.
    [1801] 1 H-NMR (400 MHz, DMSO-d 6 ) δ0.87-0.99 (2H, m), 1.10-1.79 (16H, m), 1.83-1.92 (2H, m), 2.51-2.60 (4H, m), 2.92 (2H, br s), 3.34 (2H, br s), 4.04 (2H, br s), 6.03 (1H, t, J = 6.8 Hz), 7.06-7.16 (4H, m), 7.54 (1H, dd , J = 6.8, 2.4 Hz), 7.69 (1H, br d, J = 10.0 Hz)
    [1802] Example 313
    [1803] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (benzylamino) phenyl] ethyl] piperidine dihydrochloride
    [1804] 294 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4- [2- [2- (benzylamino) phenyl] ethyl] piperidine is dissolved in 8 ml of ethanol and 4N-hydrogen chloride -3 ml of methanol solution was added and heated to reflux for 3 hours. After cooling, the precipitate was filtered and recrystallized from ethanol to give 273 mg of the title compound as a white powder.
    [1805] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.42-1.58 (4H, m), 1.61-1.76 (1H, m), 1.86-1.96 (2H, m), 2.51-2.60 (2H, m), 2.95 (2H, brt, J = 11.6 Hz), 3.28 (2H, br d, J = 12.4 Hz), 4.06 (2H, s), 4.36 (2H, s), 6.31 (1H, t, J = 6.4 Hz ), 6.53 (1H, m), 6.63 (1H, m), 6.94 (1H, brt J = 7.6 Hz), 7.00 (1H, br d, J = 7.2 Hz), 7.18-7.37 (5H, m), 7.54 (1H, dd, J = 6.4, 2.0 Hz), 7.79 (1H, dd, J = 6.8, 2.0 Hz)
    [1806] Example 314 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (N-benzyl-N-methylamino) phenyl] ethyl] piperi Dean oxalate
    [1807] The title compound was obtained using the compound according to the method of Example 302.
    [1808] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.36-1.61 (5H, m), 1.80-1.92 (2H, m), 2.51 (3H, s), 2.68-2.76 (2H, m), 2.87 ( 2H, m), 3.28 (2H, br d, J = 9.6 Hz), 3.98 (2H, s), 4.00 (2H, s), 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), 7.30-7.36 (4H, m), 7.52 (1H, dd, J = 6.4, 2.0 Hz ), 7.68 (1H, doublet of doublets, J = 6.8, 2.0 Hz)
    [1809] Example 315
    [1810] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2-[(cyclohexylmethyl) amino] phenyl] ethyl] piperidine dihydrochloride
    [1811] The title compound was obtained using the compound according to the method of Example 313.
    [1812] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.93-1.06 (2H, m), 1.10-1.26 (3H, m), 1.46-1.66 (5H, m), 1.66-1.81 (4H, m), 1.82- 1.96 (4H, m), 2.67 (2H, m), 2.90-3.04 (2H, m), 3.00 (2H, d, J = 6.4 Hz), 3.34-3.42 (2H, m), 4.06 (2H, s) , 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)
    [1813] Example 316
    [1814] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- [N- (cyclohexylmethyl) -N-methylamino] phenyl] ethyl] py Ferridine Oxalate
    [1815] The title compound was obtained using the compound according to the method of Example 302.
    [1816] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.03-1.34 (5H, m), 1.63-2.00 (10H, m), 3.04-3.18 (3H, m), 3.42 (2H, br d, J = 12.8 Hz), 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, br d, 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, doublet of doublets, J = 6.8, 2.0 Hz)
    [1817] Example 317
    [1818] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (cyclohexylmethyloxy) phenyl] piperidine oxalate
    [1819] The title compound was obtained using the compound according to the method of Example 302.
    [1820] 1 H-NMR (400 MHz, CDCl 3 ) δ 0.80-0.92 (2H, m), 1.08-1.23 (3H, m), 1.37-1.56 (6H, m), 1.57-1.70 (3H, m), 1.72- 1.81 (2H, m), 1.81-1.90 (2H, m), 2.51 (3H, s), 2.62 (2H, d, J = 7.2 Hz), 2.62-2.70 (2H, m), 2.92 (2H, m) , 3.26-3.38 (2H, m), 4.04 (2H, s), 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), 7.70 (1H, dd, J = 6.8, 2.0 Hz)
    [1821] Example 318
    [1822] 1-[(5- (methylsulfonyl) -2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] pi Ferridine
    [1823] 138 mg of 1-[(5- (methylsulfonyl) -2-methoxy-3-pyridinyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) phenyl] ethyl] piperidine It was dissolved in 10 ml, 1 ml of thionyl chloride was added and heated to reflux for 2 hours 30 minutes. An aqueous sodium carbonate solution was added to the reaction solution, and the precipitate was filtered to give 127 mg of the title compound as a white powder.
    [1824] 1 H-NMR (400 MHz, CDCl 3 ) δ1.05-1.45 (8H, m), 1.53-1.61 (2H, m), 1.67-1.90 (8H, m), 2.15-2.27 (2H, m), 2.60- 2.68 (2H, m), 2.92 (2H, br d, J = 10.8 Hz), 3.08 (3H, s), 3.60 (2H, s), 3.76 (2H, d, J = 6.0 Hz), 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), 7.15 (1H, dt, J = 8.0, 2.0 Hz), 7.83 (1H, broad doublet, J = 2.4 Hz), 8.35 (1H deep, brm)
    [1825] Example 319
    [1826] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- [2,3- (methylenedioxy) phenyl] ethyl] pi Ferridine
    [1827] The title compound was obtained according to the method of Example 318 using the compound.
    [1828] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.08-1.23 (3H, m), 1.42-1.50 (2H, m), 1.60-1.70 (2H, m), 1.88-2.00 (2H, m), 2.40-2.60 (2H, m), 2.73-2.83 (2H, m), 3.24 (2H, s), 5.95 (2H, s), 6.64-6.76 (3H, m), 7.34 (1H, s), 7.50 ( 1H, s)
    [1829] Example 320
    [1830] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (2-fluorophenyl) ethyl] piperidine
    [1831] The title compound was obtained according to the method of Example 318 using the compound.
    [1832] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.00-1.26 (3H, m), 1.40-1.54 (2H, m), 1.67 (2H, br d, J = 9.6 Hz), 1.94 (2H, br t, J = 10.4 Hz), 2.60 (2H, d, J = 7.6 Hz), 2.77 (2H, br d, 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), 7.50 (1H, d, J = 3.2 Hz)
    [1833] Example 321
    [1834] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (2-methoxyethoxy) phenyl] ethyl] piperidine
    [1835] The title compound was obtained according to the method of Example 318 using the compound.
    [1836] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.10-1.25 (3H, m), 1.40-1.50 (2H, m), 1.67 (2H, br d, J = 8.8 Hz), 1.95 (2H, br t, J = 10.8 Hz), 2.54 (2H, t, J = 8.0 Hz), 2.76 (2H, br d, J = 11.2 Hz), 3.24 (2H, s), 3.31 (3H, s), 3.65 (2H , t, J = 4.4 Hz), 4.05 (2H, t, J = 4.4 Hz), 6.83 (1H, t, J = 7.2 Hz), 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), 7.50 (1H, d, J = 2.8 Hz)
    [1837] Example 322 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2,5-dimethylphenyl) ethyl] piperidine
    [1838] The title compound was obtained according to the method of Example 318 using the compound.
    [1839] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.16-1.36 (3H, m), 1.32-1.46 (2H, m), 1.72 (2H, br d, J = 10.8 Hz), 2.03 (1H, br s), 2.19 (3H, s), 2.22 (3H, s), 2.51 (2H, t, J = 7.6 Hz), 2.85 (2H, br d, J = 10.4 Hz), 3.20-3.42 (2H, m) , 6.18 (1H, t, J = 6.4 Hz), 6.87 (1H, d, J = 7.6 Hz), 6.92 (1H, s), 6.99 (1H, d, J = 7.6 Hz), 7.28 (1H, d, J = 6.4 Hz), 7.41 (1H, d, J = 6.0 Hz)
    [1840] Example 323
    [1841] 1-[(5-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine oxalate
    [1842] Dissolve 443 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine in 10 ml of ethanol and And 0.5 ml of thionyl chloride were added, and it heated and refluxed for 3 hours. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The resulting oil was dissolved in ethanol, 99 mg of oxalic acid was added, and the precipitate was filtered to give 382 mg of the title compound as a white powder.
    [1843] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.01 (6H, d, J = 6.8 Hz), 1.24-1.42 (3H, m), 1.43-1.51 (2H, m), 1.73-1.82 (2H, m), 2.03 (1H, m), 2.45 (2H, m), 2.54-2.60 (2H, m), 3.08 (2H, br d, J = 11.6 Hz), 3.64 (2H, br s), 3.73 (2H , d, J = 6.4 Hz), 6.83 (1H, dt, J = 7.6, 1.2 Hz), 6.89 (1H, d, J = 7.6 Hz), 7.09-7.16 (2H, m), 7.58 (1H, d, J = 2.4 Hz), 7.65 (1H, d, J = 2.4 Hz)
    [1844] Example 324
    [1845] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (3,5-dimethylphenyl) ethyl] piperidine oxalate
    [1846] The title compound was obtained using the compound according to the method of Example 323.
