HK1073312B - Cyclic amine compound - Google Patents

Description

Cyclic amine compound

Technical Field

The present invention relates to novel cyclic amine compounds which have an inhibitory effect on cell adhesion and cell infiltration and are useful as anti-asthma agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents and the like, and a pharmaceutical comprising the same.

Background of the field

In various inflammatory diseases, infiltration of leukocytes into the site of inflammation is observed. Infiltration of eosinophils into the bronchi in asthma has been reported (Ohkawara, Y.et al. am. J. Respir. cell mol. biol.12, 4-12(1995)), infiltration of macrophages and T lymphocytes into the aorta in arteriosclerosis (Sakai, A.et al. Arterioscler Thromb. Vasc. biol.17, 310. 316(1997)), in atopic dermatitis (Wakita H.et al. J. Current. Pathol.21, 33-39(1994)) or contact dermatitis (Satoh, T.et al Eur. J. Immunol.27, 85-91(1997)), infiltration of T lymphocytes and eosinophils into the skin, and infiltration of various leukocytes into the synovial tissue of rheumatoid arthritis (Tak, PP. Immunol. Clin. Clonol.77, 236. 242 (1995)).

Sjogren's syndrome in humans is an autoimmune disease of a specific organ characterized by invasion of leukocytes into the salivary and lacrimal glands, destruction of the glandular system, and resulting in symptoms of dry mouth and eye due to inadequate glandular secretion (Fox RI et al, "Sjogren's syndrome: advanced criteria for classification" Arthritis Rheum 1986, 29: 577-.

Infiltration of these leukocytes is induced by cytokines, chemokines, lipids, and complement produced at the site of inflammation (albolda, sm. et al. faseb j.8, 504-512 (1994)). Activated leukocytes adhere to vascular endothelial cells by a so-called rolling or tethering interaction with the endothelial cells that are also activated. Then, the leukocytes migrate through the endothelium to infiltrate the site of inflammation (Springer, TA. Annu. Rev. physiol.57, 827-872 (1995)). In this process, various cell adhesion molecules such as immunoglobulin superfamily (ICAM-1, VCAM-1, etc.), selectin family (E-selectin, etc.), integrin family (LFA-1, VLA-4, etc.) and CD44 (induced on the cell surface by stimulation of cytokines, etc.) play important roles ("Rinsho Meneki (clinical Immune)", 30, Supple.18(1998)) when leukocytes adhere to vascular endothelial cells, and a relationship between a disease state and abnormal expression of cell adhesion factors has also been noted.

Therefore, agents capable of inhibiting cell adhesion are useful as agents for preventing or treating allergic diseases (such as bronchial asthma, dermatitis, rhinitis and conjunctivitis); autoimmune diseases (such as rheumatoid arthritis, nephritis, Sjogren's syndrome, inflammatory abdominal disease, diabetes and arteriosclerosis); and agents for chronic inflammatory diseases. In fact, it has been reported that antibodies against leukocyte adhesion molecules (such as LFA-1, Mac-1 and VLA-4) or antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin and the like on vascular endothelial cells, which become ligands for these molecules, inhibit leukocyte infiltration into inflammatory sites in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, which are their counter receptors, can delay the development of diabetes in a NOD mouse model that spontaneously develops diabetes (Michie, SA. et al. curr. Top. Microbiol. Immunol.231, 65-83 (1998)). Antibodies against VLA-4 and ICAM-1 and its counter receptor LFA-1 have also been reported to inhibit eosinophil infiltration in a mouse and guinea pig model of allergic conjunctivitis (Ebihara et al Current eye Res.19, 20-25 (1999); whitcup, SM et al, Clin.Immunol.93, 107-113(1999), and monoclonal antibodies against VACM-1 in the mouse DSS-induced colitis model inhibited leukocyte infiltration (Soriano, A.et al. Lab. invest.80, 1541-1551 (2000)). In addition, anti-VLA-4 and anti-CD 44 antibodies reduced the onset of disease symptoms in a mouse collagen arthritis model (Zeidler, A.et al. autoimmunity, 21, 245-. Even in mice deficient in cell adhesion molecules, inhibition of leukocyte infiltration into inflammatory tissues was also observed in an inflammation model (Bendjelloul, f.et al, clin.exp.immunol.119, 57-63 (2000)); wolyniec, WW.Et al.am.J.Respir.cell mol.biol.18, 777-785 (1998); bullard, DC, et al J.Immunol.157, 3153-3158 (1996)).

However, it is difficult to develop antibody-based drugs because they are polypeptides and thus oral administration is a problem. Moreover, it is problematic that side effects may be caused due to antigenicity and allergic reactions.

On the other hand, in the case of oral administration, various studies have been made on small molecule compounds having an inhibitory effect on cell adhesion. These compounds include benzothiophene derivatives (Boschelli, DH. et al. J. Exp. Med.38, 4597-4614(1995)), naphthalene derivatives (Japanese patent application laid-open No. 10-147568), hydroxybenzoic acid derivatives (Japanese patent application laid-open No. 10-182550), lignans (Japanese patent application laid-open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese patent application laid-open No. 2000-086641 via the PCT pathway), fused pyrazine compounds (Japanese patent application laid-open No. 2000-319277 via the PCT pathway), 2, 6-dialkyl-4-silylphenol (Japanese patent application laid-open No. 2000-509070 via the PCT pathway), and the like. However, in these cases, the object is often not sufficiently achieved. The cyclic amine compounds described in Japanese patent application laid-open Nos. 9-143075 and 11-92382 do not exhibit sufficient inhibitory effects on cell adhesion, and thus there is a demand for further improvement in activity.

The object of the present invention is to provide a substance having an inhibitory effect on both cell adhesion and cell infiltration and having excellent anti-asthmatic action, anti-allergic action, anti-rheumatic action, anti-arteriosclerotic action, and anti-inflammatory action or anti-Sjogren's syndrome.

Disclosure of Invention

With the foregoing in mind, the present inventors have conducted intensive studies and have found a substance capable of inhibiting cell adhesion and cell infiltration. As a result, we have found that the compound represented by the general formula (1) has excellent cell adhesion-inhibiting effect and cell infiltration-inhibiting effect and is useful as an antiallergic agent, an anti-asthmatic agent, an antirheumatic agent, an antiarteriosclerotic agent or an anti-inflammatory agent.

The present invention provides a cyclic amine compound represented by the following general formula (1), or an acid addition salt thereof or a hydrate thereof:

wherein the content of the first and second substances,

R¹、R²and R³Each independently represents a hydrogen atom, a halogen atom or a hydroxyl group, an alkyl group, a halogen-substituted alkyl group, an alkoxy group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group or an alkanoyl group;

W¹and W²Each independently represents N or CH;

x represents O, NR⁴，CONR⁴Or NR⁴CO；

R⁴Each independently represents a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroaralkyl group;

l, m and n each represent a number of 0 or 1.

The present invention also provides a medicament comprising the above cyclic amine compound, an acid addition salt thereof, or a hydrate thereof as an active ingredient.

The present invention also provides a pharmaceutical composition comprising the above cyclic amine compound, an acid addition salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier.

The present invention further provides the use of the above cyclic amine compound, an acid addition salt thereof or a hydrate thereof for the preparation of a medicament.

According to the present invention, there is also provided a method for treating a disease caused by cell adhesion and/or cell infiltration, which comprises administering an effective amount of a compound represented by the general formula (1), an acid addition salt thereof, or a hydrate thereof to a patient in need of such treatment.

Best Mode for Carrying Out The Invention

The compounds of the invention are characterized in that the cyclic amine has two phenyl-pyridyl or biphenyl groups at both ends thereof. To date, none of these compounds have been known which have both an excellent cell adhesion-inhibiting effect and a cell infiltration-inhibiting effect.

In the general formula (1), for R¹，R²And R³The halogen atom of (b) includes fluorine, chlorine, bromine and iodine atoms.

To R¹，R²，R³And R⁴The alkyl group of (A) generally includes a straight chain, branched chain or cyclic C₁-C₈Alkyl radicals, e.g. straight-chain or branched C₁-C₈Alkyl radicals, such as the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl radicals, and C₃-C₈Cycloalkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl. Among them, C is preferable₁-C₆Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like.

To R¹，R²And R³The halogen-substituted alkyl group of (A) generally includes C substituted with 1 to 3 halogen atoms₁-C₈An alkyl group. Among them, C substituted by 1 to 3 halogen atoms is preferable₁-C₆Alkyl groups such as trifluoromethyl, 2, 2, 2-trifluoroethyl, and the like.

Alkoxy generally includes straight, branched or cyclic C₁-C₈Alkoxy, e.g. straight or branched C₁-C₈Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy; and C₃-C₈Cycloalkoxy, e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyCyclohexylmethoxy and cyclohexylethoxy. Among them, C is preferable₁-C₆Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

Alkylthio generally includes C₁-C₈Alkylthio, preferably C₁-C₆Alkylthio groups, such as methylthio, ethylthio, n-propylthio, isopropylthio and the like.

Alkoxycarbonyl typically comprises C₁-C₆Alkoxycarbonyl, preferably C₁-C₄Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.

Alkanoyl generally includes C₁-C₆Alkanoyl, preferably C₁-C₄Such as acetyl, propionyl, butyryl, isobutyryl, and the like.

To R⁴Alkenyl groups of (A) generally include C₃-C₈Alkenyl, preferably C₃-C₆Alkenyl groups such as 2-propenyl, 3-butenyl, and the like. Alkynyl generally includes C₃-C₈Alkynyl, preferably C₃-C₆Alkynyl groups such as 2-propynyl, 3-butynyl and the like.

To R⁴Aryl of (2) generally includes C₆-C₁₄Aryl is preferably phenyl, naphthyl, anthryl, indenyl, indanyl, 5, 6, 7, 8-tetrahydronaphthyl, etc.

To R⁴The heteroaryl group of (1) includes a 5-or 6-membered ring having 1 to 4 nitrogen atoms in the ring, preferably an imidazolyl group, a pyridyl group, a pyrimidyl group and the like. Aralkyl generally includes C₆-C₁₄aryl-C₁-C₆Alkyl radicals such as phenyl C₁-C₆Alkyl and naphthyl C₁-C₆Alkyl groups such as benzyl, naphthylmethyl, phenylethyl, phenylpropyl and the like. To R⁴The heteroaralkyl group of (a) generally includes heteroaryl groups having 5-or 6-membered rings containing 1 to 4 nitrogen atoms, e.g. imidazolyl-C₁-C₆Alkyl, pyridyl-C₁-C₆Alkyl radicalpyrimidinyl-C₁-C₆Alkyl groups, and the like.

The group which may be substituted for the above aryl, heteroaryl, aralkyl or heteroaralkyl group includes 1 to 3 groups or atoms selected from the group consisting of: alkyl, alkoxy, halo-substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, nitro, amino, acetamido, trifluoromethyl and alkylenedioxy, said alkyl, alkoxy and alkylthio groups including the group consisting of the group p-R¹-R³Those groups described. The alkyl group contained in the alkylsulfinyl and alkylsulfonyl group includes C₁-C₃Alkyl groups such as methyl, ethyl, n-propyl and isopropyl. Halogen-substituted alkoxy includes C substituted by 1-3 halogen atoms₁-C₈Alkoxy, preferably C, substituted by 1 to 3 halogen atoms₁-C₄Alkoxy, such as trifluoromethoxy or 2, 2, 2-trifluoroethoxy. The alkylenedioxy group generally comprises C₁-C₃Alkylenedioxy groups such as methylenedioxy, ethylenedioxy and propylenedioxy.

Preferably, X represents NR⁴. More preferably, X represents NR⁴，R⁴Represents substituted or unsubstituted C₆-C₁₄Aryl or a substituted or unsubstituted 5-or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring thereof. Wherein X represents NR⁴The compound of the general formula (1) has a particularly strong cell adhesion inhibitory effect as shown in test example 1 below.

Preferably, R is¹，R²And R³Attached at the 3, 4 and 5-positions of the phenyl group. In this case, preferably, R¹And R³(in the 3-and 5-positions of the phenyl ring) is an alkoxy group or a halogen. Preferably, R is²(at the 4-position of the phenyl ring) is a hydrogen atom, a halogen atom, or a hydroxyl group, an alkyl group, a halogen-substituted alkyl group, an alkoxy group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group or an alkanoyl group.

l represents 0 or 1, preferably 1.

Preferably, W¹Represents N. Preferably, W²Represents N.

Preferred compounds include compounds of the general formula (1) wherein X represents NR⁴，R⁴Represents substituted or unsubstituted C₆-C₁₄Aryl or a substituted or unsubstituted 5-or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring. Preferably, R is⁴Represents phenyl or pyridyl substituted by one or two groups or atoms selected from: halogen, alkyl, alkoxy, alkylthio, trifluoromethyl and alkylenedioxy.

There is no particular limitation on the acid addition salts of the compound (1) of the present invention as long as they are pharmaceutically acceptable salts. Examples include acid addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate and phosphate; addition salts of organic acids, for example, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate and acetate salts.

The compounds of formula (1) may exist as solvates, typically hydrates, and solvates are included within the scope of the present invention.

The compounds of formula (1) can be prepared according to the following methods A to L:

the method A comprises the following steps: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 1, and X ═ CONR⁴

Wherein, W¹，W²，R¹，R²，R³And R⁴According to the above definition, W³Has a sum of W¹Or W²In the same definition, B represents a leaving group such as a halogen atom, or a methanesulfonyloxy group or a p-toluenesulfonyloxy group.

The compound (2) reacts with the N- (2-nitryl) benzenesulfonyl amine derivative (3) to obtain a compoundAn object (4). The resulting compound (4) is treated with thiophenol in the presence of a base such as potassium carbonate to remove 2-nitrobenzenesulfonyl group, thereby obtaining an amine compound (5). Or, when R is⁴When it is H, the compound (2) may be reacted with phthalimide, and the resulting phthalimide derivative (6) may be treated with hydrazine to give the corresponding amine compound (5).

On the other hand, compound (2) is reacted with ethyl isopiperidinecarboxylate (7) in the presence of a base such as potassium carbonate or the like at 0 ℃ to reflux temperature in a solvent such as acetonitrile, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Tetrahydrofuran (THF), dioxane, toluene, benzene or the like for several hours to several days, preferably at room temperature overnight to give compound (8). The compound (8) is subjected to conventional alkaline hydrolysis to give the corresponding carboxyl compound (9).

The compound (9) is reacted with an amine compound (5) in a solvent such as chloroform, dichloroethane, THF, dioxane, acetonitrile or the like at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 12 hours, using a dehydration condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate ((2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate) (HBTU) or the like to obtain the final product (1A).

The method B comprises the following steps: compounds of general formula (1) were prepared wherein l ═ 1, m ═ 0, n ═ 1, and X ═ 0.

Wherein, B, W¹，W²，R¹，R²And R³J represents a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzoyl or benzyl according to the above definition.

Incidentally, the reactions described above and belowIn the process, "(W)²→W¹) "means W²In the formula representing the compound (2), W is substituted¹. A similar approach can be applied to the following reaction process.