    [1847] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.48 (5H, br s), 1.84 (2H, br d, J = 9.2 Hz), 2.22 (6H, s), 2.45-2.55 (2H, m) , 2.85-3.00 (2H, m), 3.25-3.40 (2H, m), 4.04 (2H, s), 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)
    [1848] Example 325
    [1849] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-methoxy-5-methylphenyl) ethyl] piperidine oxalate
    [1850] The title compound was obtained using the compound according to the method of Example 323.
    [1851] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.45 (5H, br s), 1.86 (2H, br d, J = 10.4 Hz), 2.20 (3H, s), 2.44-2.54 (2H, m) , 2.93 (2H, br s), 3.24-3.40 (2H, m), 3.73 (3H, s), 4.05 (2H, s), 6.30 (1H, t, J = 6.4 Hz), 6.82 (1H, d, J = 8.0 Hz), 6.94 (1H, s), 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)
    [1852] Example 326
    [1853] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (trifluoro methoxy) phenyl] ethyl] piperidine oxalate
    [1854] The title compound was obtained using the compound according to the method of Example 323.
    [1855] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.34-1.60 (5H, br s), 1.86 (2H, br d, J = 11.2 Hz), 2.64 (2H, t, J = 7.6 Hz), 2.94 (2H, br s), 3.24-3.44 (2H, m) 4.05 (2H, s), 6.30 (1H, t, J = 6.4 Hz), 7.28-7.40 (3H, m), 7.38-7.48 (1H, m ), 7.54 (1H, d, J = 6.4 Hz), 7.71 (1H, d, J = 5.6 Hz)
    [1856] Example 327
    [1857] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (3-pyridyl) phenyl] ethyl] piperidine oxalate
    [1858] The title compound was obtained using the compound according to the method of Example 323.
    [1859] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.34-1.65 (5H, m), 1.80-1.94 (2H, m), 2.66 (2H, t, J = 7.6 Hz), 2.85-3.00 (2H, m), 3.25-3.40 (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), 7.40-7.60 (3H, m), 7.69 (1H, d, J = 6.4 Hz), 8.00-8.10 (1H, m), 8.55 (1H, dd, J = 4.8, 1.6 Hz), 8.87 (1H, d, J = 1.6 Hz)
    [1860] Example 328
    [1861] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [3-[(tetrahydropyran-2-yl) methyloxy] phenyl] ethyl] piperi Dean
    [1862] The title compound was obtained using the compound according to the method of Example 323.
    [1863] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.20-1.60 (9H, m), 1.62 (1H, br d, J = 12.4 Hz), 1.70-1.90 (3H, m), 2.40-2.60 (2H , m), 2.80-3.00 (2H, m) 3.20-3.43 (3H, m), 3.50-3.63 (1H, m), 3.75-3.95 (3H, m), 4.02 (2H, s), 6.27 (1H, t, J = 6.4 Hz), 6.66-6.80 (3H, m), 7.14 (1H, t, J = 8.0 Hz), 7.52 (1H, d, J = 6.4 Hz), 7.68 (1H, d, J = 6.0 Hz)
    [1864] Example 329
    [1865] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2-[(tetrahydropyran-2-yl) methyloxy] phenyl] ethyl] piperi Dean
    [1866] The title compound was obtained using the compound according to the method of Example 323.
    [1867] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.25-1.55 (9H, m), 1.64 (1H, br d, J = 12.0 Hz), 1.75-1.93 (3H, m), 2.53 (2H, t , J = 6.4 Hz), 2.80-3.00 (2H, m), 3.20-3.43 (3H, m), 3.53-3.63 (1H, m), 3.83-3.93 (3H, m), 4.03 (2H, s), 6.28 (1H, t, J = 6.4 Hz), 6.82 (1H, t, J = 7.2 Hz), 6.89 (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), 7.64-7.72 (1H, m)
    [1868] Example 330
    [1869] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- [2- (2-methoxyethoxy) phenyl] ethyl] piperidine oxalate
    [1870] The title compound was obtained using the compound according to the method of Example 323.
    [1871] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.34-1.50 (5H, m), 1.76-1.90 (2H, m), 2.46-2.56 (2H, m), 2.80-2.98 (2H, m), 3.20-3.38 (2H, m) 3.30 (3H, s), 3.64 (2H, t, J = 4.0 Hz), 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)
    [1872] Example 331
    [1873] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (2-phenoxyphenyl) ethyl] piperidine oxalate
    [1874] The title compound was obtained using the compound according to the method of Example 323.
    [1875] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.25-1.60 (5H, m), 1.78 (2H, br d, J = 12.8 Hz), 2.56 (2H, t, J = 7.6 Hz), 2.66- 2.95 (2H, m), 3.20-3.35 (2H, m), 4.02 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.84-6.92 (3H, m), 7.08 (1H, t, J = 7.2 Hz), 7.13 (1H, t, J = 7.2 Hz), 7.23 (1H, t, J = 7.2 Hz), 7.30-7.40 (3H, m), 7.54 (1H, d, J = 5.2 Hz) , 7.68 (1H, doublet, J = 6.0 Hz)
    [1876] Example 332
    [1877] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[2- (2-phenylethyl) phenyl] ethyl] piperidine oxalate
    [1878] The title compound was obtained using the compound according to the method of Example 323.
    [1879] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.25-1.48 (5H, m), 1.74-1.84 (2H, m), 2.48 (2H, m), 2.53-2.61 (2H, m), 2.76- 2.89 (4H, m), 3.06 (2H, br d, J = 10.8 Hz), 3.65 (2H, br s), 6.98-7.32 (9H, m), 7.58 (1H, m), 7.65 (1H, d, J = 2.8 Hz)
    [1880] Example 333
    [1881] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2,2-diphenyl-1-ethenyl) piperidine
    [1882] The title compound was obtained using the compound according to the method of Example 285.
    [1883] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.52-1.76 (4H, m), 1.98-2.09 (2H, m), 2.16 (1H, m), 2.90 (2H, br d, J = 10.4 Hz), 3.46 (2H, s), 5.92 (1H, d, J = 9.6 Hz), 6.33 (1H, br t, J = 6.4 Hz), 7.14-7.40 (11H, m), 7.55 (1H, m)
    [1884] Example 334
    [1885] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] pi Ferridine
    [1886] 245 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine It was dissolved in 8 ml, 7 ml of 4N-hydrogen chloride-methanol solution was added and heated to reflux for 7 hours. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Ether was added to the obtained oil and crystallized to obtain 116 mg of the title compound as a light yellow powder.
    [1887] 1 H-NMR (400 MHz, CDCl 3 ) δ1.56-1.68 (2H, m), 1.80-1.89 (2H, m), 2.18-2.30 (3H, m), 2.96-3.02 (2H, m), 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, 8.4, 1.6 Hz), 7.08 (1H , dt, J = 8.0, 1.2 Hz), 7.17 (1H, m), 7.40-7.48 (2H, m), 7.73 (1H, br s)
    [1888] Example 335
    [1889] 1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] Piperidine
    [1890] 221 mg of 1-[(5-fluoro-2-methoxy-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine It was dissolved in 12 ml of ethanol, 12 ml of 4N-hydrogen chloride-methanol solution was added and heated to reflux for 11 hours. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Ether was added to the obtained oil and crystallized to give 176 mg of the title compound as a pale pink powder.
    [1891] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.57-1.69 (2H, m), 1.81-1.89 (2H, m), 2.20-2.31 (3H, m), 2.96-3.04 (2H, m), 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, 8.0, 1.2 Hz), 7.08 (1H , dt, J = 8.0, 1.2 Hz), 7.17 (1H, m), 7.28 (1H, dd, J = 8.0, 2.8 Hz), 7.44 (1H, dt, J = 7.6, 2.0 Hz), 7.72 (1H, br m)
    [1892] Example 336 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-chlorophenyl) -1-ethenyl ] Piperidine
    [1893] The title compound was obtained using the compound according to the method of Example 285.
    [1894] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.46-1.69 (2H, m), 1.82-1.90 (2H, m), 2.18-2.34 (3H, m), 2.95-3.02 (2H, m), 3.55 ( 2H, s), 6.15 (1H, dd, J = 16.0, 6.8 Hz), 6.78 (1H, d, J = 16.0 Hz), 7.15 (1H, dd, J = 8.0, 1.6 Hz), 7.20 (1H, dt , J = 8.0, 1.6 Hz), 7.34 (1H, dd, J = 8.0, 1.6 Hz), 7.45 (1H, d, J = 2.8 Hz), 7.51 (1H, dd, J = 8.0, 1.6 Hz), 7.69 (1H, br s)
    [1895] Example 337
    [1896] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-methylphenyl) -1-ethenyl] piperidine
    [1897] The title compound was obtained using the compound according to the method of Example 285.