The 4-hydroxypiperidine compound (10) having a protected amino group is reacted with the compound (2) in a solvent such as DMF, DMSO or the like at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 2 days in the presence of sodium hydride or potassium iodide to obtain the compound (11). The protecting group of compound (11) is removed in a known manner. The resulting compound (12) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., in the presence of a base such as potassium carbonate, at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give the final product (1B).

The method C comprises the following steps: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 0, X ═ NR⁴CO and R⁴H or Me

Wherein, B, W¹，W^2，，R¹，R²And R³According to the above definition, R⁴Represents a hydrogen atom or a methyl group.

In the presence of a base such as potassium carbonate, sodium carbonate, etc., isopiperidinecarboxamide (13) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (14). Compound (14) is subjected to Hofmann rearrangement reaction to give amine compound (15).

On the other hand, by subjecting the compound (14) to Hofmann rearrangement reaction in ethanol, the carbamate compound (16) is obtained. Then, the compound (16) is subjected to a reduction reaction using lithium aluminum hydride to obtain a methylamine compound (17).

The final compound (1C) is obtained by subjecting the carboxylic acid compound (18) to a condensation reaction with the amine compound (15) or methylamine compound (17) in a similar manner to the method a.

The method D comprises the following steps: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 1, and X ═ NR⁴

Wherein, B, W¹，W²，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl, aralkyl or heteroaralkyl.

The above amine compound (15) is reacted with 2-nitrobenzenesulfonyl chloride (19) in a known manner to obtain compound (20). Compound (20) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. in the presence of a base such as potassium carbonate at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give compound (21). The benzenesulfonyl group of compound (21) was removed in a similar manner to compound (4) in Process A to give the final compound (1D) (R)⁴H). Compound (1D) with R in the presence of a base such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate and the like⁴Reaction of-B in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO, etc. at 0 ℃ to reflux temperature for several hours to several days, preferably 80 ℃ for 12 hours gives compound (1D').

On the other hand, methylamine compound (17) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane and the like in the presence of a base such as potassium carbonate at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to obtain the final compound (1D ") (R ″) (R)⁴＝Me)。

The method E comprises the following steps: preparing a compound of formula (1) wherein l ═ 1, m ═ 0 or 1, n ═ 1, and X ═ NR⁴，

Wherein, B, J, W¹，W²，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl, aralkyl or heteroaralkyl.

Aminopiperidine derivatives (22) in which the amino group on the ring is protected are reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane and the like at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours in the presence of a base such as potassium carbonate to give compound (23). Compound (23) with R in the presence of a base such as sodium carbonate, sodium hydrogencarbonate, cesium carbonate or the like⁴Reaction of-B in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO or the like at 0 ℃ to reflux temperature for several hours to several days, preferably at 80 ℃ for 12 hours gives compound (24). After removing the protecting group of compound (24), the resulting compound is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours in the presence of a base such as potassium carbonate to give compound (1E).

Method F: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 1, and X ═ NR⁴，

Wherein, B, W¹，W²_，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl.

4-piperidone ethylene ketal (26) is reacted with the compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours in the presence of a base such as potassium carbonate to give a compound (27), which is subjected to de-ketalization by using an acid to give a ketone compound (28).

On the other hand, 4-piperidone (29) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours in the presence of a base such as potassium carbonate to give compound (28). Using this compound (28), an amine compound (30) can be produced according to any of the following synthetic methods:

the synthesis method 1: compound (28) and formula R⁴-NH₂The amine compound of (a) is reacted in toluene or benzene in the presence of a molecular sieve at a temperature of from 0 ℃ to reflux temperature for several hours to several days, preferably at reflux temperature for 12 hours, and then reacted with a reducing agent such as sodium borohydride or sodium cyanoborohydride at a temperature of from 0 ℃ to reflux temperature for several minutes to several days, preferably at room temperature for 1 hour, to give the amine compound (30).

The synthesis method 2 comprises the following steps: compound (28) and formula R⁴-NH₂The amine compound (30) is obtained by reacting in the presence of a reducing agent such as sodium triacetoxyborohydride (sodium triacetoxy boron hydride) in a solvent such as dichloromethane, 1, 2-dichloroethane, methanol, ethanol, etc., at 0 ℃ to reflux temperature for several minutes to several days, preferably at room temperature for 4 hours.

The resulting compound (30) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to obtain the final product (IF).

Method G: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 1, and X ═ NR⁴

Wherein, B, J, W¹，W²，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl.

4-piperidone derivative (31) having protected amino group, which was reacted with amine compound R according to a similar manner to the production of compound (30) in Process F⁴-NH₂Reaction to give compound (32). Compound (32) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. in the presence of a base such as potassium carbonate at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give compound (33). After removing the protecting group of compound (33), the resulting compound (34) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours in the presence of a base such as potassium carbonate to give the final product (1G).

Method H: preparing a compound of formula (1) wherein 1 ═ 0, m ═ 0, n ═ 1, and X ═ NH

Wherein, B, J, W¹，W²，R¹，R²And R³As defined above.

3-Aminopyrrolidine derivatives (35) having a protected amino group on the ring, which are reacted with 2-nitrobenzenesulfonyl chloride (19) under conventional conditions to give benzenesulfonyl derivatives (36). This derivative (36) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. in the presence of a base such as potassium carbonate at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give compound (37). The amino protecting group of compound (37) is removed to give compound (38), which is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give compound (39). Compound (39) is reacted according to a production method of compound (5) similar to method a to obtain final product (1H).

The method I comprises the following steps: preparing a compound of formula (1) wherein l ═ 0, m ═ 0, n ═ 1, and X ═ NR⁴

Wherein, B, J, W¹，_W²，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl or aralkyl.

Compound (36) with R in the presence of a base such as sodium carbonate, potassium carbonate or the like⁴Reaction of-B in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. at 0 ℃ to reflux temperature for several hours to several days, preferably at 80 ℃ for 12 hours, gives compound (40). The amino protecting group of compound (40) is removed, and the resulting compound (41) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours, in the presence of a base such as potassium carbonate, to give compound (42). Compound (42) is allowed to continue to react in a similar manner to the production of compound (5) in Process A to obtain compound (43). Compound (43) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., in the presence of a base such as potassium carbonate at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give the final product (1I).

Method J: preparation of a Compound of the general formula (1), wherein R²＝OH

Wherein, X, W¹，W²，R¹，R³L, m and n have the same meanings as defined above.

The methoxy compound (1J) is reacted with iodotrimethylsilane in a solvent such as toluene, chloroform, dichloromethane, etc., at-25 ℃ to reflux temperature for several minutes to several days, preferably at 0 ℃ for 2 hours to obtain the final product (1J').

Method K: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 0, and X ═ NR⁴CO

Wherein, B, J, W¹，W²，R¹，R²And R³According to the above definition, R⁴Represents alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl.

Compound (32) described in Process G is reacted with compound (18) successively in a similar manner to the process for the preparation of compound (1A) in Process A to give compound (44). After removing the protecting group of compound (44), the resulting compound (45) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at 0 ℃ to reflux temperature for several hours to several days, preferably at room temperature for 4 hours to give the final product (1K).

The method L comprises the following steps: preparing a compound of formula (1) wherein l ═ 1, m ═ 0, n ═ 1, and X ═ alkylsulfonylphenylamino

Wherein, B, W¹，W²，R¹，R²And R³As defined above.

Compound (34) synthesized according to method G, wherein X is an alkylthiophenylamino group, is reacted with an oxidizing agent such as 3-chloroperbenzoic acid, peracetic acid or hydrogen peroxide according to a known method to give an alkyl sulfoxide derivative (46). Compound (46) is reacted with compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF or dioxane at 0 ℃ to reflux temperature for several hours to several days, preferably at 70 ℃ overnight in the presence of a base such as potassium carbonate to give the final product (1L).

The compound (1) of the present invention can be prepared by any of the above-mentioned methods, and can be purified by a conventional purification method such as recrystallization or column chromatography, if necessary, and the compound can be converted into a desired salt or solvate according to a method known in the art.

When the compound (1) has an asymmetric carbon atom, the present invention includes any configurational isomer.

The compound (1) of the present invention, or a salt or solvate thereof, has an excellent cell adhesion-inhibiting effect as confirmed by the test examples described below, and is useful as a medicament for treating and preventing diseases caused by cell adhesion or cell infiltration, for example, asthma, allergy, rheumatism, arteriosclerosis, inflammation, Sjogren's complications and the like, in animals including human beings.

The medicament of the present invention contains the compound (1), a salt or a solvate thereof as an active ingredient. The administration form may be appropriately selected depending on the requirements of the therapeutic application without particular limitation, and includes oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops and plasters. Compositions suitable for use in these administration forms may be prepared by conventional methods of preparation known to those skilled in the art, in admixture with a pharmaceutically acceptable carrier.

When an oral solid preparation is formulated, an excipient, and optionally a binder, a disintegrant, a lubricant, a coloring agent, a taste corrigent, an odor corrigent, etc. are added to compound (1), and the resulting composition can be formulated into tablets, coated tablets, granules, powders, capsules, etc. according to a method known in the art. Any additive commonly used in the pharmaceutical field may be used as the above-mentioned additive. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid; binders such as water, ethanol, propanol, syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate and polyvinyl pyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, glyceryl monostearate and lactose; lubricants such as purified talc, stearate, borax and polyethylene glycol; and taste correctors such as sucrose, orange peel (orange peel), citric acid and tartaric acid.

When an oral liquid preparation is formulated, a flavoring agent, a buffer, a stabilizer, a flavoring agent and/or the like may be added to the compound (1), and the resulting composition may be formulated into a liquid preparation for oral administration, a syrup preparation, an elixir, and the like according to a method known in the art. In this case, vanilla extract can be used as flavoring agent. As the buffer, sodium citrate may be mentioned. Examples of stabilizers are gum tragacanth, gum acacia and gelatin.

When an injection is prepared, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, and the like may be added to the compound (1) of the present invention, and the resulting composition may be prepared into subcutaneous, intramuscular, and intravenous injections according to a method known in the art. In this case, examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, and sodium phosphate. Examples of stabilizers include sodium metabisulfite, EDTA, thioglycolic acid and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

When suppositories are formulated, carriers for formulation well known in the art, for example, polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride and the like, and optionally a surfactant such as Tween (trademark) and the like may be added to the compound (1), and the resulting composition may be prepared into suppositories according to methods well known in the art.

When an ointment is to be prepared, a base material, a stabilizer, a wetting agent, a preservative and the like which are generally used are mixed with the compound (1) as needed, and the resulting mixture is mixed and made into an ointment according to a known method. Examples of base materials include liquid paraffin, white petrolatum, bleached beeswax, octyldodecanol (octydedochylenealcohol) and paraffin wax. Examples of preservatives are methyl, ethyl and propyl p-hydroxybenzoate.

In addition to the above-mentioned formulations, inhalants, eye drops and nasal drops can be formulated according to methods well known in the art.

The dose of the drug of the present invention varies depending on the age, body weight and condition of the patient to be treated, administration method, administration frequency and the like. However, it is preferred that the medicament is administered orally or parenterally, usually 1 time or in several portions, in a dose of 1 to 1000 mg of compound (1) per day for adults.

Examples

The present invention will be described in detail below with reference to examples. However, the present invention is not limited to these examples.

Preparation example 1

Synthesis of ethyl 2- (3, 4, 5-trimethoxyphenyl) isonicotinate

3, 4, 5-Trimethoxyphenylboronic acid (20.10g) and ethyl 2-chloroisonicotinate (18.56g) were suspended in a mixed solvent of toluene (200mL) and THF (100mL), and 2M sodium carbonate (200mL) and tetrakis (triphenylphosphine) palladium (0) (5.78g) were added to the suspension. The mixture was stirred at 90 ℃ overnight under argon. Ethyl acetate was added to the reaction mixture to conduct extraction, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (5: 1) to give the title compound.

Yield: 27.99g (88%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(t，3H，J＝7.0Hz)，3.92(s，3H)，3.99(s，6H)，4.46(q，2H，J＝7.0Hz)，7.30(s，2H)，7.76(dd，1H，J＝5.1Hz，1.6Hz)，8.24(dd，1H，J＝1.6Hz，0.8Hz)，8.81(dd，1H，J＝5.1Hz，0.8Hz)。

Preparation example 2

Synthesis of 4-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine

Ethyl 2- (3, 4, 5-trimethoxyphenyl) isonicotinate (24.57g) was dissolved in dry THF (200mL) and lithium aluminum hydride (2.94g) was added to the solution at 0 ℃ under argon atmosphere. The mixture was stirred at 0 ℃ for 1 hour. After a small amount of water was added to the reaction mixture, sodium sulfate was added thereto, and the resultant insoluble matter was filtered off through celite. The filtrate was concentrated under reduced pressure, and the resulting crude crystals were recrystallized from ethyl acetate-hexane to give the title compound.

Yield: 17.53g (82%).

¹H-NMR(400MHz，CDCl₃)δ：3.90(s，3H)，3.95(s，6H)，4.79(s，2H)，7.19(d，1H，J＝5.1Hz)，7.21(s，2H)，7.66(s，1H)，8.60(d，1H，J＝5.1Hz)。

Preparation example 3

Synthesis of 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine

4-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (19.18g) was dissolved in chloroform (100mL), and thionyl chloride (thinly chloride) (10.2mL) was added to the solution at 0 ℃. After 30 minutes, the mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was then recrystallized from ethyl acetate-hexane to give the title compound as a pale yellow crystalline powder.

Yield: 18.24g (89%).

¹H-NMR(400MHz，CDCl₃)δ：3.91(s，3H)，3.97(s，6H)，4.61(s，2H)，7.24(s，2H)，7.26(d，1H，J＝5.1Hz)，7.68(s，1H)，8.67(d，1H，J＝5.1Hz)。

Preparation example 4

Synthesis of N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] phthalimide

To a solution of 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (881mg) in chloroform (10mL) was added potassium phthalimide (556 mg). The mixture was stirred at room temperature overnight and water was added. After separating the organic layer, the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a white powder.

Yield: 1.16g (96%).

Preparation example 5

Synthesis of 4-aminomethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine

To a solution of N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] phthalimide (1.16g) in ethanol (30mL) was added hydrazine monohydrate (1 mL). The mixture was refluxed for 3 hours. After cooling, insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow oil. Yield: 418mg (53%).

Preparation example 6

Synthesis of ethyl 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxylate

Ethyl piperidine-4-carboxylate (514mg), 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (969mg) and potassium carbonate (452mg) were suspended in acetonitrile (20 mL). The suspension was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then chloroform and water were added thereto, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (1: 1) and then chloroform-methanol (40: 1) to give the title compound as white prisms.

Yield: 1.20g (88%).

¹H-NMR(400MHz，CDCl₃)δ：1.25(t，3H，J＝7.0Hz)，1.72-1.93(m，4H)，2.10(t，2H，J＝9.8Hz)，2.27-2.35(m，1H)，2.86(d，2H，J＝11.3Hz)，3.55(s，2H)，3.91(s，3H)，3.98(s，6H)，4.14(q，2H，J＝7.0Hz)，7.21(d，1H，J＝4.9Hz)，7.24(s，2H)，7.63(s，1H)，8.59(d，1H，J＝5.1Hz)。

Preparation example 7

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxylic acid

To a solution of ethyl 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxylate (760mg) in ethanol (10mL) was added 1M sodium hydroxide (10 mL). The mixture was stirred at room temperature for 4 hours, and ethanol was removed by distillation under the reduced pressure. Water (20mL) was added to the residue, and a 5% aqueous solution of potassium hydrogensulfate was gradually added until the solution had a pH of 7. The precipitated crystals were collected by filtration and the product was used in the next reaction without purification. Yield: 779mg (theoretical amount).

Example 1

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methylaminocarbonyl ] piperidine maleate

To a solution of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxylic acid (97mg) and 4-aminomethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (68mg) in acetonitrile (5mL) was added 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium fluorophosphate (95 mg). The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (40: 1 to 20: 1). The title compound was obtained as the free base. Maleic acid is added to convert the free base to the maleate salt.

Yield: 93mg (49%).

¹H-NMR (400MHz, determined as maleate, DMSO-d)₆)δ：1.87-2.01(m，4H)，2.48-2.56(m，1H)，2.78-2.86(m，2H)，3.26-3.31(m，2H)，3.78(s，3H)，3.79(s，3H)，3.87(s，6H)，3.90(s，6H)，4.15(s，2H)，4.39(d，2H，J＝5.9Hz)，6.16(s，2H)，7.16(d，1H，J＝5.9Hz)，7.35(s，2H)，7.39(d，1H，J＝5.9Hz)，7.39(s，2H)，7.73(s，1H)，7.95(s，1H)，8.15(d，1H，J＝5.9Hz)，8.54(d，1H，J＝4.9Hz)，8.68(d，1H，J＝4.9Hz)。

Preparation example 8

Synthesis of 1- (benzyloxycarbonyl) -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methoxy ] piperidine

To a solution of 1- (benzyloxycarbonyl) -4-hydroxypiperidine (1.0g) in DMF (20mL) was added sodium hydride (55% dispersion in mineral oil, 222 mg). The mixture was stirred at room temperature for 1 hour, and then 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (1.37g) and potassium iodide (755mg) were added. The mixture was stirred at 70 ℃ overnight, water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (99: 1) as eluent. The title compound was obtained.

Yield: 213mg (10%).

¹H NMR(400MHz，CDCl₃)δ：1.63(br，2H)，1.89(br，2H)，3.20-3.35(m，2H)，3.57-3.68(m，1H)，3.84-3.92(m，5H)，3.94(s，6H)，4.62(s，2H)，5.11(s，2H)，7.21-7.35(m，8H)，7.61(s，1H)，8.61(d，1H，J＝5.0Hz)。

Preparation example 9

Synthesis of 4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methoxy ] piperidine

To a solution of 1- (benzyloxycarbonyl) -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methoxy ] piperidine (213mg) in methanol (10mL) was added 40% aqueous potassium hydroxide solution (10 mL). The mixture was stirred at 100 ℃ for 3 hours. After concentration under reduced pressure, water was added to the residue and extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with chloroform-ammonia saturated methanol (20: 1). The title compound was obtained.

Yield: 93mg (60%).

¹H NMR(400MHz，CDCl₃)δ：1.55-1.68(m，2H)，2.01(br，2H)，2.67-2.72(m，2H)，3.13-3.18(m，2H)，3.50-3.60(m，1H)，3.91(s，3H)，3.97(s，6H)，4.64(s，2H)，7.22(d，1H，J＝4.3Hz)，7.24(s，2H)，7.64(s，1H)，8.63(d，1H，J＝5.1Hz)。

Example 2

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methoxy ] piperidine trihydrochloride

4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methoxy ] piperidine (70mg), 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (22mg), potassium carbonate (56mg) and potassium iodide (40mg) were suspended in acetonitrile (5 mL). The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. Chloroform and water were added to the residue, and the organic layer was separated. Then, the aqueous layer was extracted with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (40: 1) as eluent. The resulting free base is converted to the trihydrochloride salt using conventional methods.

Yield: 42mg (39%).

¹H NMR (400MHz, determined as free base, CDCl)₃)δ：1.53-2.42(m，6H)，2.80(br，2H)，3.57(br，3H)，3.88(s，6H)，3.94(s，6H)，3.95(s，6H)，4.60(s，2H)，7.18-7.24(m，6H)，7.61(s，2H)，8.58-8.61(m，2H)。

Preparation example 10

Synthesis of (3S) -1- (tert-butoxycarbonyl) -3- [ (2-nitrophenyl) sulfonylamino ] pyrrolidine

To an ice-cooled solution of (3S) -3-amino-1- (tert-butoxycarbonyl) pyrrolidine (404mg) and triethylamine (220mg) in THF (5mL) was added 2-nitrobenzenesulfonyl chloride (481 mg). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the residue was added ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (20: 1) as eluent. The title compound was obtained as a pale yellow amorphous.

Yield: 597mg (74%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.80-2.12(m，2H)，3.14-3.44(m，4H)，4.02(br，1H)，5.48(d，1H，J＝7.2Hz)，7.77(t，2H，J＝4.4Hz)，7.87-7.90(m，1H)，8.17-8.19(m，1H)。

Preparation example 11

Synthesis of (3S) -1- (tert-butoxycarbonyl) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] pyrrolidine

To a suspension of (3S) -1- (tert-butoxycarbonyl) -3- [ (2-nitrophenyl) sulfonylamino ] pyrrolidine (371mg) and potassium carbonate (138mg) in acetonitrile (10mL) was added iodomethane (141 mg). The mixture was stirred at 60 ℃ for 2 hours and concentrated under reduced pressure. Ethyl acetate was added to the mixture. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (2: 1) as eluent. The title compound was obtained as a yellow oil.

Yield: 365mg (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.95(br，1H)，2.09(br，1H)，2.87(s，3H)，3.20-3.31(m，2H)，3.53(br，2H)，4.58(br，1H)，7.65(br，1H)，7.71(br，2H)，8.04(br，1H)。

Preparation example 12

Synthesis of (3S) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] pyrrolidine

Trifluoroacetic acid (1mL) was added to a solution of (3S) -1- (tert-butoxycarbonyl) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] pyrrolidine (365mg) in dichlorohexane (25mL) at 0 ℃. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and chloroform was added. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a yellow oil.

Yield: 135mg (50%).

¹H-NMR(400MHz，CDCl₃)δ：1.69-1.74(m，1H)，1.87(br，1H)，1.95-2.02(m，1H)，2.80(dd，1H，J＝11.7Hz，5.7Hz)，2.84-2.91(m，4H)，2.96-3.05(m，1H)，3.10(dd，1H，J＝11.7Hz，8.2Hz)，4.48-4.56(m，1H)，7.61-7.63(m，1H)，7.66-7.73(m，2H)，8.01-8.04(m，1H)。

Preparation example 13

Synthesis of (3S) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine

(3S) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] pyrrolidine (135mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (139mg) were treated in the same manner as described in example 2 to obtain the title compound as a yellow amorphous substance.

Yield: 247mg (96%).

¹H-NMR(400MHz，CDCl₃)δ：1.80-1.87(m，1H)，2.15-2.30(m，2H)，2.52(dd，1H，J＝10.5Hz，8.2Hz)，2.71(dd，1H，J＝10.5Hz，8.2Hz)，2.90(dt，1H，J＝8.8Hz，2.9Hz)，2.96(s，3H)，3.53(d，1H，J＝13.9Hz)，3.68(d，1H，J＝13.9Hz)，3.90(s，3H)，3.96(s，6H)，4.61-4.68(m，1H)，7.16(dd，1H，J＝4.9Hz，1.2Hz)，7.21(s，2H)，7.58-7.60(m，2H)，7.64-7.69(m，2H)，7.99-8.02(m，1H)，8.58(d，1H，J＝4.9Hz，)。

Preparation example 14

Synthesis of (3S) -3-methylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine

To a solution of (3S) -3- [ N-methyl-N- (2-nitrobenzenesulfonyl) amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine (242mg) in acetonitrile (5mL) was added potassium carbonate (94mg) and thiophenol (75 mg). The mixture was stirred at 80 ℃ for 1 hour. After cooling, ethyl acetate was added to the mixture, and the solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine. The residue was purified by TLC using chloroform-methanol (20: 1) as eluent to give the title compound as a yellow oil.

Yield: 104mg (64%).

¹H-NMR(400MHz，CDCl₃)δ：1.32(br，1H)，1.56-1.64(m，1H)，2.11-2.17(m，1H)，2.38(s，3H)，2.44(dd，1H，J＝7.4Hz，4.5Hz)，2.50-2.55(m，1H)，2.66-2.75(m，2H)，3.20-3.26(m，1H)，3.66(s，2H)，3.90(s，3H)，3.97(s，6H)，7.21(d，1H，J＝4.1Hz)，7.25(s，2H)，7.64(s，1H)，8.59(d，1H，J＝4.9Hz)。

Example 3

Synthesis of (3S) -3- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine Tetrahydrochloride

(3S) -3-methylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine (104mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (85mg) were reacted in the same manner as described in example 2. The product was converted to the tetrahydrochloride salt to give the title compound as a yellow powder.

Yield: 151mg (68%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.89-1.92(m，1H)，2.04-2.08(m，1H)，2.18(s，3H)，2.60-2.76(m，4H)，3.25-3.29(m，1H)，3.53(d，1H，J＝14.3Hz)，3.62(d，1H，J＝14.3Hz)，3.64(d，1H，J＝13.9Hz)，3.73(d，1H，J＝13.9Hz)，3.89(s，6H)，3.95(s，6H)，3.96(s，6H)，7.20-7.21(m，2H)，7.23(s，2H)，7.24(s，2H)，7.61(s，1H)，7.65(s，1H)，8.59(d，1H，J＝5.7Hz)，8.60(d，1H，J＝5.3Hz)。

Preparation example 15

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxamide (carboxamide):

piperidine-4-carboxamide (385mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (881mg) were reacted by the same method as in example 2 to obtain the title compound as white needles.

Yield: 1.01g (87%).

¹H-NMR(400MHz，CDCl₃)δ：1.70-1.88(m，4H)，2.01-2.23(m，3H)，2.95(d，2H，J＝11.0Hz)，3.56(s，2H)，3.90(s，3H)，3.98(s，6H)，5.46(d，2H，J＝16.3Hz)，7.21(d，1H，J＝5.0Hz)，7.24(s，2H)，7.64(s，1H)，8.59(d，1H，J＝5.0Hz)。

Preparation example 16

Synthesis of 4-amino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxamide (192mg) to a solution of water (50mL) and acetonitrile (50mL) in a mixed solvent was added [ bis (trifluoroacetato) iodo ] benzene (323 mg). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate, and the residue was basified and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The yellow oil thus obtained was converted into the hydrochloride salt as a yellow powder. The title compound was used in the next reaction without purification.

Yield: 201mg (theoretical amount).

Preparation example 17

Synthesizing 2- (3, 4, 5-trimethoxyphenyl) isonicotinic acid:

to a solution of ethyl 2- (3, 4, 5-trimethoxyphenyl) isonicotinate (3.17g) in ethanol (40mL) was added 10% potassium hydroxide (2.42 g). The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. Water was added to the residue and the pH was adjusted to 7. The resulting white precipitate was filtered. The title compound was produced and used in the next reaction without further purification.

Yield: 2.60g (90%).

Example 4

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] -carbonylamino ] piperidine maleate:

2- (3, 4, 5-trimethoxyphenyl) pyridine-4-carboxylic acid (72mg) and 4-amino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (117mg) were reacted in the same manner as described in example 1. The product was converted to the maleate salt to give the title compound.

Yield: 173mg (93%).

¹H-NMR (400MHz, determined as maleate, DMSO-d)₆)δ：1.82-1.94(m，2H)，2.03-2.08(m，2H)，2.77-2.83(m，2H)，3.20-3.27(m，2H)，3.79(s，6H)，3.90(s，12H)，4.00(br，1H)，4.06(s，2H)，6.15(s，2H)，7.36-7.38(m，1H)，7.39(s，2H)，7.41(s，2H)，7.61-7.63(m，1H)，7.90(s，1H)，8.12(s，1H)，8.27-8.32(m，1H)，8.67(d，1H，J＝4.9Hz)，8.74(d，1H，J＝5.1Hz)。

Preparation example 18

Synthesis of 4- [ (2-nitrobenzenesulfonyl) amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

4-amino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (467mg) and 2-nitrobenzenesulfonyl chloride (244mg) were reacted in the same manner as described in preparation example 10 to give the title compound.

Yield: 494mg (91%).

Preparation example 19

Synthesis of 4- [ N- (2-nitrobenzenesulfonyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) -pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

4- [ (2-Nitrobenzene) sulfonylamino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (494mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (267mg) were reacted by the same way with the one described in example 2 to give the title compound.

Yield: 443mg (61%).

Example 5-

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ [2- (3, 4, 5-

Trimethoxyphenyl) pyridin-4-yl ] methylamino ] piperidine difumarate:

4- [ N- (2-Nitrophenylsulfonyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (443mg) was reacted in the same manner as described in preparation example 14. The title compound was obtained as difumarate salt.

Yield: 103mg (24%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.44-1.53(m，2H)，1.87-1.91(m，2H)，2.15(t，2H，J＝1.1Hz)，2.57-2.64(m，1H)，2.82-2.85(m，2H)，3.59(s，2H)，3.78(s，6H)，3.89(s，12H)，3.90(s，2H)，6.63(s，4H)，7.24(d，1H，J＝4.9Hz)，7.29(d，1H，J＝4.9Hz)，7.35(s，2H)，7.37(s，2H)，7.76(s，1H)，7.85(s，1H)，8.53-8.56(m，2H)。

Preparation example 20

Synthesis of 4- (ethoxycarbonylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxamide (528mg) to a solution of [ bis (trifluoroacetoxy) iodo ] benzene (884mg) in a mixed solvent of ethanol (10mL) and acetonitrile (10 mL). The mixture was stirred at room temperature overnight. After concentration under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (20: 1) as eluent to give the title compound.

Yield: 566mg (96%).

¹H-NMR(400MHz，CDCl₃)δ：1.21(t，3H，J＝7.0Hz)，1.40-1.51(m，2H)，1.92(d，2H，J＝10.9Hz)，2.15(t，2H，J＝10.9Hz)，2.78(d，2H，J＝11.6Hz)，3.52(br，3H)，3.87(s，3H)，3.94(s，6H)，4.07(q，2H，J＝7.0Hz)，4.56(br，1H)，7.17(d，1H，J＝4.9Hz)，7.21(s，2H)，7.59(s，1H)，8.56(d，1H，J＝5.1Hz)。

Preparation example 21

Synthesis of 4- (methylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

to a suspension of lithium aluminum hydride (100mg) in dry THF (50mL) under argon was gradually added a solution of 4- (ethoxycarbonylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (566mg) in dry THF (50 mL). The mixture was refluxed overnight and allowed to cool. To the mixture was added a saturated aqueous solution of ammonium chloride, and the resultant mixture was extracted with ethyl acetate after bubbling was stopped. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-ammonia saturated methanol (9: 1) to give the title compound as a yellow oil.