    [1898] 1 H-NMR (400 MHz, CDCl 3 ) δ1.56-1.68 (2H, m), 1.81-1.88 (2H, m), 2.16-2.29 (3H, m), 2.33 (3H, s), 2.94-3.02 ( 2H, m), 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 = 7.6, 1.6 Hz), 7.45 (1H, d, J = 2.4 Hz), 7.69 (1H, br s)
    [1899] Example 338
    [1900] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (benzyloxy) phenyl] -1-ethenyl] piperidine Oxalate
    [1901] The title compound was obtained using the compound according to the method of Example 302.
    [1902] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.58-1.78 (4H, m), 1.83-1.94 (2H, m), 2.40 (7 / 8H, m), 2.64 (1 / 8H, m), 2.82-3.05 (2H, m), 3.20-3.42 (2H, m), 4.01 (2H, br s), 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), 6.89-7.04 (1H, m ), 7.05-7.15 (1H, m), 7.18-7.55 (8H, m), 7.66 (1 / 8H, br d, J = 5.2 Hz), 7.69 (7 / 8H, br d, J = 5.2 Hz)
    [1903] Example 339 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2-[(2-phenylethyl) phenyl] -1-ethenyl] Piperidine Oxalate
    [1904] The title compound was obtained using the compound according to the method of Example 302.
    [1905] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.60-1.78 (2H, m), 1.86-1.96 (2H, m), 2.45 (1H, m), 2.52-3.04 (6H, m), 3.21 ( 2 / 7H, br d, J = 11.2 Hz), 3.34 (12 / 7H, br d, J = 11.2 Hz), 3.92 (2 / 7H, br s), 4.00 (12 / 7H, br s), 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), 7.10-7.32 (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, br d, J = 6.8 Hz), 7.68 (6 / 7H, dd, J = 6.8, 1.6 Hz)
    [1906] Example 340
    [1907] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (isobutyloxy) phenyl] -1-ethenyl] piperi Dean oxalate
    [1908] The title compound was obtained using the compound according to the method of Example 302.
    [1909] 1 H-NMR (400 MHz, DMSO-d 6 ) δ0.97 (3 / 2H, d, J = 6.8 Hz), 1.01 (9 / 2H, d, J = 6.8 Hz), 1.58-1.94 (4H, m) , 1.95-2.10 (1H, m), 2.40 (1 / 4H, m), 2.66 (3 / 4H, m), 2.94 (2H, m), 3.20-3.38 (2H, m), 3.74 (1 / 2H, d, J = 6.8 Hz), 3.76 (3 / 2H, d, J = 6.8 Hz), 3.92-4.05 (2H, m), 6.20-6.33 (2H, m), 6.48 (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, 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, br d, J = 6.4 Hz) , 8.06 (3 / 4H, broad doublet, J = 6.4 Hz)
    [1910] Example 341
    [1911] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclopentylmethyloxy) phenyl] -1-ethenyl] pi Ferridine Oxalate
    [1912] The title compound was obtained using the compound according to the method of Example 302.
    [1913] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.12-1.96 (13H, m), 2.12-2.54 (1H, m), 2.64 (1 / 4H, m), 2.80-3.02 (7 / 4H, m ), 3.08-3.39 (2H, m), 3.82 (1 / 2H, d, J = 6.8 Hz), 3.83 (3 / 2H, d, J = 6.8 Hz), 4.00 (2H, m), 5.45 (1 / 4H, dd, J = 12.0, 10.0 Hz), 6.20-6.35 (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 = 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), 7.64 (1 / 4H, dd, J = 5.2, 2.0 Hz), 7.65 (3 / 4H, dd, J = 5.2, 2.0 Hz)
    [1914] Example 342
    [1915] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (2-cyclohexylethyl) phenyl] -1-ethenyl] Piperidine Oxalate
    [1916] The title compound was obtained using the compound according to the method of Example 302.
    [1917] 1 H-NMR (400 MHz, DMSO-d 6 ) δ0.85-0.98 (2H, m), 1.07-1.29 (4H, m), 1.30-1.40 (2H, m), 1.57-1.76 (7H, m), 1.86-1.95 (2H, m), 2.33 (1 / 7H, m), 2.43 (6 / 7H, m), 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 (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)
    [1918] Example 343
    [1919] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] pi Ferridine Oxalate
    [1920] 961 mg of 1-[(2-methoxy-3-pyridinyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] piperidine It was dissolved in 16 ml, 4 ml of 4N-hydrogen chloride-methanol solution was added and heated to reflux for 3 hours. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The resulting oil was dissolved in ethanol, 207 mg of oxalic acid and ethyl acetate were added, and the precipitate was filtered to give 765 mg of the title compound as a white powder.
    [1921] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.02-1.34 (5H, m), 1.57-1.93 (10H, m), 2.39 (1H, m), 2.88 (2H, m), 3.29 (2H, br d, J = 9.6 Hz), 3.79 (2H, d, J = 6.0 Hz), 3.94 (2H, s), 6.19-6.32 (2H, m), 6.64 (1H, d, J = 16.4 Hz), 6.88 (1H, t, J = 7.2 Hz), 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) , 7.50 (1H, doublet of doublets, J = 7.2, 2.0 Hz), 7.67 (1H, high d, J = 5.6 Hz)
    [1922] Example 344
    [1923] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(Z) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] pi Ferridine Oxalate
    [1924] The title compound was obtained using the compound according to the method of Example 302.
    [1925] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 0.97-1.32 (5H, m), 1.60-1.84 (10H, m), 2.65 (1H, m), 2.70-3.00 (2H, m), 3.26 ( 2H, br d, J = 12.0 Hz), 3.77 (2H, d, J = 7.2 Hz), 3.96 (2H, s), 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), 6.95 (1H, d, J = 8.0 Hz), 7.18 (1H, dd, J = 7.6, 1.2 Hz), 7.23 (1H, dt, J = 7.6, 1.2 Hz), 7.50 (1H, dd, J = 6.8, 2.0 Hz), 7.66 (1H, br d, J = 6.0 Hz)
    [1926] Example 345
    [1927] 1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1 -Ethenyl] piperidine oxalate
    [1928] The title compound was obtained using the compound according to the method of Example 302.
    [1929] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.03-1.34 (5H, m), 1.47-1.88 (10H, m), 2.28 (1H, m), 2.42-2.60 (2H, m), 3.00- 3.18 (2H, m), 3.62-3.74 (2H, m), 3.79 (2H, d, J = 6.0 Hz), 6.26 (1H, dd, J = 16.0, 6.8 Hz), 6.64 (1H, d, J = 16.0 Hz), 6.88 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 7.6 Hz), 7.17 (1H, dt, J = 7.6, 2.0 Hz), 7.42 (1H, dd, J = 7.6, 2.0 Hz), 7.65 (2H, br s)
    [1930] Example 346
    [1931] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclohexylmethyloxy) -5-fluorophenyl] -1 -Ethenyl] piperidine
    [1932] The title compound was obtained using the compound according to the method of Example 302.
    [1933] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 0.96-1.32 (5H, m), 1.57-1.92 (10H, m), 2.41 (7 / 4H, m), 2.66 (1 / 4H, m), 2.84-3.00 (2H, m), 3.21-3.36 (2H, m), 3.75 (1 / 2H, d, J = 6.4 Hz), 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 (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)
    [1934] Example 347
    [1935] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclohexylmethyloxy) -4-fluorophenyl] -1 -Ethenyl] piperidine
    [1936] The title compound was obtained using the compound according to the method of Example 302.
    [1937] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 0.96-1.34 (5H, m), 1.57-1.92 (10H, m), 2.38 (1H, m), 2.59 (1 / 5H, m), 2.78- 3.02 (9 / 5H, m), 3.20-3.38 (2H, m), 3.79 (2 / 5H, d, J = 6.4 Hz), 3.81 (8 / 5H, d, J = 6.0 Hz), 3.94 (2 / 5H, br s), 3.99 (8 / 5H, br s), 5.56 (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)
    [1938] Example 348
    [1939] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- [2- (cyclohexylmethyloxy) -6-fluorophenyl] -1 -Ethenyl] piperidine
    [1940] The title compound was obtained using the compound according to the method of Example 302.