Yield: 379mg (78%).

¹H-NMR(400MHz，CDCl₃)δ：1.36-1.46(m，2H)，1.89(d，2H，J＝12.5Hz)，2.10(dt，2H，J＝11.5Hz，1.1Hz)，2.35-2.43(m，1H)，2.43(s，3H)，2.86(d，2H，J＝11.6Hz)，3.56(s，2H)，3.90(s，3H)，3.97(s，6H)，7.21(d，1H，J＝5.1Hz)，7.24(s，2H)，7.64(s，1H)，8.59(d，1H，J＝4.9Hz)。

Preparation example 22

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone ethylidene ketal:

4-Piperidinoethylethylene ketal (12.0g) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (12.3g) were reacted by the same way with the one described in example 2 to obtain the title compound.

Yield: 19.0g (theoretical amount).

¹H-NMR(400MHz，CDCl₃)δ：1.68(t，4H，J＝5.6Hz)，2.48(br，4H)，3.50(s，2H)，3.82(s，3H)，3.86(s，4H)，3.88(s，6H)，7.13(d，1H，J＝4.9Hz)，7.17(s，2H)，7.57(s，1H)，8.51(d，1H，J＝4.9Hz)。

Preparation example 23

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone:

to a solution of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone ethylene ketal (19.0g) in THF (200mL) was added 1M hydrochloric acid (200 mL). The mixture was stirred at 90 ℃ overnight, then neutralized with 2M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (40: 1) as eluent to give the title compound.

Yield: 15.0g (75%).

¹H-NMR(400MHz，CDCl₃)δ：2.48(t，4H，J＝6.1Hz)，2.79(t，4H，J＝6.0Hz)，3.69(s，2H)，3.89(s，3H)，3.96(s，6H)，7.24(s，2H)，7.26(d，1H，J＝4.9Hz)，7.66(s，1H)，8.62(d，1H，J＝4.9Hz)。

Preparation example 24

Synthesis of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone:

4-Piperidinone hydrochloride-hydrate (3.07g) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (2.94g) were reacted in the same manner as described in example 2 to give the title compound.

Yield: 3.55g (99%).

Preparation example 25

Synthesis of 4- (methylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

to a solution of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (1.00g) in 1, 2-dichloroethane (60mL) were added a solution of 30% methylamine in ethanol (750mg) and sodium triacetoxyborohydride (1.66 g). The mixture was stirred at room temperature for 3 hours, water was added and concentrated under reduced pressure. After addition of water, the residue was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (40: 1) as eluent to give the title compound.

Yield: 640mg (62%).

Preparation example 26

Synthesis of ethyl 3- (3, 4, 5-trimethoxyphenyl) benzoate:

3, 4, 5-trimethoxyphenylboronic acid (3.7g) and ethyl 3-bromobenzoate (4.02g) were reacted in the same manner as described in preparation example 1 to give the title compound.

Yield: 5.09g (92%).

¹H-NMR(400MHz，CDCl₃)δ：1.42(t，3H，J＝7.1Hz)，3.90(s，3H)，3.94(s，6H)，4.41(q，2H，J＝7.1Hz)，6.79(s，2H)，7.50(t，1H，J＝7.8Hz)，7.73(dt，1H，J＝7.1Hz，1.5Hz)，8.01(dt，1H，J＝7.8Hz，1.4Hz)，8.23(t，1H，J＝1.8Hz)。

Preparation example 27

Synthesis of 3- (3, 4, 5-trimethoxyphenyl) benzoic acid:

ethyl 3- (3, 4, 5-trimethoxyphenyl) benzoate (1.19g) was treated in the same manner as described in preparation example 17 to give the title compound.

Yield: 986mg (91%).

Example 6

Synthesis of 4- [ N-methyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzoyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

3- (3, 4, 5-trimethoxyphenyl) benzoic acid (1.03g) and 4- (methylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (1.32g) were reacted in the same manner as described in example 1 to give the title compound as the dihydrochloride.

Yield: 1.44g (57%).

¹H-NMR (400MHz, determined as dihydrochloride, DMSO-d)₆)δ：1.89(d，2H，J＝11.7Hz)，2.54-2.62(m，2H)，2.89(s，3H)，3.09(t，2H，J＝12.7Hz)，3.43(d，2H，J＝14.4Hz)，3.76(s，3H)，3.78(s，3H)，3.88(s，6H)，3.91(s，6H)，4.34(br，3H)，6.91(s，2H)，7.33(d，1H，J＝7.6Hz)，7.47-7.51(m，2H)，7.54(s，2H)，7.60(s，1H)，7.71(d，1H，J＝7.8Hz)，8.55(s，1H)，8.68(d，1H，J＝5.1Hz)。

Example 7

Synthesis of 4- [ N-methyl-N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine difumarate:

4-methylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (135mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (107mg) were reacted in the same manner as described in example 2 to obtain the title compound as a difumarate salt.

Yield: 180mg (58%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.69-1.73(m，2H)，1.82-1.85(m，2H)，2.03-2.08(m，2H)，2.25(s，3H)，2.48-2.51(m，1H)，2.97-2.99(m，2H)，3.56(s，2H)，3.67(s，2H)，3.90(s，3H)，3.91(s，3H)，3.94(s，6H)，3.98(s，6H)，6.76(s，2H)，7.22(d，1H，J＝5.1Hz)，7.24(s，2H)，7.62(s，1H)，7.80(s，1H)，8.50(d，1H，J＝2.0Hz)，8.60(d，1H，J＝4.3Hz)，8.69(d，1H，J＝5.1Hz)。

Preparation example 28

Synthesis of 1-bromo-4-chloro-3, 5-dimethoxybenzene:

a solution of sodium nitrite (97mg) in water (2.0mL) was added dropwise to an ice-cooled suspension of 4-bromo-2, 6-dimethoxyaniline (232mg) in 6.0M hydrochloric acid (2.5mL) to which crushed ice was added. After stirring the mixture in an ice bath for 30 minutes, a solution of copper chloride (495mg) in concentrated hydrochloric acid (2.0mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at 100 ℃ for 2 hours, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (10: 1) as eluent to give the title compound as a white powder.

Yield: 230mg (92%).

Preparation example 29

Synthesis of 4-chloro-3, 5-dimethoxyphenylboronic acid:

A1.57M solution of n-butyllithium in hexane (0.8mL) was added dropwise to dry THF (2mL) cooled in a dry ice-methanol bath under argon, followed by a solution of 1-bromo-4-chloro-3, 5-dimethoxybenzene (160mg) in dry THF (2 mL). After the mixture was stirred in a dry ice-methanol bath for 20 minutes, triisopropyl borate (0.18mL) was added and the mixture was stirred for an additional 20 minutes. Then, the reaction mixture was stirred at room temperature for 1 hour, and its pH was adjusted to 3 with 4M hydrochloric acid. The mixture was stirred at 0 ℃ for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as a white powder.

Yield: 90mg (66%).

Preparation example 30

Synthesis of ethyl 2- (4-chloro-3, 5-dimethoxyphenyl) isonicotinate:

4-chloro-3, 5-dimethoxyphenylboronic acid (7.45g) and ethyl 2-chloroisonicotinate (6.39g) were treated in the same manner as described in preparation example 1 to give the title compound.

Yield: 8.55g (77%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(t，3H，J＝7.3Hz)，4.03(s，6H)，4.45(q，2H，J＝7.3Hz)，7.32(s，2H)，7.80(d，1H，J＝5.1Hz)，8.27(s，1H)，8.83(d，1H，J＝5.0Hz)。

Preparation example 31

Synthesis of 2- (4-chloro-3, 5-dimethoxyphenyl) isonicotinic acid:

to a solution of ethyl 2- (4-chloro-3, 5-dimethoxyphenyl) isonicotinate (8.55g) in ethanol (80mL) was added 2M sodium hydroxide (100 mL). The mixture was stirred under reflux for 30 minutes, and ethanol was distilled off under reduced pressure. The mixture was neutralized by adding 1M hydrochloric acid. The resulting precipitate was dissolved in a mixed solvent of ethyl acetate-THF (3: 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound.

Yield: 7.20g (92%).

¹H-NMR(400MHz，CDCl₃)δ：4.02(s，6H)，7.34(s，2H)，7.83(d，1H，J＝4.9Hz)，7.84(s，1H)，8.82(d，1H，J＝4.9Hz)。

Preparation example 32

Synthesis of 2- (4-chloro-3, 5-dimethoxyphenyl) -4-hydroxymethylpyridine:

to a solution of 2- (4-chloro-3, 5-dimethoxyphenyl) isonicotinic acid (7.20g) and triethylamine (5.6mL) in THF (70mL) at 0 deg.C was added ethyl chloroformate (2.8 mL). The mixture was stirred at room temperature for 1 hour, and insoluble matter was removed by filtration. Then, a solution of sodium borohydride (1.25g) in water (4mL) was added to the filtrate. The mixture was stirred at room temperature for a further 1 hour and concentrated under reduced pressure. After addition of water, the residue was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (20: 1 to 15: 1) to give the title compound.

Yield: 4.10g (60%).

¹H-NMR(400MHz，CDCl₃+DMSO-d₆)δ：4.01(s，6H)，4.76(s，2H)，7.20-7.35(m，3H)，7.78(s，1H)，8.62(s，1H)。

Preparation example 33

Synthesis of 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine:

2- (4-chloro-3, 5-dimethoxyphenyl) -4-hydroxymethylpyridine (4.10g) was dissolved in chloroform (20mL), thionyl chloride (5.2mL) was added, and the mixture was stirred at 70 ℃ for 1 hour. After the mixture was concentrated under reduced pressure, the resultant residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.

Yield: 4.20g (96%).

¹H-NMR(400MHz，CDCl₃)δ：4.02(s，6H)，4.63(s，2H)，7.26(s，2H)，7.29(d，1H，J＝4.9Hz)，7.72(s，1H)，8.69(d，1H，J＝4.9Hz)。

Preparation example 34

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxamide:

piperidine-4-carboxamide (301mg) and 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine (600mg) were reacted in the same manner with example 2 to obtain the title compound.

Yield: 743mg (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.75-1.90(m，4H)，2.07-2.25(m，3H)，2.94(d，2H，J＝11.6Hz)，3.57(s，2H)，4.02(s，6H)，7.24-7.31(m，3H)，7.67(s，1H)，8.61(d，1H，J＝5.1Hz)。

Preparation example 35

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- (ethoxycarbonylamino) piperidine:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxamide (743mg) was treated in the same manner as described in preparation 20 to give the title compound.

Yield: 887mg (theoretical amount).

¹H-NMR(400MHz，CDCl₃)δ：1.24(t，3H，J＝7.1Hz)，1.43-1.59(m，2H)，1.96(d，2H，J＝11.4Hz)，2.19(t，2H，J＝11.0Hz)，2.82(d，2H，J＝11.5Hz)，3.56(s，2H)，4.02(s，6H)，4.10(q，2H，J＝7.1Hz)，7.26(s，2H)，7.66(s，1H)，7.71(dd，1H，J＝5.6Hz，1.0Hz)，8.6(dd，1H，J＝4.9Hz，0.5Hz)。

Preparation example 36

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-methylaminopiperidine:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- (ethoxy-carbonylamino) piperidine (887mg) was treated in the same manner as described in preparation 21 to give the title compound.

Yield: 195mg (27%).

¹H-NMR(400MHz，CDCl₃)δ：1.35-1.49(m，2H)，1.89(d，2H，J＝12.3Hz)，2.11(t，2H，J＝9.4Hz)，2.38-2.45(m，1H)，2.44(s，3H)，2.87(d，2H，J＝10.7Hz)，3.57(s，2H)，4.02(s，6H)，7.23-7.29(m，3H)，7.68(s，1H)，8.61(d，1H，J＝4.9Hz)。

Example 8

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ N- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N-methylamino ] piperidine tetrahydrate hydrochloride:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-methylamino-piperidine (195mg) and 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine (152mg) were reacted in the same manner as described in example 2. The free base obtained was converted to the tetrahydrochloride salt to give the title compound as a yellow powder.

Yield: 300mg (75%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.90(m，4H)，2.06(t，2H，J＝11.7Hz)，2.26(s，3H)，2.45-2.55(m，1H)，2.97(d，2H，J＝11.3Hz)，3.57(s，2H)，3.67(s，2H)，4.01(s，6H)，4.02(s，6H)，7.24-7.28(m，6H)，7.65(s，1H)，7.67(s，1H)，8.61(d，1H，J＝5.4Hz)，8.62(d，1H，J＝5.4Hz)。

Preparation example 37

Synthesis of 4- (p-methoxybenzylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -piperidine:

to a solution of 1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl-4-piperidone (2.17g) in toluene (40mL) was added p-methoxyaniline (900mg) and molecular sieve 4A (6.0 g). The mixture was refluxed overnight, then filtered to remove the molecular sieve and the filtrate was evaporated. The residue was dissolved in ethanol (40mL), and sodium borohydride (276mg) was added. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. Water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (50: 1) to give the title compound.

Yield: 1.56g (55%).

¹H-NMR(400MHz，CDCl₃)δ：1.48(br，2H)，2.05(br，2H)，2.20(br，2H)，2.86(br，2H)，3.23(s，1H)，3.58(s，2H)，3.74(s，3H)，3.91(s，3H)，3.97(s，6H)，6.58(d，2H，J＝8.8Hz)，6.77(d，2H，J＝9.0Hz)，7.22(d，1H，J＝5.1Hz)，7.26(s，2H)，7.64(s，1H)，8.59(d，1H，J＝4.9Hz)。

Preparation example 38

Synthesizing 2- (3, 4, 5-trimethoxyphenyl) ethyl nicotinate:

3, 4, 5-trimethoxyphenylboronic acid (694mg) and ethyl 2-chloronicotinate (608mg) were reacted in the same manner as described in preparation example 1 to give the title compound.

Yield: 799mg (77%).

¹H-NMR(400MHz，CDCl₃)δ：1.10(t，3H，J＝7.2Hz)，3.89(s，9H)，4.19(q，2H，J＝7.2Hz)，6.79(s，2H)，7.34(dd，1H，J＝7.8Hz，4.8Hz)，8.06(dd，1H，J＝7.8Hz，1.7Hz)，8.75(dd，1H，J＝4.8Hz，1.7Hz)。

Preparation example 39

Synthesizing 3-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine:

ethyl 2- (3, 4, 5-trimethoxyphenyl) nicotinate (468mg) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield: 293mg (72%).

¹H-NMR(400MHz，CDCl₃)δ：3.90(s，9H)，4.72(s，2H)，6.83(s，2H)，7.32(dd，1H，J＝7.9Hz，4.8Hz)，7.92(dd，1H，J＝7.9Hz，1.7Hz)，8.62(dd，1H，J＝4.8Hz，1.7Hz)。

Preparation example 40

Synthesis of 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine:

3-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (293mg) was treated in the same manner as described in preparation example 3 to give the title compound.

Yield: 311mg (theoretical amount).

Example 9

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (139mg) and 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in a solution of acetonitrile (5ml) were added potassium carbonate (83mg) and potassium iodide (63 mg). The mixture was stirred at 70 ℃ overnight and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ether-methanol (20: 1) as eluent. The obtained free base was converted into the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 16mg (8%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60(br，2H)，1.77(br，2H)，2.09(br，2H)，2.93(br，2H)，3.45(br，1H)，3.54(s，2H)，3.73(s，3H)，3.90(s，6H)，3.91(s，6H)，3.96(s，6H)，4.34(s，2H)，6.65(d，2H，J＝9.0Hz)，6.71(s，2H)，6.74(d，2H，J＝9.0Hz)，7.16-7.19(m，2H)，7.22(s，2H)，7.55(s，1H)，7.79(d，1H，J＝7.0Hz)，8.50(br，1H)，8.58(d，1H，J＝4.9Hz)。

Example 10

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (1.56g) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (1.08g) were reacted in the same manner as in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder. Yield: 1.17g (40%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.68-1.97(m，4H)，2.09-2.23(m，2H)，2.98(br，2H)，3.54-3.66(m，3H)，3.73(s，3H)，3.89(s，3H)，3.90(s，3H)，3.93(s，6H)，3.96(s，6H)，4.45(s，2H)，6.74(d，2H，J＝9.2Hz)，6.79(d，2H，J＝9.2Hz)，7.15(s，2H)，7.16-7.21(m，2H)，7.23(s，2H)，7.57(s，1H)，7.60(s，1H)，8.54(d，1H，J＝5.1Hz)，8.59(d，1H，J＝4.9Hz)。

Preparation example 41

Synthesis of 3- (3, 4, 5-trimethoxyphenyl) benzyl alcohol:

ethyl 3- (3, 4, 5-trimethoxyphenyl) benzoate (5.09g) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield: 4.25g (97%).

¹H-NMR(400MHz，CDCl₃)δ：1.87(t，1H，J＝6.0Hz)，3.89(s，3H)，3.92(s，6H)，4.76(d，1H，J＝5.6Hz)，6.77(s，2H)，7.34(d，1H，J＝7.4Hz)，7.42(t，1H，J＝7.5Hz)，7.48(d，1H，J＝7.6Hz)，7.55(s，1H)。

Preparation example 42

Synthesis of 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride:

3- (3, 4, 5-trimethoxyphenyl) benzyl alcohol (1.21g) was treated in the same manner as in preparation example 3 to give the title compound.

Yield: 893mg (69%).

¹H-NMR(400MHz，CDCl₃)δ：3.87(s，3H)，3.90(s，6H)，4.62(s，2H)，6.75(s，2H)，7.33(d，1H，J＝7.6Hz)，7.39(t，1H，J＝7.7Hz)，7.48(d，1H，J＝7.6Hz)，7.54(s，1H)。

Example 11

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (139mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the dihydrochloride salt to give the title compound as a yellow powder.

Yield: 52mg (22%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.77-1.92(m，5H)，2.14-2.20(m，2H)，2.95-3.00(m，5H)，2.14-2.20(m，2H)，2.95-3.00(m，2H)，3.58(s，2H)，3.72(s，3H)，3.88(s，3H)，3.89(s，6H)，3.90(s，3H)，3.96(s，6H)，4.47(s，2H)，6.70(s，2H)，6.74-6.83(m，4H)，7.20(d，1H，J＝7.4Hz)，7.23(s，2H)，7.25-7.27(m，1H)，7.33(t，1H，J＝7.4Hz)，7.38(d，1H，J＝8.7Hz)，7.43(s，1H)，7.62(s，1H)，8.59(d，1H，J＝5.1Hz)。

Preparation example 43

Synthesis of ethyl 6- (3, 4, 5-trimethoxyphenyl) nicotinate:

3, 4, 5-trimethoxyphenylboronic acid (1.16g) and ethyl 6-chloronicotinate (1.02g) were reacted in the same manner as described in preparation example 1 to obtain the title compound.

Yield: 1.42g (82%).

¹H-NMR(400MHz，CDCl₃)δ：1.43(t，3H，J＝7.2Hz)，3.92(s，3H)，3.98(s，6H)，4.44(q，2H，J＝7.2Hz)，7.32(s，2H)，7.76(d，1H，J＝8.3Hz)，8.33(dd，1H，J＝8.2Hz，2.2Hz)，9.26(d，1H，J＝2.2Hz)。

Preparation example 44

Synthesizing 5-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine:

ethyl 6- (3, 4, 5-trimethoxyphenyl) nicotinate (658mg) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield: 482mg (85%).

¹H-NMR(400MHz，CDCl₃)δ：3.91(s，3H)，3.97(s，6H)，4.76(s，2H)，7.23(s，2H)，7.68(d，1H，J＝7.4Hz)，7.78(dd，1H，J＝7.4Hz，2.3Hz)，8.63(d，1H，J＝2.3Hz)。

Preparation example 45

Synthesis of 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine:

5-hydroxymethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (685mg) was treated in the same manner as described in preparation example 3 to give the title compound.

Yield: 717mg (theoretical amount).

Example 12

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (139mg) and 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 13mg (5%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.76(br，2H)，1.88(br，2H)，2.14(br，2H)，2.97(br，2H)，3.51(br，1H)，3.57(s，2H)，3.73(s，3H)，3.89(s，3H)，3.90(s，3H)，3.94(s，6H)，3.96(s，6H)，4.42(s，2H)，6.78(br，4H)，7.20(br，3H)，7.23(s，2H)，7.57-7.70(m，3H)，8.58-8.60(m，2H)。

Preparation example 46

Synthesis of ethyl 5- (3, 4, 5-trimethoxyphenyl) nicotinate:

3, 4, 5-trimethoxyphenylboronic acid (6.36g) and ethyl 5-bromonicotinate (6.90g) were reacted in the same manner as described in preparation example 1 to give the title compound.

Yield: 7.19g (76%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(t，3H，J＝7.1Hz)，3.91(s，3H)，3.95(s，6H)，4.46(q，2H，J＝7.1Hz)，6.79(s，2H)，8.44(t，1H，J＝2.1Hz)，8.96(d，1H，J＝2.1Hz)，9.18(d，1H，J＝1.8Hz)。

Preparation example 47

Synthesizing 3-hydroxymethyl-5- (3, 4, 5-trimethoxyphenyl) pyridine:

ethyl 5- (3, 4, 5-trimethoxyphenyl) nicotinate (7.19g) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield; 3.83g (61%).

¹H-NMR(400MHz，CDCl₃)δ：3.88(s，3H)，3.89(s，6H)，4.39(br，1H)，4.80(s，2H)，6.72(s，2H)，7.89(t，1H，J＝1.2Hz)，8.47(d，1H，J＝2.1Hz)，8.63(d，1H，J＝2.2Hz)。

Preparation example 48

Synthesis of 3-chloromethyl-5- (3, 4, 5-trimethoxyphenyl) pyridine:

3-hydroxymethyl-5- (3, 4, 5-trimethoxyphenyl) pyridine (2.85g) was treated in the same manner as described in preparation example 3 to give the title compound.

Yield: 1.97g (65%).

¹H-NMR(400MHz，CDCl₃)δ：3.90(s，3H)，3.94(s，6H)，4.67(s，2H)，6.75(s，2H)，7.87(t，1H，J＝2.1Hz)，8.59(d，1H，J＝2.0Hz)，8.76(d，1H，J＝2.1Hz)。

Example 13-

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [5- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (139mg) and 3-chloromethyl-5- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the trihydrochloride to give the title compound as a yellow powder.

Yield: 14mg (5%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)；1.73-1.75(m，2H)，1.88(d，2H，J＝11.3Hz)，2.13(t，2H，J＝11.3Hz)，2.96(d，2H，J＝11.5Hz)，3.50(br，1H)，3.55(s，2H)，3.72(s，3H)，3.88(s，3H)，3.89(s，9H)，3.96(s，6H)，4.45(s，2H)，6.65(s，2H)，6.76(d，2H，J＝9.6Hz)，6.80(d，2H，J＝9.4Hz)，7.20(d，1H，J＝5.3Hz)，7.22(s，2H)，7.59(s，1H)，7.67(s，1H)，8.50(s，1H)，8.59(d，1H，J＝4.7Hz)，8.62(s，1H)。

Preparation example 49

Synthesis of 4-iodo-2, 6-dimethoxyphenol:

to a solution of 5-iodo-1, 2, 3-trimethoxybenzene (3.2g) in 1, 2-dichloroethane (40mL) was added aluminum chloride (1.6 g). The mixture was stirred at 60 ℃ for 4 hours and concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was acidified and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a white crystalline powder.

Yield: 1.0g (31%)

Preparation example 50

Synthesis of 1, 3-dimethoxy-5-iodo-2-isopropoxybenzene:

to a solution of 2, 6-dimethoxy-4-iodophenol (1.0g) and potassium carbonate (938mg) in DMF (10mL) was added 2-iodopropane (507 mL). The mixture was stirred at 60 ℃ for 3 hours and concentrated under reduced pressure. To the residue were added ethyl acetate and water, and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (5: 1) as eluent to give the title compound.

Yield: 788mg (72%).

Preparation example 51

Synthesis of 3, 5-dimethoxy-4-isopropoxyphenylboronic acid:

1, 3-dimethoxy-5-iodo-2-isopropoxybenzene (2.25g) was treated in the same manner as in preparation 29 to give the title compound in preparation 29.

Yield: 1.23g (74%).

Preparation example 52

Synthesis of ethyl 2- (3, 5-dimethoxy-4-isopropoxyphenyl) isonicotinate:

3, 5-dimethoxy-4-isopropoxyphenylboronic acid (1.23g) and ethyl 2-chloroisonicotinate (0.95g) were reacted in the same manner as described in preparation example 1 to give the title compound.

Yield: 1.57g (89%).

¹H-NMR(400MHz，CDCl₃)δ：1.33(d，6H，J＝4.9Hz)，1.44(t，3H，J＝7.1Hz)，3.95(s，6H)，4.42-4.49(m，3H)，7.29(s，2H)，7.75(dd，1H，J＝4.9Hz，1.4Hz)，8.24(s，1H)，8.80(d，1H，J＝4.9Hz)。

Preparation example 53

Synthesis of 2- (3, 5-dimethoxy-4-isopropoxyphenyl) -4-hydroxymethylpyridine:

a solution of 2- (4-isopropoxy-3, 5-dimethoxyphenyl) isonicotinate (1.57g) in THF (30mL) was added dropwise to a suspension of lithium aluminum hydride (190mg) in THF (20mL) under ice-cooling under argon atmosphere. The mixture was stirred at 0 ℃ for 30 minutes, and a saturated aqueous solution of ammonium chloride was added. After the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (3: 1) then chloroform-methanol (15: 1) to give the title compound.

Yield: 1.31g (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.32(d，6H，J＝6.1Hz)，3.93(s，6H)，4.45(quint，1H，J＝6.1Hz)，4.81(s，2H)，7.20(d，1H，J＝5.1Hz)，7.23(s，2H)，7.68(s，1H)，8.62(d，1H，J＝5.1Hz)。

Preparation example 54

Synthesis of 4-chloromethyl-2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridine:

2- (3, 5-dimethoxy-4-isopropoxyphenyl) -4-hydroxymethylpyridine (1.49g) was treated in the same manner as in preparation example 3 to give the title compound.

Yield: 1.33g (84%).

¹H-NMR(400MHz，CDCl₃)δ：1.32(d，6H，J＝6.2Hz)，3.94(s，6H)，4.45(quint，1H，J＝6.1Hz)，4.61(s，2H)，7.23-7.26(m，3H)，7.69(s，1H)，8.66(d，1H，J＝5.1Hz)。

Preparation example 55

Synthesis of 1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] -4-

Piperidone ethylene ketal:

4-chloromethyl-2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridine (643mg) and 4-piperidone ethylene ketal (287mg) were reacted by the same way with the example 2 to give the title compound.

Yield: 818mg (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.32(d，6H，J＝6.1Hz)，1.78(t，4H，J＝5.7Hz)，2.57(br，4H)，3.49(s，4H)，3.59(s，2H)，3.94(s，6H)，4.44(quint，1H，J＝6.1Hz)，7.21(d，1H，J＝5.1Hz)，7.23(s，2H)，7.65(s，1H)，8.59(d，1H，J＝5.1Hz)。

Preparation example 56

Synthesis of 1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone:

1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone ethylene ketal (818mg) was treated in the same manner as described in preparation example 23 to give the title compound.

Yield: 717mg (98%).

¹H-NMR(400MHz，CDCl₃)δ：1.32(d，6H，J＝6.2Hz)，2.50(t，4H，J＝6.1Hz)，2.81(t，4H，J＝6.1Hz)，3.69(s，2H)，3.95(s，6H)，4.45(quint，1H，J＝6.2Hz)，7.24(s，2H)，7.25-7.27(m，1H)，7.68(s，1H)，8.63(d，1H，J＝5.1Hz)。

Preparation example 57

Synthesis of 4- (p-methoxybenzylamino) -1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (350mg) and p-methoxyaniline (123mg) were treated in the same manner as described in preparation example 37 to give the title compound.

Yield: 307mg (69%).

¹H-NMR (400MHz，CDCl₃)δ：1.32(d，6H，J＝6.3Hz)，1.46-1.52(m，2H)，2.00-2.24(m，2H)，2.22(t，2H，J＝11.1Hz)，2.86(d，2H，J＝12.1Hz)，3.18-3.28(m，1H)，3.58(s，2H)，3.74(s，3H)，3.94(s，6H)，4.40(quint，1H，J＝6.3Hz)，6.58(d，2H，J＝6.6Hz)，6.78(d，2H，J＝6.6Hz)，7.20(d，1H，J＝5.1Hz)，7.24(s，2H)，7.64(s，1H)，8.59(d，1H，J＝5.1Hz)。

Example 14

Synthesis of 1- [ [2- (4-isopropoxy-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ N- [ [2- (4-isopropoxy-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl ] methyl ] piperidine (307mg) and 4-chloromethyl-2- (3, 5-dimethoxy-4-isopropoxyphenyl) pyridine (201mg) were treated in the same manner as described in example 9. The free base obtained was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 230mg (46%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.31(d，6H，J＝3.3Hz)，1.32(d，6H，J＝6.8Hz)，1.70-1.92(m，4H)，2.10-2.20(m，2H)，2.92-3.01(m，2H)，3.56(s，2H)，3.73(s，3H)，3.85-3.95(m，1H)，3.90(s，6H)，3.93(s，6H)，4.39-4.49(m，4H)，6.73(d，2H，J＝4.8Hz)，6.78(d，2H，J＝4.8Hz)，7.14(s，2H)，7.15-7.20(m，2H)，7.23(s，2H)，7.58(s，1H)，7.60(s，1H)，8.53(d，1H，J＝5.1Hz)，8.58(d，1H，J＝5.1Hz)。

Preparation example 58

Synthesis of 4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl-4-piperidone (1.40g) and benzylamine (0.51g) were reacted in the same manner as in preparation example 37 to give the title compound as a yellow amorphous substance.