    [1941] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.04-1.34 (5H, m), 1.56-1.92 (10H, m), 2.39 (1H, m), 2.83-2.98 (2H, m), 3.24- 3.36 (2H, m), 3.84 (2H, d, J = 5.6 Hz), 3.97 (2H, br s), 6.29 (1H, t, J = 6.4 Hz), 6.39-6.51 (2H, m), 7.78 ( 1H, dd, J = 10.8, 8.4 Hz), 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, broad doublet, J = 4.8 Hz)
    [1942] Example 349
    [1943] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine oxalate
    [1944] 111 mg of 4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine are dissolved in 3 ml of 1,2-dichloroethane and 2-oxo-1,2-dihydro 50 mg of -3-pyridinecarboxaldehyde, 0.03 ml of acetic acid and 94 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 5 hours 30 minutes. 50 mg of 2-oxo-1,2-dihydro-3-pyridinecarboxaldehyde, 0.03 ml of acetic acid and 94 mg of sodium triacetoxyborohydride were added and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by NH-foam silica gel column chromatography (ethyl acetate: methanol = 30: 1) to obtain 140 mg of a colorless oil. The oily substance was dissolved in ethanol, 33 mg of oxalic acid and ethyl acetate were added, and the precipitate was filtered off to obtain 120 mg of the title compound as a white powder.
    [1945] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.02-1.32 (5H, m), 1.60-1.87 (8H, m), 1.99-2.08 (2H, m), 2.86-3.04 (3H, m), 3.11-3.22 (2H, m), 3.82 (2H, d, J = 6.0 Hz), 3.92 (2H, br s), 6.28 (1H, t, J = 6.8 Hz), 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)
    [1946] Example 350
    [1947] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-phenoxyphenyl) -1-ethenyl] piperidine oxalate
    [1948] The title compound was obtained using the compound according to the method of Example 323.
    [1949] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.56-1.78 (3H, m), 1.76-1.88 (1H, m), 2.10-2.50 (1H, m), 2.90-3.10 (2H, m), 3.22-3.40 (2H, m), 4.05 (2H, s), 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), 7.64-7.74 (1H, m)
    [1950] Example 351
    [1951] 1-[(5-cyano-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] Piperidine
    [1952] 214 mg of 1-[(5-cyano-2-methoxy-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] piperidine, 137 mg of sodium iodide and 0.1 ml of trimethylsilane chloride were added to 10 ml of acetonitrile and stirred at room temperature. After 5 hours, 685 mg of sodium iodide and 0.5 ml of chlorotrimethylsilane were added and stirred at room temperature for 20 minutes. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with aqueous sodium carbonate solution, aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was suspended in aqueous sodium carbonate solution and stirred at room temperature. The crystals were filtered to give 185 mg of the title compound as a pale yellow powder.
    [1953] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.41-1.54 (2H, m), 1.68-1.74 (2H, m), 2.08 (2H, brt, J = 10.8 Hz), 2.17 (1H, m ), 2.85 (2H, br d, 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 = 8.4,1.6 Hz), 8.19 (1H, d, J = 2.4 Hz )
    [1954] Example 352
    [1955] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (cyclohexylmethyloxy) benzyloxy] piperidine oxalate
    [1956] The title compound was obtained using the compound according to the method of Example 302.
    [1957] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.00-1.32 (5H, m), 1.62-2.07 (10H, m), 3.01 (2H, m), 3.17 (2H, m), 3.66 (1H, m), 3.79 (2H, d, J = 6.4 Hz), 4.00 (2H, s), 4.49 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.91 (1H, t, J = 7.6 Hz), 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), 7.68 (1H, dd, J = 6.4, 2.0 Hz)
    [1958] Example 353
    [1959] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (benzyloxy) benzyloxy] piperidine oxalate
    [1960] The title compound was obtained using the compound according to the method of Example 349.
    [1961] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.72-1.86 (2H, m), 1.90-2.02 (2H, m), 2.85-2.98 (2H, m), 3.05-3.17 (2H, m), 3.64 (1H, m), 3.93 (2H, s), 4.53 (2H, s), 5.14 (2H, s), 6.29 (1H, t, J = 6.8 Hz), 6.95 (1H, dt, J = 7.6, 1.2 Hz), 7.17 (1H, d, J = 7.6 Hz), 7.26-7.42 (5H, m), 7.43-7.48 (2H, m), 7.51 (1H, dd, J = 6.8, 2.0 Hz), 7.65 (1H , dd, J = 6.8, 2.0 Hz)
    [1962] Example 354
    [1963] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-chloro-6-fluorobenzyloxy) piperidine
    [1964] The title compound was obtained according to the method of Example 318 using the compound.
    [1965] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.40-1.55 (2H, m), 1.78-1.90 (2H, m), 2.10 (2H, brt, J = 9.2 Hz), 2.58-2.70 (2H , m), 3.22 (2H, s), 3.33-3.45 (1H, m), 4.56 (2H, d, J = 2.0 Hz), 6.15 (1H, t, J = 6.4 Hz), 7.18-7.28 (2H, m), 7.30-7.46 (3H, m), 11.50 (1H, s)
    [1966] Example 355
    [1967] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-chloro-6-fluorobenzyloxy) piperidine
    [1968] The title compound was obtained according to the method of Example 318 using the compound.
    [1969] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.42-1.55 (2H, m), 1.80-1.90 (2H, m), 2.14 (2H, brt, J = 9.2 Hz), 2.58-2.70 (2H , m), 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)
    [1970] Example 356
    [1971] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2,6-difluorobenzyloxy) piperidine
    [1972] The title compound was obtained according to the method of Example 318 using the compound.
    [1973] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.38-1.52 (2H, m), 1.78-1.90 (2H, m), 2.08 (2H, brt, J = 9.6 Hz), 2.56-2.70 (2H , m), 3.21 (2H, s), 3.30-3.43 (1H, m), 4.50 (2H, s), 6.14 (1H, t, J = 6.4 Hz), 7.09 (2H, t, J = 8.0 Hz) , 7.23 (1H, dd, J = 6.4, 1.6 Hz), 7.35 (1H, dd, J = 6.4, 1.2 Hz), 7.36-7.48 (1H, m)
    [1974] Example 357
    [1975] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2,6-difluorobenzyloxy) piperidine
    [1976] The title compound was obtained according to the method of Example 318 using the compound.
    [1977] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.40-1.53 (2H, m), 1.78-1.90 (2H, m), 2.13 (2H, brt, J = 9.2 Hz), 2.56-2.70 (2H, m), 3.24 (2H, s), 3.30-3.48 (1H, m), 4.50 (2H, s), 7.09 (2H, t, J = 8.0 Hz), 7.35 (1H, d, J = 2.0 Hz), 7.38-7.48 (1H, m), 7.50 (1H, d, J = 2.8 Hz)
    [1978] Example 358
    [1979] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-chlorobenzyloxy) piperidine
    [1980] The title compound was obtained according to the method of Example 318 using the compound.
    [1981] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.45-1.60 (2H, m), 1.82-1.93 (2H, br.d, J = 10.0 Hz), 2.12 (2H, br t, J = 10.0 Hz ), 2.60-2.73 (2H, m), 3.23 (2H, s), 3.38-3.50 (1H, m), 4.54 (2H, s), 6.15 (1H, t, J = 6.4 Hz), 7.24 (1H, d, J = 6.4 Hz), 7.26-7.44 (4H, m), 7.50 (1H, d, J = 7.6 Hz), 11.50 (1H, s)
    [1982] Example 359
    [1983] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-chlorobenzyloxy) piperidine
    [1984] The title compound was obtained according to the method of Example 318 using the compound.
    [1985] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.47-1.62 (2H, m), 1.82-1.94 (2H, m), 2.16 (2H, brt, J = 9.6 Hz), 2.60-2.75 (2H , m), 3.27 (2H, s), 3.46 (1H, m), 4.54 (2H, s), 7.26-7.45 (4H, m), 7.48-7.56 (2H, m)
    [1986] Example 360
    [1987] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-fluorobenzyloxy) piperidine oxalate
    [1988] The title compound was obtained using the compound according to the method of Example 323.
    [1989] 1 H-NMR (400 MHz, DMSO-d 6 ) 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), 3.97 (2H, s), 4.53 (2H, s), 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), 7.67 (1H, d, J = 5.2 Hz)
    [1990] Example 361
    [1991] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- (2-fluorobenzyloxy) piperidine
    [1992] The title compound was obtained using the compound according to the method of Example 323.
    [1993] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.70-1.85 (2H, m), 1.90-2.05 (2H, m), 2.77-3.00 (2H, m), 3.05-3.20 (2H, m), 3.60-3.70 (1H, m), 3.92 (2H, s), 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)
    [1994] Example 362
    [1995] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-methoxyphenoxy) methyl] piperidine
    [1996] The title compound was obtained using the compound according to the method of Example 285.
    [1997] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.38-1.52 (2H, m), 1.85-2.00 (3H, m), 2.15 (2H, m), 2.98 (2H, br d, J = 11.6 Hz), 3.50 (2H s), 3.86 (3H, s), 3.88 (2H, s), 6.33 (1H, d, J = 6.8 Hz), 6.86-6.94 (4H, m), 7.36 (1H, br dd, J = 6.0, 1.2 Hz), 7.57 (1H, broad doublet, J = 6.0 Hz)
    [1998] Example 363 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (cyclohexylmethyloxy) phenoxymethyl] piperidine
    [1999] The title compound was obtained using the compound according to the method of Example 285.