Yield: 1.20g (68%).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.60(m，2H)，1.88-2.09(m，5H)，2.54(br，1H)，2.82-2.85(m，2H)，3.52(s，2H)，3.80(s，2H)，3.89(s，2H)，3.95(s，6H)，7.18-7.31(m，8H)，7.64(s，1H)，8.57(d，1H，J＝5.1Hz)。

Example 15

Synthesis of 4- [ N-benzyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (134mg) and 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The free base was converted to the tetrahydrochloride salt to give the title compound as a yellow powder.

Yield: 43mg (17%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.63(br，4H)，1.87(br，2H)，2.39(br，1H)，2.88(br，2H)，3.49(s，2H)，3.57(s，2H)，3.68(s，2H)，3.86(s，6H)，3.88(s，3H)，3.90(s，3H)，3.96(s，6H)，6.60(s，2H)，7.17(d，1H，J＝5.1Hz)，7.22-7.29(m，8H)，7.56(s，1H)，8.02(d，1H，J＝8.0Hz)，8.50(d，1H，J＝6.4Hz)，8.58(d，1H，J＝5.1Hz)。

Example 16

Synthesis of 4- [ N-benzyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (230mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (158mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the tetrahydrochloride salt to give the title compound as a yellow powder. Yield: 172mg (47%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.69-1.85(m，4H)，1.93-1.99(m，2H)，2.56(br，1H)，2.93-3.00(m，2H)，3.51(s，2H)，3.71(s，2H)，3.74(s，2H)，3.90(s，6H)，3.96(s，6H)，3.96(s，6H)，7.18-7.32(m，9H)，7.38(d，2H，J＝7.1Hz)，7.59(s，1H)，7.68(s，1H)，8.56(d，1H，J＝5.1Hz)，8.60(d，1H，J＝5.1Hz)。

Example 17

Synthesis of 4- [ N-benzyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (134mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 47mg (18%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.86(m，4H)，1.96(br，2H)，2.59(br，1H)，2.94(br，2H)，3.51(s，2H)，3.70(s，2H)，3.74(s，2H)，3.89(s，3H)，3.90(s，3H)，3.92(s，6H)，3.96(s，6H)，6.75(s，2H)，7.18-7.30(m，6H)，7.35-7.40(m，5H)，7.56(s，1H)，7.60(s，1H)，8.58(d，1H，J＝5.1Hz)。

Example 18

Synthesis of 4- [ N-benzyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (134mg) and 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the tetrahydrochloride salt to give the title compound as a yellow powder.

Yield: 44mg (17%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.81(br，4H)，1.96(br，2H)，2.55(br，1H)，2.96(br，2H)，3.52(s，2H)，3.69(s，4H)，3.89(s，6H)，3.95(s，6H)，3.96(s，6H)，7.19-7.32(m，8H)，7.35-7.38(m，2H)，7.61(d，2H，J＝7.6Hz)，7.69-7.73(m，1H)，8.59(d，1H，J＝4.9Hz)，8.63(s，1H)。

Example 19

Synthesis of 4- [ N-benzyl-N- [ [5- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahyd rate:

4-benzylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (134mg) and 3-chloromethyl-5- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the tetrahydrochloride salt to give the title compound as a yellow powder.

Yield: 26mg (10%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.83(br，4H)，1.97(br，2H)，2.58(br，1H)，2.95(br，2H)，3.53(s，2H)，3.71(s，2H)，3.75(s，2H)，3.90(s，6H)，3.93(s，6H)，3.96(s，6H)，6.74(s，2H)，7.19-7.30(m，6H)，7.36(d，2H，J＝6.8Hz)，7.60(s，1H)，7.79(s，1H)，8.54(s，1H)，8.59(d，1H，J＝5.1Hz)，8.64(s，1H)。

Preparation example 59

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] piperidine:

1- (tert-Butoxycarbonyl) -4-aminomethylpiperidine (200mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (183mg) were reacted by the same way with the one described in example 2 to obtain the title compound as a yellow oil.

Yield: 264mg (90%).

¹H-NMR (400MHz，CDCl₃)δ：1.12-1.27(m，3H)，1.45(s，9H)，1.60(br，1H)，1.74(d，2H，J＝12.9Hz)，2.54(d，2H，J＝6.6Hz)，2.69(br，2H)，3.87(s，2H)，3.90(s，3H)，3.97(s，6H)，4.03-4.14(m，2H)，7.20(d，1H，J＝3.9Hz)，7.24(s，2H)，7.65(s，1H)，8.60(d，1H，J＝4.9Hz)。

Preparation example 60

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] piperidine:

1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] piperidine (264mg) was treated in the same manner as described in example 11 to give the title compound as a yellow oil.

Yield: 157mg (58%).

¹H-NMR(400MHz，CDCl₃)δ：1.00-1.09(m，2H)，1.43(s，9H)，1.65-1.70(m，1H)，1.79(d，2H，J＝12.7Hz)，2.21(d，2H，J＝7.4Hz)，2.23(s，3H)，2.69(br，2H)，3.52(s，2H)，3.89(s，3H)，3.96(s，6H)，4.07-4.13(m，2H)，7.20(d，1H，J＝4.9Hz)，7.24(s，2H)，7.64(s，1H)，8.58(d，1H，J＝5.1Hz)。

Preparation example 61

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] piperidine (152mg) was treated in the same manner as described in preparation example 12 to give the title compound as yellow crystals.

Yield: 105mg (88%).

¹H-NMR(400MHz，CDCl₃)δ：1.00-1.10(m，2H)，1.60-1.68(m，1H)，1.80(d，2H，J＝12.5Hz)，2.03(br，1H)，2.20(d，2H，J＝8.4Hz)，2.21(s，3H)，2.58(dt，2H，J＝12.1Hz，2.1Hz)，3.05(d，2H，J＝12.1Hz)，3.51(s，2H)，3.89(s，3H)，3.95(s，6H)，7.20(d，1H，J＝5.1Hz)，7.24(s，2H)，7.65(s，1H)，8.57(d，1H，J＝5.9Hz)。

Example 20

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminomethyl ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dioxalate:

4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino-methyl ] piperidine (96mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (73mg) were reacted in the same manner as described in example 2. The title compound was obtained as a white powder after conversion of the product to the di-oxalic acid salt.

Yield: 109mg (40%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.19-1.27(m，2H)，1.56(br，1H)，1.81(d，2H，J＝11.1Hz)，1.99-2.04(m，2H)，2.23(s，5H)，2.88(d，2H，J＝11.1Hz)，3.53(s，4H)，3.89(s，3H)，3.90(s，3H)，3.94(s，6H)，3.96(s，6H)，7.20(br，2H)，7.23(s，4H)，7.61(s，1H)，7.64(s，1H)，8.58(d，2H，J＝4.9Hz)。

Preparation example 62

Synthesis of 4- (3, 5-dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl-4-piperidone (1.40g) and 3, 5-dimethoxyaniline (722mg) were reacted in the same manner as described in preparation example 37 to give the title compound.

Yield: 800mg (41%).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.90(m，2H)，1.95-2.50(m，4H)，2.93(br，2H)，3.31(br，1H)，3.65(br，2H)，3.72(s，6H)，3.88(s，3H)，3.96(s，6H)，5.76(s，2H)，5.85(s，1H)，7.20-7.35(m，3H)，7.73(br，1H)，8.60(d，1H，J＝4.9Hz)。

Example 21

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to a trihydrochloride to give the title compound as yellow powder of fen.

Yield: 29mg (11%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.63(m，2H)，1.79(d，2H，J＝11.7Hz)，2.13(t，2H，J＝11.4Hz)，2.94(d，2H，J＝11.3Hz)，3.54(s，2H)，3.71(s，6H)，3.78-3.84(m，1H)，3.90(s，3H)，3.91(s，6H)，3.92(s，3H)，3.96(s，6H)，4.41(s，2H)，5.84(s，2H)，6.72(s，2H)，7.09-7.24(m，5H)，7.53(s，1H)，7.71(d，1H，J＝6.6Hz)，8.51(dd，1H，J＝4.7Hz，1.6Hz)，8.59(d，1H，J＝4.9Hz)。

Preparation example 63

Synthesis of ethyl 2- (3, 4, 5-trimethoxyphenyl) benzoate:

3, 4, 5-trimethoxyphenylboronic acid (649mg) and ethyl 2-bromobenzoate (479mg) were reacted in the same manner as described in preparation example 1 to obtain the title compound.

Yield: 655mg (69%).

¹H-NMR(400MHz，CDCl₃)δ：1.04(t，3H，J＝7.2Hz)，3.86(s，6H)，3.89(s，3H)，4.12(q，2H，J＝7.2Hz)，6.54(s，2H)，7.40-7.42(m，2H)，7.51(t，1H，J＝7.8Hz)，7.77(d，1H，J＝6.8Hz)。

Preparation 64

Synthesis of 2- (3, 4, 5-trimethoxyphenyl) benzyl alcohol:

ethyl 2- (3, 4, 5-trimethoxyphenyl) benzoate (655mg) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield: 630mg (theoretical amount).

¹H-NMR(400MHz，CDCl₃)δ：3.85(s，6H)，3.90(s，3H)，4.61(s，2H)，6.61(s，2H)，7.26-7.39(m，3H)，7.53(d，1H，J＝6.8Hz)。

Preparation example 65

Synthesis of 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride:

2- (3, 4, 5-trimethoxyphenyl) benzyl alcohol (630mg) was treated in the same manner as described in preparation example 3 to give the title compound.

Yield: 615mg (theoretical amount).

¹H-NMR(400MHz，CDCl₃)δ：3.87(s，6H)，3.90(s，3H)，4.53(s，2H)，6.66(s，2H)，7.29-7.32(m，1H)，7.34-7.39(m，2H)，7.50-7.52(m，1H)。

Example 22

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [2- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The obtained free base was converted into dihydrochloride to give the title compound as yellow powder.

Yield: 20mg (8%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.50-1.90(m，4H)，2.05-2.20(m，2H)，2.92(br，2H)，3.52(br，3H)，3.68(s，6H)，3.85(s，6H)，3.88(s，3H)，3.89(s，3H)，3.94(s，6H)，4.31(s，2H)，5.85(br，3H)，6.52(s，2H)，7.05-7.27(m，6H)，7.34(s，1H)，7.51(s，1H)，8.56(s，1H)。

Example 23

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 40mg (18%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.68-1.90(m，4H)，2.12-2.22(m，2H)，2.94-3.02(m，2H)，3.57(s，2H)，3.71(s，6H)，3.81-3.83(m，1H)，3.89(s，3H)，3.90(s，3H)，3.93(s，6H)，3.96(s，6H)，4.52(s，2H)，5.89-5.94(m，3H)，7.14(d，1H，J＝5.3Hz)，7.16(s，2H)，7.20(d，1H，J＝3.7Hz)，7.22(s，2H)，7.54-7.60(m，2H)，8.55(d，1H，J＝5.1Hz)，8.59(d，1H，J＝5.1Hz)。

Example 24

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the dihydrochloride salt to give the title compound as a yellow powder.

Yield: 41mg (16%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.78-1.88(m，4H)，2.16(t，2H，J＝10.7Hz)，2.96(d，2H，J＝11.3Hz)，3.56(s，2H)，3.70(s，6H)，3.73-3.84(m，1H)，3.87(s，3H)，3.89(s，6H)，3.90(s，3H)，3.95(s，6H)，4.54(s，2H)，5.95(s，2H)，6.71(s，2H)，7.19-7.26(m，4H)，7.31-7.39(m，3H)，7.42(s，1H)，7.59(s，1H)，8.58(d，1H，J＝4.9Hz)。

Example 25

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to a trihydrochloride to give the title compound as yellow powder of fen.

Yield: 23mg (10%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.64(br，2H)，1.82(br，2H)，2.10(br，2H)，2.94(br，2H)，3.48-3.60(m，3H)，3.64(s，6H)，3.82(s，3H)，3.83(s，3H)，3.87(s，6H)，3.90(s，6H)，4.46(s，2H)，5.85(br，3H)，7.05-7.24(m，6H)，7.53-7.54(m，2H)，8.51(s，1H)，8.54(br，1H)。

Preparation example 66

Synthesis of ethyl 4- (3, 4, 5-trimethoxyphenyl) benzoate:

3, 4, 5-trimethoxyphenylboronic acid (2.01g) and ethyl 4-bromobenzoate (2.29g) were treated in the same manner as described in preparation example 1 to give the title compound.

Yield: 2.99g (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.42(t，3H，J＝7.2Hz)，3.90(s，3H)，3.94(s，6H)，4.38(q，2H，J＝7.2Hz)，6.81(s，2H)，7.62(d，2H，J＝8.2Hz)，8.10(d，2H，J＝8.2Hz)。

Preparation example 67

Synthesis of 4- (3, 4, 5-trimethoxyphenyl) benzyl alcohol:

ethyl 4- (3, 4, 5-trimethoxyphenyl) benzoate (2.99g) was treated in the same manner as described in preparation example 2 to give the title compound.

Yield: 1.83g (71%).

Preparation example 68

Synthesis of 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride:

4- (3, 4, 5-trimethoxyphenyl) benzyl alcohol (1.83g) was treated in the same manner as described in preparation example 3 to give the title compound.

Yield: 1.65g (84%.

¹H-NMR(400MHz，CDCl₃)δ：3.90(s，3H)，3.93(s，6H)，4.65(s，2H)，6.77(s，2H)，7.46(d，2H，J＝8.0Hz)，7.55(d，2H，J＝8.0Hz)。

Example 26

Synthesis of 4- [ N- (3, 5-dimethoxyphenyl) -N- [ [4- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 5-Dimethoxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (148mg) and 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the dihydrochloride salt to give the title compound as a yellow powder.

Yield: 35mg (14%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ；1.80-1.89(m，4H)，2.17(br，2H)，2.97(d，2H，J＝10.5Hz)，3.57(s，2H)，3.70(s，6H)，3.77-3.84(m，1H)，3.87(s，3H)，3.90(s，3H)，3.91(s，6H)，3.96(s，6H)，4.52(s，2H)，5.93(s，2H)，6.74(s，2H)，7.19-7.22(m，4H)，7.31(d，2H，J＝8.2Hz)，7.46(d，2H，J＝8.2Hz)，7.60(s，1H)，8.59(d，1H，J＝5.1Hz)。

Preparation example 69

Synthesis of 4- (3, 4-Methylenedioxy (Methylenedioxy) phenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl-4-piperidone (1.40g) and 3, 4-methylenedioxyaniline (646mg) were reacted in the same manner as described in preparation example 37 to give the title compound.

Yield: 810mg (43%).

¹H-NMR(400MHz，CDCl₃)δ：1.63(br，2H)，2.02-2.60(m，4H)，2.80-3.15(m，2H)，3.25(br，1H)，3.70(br，2H)，3.88(s，3H)，3.96(s，6H)，5.83(s，2H)，6.02(d，1H，J＝8.3Hz)，6.22(s，1H)，6.61(d，1H，J＝8.3Hz)，7.18-7.28(m，3H)，7.64(br，1H)，8.60(d，1H，J＝4.9Hz)。

Example 27

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted by the same way with the method described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 30mg (14%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.45-2.25(m，6H)，2.90(br，2H)，3.40(br，1H)，3.55(br，2H)，3.87(s，3H)，3.88(s，9H)，3.93(s，6H)，4.28(s，2H)，5.82(s，2H)，6.10(br，1H)，6.28(s，1H)，6.58(d，1H，J＝8.4Hz)，6.67(s，2H)，7.12-7.30(m，4H)，7.52(br，1H)，7.75(br，1H)，8.51(br，1H)，8.57(br，1H)。

Example 28

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [2- (3, 4, 5-trimethoxyphenyl) benzyl ] amino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The obtained free base was converted into dihydrochloride to give the title compound as yellow powder.

Yield: 13mg (6%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.61(br，2H)，1.78(br，2H)，2.10(br，2H)，2.91(br，2H)，3.50-3.54(m，3H)，3.87(s，6H)，3.90(s，3H)，3.92(s，3H)，3.99(s，6H)，4.26(s，2H)，5.82(s，2H)，6.12(d，1H，J＝8.6Hz)，6.32(s，1H)，6.53(s，2H)，6.62(d，1H，J＝8.6Hz)，7.17-7.26(m，6H)，7.42(br，1H)，7.55(s，1H)，8.58(d，1H，J＝4.9Hz)。

Example 29

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted by the same way with the method described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 52mg (25%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.95(m，4H)，2.20(br，2H)，3.00(br，2H)，3.58(br，3H)，3.86(s，3H)，3.87(s，3H)，3.91(s，6H)，3.94(s，6H)，4.41(s，2H)，5.82(s，2H)，6.17(d，1H，J＝8.4Hz)，6.39(s，1H)，6.62(d，1H，J＝8.4Hz)，7.12-7.13(m，3H)，7.18(d，1H，J＝4.1Hz)，7.23(br，2H)，7.54(br，2H)，8.51(d，1H，J＝5.1Hz)，8.57(d，1H，J＝4.9Hz)。

Example 30

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the dihydrochloride salt to give the title compound as a yellow powder.

Yield: 58mg (29%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.97(m，4H)，2.15(br，2H)，3.00(br，2H)，3.58(br，3H)，3.86(s，3H)，3.88(s，9H)，3.94(s，6H)，4.43(s，2H)，5.81(s，2H)，6.21(br，1H)，6.42(s，1H)，6.62(d，1H，J＝8.4Hz)，6.69(s，2H)，7.18(d，1H，J＝4.9Hz)，7.22-7.39(m，6H)，7.60(br，1H)，8.57(d，1H，J＝4.9Hz)。

Example 31

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) were reacted by the same way with the method described in example 9. The resulting free base was converted to the trihydrochloride salt to give the title compound as a yellow powder.

Yield: 69mg (27%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.71-1.88(m，4H)，2.14(d，2H，J＝11.2Hz)，2.97(d，2H，J＝11.5Hz)，3.45-3.52(m，1H)，3.56(s，2H)，3.89(s，3H)，3.90(s，3H)，3.94(s，6H)，3.96(s，6H)，4.12(s，2H)，5.85(s，2H)，6.24(dd，1H，J＝8.5Hz，2.5Hz)，6.45(d，1H，J＝2.4Hz)，6.64(d，1H，J＝8.5Hz)，7.20-7.21(m，1H)，7.21(s，2H)，7.23(s，2H)，7.58-7.65(m，3H)，8.57(d，1H，J＝1.5Hz)，8.59(d，1H，J＝4.9Hz)。

Example 32

Synthesis of 4- [ N- (3, 4-methylenedioxyphenyl) -N- [4- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3, 4-methylenedioxyphenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (119mg) and 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) were reacted in the same manner as described in example 9. The resulting free base was converted to the dihydrochloride salt to give the title compound as a yellow powder.

Yield: 29mg (14%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ；1.62-2.00(m，4H)，2.20(br，2H)，2.99(br，2H)，3.58(br，3H)，3.86(s，3H)，3.87(s，3H)，3.88(s，6H)，3.89(s，6H)，4.41(s，2H)，5.82(s，2H)，6.19(d，1H，J＝8.6Hz)，6.39(s，1H)，6.63(d，1H，J＝8.4Hz)，6.72(s，2H)，7.18(d，1H，J＝5.1Hz)，7.23(s，2H)，7.29(d，2H，J＝8.0Hz)，7.43(d，2H，J＝8.2Hz)，7.60(br，1H)，8.57(d，1H，J＝4.9Hz)。

Preparation example 70

Synthesis of 4- [ N-methyl-N- [ (2-nitrophenyl) sulfonyl ] aminomethyl ] -2- (3, 4, 5-trimethoxyphenyl) pyridine:

4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (232mg), N-methyl-2-nitrobenzenesulfonamide (171mg) and potassium carbonate (138mg) were suspended in acetonitrile (10 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.

Yield: 362mg (97.0%).

Preparation example 71-

Synthesis of 4- (methylaminomethyl) -2- (3, 4, 5-trimethoxyphenyl) pyridine:

to a suspension of 4- [ N-methyl-N- [ (2-nitrophenyl) sulfonyl ] aminomethyl ] -2- (3, 4, 5-trimethoxyphenyl) pyridine (691mg) and potassium carbonate (203mg) in acetonitrile (20mL) was added thiophenol (228. mu.L). The mixture was stirred at 50 ℃ overnight and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (40: 1 to 10: 1) as an eluent to give the title compound.

Yield: 356mg (84%).

Example 33

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] aminocarbonyl ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine maleate:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine-4-carboxylic acid (98mg) and 4- (methylaminomethyl) -2- (3, 4, 5-trimethoxyphenyl) pyridine (73mg) were treated in the same manner as described in example 1 to give the maleate salt of the title compound.

Yield: 145mg (75%).

¹H-NMR (400MHz, determined as maleate, DMSO-d)₆)δ：1.89-1.97(m，4H)，2.75-2.96(m，3H)，3.03(s，3H)，3.27(d，2H，J＝12.0Hz)，3.78(s，3H)，3.79(s，3H)，3.87(s，6H)，3.90(s，6H)，4.09(s，2H)，4.64(s，2H)，6.14(s，2H)，7.09(d，1H，J＝5.0Hz)，7.33(s，2H)，7.37(d，1H，J＝5.0Hz)，7.38(s，2H)，7.65(s，1H)，7.90(s，1H)，8.57(d，1H，J＝5.0Hz)，8.67(d，1H，J＝5.0Hz)。

Preparation example 72

Synthesis of (3S) -1- (tert-butoxycarbonyl) -3- [ N- [ (2-nitrophenyl) sulfonyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] pyrrolidine:

(3S) -1- (tert-butoxycarbonyl) -3- [ (2-nitrophenyl) sulfonylamino ] pyrrolidine (72mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (57mg) were reacted in the same manner as described in example 2 to give the title compound as a colorless amorphous form.

Yield: 103mg (85%).

Preparation example 73

Synthesis of (3S) -3- [ N- [ (2-nitrophenyl) sulfonyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] pyrrolidine:

(3S) -1- (tert-butoxycarbonyl) -3- [ N- [ (2-nitrophenyl) sulfonyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] pyrrolidine (103mg) was treated in the same manner as described in preparation example 12 to give the title compound as a yellow amorphous form.

Yield: 72mg (84%).

¹H-NMR(400MHz，CDCl₃)δ：1.66-1.75(m，1H)，2.03-2.05(m，1H)，2.78-2.85(m，2H)，3.00-3.10(m，2H)，3.39(br，1H)，3.90(s，3H)，3.96(s，6H)，4.59-4.67(m，1H)，4.70(s，2H)，7.13-7.18(m，1H)，7.20(s，2H)，7.52-7.64(m，4H)，7.95(dd，1H，J＝7.9Hz，1.1Hz)，8.52(d，1H，J＝5.1Hz)。

Preparation example 74

Synthesis of (3S) -3- [ N- [ (2-nitrophenyl) sulfonyl ] -N- [ [2- (3, 4, 5-)

Trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine:

(3S) -3- [ N- [ (2-Nitrobenzene) sulfonyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] pyrrolidine (72mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (40mg) were reacted in the same manner as described in example 2 to give the title compound as a yellow amorphous form.

Yield: 97mg (91%).

¹H-NMR(400MHz，CDCl₃)δ：1.59(br，1H)，1.80-1.90(m，1H)，2.20-2.30(m，2H)，2.55(dd，1H，J＝10.5Hz，8.2Hz)，2.78(dd，1H，J＝10.6Hz，3.2Hz)，2.87(t，1H，J＝7.2Hz)，3.50(d，1H，J＝13.7Hz)，3.64(d，1H，J＝13.7Hz)，3.89(s，3H)，3.90(s，3H)，3.92(s，6H)，3.93(s，6H)，4.83(d，2H，J＝4.5Hz)，7.07(d，1H，J＝5.1Hz)，7.10(d，1H，J＝4.9Hz)，7.15(s，2H)，7.17(s，2H)，7.41-7.45(m，1H)，7.50-7.55(m，3H)，7.61(s，1H)，7.81(d，1H，J＝7.4Hz)，8.45(d，1H，J＝4.9Hz)，8.51(d，1H，J＝5.1Hz)。

Example 34

Synthesis of (3S) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -3- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-y ] methylamino ] pyrrolidine trihydrochloride:

(3S) -3- [ N- (2-Nitrophenylsulfonyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] pyrrolidine (97mg) was treated in the same manner as described in preparation 14.

Yield: 80mg (89%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.71(br，2H)，2.19-2.21(m，1H)，2.52-2.55(m，2H)，2.73-2.77(m，2H)，3.39(br，1H)，3.66(d，1H，J＝13.7Hz)，3.71(d，1H，J＝13.7Hz)，3.82(s，2H)，3.90(s，6H)，3.95(s，12H)，7.18-7.21(m，2H)，7.23(s，2H)，7.24(s，2H)，7.63(s，2H)，8.59(d，1H，J＝4.3Hz)，8.60(d，1H，J＝4.3Hz)。

Example 35

Synthesis of 4- [3- (3, 4, 5-trimethoxyphenyl) benzoylamino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine maleate:

3- (3, 4, 5-trimethoxyphenyl) benzoic acid (69mg) and 4-amino-1- [ [2- (3, 4, 5-)

Trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (114mg) was reacted in the same manner as described in example 1. The title compound was obtained after conversion of the product to the maleate salt.

Yield: 100mg (56%).

¹H-NMR (400MHz, determined as maleate, DMSO-d)₆)δ：1.85-2.10(m，4H)，2.77-2.93(m，2H)，3.20-3.31(m，2H)，3.77(s，3H，3.79(s，3H)，3.89(s，6H)，3.91(s，6H)，3.98-4.07(m，1H)，4.13(s，2H)，6.15(s，2H)，6.94(s，2H)，7.40-7.52(m，4H)，7.73-7.80(m，2H)，8.02-8.10(m，3H)，8.67-8.68(m，1H)。

Example 36

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4- (methylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (2.67g) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (2.12g) were reacted in the same manner as described in example 2. The title compound was obtained after conversion of the product to the tetrahydrochloride salt.

Yield: 2.55g (46%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.66-1.74(m，2H)，1.82(d，2H，J＝10.7Hz)，2.04(t，2H，J＝11.0Hz)，2.25(s，3H)，2.45-2.51(m，1H)，2.98(d，2H，J＝11.7Hz)，3.55(s，2H)，3.66(s，2H)，3.90(s，3H)，3.91(s，3H)，3.96(s，6H)，3.97(s，6H)，7.21-7.23(m，2H)，7.24(s，2H)，7.25(s，2H)，7.62(s，1H)，7.63(s，1H)，8.59(d，1H，J＝5.1Hz)，8.60(d，1H，J＝5.3Hz)。

Preparation example 75

Synthesis of 1- (ethoxycarbonyl) -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methylamino ] piperidine:

1- (ethoxycarbonyl) piperidine (341mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (300mg) were reacted in the same manner as described in example 2 to obtain the title compound.

Yield: 438mg (theoretical yield).

¹H-NMR(400MHz，CDCl₃)δ：1.25(t，3H，J＝7.1Hz)，1.27-1.34(m，2H)，1.60(br，1H)，1.90(d，2H，J＝10.9Hz)，2.67-2.72(m，1H)，2.87(t，2H，J＝11.5Hz)，3.90(s，3H)，3.91(br，2H)，3.96(s，6H)，4.09(br，2H)，4.12(q，2H，J＝7.0Hz)，7.21(d，1H，J＝3.5Hz)，7.24(s，2H)，7.65(s，1H)，8.59(d，1H，J＝4.9Hz)。

Preparation example 76

Synthesis of 1- (ethoxycarbonyl) -4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (ethoxycarbonyl) -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methylamino ] piperidine (438mg) was treated in the same manner as described in preparation example 11 to give the title compound as a yellow oil.

Yield: 235mg (52%).

¹H-NMR(400MHz，CDCl₃)δ：1.26(t，3H，J＝7.1Hz)，1.42-1.57(m，2H)，1.82(d，2H，J＝11.9Hz)，2.24(s，3H)，2.59-2.65(m，1H)，2.75(t，2H，J＝12.0Hz)，3.65(s，2H)，3.90(s，3H)，3.97(s，6H)，4.13(q，2H，J＝7.0Hz)，4.23(br，2H)，7，22(dd，1H，J＝5.0Hz，1.3Hz)，7.24(s，2H)，7.63(s，1H)，8.59(d，1H，J＝4.5Hz)。

Preparation example 77

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

to a solution of 1- (ethoxycarbonyl) -4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (100mg) in ethanol (2mL) was added 4M sodium hydroxide (8 mL). The mixture was stirred overnight and extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (20: 1) to give the title compound as a yellow oil.

Yield: 73mg (88%).

¹H-NMR(400MHz，CDCl₃)δ：1.50-1.55(m，2H)，1.84(d，2H，J＝12.0Hz)，1.99(br，1H)，2.25(s，3H)，2.55-2.63(m，3H)，3.16(d，2H，J＝12.2Hz)，3.65(s，2H)，3.90(s，3H)，3.97(s，6H)，7.22(d，1H，J＝6.1Hz)，7.24(s，2H)，7.64(s，1H)，8.58(d，1H，J＝5.1Hz)。

Example 37

Synthesis of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (73mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (58mg) were reacted in the same manner as described in example 2. The title compound is obtained after conversion of the product to the tetrahydrochloride salt.

Yield: 126mg (84%).

Example 38

Synthesis of 4- [ N-methyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine difumarate:

4- (methylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (111mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (88mg) were reacted in the same manner as described in example 2. The title compound was obtained as a white powder after conversion of the product to the difumarate salt.