    [2000] 1 H-NMR (400 MHz, CDCl 3 ) δ1.00-1.36 (5H, m), 1.41-1.54 (2H, m), 1.65-2.00 (7H, m), 2.16-2.26 (2H, m), 2.99 ( 2H, br d, J = 11.6 Hz), 3.58 (2H, s), 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, br s)
    [2001] Example 364
    [2002] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (cyclohexylmethyloxy) phenoxymethyl] piperidine oxalate
    [2003] The title compound was obtained using the compound according to the method of Example 302.
    [2004] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 0.98-1.12 (2H, m), 1.12-1.30 (3H, m), 1.46-1.84 (8H, m), 1.88-2.08 (3H, m), 3.12 (2H, m), 3.33 (2H, m), 3.75 (2H, d, J = 6.4 Hz), 3.83 (2H, m), 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, br d, J = 5.2 Hz), 7.68 (1H, br d, J = 6.4 Hz)
    [2005] Example 365
    [2006] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[[2- (cyclohexylethyl) phenoxy] methyl] piperidine oxalate
    [2007] The title compound was obtained using the compound according to the method of Example 302.
    [2008] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 0.84-0.96 (2H, m), 1.06-1.27 (4H, m), 1.35-1.43 (2H, m), 1.50-1.77 (7H, m), 1.86-1.96 (2H, m), 2.00 (1H, m), 2.55-2.58 (2H, m), 2.88 (2H, m), 3.04 (2H, m), 3.83 (2H, m), 3.95 (2H, s), 6.29 (1H, t, J = 6.8 Hz), 6.84 (1H, dt, J = 7.6, 0.8 Hz), 6.91 (1H, d, J = 7.6 Hz), 7.08-7.16 (2H, m), 7.50 (1 H, br d, J = 5.2 Hz), 7.66 (1 H, br d, J = 4.8 Hz)
    [2009] Example 366
    [2010] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4- [2- (benzyloxy) phenoxymethyl] piperidine oxalate
    [2011] The title compound was obtained using the compound according to the method of Example 249.
    [2012] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.40-1.65 (2H, m), 1.86-1.96 (2H, m), 2.02 (1H, m), 2.85-2.96 (2H, m), 3.26- 3.36 (2H, m), 3.88 (2H, d, J = 6.4 Hz), 3.97 (2H, s), 5.10 (2H, s), 6.29 (1H, t, J = 6.4 Hz), 6.84-6.93 (2H , m), 6.97-7.06 (2H, m), 7.28-7.47 (5H, m), 7.51 (1H, dd, J = 6.4, 2.0 Hz), 7.67 (1H, dd, J = 6.8, 2.0 Hz)
    [2013] Example 367
    [2014] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-fluorophenoxy) methyl] piperidine
    [2015] The title compound was obtained according to the method of Example 318 using the compound.
    [2016] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.24-1.38 (2H, m), 1.72 (3H, br d, J = 10 Hz), 1.98 (2H, br t, J = 10.8 Hz), 2.83 (2H, br d, J = 11.2 Hz), 3.25 (2H, s), 3.88 (2H, d, J = 5.6 Hz), 6.15 (1H, t, J = 6.4 Hz), 6.86-6.94 (1H, m ), 7.04-7.20 (3H, m), 7.24 (1H, d, J = 6.4 Hz), 7.37 (1H, d, J = 6.8 Hz), 11.50 (1H, s)
    [2017] Example 368
    [2018] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-fluorophenoxy) methyl] piperidine
    [2019] The title compound was obtained according to the method of Example 318 using the compound.
    [2020] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.24-1.40 (2H, m), 1.74 (3H, br d, J = 9.6 Hz), 2.01 (2H, br t, J = 10.8 Hz), 2.82 (2H, br d, J = 10.8 Hz), 3.27 (2H, s), 3.86 (2H, d, J = 6.0 Hz), 6.86-6.93 (1H, m), 7.05-7.20 (3H, m), 7.36 (1H, d, J = 2.8 Hz), 7.51 (1H, d, J = 3.2 Hz)
    [2021] Example 369
    [2022] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,4-difluorophenoxy) methyl] piperidine
    [2023] The title compound was obtained according to the method of Example 318 using the compound.
    [2024] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.22-1.38 (2H, m), 1.71 (3H, br d, J = 10.8 Hz), 1.96 (2H, br t, J = 10.8 Hz), 2.82 (2H, br d, J = 11.2 Hz), 3.23 (2H, s), 3.86 (2H, d, J = 5.6 Hz), 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), 7.36 (1H, dd, J = 6.4, 1.2 Hz), 11.41 (1H, s)
    [2025] Example 370
    [2026] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,4-difluorophenoxy) methyl] piperidine
    [2027] The title compound was obtained according to the method of Example 318 using the compound.
    [2028] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.24-1.38 (2H, m), 1.72 (3H, br d, J = 10.4 Hz), 2.01 (2H, br t, J = 10.4 Hz), 2.82 (2H, br d, J = 11.6 Hz), 3.27 (2H, s), 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), 7.36 (1H, d, J = 2.8 Hz), 7.50 (1H, d, J = 2.8 Hz)
    [2029] Example 371
    [2030] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,5-difluorophenoxy) methyl] piperidine
    [2031] The title compound was obtained according to the method of Example 318 using the compound.
    [2032] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.20-1.38 (2H, m), 1.65-1.83 (1H, m), 1.71 (2H, br d, J = 10.8 Hz), 1.97 (2H, br t, J = 11.2 Hz), 2.82 (2H, br d, J = 11.2 Hz), 3.24 (2H, s), 3.90 (2H, d, J = 6.0 Hz), 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), 7.36 (1H, dd, J = 6.4,1.2 Hz), 11.51 (1H, m)
    [2033] Example 372
    [2034] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,5-difluorophenoxy) methyl] piperidine
    [2035] The title compound was obtained according to the method of Example 318 using the compound.
    [2036] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.24-1.39 (2H, m), 1.67-1.80 (1H, m), 1.73 (2H, br d, J = 11.2 Hz), 1.95-2.08 (2H, m), 2.82 (2H, broad doublet, J = 11.2 Hz), 3.27 (2H, s), 3.91 (2H, d, J = 6.0 Hz), 6.68-6.76 (1H, m), 7.06-7.13 (1H, m), 7.18-7.26 (1H, m), 7.36 (1H, d, J = 2.8 Hz), 7.51 (1H, d, J = 2.8 Hz)
    [2037] Example 373
    [2038] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,6-difluorophenoxy) methyl] piperidine
    [2039] The title compound was obtained according to the method of Example 318 using the compound.
    [2040] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.20-1.38 (2H, m), 1.60-1.80 (1H, m), 1.72 (2H, br d, J = 12.4 Hz), 1.96 (2H, br t, J = 11.2 Hz), 2.81 (2H, br d, J = 11.2 Hz), 3.23 (2H, s), 3.93 (2H, d, J = 6.0 Hz), 6.15 (1H, t, J = 6.8 Hz ), 7.04-7.18 (3H, m), 7.23 (1H, d, J = 6.4 Hz) 7.36 (1H, d, J = 6.4 Hz), 11.49 (1H, s)
    [2041] Example 374
    [2042] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,6-difluorophenoxy) methyl] piperidine
    [2043] The title compound was obtained according to the method of Example 318 using the compound.
    [2044] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.22-1.38 (2H, m), 1.60-1.80 (1H, m), 1.73 (2H, br d, J = 12.8 Hz), 1.95-2.05 (2H, m), 2.81 (2H, br d, J = 11.2 Hz), 3.26 (2H, s), 3.94 (2H, d, J = 6.0 Hz), 7.04-7.16 (3H, m), 7.35 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J = 2.8 Hz)
    [2045] Example 375 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-methoxyphenoxy) methyl] piperidine
    [2046] The title compound was obtained according to the method of Example 318 using the compound.
    [2047] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.22-1.36 (2H, m), 1.66-1.78 (3H, m), 2.01 (2H, brt, J = 10.4 Hz), 2.82 (2H, br d, J = 11.6 Hz), 3.27 (2H, s), 3.72 (3H, s), 3.78 (2H, d, J = 6.0 Hz), 6.80-6.88 (2H, m,), 6.88-6.95 (2H, m), 7.36 (1H, d, J = 2.8 Hz), 7.51 (1H, d, J = 3.2 Hz)
    [2048] Example 376
    [2049] 1-[(2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-chlorophenoxy) methyl] piperidine
    [2050] The title compound was obtained according to the method of Example 318 using the compound.
    [2051] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.26-1.40 (2H, m), 1.74 (3H, br d, J = 10.8 Hz), 1.98 (2H, br t, J = 11.2 Hz), 2.83 (2H, br d, J = 11.2 Hz), 3.24 (2H, s), 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), 11.5 (1H, br s)
    [2052] Example 377
    [2053] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2-chloro-6-fluorophenoxy) methyl] piperidine
    [2054] The title compound was obtained according to the method of Example 318 using the compound.
    [2055] 1 H-NMR (400 MHz, DMSO-d 6 ) δ1.22-1.36 (2H, m), 1.58-1.73 (1H, m), 1.74 (2H, br d, J = 12 Hz), 1.94-2.04 (2H , m), 2.80 (2H, br d, J = 11.6 Hz), 3.26 (2H, s), 3.79 (3H, s), 3.79 (2H, d, J = 6.0 Hz), 6.80 (1H, t, J = 9.6 Hz), 6.85 (1H, d, J = 7.6 Hz), 6.96-7.05 (2H, m), 7.36 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J = 2.8 Hz)
    [2056] Example 378
    [2057] 1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridyl) methyl] -4-[(2,3-difluorophenoxy) methyl] piperidine
    [2058] The title compound was obtained according to the method of Example 318 using the compound.
    [2059] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.26-1.38 (2H, m), 1.73 (3H, br.d, J = 12.8 Hz), 1.96-2.10 (2H, m), 2.83 (2H, br.d, J = 11.6 Hz), 3.28 (2H, s), 3.93 (2H, d, J = 6.4 Hz), 6.90-7.04 (2H, m), 7.06-7.14 (1H, m), 7.36 (1H , d, J = 2.8Hz), 7.51 (1H, d, J = 2.4Hz)
    [2060] Example 379
    [2061] 1-[(4-oxo-1,4-dihydro-3-pyridyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [2062] 259 mg of 1-[(4-methoxy-3-pyridinyl) methyl] -4- [2- (2-methylphenyl) ethyl] piperidine is dissolved in 5 ml of ethanol, and 4 N-hydrogen chloride-methanol solution 1.91 ml was added and heated to reflux overnight. The solvent was removed under reduced pressure, and 15 ml of 2N hydrochloric acid was added to the residue and heated to reflux for 7 hours. An aqueous sodium carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The crude product was purified by NH-foam silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 42 mg of the title compound as a white powder.
    [2063] 1 H-NMR (400 MHz, CDCl 3 ) δ 1.24-1.44 (3H, m), 1.56-1.64 (2H, m), 1.78-1.88 (2H, m), 2.10-2.20 (2H, m), 2.56- 2.64 (2H, m), 3.00 (2H, br d, J = 11.6 Hz), 3.73 (2H, s), 5.93 (2H, s), 6.64 (1H, dd, J = 7.6, 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), 8.25 (1H, d, J = 5.6 Hz)
    [2064] Example 380
    [2065] 1-[(2-oxo-3,4-dihydro-3-quinolinyl) methyl] -4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine
    [2066] 0.24 g of 2-oxo-3,4-dihydro-3-quinolinecarboxaldehyde, 0.3 g of 4- [2- [2,3- (methylenedioxy) phenyl] ethyl] piperidine, 50 ml of tetrahydrofuran It dissolved in, 0.5 ml of acetic acid and 0.42 g of sodium triacetoxy borohydride were added, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the precipitated solid was filtered to give 130 mg of the title compound as a pale brown solid.
    [2067] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.18-1.28 (3H, m), 1.68 (2H, br d, J = 7.6 Hz), 1.90-2.00 (2H, m), 2.53 (2H, br t, J = 8.0 Hz), 2.84 (2H, br d, 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), 7.43 (1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz), 7.80 (1H, s), 11.74 (1H, s)
    [2068] Example 381
    [2069] 1-[(2-oxo-3,4-dihydro-3-quinolinyl) methyl] -4- [2- (3- (phenylphenyl) ethyl) piperidine oxalate
    [2070] The title compound was obtained using the compound according to the method of Example 349.
    [2071] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.30-1.70 (5H, m), 1.86 (2H, br d, J = 10.8 Hz), 2.54-2.76 (2H, m), 2.88 (2H, br s), 3.33 (2H, br d, J = 10.8 Hz), 4.07 (2H, s), 7.14-7.26 (2H, m), 7.30-7.40 (3H, m), 7.40-7.50 (4H, m), 7.55 (1H, t, J = 7.6 Hz), 7.60-7.70 (3H, m), 8.14 (1H, s)
    [2072]
    [2073]
    [2074]
    [2075]
    [2076]
    [2077]
    [2078]
    [2079]
    [2080]
    [2081]
    [2082]
    [2083]
    [2084]
    [2085]
    [2086]
    [2087]
    [2088]
    [2089]
    [2090]
    [2091]
    [2092]
    [2093]
    [2094]
    [2095]
    [2096]
    [2097]
    [2098]
    [2099]
    [2100]
    [2101]
    [2102]
    [2103]
    [2104]
    [2105]
    [2106]
    [2107]
    [2108] Test Example 1
    [2109] [Stop and Prevention Effects of Atrial Fibrillation (AF) in Anesthetized Dogs with Open Thorax]
    [2110] (1) In this experiment, an anesthetized and thoracic dog was used. After the chest was opened with the median midline, the outer membrane was incised, and the bipolar electrodes for potential waveform measurement were sealed on the left and right atrial free walls, respectively. In addition, the wire electrode was fixed to the right free wall and used for electrical stimulation. The cervix was dissected into the midline, and the left and right vagus nerves were separated. Vagus nerve stimulation wire electrodes were fixed to each other along each side surface layer and used for vagus nerve stimulation.
    [2111] (2) Vagus nerve stimulation was performed by stimulation conditions of stimulation width: 0.1 mess, stimulation frequency: 20 Hz, and stimulation intensity: 3--7V. Five minutes after the onset of stimulation, the right atrium was stimulated with high frequency (10 Hz, 1 sec) to induce atrial fibrillation (hereinafter abbreviated as AF). The stimulus intensity of the right atrium high frequency stimulus was set at 1.0 V. When the AF was not induced, the stimulus intensity was increased to 5.0 V. The stimulus intensity was attempted. Confirmation (control experiment). In addition, the experiment was stopped when the induced AF did not last for 30 minutes.
    [2112] (3) After confirming that AF lasted 30 minutes or more as a control experiment, the vagus nerve stimulation was cut and stabilized for about 1 hour to recover the dog. Thereafter, AF was similarly triggered again. In addition, the vagus nerve stimulation at this time was performed with a stimulation intensity of about 2 V stronger than that of the control experiment. The test substance was administered 5 minutes after AF was induced. The test substance was administered intravenously over 5 minutes. Observation was performed for 5 minutes after the end of the administration, and when the suspension of AF was not recognized, the dose was increased to observe the same. When AF stopped, it tried to induce AF immediately after stopping. At this time, it was determined that there was no prophylactic effect when the AF which persisted for 1 minute or more was repeated, and the same experiment was carried out by increasing the dose.
    [2113] (4) Results (Table 1): One of three samples showed a stationary effect at a dose of 0.3 mg / kg. This example was also recognized as a prophylactic effect at this dose. Two samples for which no stop effect was recognized at 0.3 mg / kg were then subjected to experiments with the dose increased to 1 mg / kg. As a result, the stopping effect was recognized in two of the two samples, and the prophylactic effect was also recognized by this dose.
    [2114] TABLE 1
    [2115] Example numbercontentStop effectPreventive effect 1350.3 mg / kg1/31/1 1 mg / kg2/22/2
    [2116] In the above table, the number of denominators indicates the number of samples used for the test, and the number of molecules indicates the number of samples whose effects were recognized.
    [2117] Test Example 2
    [2118] [Effective refractory (ERP) in anesthetized dogs
    [2119] (1) In this experiment, an anesthetized and thoracic dog was used. After the chest was opened with a median midline and the outer membrane was incised, bipolar electrodes for measuring potential waveforms were sutured to the left and right atrial free walls, respectively. In addition, the wire electrode was fixed to the right atrium free wall for electric stimulation.
    [2120] (2) A program electric stimulator was connected to an electrode for electric stimulation in the right atrium, and electrical stimulation was performed at a magnetic field period of 500 messes, and the threshold value for the electric stimulus was measured. The electrical stimulation intensity of the following experiment was supposed to stimulate three times this threshold value. However, when the threshold value was 0.7V or less, electrical stimulation was performed at 2.0V. The effective refractory (ERP) gives an early extracorporeal stimulus (S2) after 10 basic stimuli (S1), shortens the connectors (S1-S2) by 5 messes, and does not generate atrial potential due to extracorporeal stimulation. The connector of was made into ERP. The same experiment was also performed for each basic magnetic field (BCL) of 400, 300, 250, and 200 messes (control experiment, 1 series). After two or more control experiments were conducted to confirm that the ERP was stable, the test substance was then administered to make the same measurement. The test substance was administered intravenously with this maintenance dose after intravenous single administration for 5 minutes. Ten minutes after the administration of the maintenance dose, the ERP was measured at each stimulus frequency. After the measurement of the 1 series was completed, the same experiment was repeated by increasing the concentration of the test substance. ERP and atrial conduction time at each stimulus frequency were compared with various indicators under control conditions. The results are shown as averages.
    [2121] (3) Results: The compounds, their salts, and their hydrates according to the present invention effectively stopped and prevent atrial fibrillation, and exhibited excellent effects in extending the effective refractory to atrial muscles (Table 2, 3).
    [2122] (1) ERP measurements (mess)
    [2123] TABLE 2
    [2124]
    [2125] (2) ERP rate of change (d%)
    [2126] TABLE 3
    [2127]
    [2128] Test Example 3
    [2129] [Evaluation of Sodium Channels in Synaptosomes of Rat Cerebral Cortex]
    [2130] In this experiment, synaptosomes extracted from rat cerebral cortex were used. After receiving the sodium ion sensitive pigment SBFI, the synaptosome was reacted with various test substances (6 concentrations of 3 cases) at room temperature for 15 minutes in a 96 well plate. The sodium channel inhibitory activity was used for FDSS2000 of HAMAMATSU Photonics Co., Ltd. The sodium ion concentration in the synaptosome was measured once every 5 seconds using the fluorescence intensity of SBFI as an index. After the control was measured 10 times, Veratridine was added 30 times to a final concentration of 20 μM. The inhibitory activity on the sodium channel of the test substance was measured by the increase in the fluorescence intensity of SBFI relative to the control value after the addition of Veratridine, and the action by the test solution without the test substance was 0%. The inhibitory effect by TTX was made 100%, and the inhibitory activity value corresponding to it was computed. As a result, as shown in Table 4 (SBFI value (IC 50 μM)), the compound according to the present invention showed excellent sodium channel inhibitory action.
    [2131] Test Example 4
    [2132] [Evaluation of Rabbit Atrial Vmax]
    [2133] In this experiment, a right atrium muscle sample from rabbits was used. The extracted right atrial muscle was subjected to electrical stimulation under stimulation conditions of stimulation width of 1 msec, stimulation frequency of 4 Hz, and stimulation intensity approximately 1.2 times the threshold. Stimulation was given for 30 minutes to 60 minutes before the start of the experiment, and the state of the specimen was stabilized. The action potential was recorded by the glass microelectrode method. 3 MKCl was charged to the glass electrode and inserted into the right atrium specimen, and the action potential was recorded. Vmax is a parameter of the maximum ascending speed of the recorded action potential, and a value calculated automatically by the action potential analysis software (CAPA 1.23, manufactured by Physiotec. Co., Ltd.) was used. After recording the action potential in the normal Tyrode solution as a control value, the action potential after 15 minutes of perfusion of the test substance at each concentration was recorded. The action of the test substance on Vmax was calculated as an IC 50 value. As a result, as shown in Table 4 (Vmax (IC 50 μM)), the compound according to the present invention was recognized for its excellent action on Vmax.
    [2134] Test Example 5
    [2135] [Inhibition of spontaneous nerve firing]
    [2136] To assess the inhibitory effect on spontaneous nerve ignition, Burchiel, KJ., Exp. Neurol., 102, 249-253 (1988). That is, rats that observed spontaneous ignition were cut at least one week before the left abdominal nerve in the vicinity of the knee joint, and cut about 3 mm so that the cut nerve did not reattach. The left abdominal nerve was exposed under urethane (1 g / kg body weight) anesthesia, and a region near 1 cm from the cut was peeled off from the surrounding tissue. In addition, a catheter was previously inserted into the right jugular vein for compound administration. The peeled nerve was attached to the platinum hook electrode, and the fluid paraffin was sprayed to prevent the nerve from drying out. The electrodes were connected to a microelectrode amplifier and recorded on a computer via an A / D converter from an oscilloscope. Recorded neural ignition was evaluated by the number of ignition every 10 seconds using the analysis software (AcqKnowledge). As a result, as shown in Table 4 (Ectopic Firing (ID 50 mg / kg), the compound according to the present invention showed an excellent inhibitory effect on spontaneous neuronal firing.
    [2137] Table 4
    [2138]
    权利要求:
    Claims (33)
    [1" claim-type="Currently amended] The compound represented by the following formula (I) or a salt thereof or a hydrate thereof:
    (I)
    In the formula, ring A is


    (In the formula,
    R 1 represents (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C 1-6 alkyl group which may be substituted, (5) a C 2-6 alkenyl group which may be substituted, (6) substituted C 2-6 alkynyl group, (7) substituted C 3-8 cycloalkyl group, (8) substituted C 3-8 cycloalkenyl group, (9) substituted It could be C 1-6 alkoxy group, (10) a C 1-6 alkyl which may be substituted, (11) which may be substituted with C 1-6 alkylsulfinyl group, (12) may be substituted A C 1-6 alkylsulfonyl group, (13) a substituted C 6-14 aromatic hydrocarbon ring group, or (14) a substituted 5 to 14 membered aromatic heterocyclic group;
    R 2 is (1) hydrogen atom, (2) C 1-6 alkyl group which may be substituted, (3) C 2-6 alkenyl group which may be substituted, (4) C 2-6 which may be substituted Alkynyl groups, (5) substituted C 3-8 cycloalkyl groups, (6) substituted C 3-8 cycloalkenyl groups, (7) substituted amino groups, (8) substituted A C 6-14 aromatic hydrocarbon ring group which may be substituted, or (9) a 5 to 14 membered aromatic heterocyclic group which may be substituted;
    R 3 is (1) a substituted C 1-6 alkoxy group, (2) a substituted C 2-6 alkenyloxy group, (3) a substituted C 3-7 cycloalkyloxy group Or (4) a C 3-7 cycloalkenyloxy group which may be substituted;
    W is (1) single bond, (2) C 1-6 alkylene group which may be substituted, (3) C 2-6 alkenylene group which may be substituted, (4) C 2- which may be substituted 6 alkynylene group, (5) Formula-UV-, wherein U is (i) a single bond, (ii) oxygen atom, (iii) sulfur atom, (iv) group represented by formula -NH-, (v) C 1-6 alkylene group, which may be substituted (vi) C 2-6 alkenyl which may be substituted seen group or (vii) C 2-6 alkynylene group which may be substituted, V is selected from: (i) single A bond, (ii) a substituted C 1-6 alkylene group, (iii) a substituted C 2-6 alkenylene group, (iv) a substituted C 2-6 alkynylene group, ( v) an oxygen atom, (vi) a sulfur atom, (vii) a group represented by the formula -CO-, (viii) -SO- or (ix) -SO 2- ;
    However, in the above definition, except that when U and V represent the same group, one of U and V is a single bond, a C 1-6 alkylene group which may be substituted, C 2- may be substituted A 6 alkenylene group or a C 2-6 alkynylene group which may be substituted;
    Z is (1) a substituted C 6-14 aromatic hydrocarbon ring group, (2) a substituted 5 to 14 membered aromatic heterocyclic group or (3) formula -N (R 4 ) R 5 (wherein R 4 and R 5 are the same or different and are (i) a hydrogen atom, (ii) a C 1-6 alkyl group which may be substituted, (iii) a C 2-6 alkenyl group which may be substituted, (iv) substituted C 2-6 alkynyl group which may be present, (v) C 3-8 cycloalkyl group which may be substituted, (vi) C 3-8 cycloalkenyl group which may be substituted, (vii) C may be substituted 6-14 aromatic hydrocarbon ring group, (viii) a 5 to 14 membered aromatic heterocyclic group which may be substituted or (ix) a C 1-6 aliphatic acyl group, or (x) R 4 and R 5 are bonded to To an 8-membered nitrogen-containing cyclic group);
    l represents an integer of 0 to 6.
    [2" claim-type="Currently amended] The method of claim 1,
    W is the formula -CH 2- , -CH 2 -CH 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5- , -CH = CH-, -C≡C -, -CO-, -O-, -O-CH 2- , -CH 2 -O-, -CH 2 -CO-,-(CH 2 ) 2 -CO-, -CH 2 -CH (CN)- , -CH 2 -CH (OH)-, -SO 2- , -CH 2 -SO 2- , -NH-CO-, -CH 2 -NH-CO-, -NH-SO 2 -or -CH 2- A compound represented by NH-SO 2 -or a salt thereof or a hydrate thereof.
    [3" claim-type="Currently amended] The method of claim 1,
    Or a salt thereof or a hydrate thereof, wherein W is a group represented by the formula -CH 2 -CH 2- , -CH = CH-, -CH≡CH- or -CH 2 -O-.
    [4" claim-type="Currently amended] The method of claim 1,
    A compound or a salt thereof or a hydrate thereof, wherein Z is a C 6-14 aromatic hydrocarbon ring group which may be substituted or a 5-14 membered aromatic heterocyclic group which may be substituted.
    [5" claim-type="Currently amended] The method of claim 1,
    Z is a phenyl group, a pyridyl group, or a thienyl group which may each be substituted, its salt, or its hydrate.
    [6" claim-type="Currently amended] The method of claim 1,
    Z is a C 6-14 aromatic hydrocarbon ring group or a 5-14 membered aromatic heterocyclic group, and the ring is (1) hydroxyl group, (2) halogen atom, (3) cyano group, (4) C 1-6 which may be substituted An alkyl group, (5) a substituted C 3-8 cycloalkyl group, (6) a substituted C 1-6 alkoxy group, (7) a substituted C 3-8 cycloalkyloxy group, ( 8) a C 1-6 alkylthio group which may be substituted, (9) a C 6-14 aryloxy group which may be substituted, (10) a 5 to 14 membered heteroaryloxy group which may be substituted, (11 ) An amino group which may be substituted, (12) a 5 to 14 membered aromatic heterocyclic group which may be substituted, (13) a 5 to 14 membered non-aromatic heterocycle which may be substituted, (14) C 1-6 alkylsulfo Compounds or salts thereof, which may be substituted with one or more groups selected from a nil group and a (15) C 1-4 alkylenedioxy group, respectively or their Luggage.
    [7" claim-type="Currently amended] The method of claim 1,
    Or a salt thereof or a hydrate thereof, wherein Z is a group represented by the formula -N (R 4 ) R 5 , wherein R 4 and R 5 each represent the same meaning as defined above.
    [8" claim-type="Currently amended] The method of claim 7, wherein
    R 4 and R 5 are the same or different and are a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-14 aryl C 1-6 A compound or a salt thereof or a hydrate thereof which is an alkyl group or a heteroaryl C 1-6 alkyl group which may be substituted.
    [9" claim-type="Currently amended] The method of claim 7, wherein
    A compound or a salt thereof or a hydrate thereof in which R 4 and R 5 are bonded to each other to form a 3- to 8-membered nitrogen-containing ring group which may be substituted.
    [10" claim-type="Currently amended] The method of claim 9,
    A compound or a salt thereof or a hydrate thereof in which Z is a piperidyl group which may be substituted, a piperazyl group which may be substituted, or a morpholinyl group which may be substituted.
    [11" claim-type="Currently amended] The method of claim 1,
    or a salt thereof or a hydrate thereof.
    [12" claim-type="Currently amended] The method of claim 1,
    Ring A

    Wherein R 1 and R 2 each represent the same meaning as defined above, or a salt thereof or a hydrate thereof.
    [13" claim-type="Currently amended] The method of claim 12,
    R 1 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group or a salt thereof or a hydrate thereof.
    [14" claim-type="Currently amended] The method of claim 12,
    Compounds or salts thereof or hydrates thereof, wherein R 1 is a hydrogen atom.
    [15" claim-type="Currently amended] The method of claim 12,
    R 2 is a hydrogen atom or a C 1-6 alkyl group which may be substituted, or a salt thereof or a hydrate thereof.
    [16" claim-type="Currently amended] The method of claim 1,
    Ring A

    Wherein R 1 and R 3 each represent the same meaning as defined above, or a salt thereof or a hydrate thereof.
    [17" claim-type="Currently amended] The method of claim 16,
    R 3 is a hydroxyl group or a C 1-6 alkoxy group, a compound thereof, or a salt thereof or a hydrate thereof.
    [18" claim-type="Currently amended] The method of claim 1,
    A compound or a salt thereof, or a hydrate thereof, wherein the bonding position of the group -W-Z is the 2 or 4 position of the piperidine ring.
    [19" claim-type="Currently amended] The method of claim 1,
    Following expression

    Wherein R 1 , R 2 , W, Z and l represent the same meaning as defined in claim 1, or a salt thereof or a hydrate thereof.
    [20" claim-type="Currently amended] The method of claim 1,
    Following expression

    Wherein R 1 , W and Z each have the same meaning as defined in claim 1 above and la represents an integer of 1 or 2, or a salt thereof or a hydrate thereof.
    [21" claim-type="Currently amended] 1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- [2- (cyclohexylmethyloxy) 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-fluorophenyl) ethyl] piperidine,
    1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2- [2- (isobutyloxy) phenyl] ethyl] piperidine,
    1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] pi Ferridine,
    1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2- (2-fluorophenyl) -1-ethenyl] Piperidine,
    1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2- [2- (benzyloxy) phenyl] -1-ethenyl] piperidine ,
    1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] pi Ferridine,
    1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(Z) -2-[(2-cyclohexylmethyloxy) phenyl] -1-ethenyl] pi Ferridine,
    1-[(5-fluoro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(E) -2-[(2-cyclohexylmethyloxy) phenyl] -1 Ethenyl] piperidine,
    1-[(2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4- [2-[(2-cyclohexylmethyloxy) phenyl] -1-ethynyl] piperidine,
    1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(2,4-difluorophenoxy) methyl] piperidine, or
    1-[(5-chloro-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -4-[(2,5-difluorophenoxy) methyl] piperidine
    Or salts or hydrates thereof.
    [22" claim-type="Currently amended] Following expression

    (Wherein ring A and l each have the same meaning as defined in claim 1, L represents a leaving group), a compound thereof, a salt thereof or a reactive derivative thereof and the following formula

    (W and Z each have the same meaning as the definition of claim 1) reacting a compound or a salt thereof, the method according to claim 1 or a method for producing a salt or a hydrate thereof.
    [23" claim-type="Currently amended] A pharmaceutical composition comprising a compound represented by the following formula (I) or a salt thereof or a hydrate thereof:
    (I)
    (Each symbol in the formula represents the same meaning as the above definition).
    [24" claim-type="Currently amended] The method of claim 23, wherein
    Pharmaceutical composition which is a sodium channel inhibitor or a potassium channel inhibitor.
    [25" claim-type="Currently amended] The method of claim 23, wherein
    A pharmaceutical composition, which is an agent for preventing and treating arrhythmia.
    [26" claim-type="Currently amended] The method of claim 23, wherein
    A pharmaceutical composition that is a Vaughan Williams class III antiarrhythmic drug.
    [27" claim-type="Currently amended] The method of claim 23, wherein
    A pharmaceutical composition that is an analgesic.
    [28" claim-type="Currently amended] The method of claim 23, wherein
    Pharmaceutical composition which is a treatment and prevention agent of neuralgia.
    [29" claim-type="Currently amended] The method of claim 28,
    A pharmaceutical composition in which the neuralgia is diabetic neuralgia, HIV neuralgia, post shingles neuralgia, trigeminal neuralgia, short-term pain, pain after spinal cord injury, thalamic pain or post-stroke pain.
    [30" claim-type="Currently amended] Use of the compound according to claim 1 or a salt thereof or a hydrate thereof for the production of sodium channel inhibitors or potassium channel inhibitors, drugs for the prevention and treatment of arrhythmias, anti-arrhythmic drugs in Vaughan Williams Group III, analgesics, and treatment and prevention of neuralgia.
    [31" claim-type="Currently amended] The method of claim 30,
    Use for neuralgia is diabetic neuralgia, HIV neuralgia, post shingles neuralgia, trigeminal neuralgia, short sting, spinal cord injury pain, thalamic pain or post-stroke pain.
    [32" claim-type="Currently amended] A disease, arrhythmia, Vaughan Williams class III antiarrhythmic disease, in which sodium channel inhibition or potassium channel inhibition, comprising administering to a patient a pharmacologically effective amount of a compound according to claim 1 or a salt thereof or a hydrate thereof, is effective for prevention and treatment, How to prevent and treat pain and neuralgia.
    [33" claim-type="Currently amended] 33. The method of claim 32,
    A method for preventing and treating neuralgia, diabetic neuralgia, HIV neuralgia, post shingles neuralgia, trigeminal neuralgia, short stinging, spinal cord injury pain, thalamic pain or post-stroke pain.
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    同族专利:
    公开号 | 公开日
    HU0204496A3|2004-07-28|
    AT327230T|2006-06-15|
    DE60119894D1|2006-06-29|
    CN1395575A|2003-02-05|
    NO20023457D0|2002-07-18|
    CA2398388A1|2001-07-26|
    RU2259365C2|2005-08-27|
    AU779442B2|2005-01-27|
    WO2001053288A1|2001-07-26|
    EP1254904A4|2003-03-19|
    MXPA02007036A|2002-12-13|
    BR0107732A|2003-03-11|
    US6784192B2|2004-08-31|
    IL150650D0|2003-02-12|
    HU0204496A2|2003-05-28|
    EP1254904A1|2002-11-06|
    NO20023457L|2002-09-13|
    US20030220368A1|2003-11-27|
    AU2705801A|2001-07-31|
    EP1254904B1|2006-05-24|
    NZ520041A|2004-11-26|
    ZA200205399B|2003-09-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-01-20|Priority to JP2000012175
    2000-01-20|Priority to JPJP-P-2000-00012175
    2001-01-18|Application filed by 에자이 가부시키가이샤
    2001-01-18|Priority to PCT/JP2001/000287
    2002-10-23|Publication of KR20020080378A
    优先权:
    申请号 | 申请日 | 专利标题
    JP2000012175|2000-01-20|
    JPJP-P-2000-00012175|2000-01-20|
    PCT/JP2001/000287|WO2001053288A1|2000-01-20|2001-01-18|Novel piperidine compounds and drugs containing the same|
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