Yield: 59mg (23%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.77(m，2H)，1.85-1.87(m，2H)，2.03-2.08(m，2H)，2.27(s，3H)，2.55-2.59(m，1H)，2.98(d，2H，J＝11.3Hz)，3.56(s，2H)，3.69(s，2H)，3.89(s，3H)，3.90(s，3H)，3.93(s，6H)，3.98(s，6H)，6.79(s，2H)，7.22(d，1H，J＝4.9Hz)，7.28(s，2H)，7.31(d，1H，J＝7.6Hz)，7.38(t，1H，J＝7.4Hz)，7.45(d，1H，J＝7.6Hz)，7.51(s，1H)，7.63(s，1H)，8.60(d，1H，J＝5.1Hz)。

Example 39

Synthesis of 1- [ [2- (4-hydroxy-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ N- [ [2- (4-hydroxy-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N-methylamino ] piperidine tetrahyd rate:

iodotrimethylsilane (173. mu.L) was added to a solution of 4- [ N-methyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (100mg) in dichloromethane (5mL) at 0 ℃. The mixture was stirred at 0 ℃ for 2 hours and then at room temperature overnight. To the mixture was added a small amount of water, ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate at 0 ℃ to separate an organic layer. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC chromatography on silica gel using chloroform-ammonia saturated methanol (15: 1) and converted to the tetrahydrochloride salt by a conventional method to give the title compound.

Yield: 50mg (52.3%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.68-1.89(m，4H)，2.03-2.12(m，2H)，2.26(s，3H)，2.48-2.60(m，1H)，2.98-3.05(m，2H)，3.57(s，2H)，3.65(s，2H)，3.94(s，6H)，3.95(s，6H)，7.16-7.19(m，2H)，7.26(s，2H)，7.27(s，2H)，7.62-7.68(m，2H)，8.56(d，1H，J＝5.3Hz)，8.58(d，1H，J＝5.2Hz)。

Preparation example 78

Synthesis of 1- (ethoxycarbonyl) -4- [ N-ethyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

to a solution of 1- (ethoxycarbonyl) -4- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methylamino ] piperidine (400mg) in acetonitrile (5mL) were added potassium carbonate (13mg) and iodoethane (145 mg). The mixture was placed in a sealed container and stirred at 80 ℃ for 2 hours. After the reaction liquid was concentrated in vacuo, ethyl acetate was added to the residue, which was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform-methanol (30: 1) as eluent to give the title compound as a yellow oil.

Yield: 242mg (57%).

¹H-NMR(400MHz，CDCl₃)δ：1.04(t，3H，J＝7.1Hz)，1.25(t，3H，J＝7.1Hz)，1.43-1.52(m，2H)，1.79(d，2H，J＝11.5Hz)，2.60(q，2H，J＝7.0Hz)，2.66-2.76(m，3H)，3.70(s，2H)，3.90(s，3H)，3.97(s，6H)，4.12(q，2H，J＝7.0Hz)，4.20(br，2H)，7.23(s，2H)，7.26(d，1H，J＝5.7Hz)，7.67(s，1H)，8.58(d，1H，J＝4.9Hz)。

Preparation example 79

Synthesis of 4- [ N-ethyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (ethoxycarbonyl) -4- [ N-ethyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (242mg) was treated in the same manner as described in preparation 77 to give the title compound as a yellow oil.

Yield: 150mg (74%).

¹H-NMR(400MHz，CDCl₃)δ：1.03(t，3H，J＝7.0Hz)，1.43-1.52(m，2H)，1.70(br，1H)，1.79(d，2H，J＝12.3Hz)，2.53-2.67(m，5H)，3.13(d，2H，J＝11.9Hz)，3.71(s，2H)，3.90(s，3H)，3.97(s，6H)，7.24(s，2H)，7.27(d，1H，J＝5.1Hz)，7.68(s，1H)，8.57(d，1H，J＝4.3Hz)。

Example 40

Synthesis of 4- [ N-ethyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4- [ N-Ethyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (65mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (50mg) in the same manner as described in example 2. The title compound was obtained after conversion of the product to the tetrahydrochloride salt.

Yield: 121mg (90%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.03(t，3H，J＝7.1Hz)，1.64-1.69(m，2H)，1.77(d，2H，J＝10.7Hz)，2.01(t，2H，J＝10.8Hz)，2.55-2.64(m，3H)，2.95(d，2H，J＝11.1Hz)，3.53(s，2H)，3.71(s，2H)，3.90(s，6H)，3.97(s，12H)，7.20-7.27(m，6H)，7.60(s，1H)，7.68(s，1H)，8.57(d，1H，J＝4.9Hz)，8.59(d，1H，J＝5.1Hz)。

Preparation example 80

Synthesis of 4- (cyclohexylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (400mg) and cyclohexylamine (134mg) were reacted in the same manner as described in preparation 37 to give the title compound.

Yield: 342mg (69%).

¹H-NMR(400MHz，CDCl₃)δ：1.05-1.30(m，6H)，1.38-1.52(m，2H)，1.53-1.80(m，3H)，1.87(br，4H)，2.07(t，2H，J＝10.7Hz)，2.59(br，2H)，2.86(br，2H)，3.54(s，2H)，3.90(s，3H)，3.97(s，6H)，7.19(d，1H，J＝4.9Hz)，7.24(s，2H)，7.64(s，1H)，8.58(d，1H，J＝4.9Hz)。

EXAMPLE 41

Synthesis of 4- [ N-cyclohexyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4- (cyclohexylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (342mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (252mg) were reacted in the same manner as described in preparation example 9. The title compound was obtained after conversion of the product to the tetrahydrochloride salt.

Yield: 55mg (8%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.00-1.39(m，6H)，1.58-1.88(m，8H)，2.07(br，2H)，2.61(br，2H)，2.96(br，2H)，3.57(br，2H)，3.85(s，2H)，3.90(s，3H)，3.91(s，3H)，3.97(s，12H)，7.19-7.28(m，6H)，7.70(br，2H)，8.56(d，1H，J＝5.1Hz)，8.60(d，1H，J＝5.1Hz)。

Preparation example 81

Synthesis of 4-anilino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (1.1g) and aniline (344mg) were reacted in the same manner as described in preparation 37 to give the title compound.

Yield: 1.09g (81%).

¹H-NMR(400MHz，CDCl₃)：1.53(br，2H)，2.02-2.13(m，2H)，2.16-2.32(m，2H)，2.86(br，2H)，3.32(br，1H)，3.59(s，2H)，3.88(s，3H)，3.95(s，6H)，6.57(d，2H，J＝8.6Hz)，6.66(t，1H，J＝7.3Hz)，7.14(t，2H，J＝7.9Hz)，7.20-7.24(m，5H)，7.65(br，1H)，8.59(d，1H，J＝5.1Hz)。

Example 42

Synthesis of 4- [ N-phenyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4-anilino-1 [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (1.64g) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (1.33g) were reacted in the same manner as described in preparation example 9. The title compound was obtained after conversion of the product to the trihydrochloride salt.

Yield: 635mg (20%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-2.00(m，4H)，2.10-2.35(m，2H)，2.99(br，2H)，3.58(br，3H)，3.86(s，3H)，3.88(s，3H)，3.90(s，6H)，3.94(s，6H)，4.52(s，2H)，6.66-6.78(m，3H)，7.13-7.28(m，8H)，7.54(br，2H)，8.53(d，1H，J＝5.1Hz)，8.58(d，1H，J＝4.9Hz)。

Preparation example 82

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone ethylidene ketal:

4-Piperidinoethylidene ketal (573mg) was reacted with 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine (1.19g) in the same manner as described in example 2 to give the title compound.

Yield: 1.67g (theoretical amount).

¹H-NMR(400MHz，CDCl₃)δ：1.78(t，4H，J＝5.6Hz)，2.58(br，4H)，3.61(s，2H)，3.67(s，4H)，4.02(s，6H)，7.25-7.29(m，3H)，7.68(s，1H)，8.61(d，1H，J＝4.9Hz)。

Preparation example 83

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone ethylene ketal (1.67g) was treated in the same manner as described in preparation example 23 to give the title compound.

Yield: 1.29g (89%).

¹H-NMR(400MHz，CDCl₃)：2.50(t，4H，J＝5.8Hz)，2.81(t，4H，J＝5.8Hz)，3.71(s，2H)，4.02(s，6H)，7.26(s，2H)，7.33(d，1H，J＝4.3Hz)，7.70(s，1H)，8.66(d，1H，J＝4.9Hz)。

Preparation example 84

Synthesis of 4-anilino-1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (600mg) and aniline (0.18mL) were treated in the same manner as in preparation 37 to give the title compound.

Yield: 465mg (63%).

¹H-NMR(400MHz，CDCl₃)δ：1.49-1.69(m，2H)，2.08(d，2H，J＝7.8Hz)，2.23(t，2H，J＝9.3Hz)，2.87(d，2H，J＝7.8Hz)，3.34(br，1H)，3.60(s，2H)，4.02(s，6H)，6.60(d，2H，J＝7.6Hz)，6.69(t，1H，J＝7.3Hz)，7.10-7.20(m，2H)，7.20-7.30(m，3H)，7.67(s，1H)，8.62(d，1H，J＝5.2Hz)。

Example 43

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ N- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N-phenylamino ] piperidine trihydrochloride:

4-anilino-1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (230mg) was reacted with 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine (157mg) in the same manner as described in example 9. After conversion of the product to the trihydrochloride salt, the title compound was obtained as a yellow powder.

Yield: 104mg (24%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.85(m，4H)，2.20(t，2H，J＝2.3Hz)，3.00(d，2H，J＝1.3Hz)，3.59(s，2H)，3.96(s，6H)，4.00(s，6H)，4.56(s，2H)，6.65-6.78(m，3H)，7.16(s，2H)，7.18-7.28(m，6H)，7.59(s，1H)，7.62(s，1H)，8.57(d，1H，J＝5.1Hz)，8.57(d，1H，J＝4.8Hz)。

Preparation example 85

Synthesis of 4- (p-methoxyphenylamino) -1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridine-4-

Alkyl ] methyl ] piperidine:

1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (690mg) and p-anisidine (283mg) were treated in the same manner as described in preparation example 37 to give the title compound.

Yield: 646mg (72%).

¹H-NMR(400MHz，CDCl₃)δ：1.45-1.55(m，2H)，2.05(d，2H，J＝11.7Hz)，2.20(t，2H，J＝11.2Hz)，2.87(d，2H，J＝11.7Hz)，3.20-3.35(m，1H)，3.59(s，2H)，3.74(s，3H)，4.02(s，6H)，6.58(d，2H，J＝8.7Hz)，6.77(d，2H，J＝8.7Hz)，7.25-7.28(m，3H)，7.67(s，1H)，8.62(d，1H，J＝4.9Hz)。

Example 44

Synthesis of 1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -4- [ N- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine trihydrochloride:

4- (p-Methoxyphenylamino) -1- [ [2- (4-chloro-3, 5-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (271mg) was reacted with 2- (4-chloro-3, 5-dimethoxyphenyl) -4-chloromethylpyridine (173mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the trihydrochloride salt.

Yield: 324mg (67%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.65-1.90(m，4H)，2.16(t，2H，J＝10.4Hz)，2.97(d，2H，J＝7.5Hz)，3.54-3.60(m，1H)，3.58(s，2H)，3.73(s，3H)，3.97(s，6H)，4.00(s，6H)，4.46(s，2H)，6.74(d，2H，J＝9.4Hz)，6.79(d，2H，J＝9.4Hz)，7.16(s，2H)，7.20-7.29(m，4H)，7.59(s，1H)，7.62(s，1H)，8.56(d，1H，J＝4.8Hz)，8.60(d，1H，J＝4.8Hz)。

Preparation example 86

Synthesis of 4- (3-methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (1.40g) and 3-methylthioaniline (655mg) were treated in the same manner as described in preparation example 37 to give the title compound.

Yield: 1.01g (54%).

¹H-NMR(400MHz，CDCl₃)δ：1.44-1.60(m，2H)，1.98-2.10(m，2H)，2.23(br，2H)，2.42(s，3H)，2.88(br，2H)，3.30(br，1H)，3.59(s，2H)，3.88(s，3H)，3.95(s，6H)，6.35(d，1H，J＝7.6Hz)，6.47(s，1H)，6.55(d，1H，J＝8.6Hz)，7.05(t，1H，J＝7.9Hz)，7.20(d，1H，J＝4.9Hz)，7.24(s，2H)，7.68(br，1H)，8.58(d，1H，J＝4.9Hz)。

Example 45

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3-Methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the trihydrochloride salt.

Yield: 45mg (18%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.58-1.71(s，2H)，1.79(d，2H，J＝10.7Hz)，2.16(t，2H，J＝11.2Hz)，2.38(s，3H)，2.96(d，2H，J＝11.2Hz)，3.56(s，3H)，3.68-3.97(m，1H)，3.90(s，3H)，3.92(s，9H)，3.96(s，9H)，4.42(s，2H)，6.45(d，1H，J＝8.3Hz)，6.52(s，1H)，6.61(d，1H，J＝7.3Hz)，6.74(s，2H)，7.11(t，1H，J＝8.1Hz)，7.15-7.26(m，4H)，7.54(s，1H)，7.68(d，1H，J＝7.8Hz)，8.53(d，1H，J＝3.2Hz)，8.59(d，1H，J＝4.8Hz)。

Example 46

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [2- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3-methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 51mg (23%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.56-1.73(m，2H)，1.78-1.87(m，2H)，2.10-2.20(m，2H)，2.38(s，3H)，2.91-2.98(m，2H)，3.55(s，2H)，3.70-3.80(m，1H)，3.88(s，6H)，3.90(s，3H)，3.92(s，3H)，3.96(s，6H)，4.35(s，2H)，6.47(d，1H，J＝8.2Hz)，6.53-6.62(m，5H)，7.09(t，1H，J＝8.0Hz)，7.18-7.40(m，6H)，7.54(s，1H)，8.58(d，1H，J＝4.7Hz)。

Example 47

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine fumarate:

4- (3-Methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a white powder after conversion of the product to the fumarate salt.

Yield: 14mg (5%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.76-1.86(m，5H)，2.17-2.23(m，2H)，2.39(s，3H)，2.97-3.00(m，2H)，3.58(s，2H)，3.89(s，3H)，3.90(s，3H)，3.93(s，6H)，3.96(s，6H)，4.54(s，2H)，6.47-6.50(m，1H)，6.63(s，1H)，6.64(s，1H)，7.10-7.15(m，2H)，7.15(s，2H)，7.20-7.21(m，1H)，7.22(s，2H)，7.55(s，1H)，7.59(s，1H)，8.56(d，1H，J＝5.1Hz)，8.59(d，1H，J＝5.1Hz)。

Example 48

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3-methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 60mg (24%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.65-1.91(m，4H)，2.18(t，2H，J＝10.5Hz)，2.38(s，3H)，2.97(d，2H，J＝10.9Hz)，3.58(s，2H)，3.70-3.85(m，1H)，3.88(s，3H)，3.89(s，6H)，3.90(s，3H)，3.96(s，6H)，4.56(s，2H)，6.52(d，1H，J＝8.4Hz)，6.59(d，1H，J＝7.6Hz)，6.65(s，1H)，6.72(s，2H)，7.10(t，2H，J＝8.0Hz)，7.19-7.25(m，4H)，7.31-7.42(m，3H)，7.60(s，1H)，8.59(d，1H，J＝7.8Hz)。

Example 49

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (3-Methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the trihydrochloride salt.

Yield: 22mg (9%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.50-2.05(m，4H)，2.20(br，2H)，2.37(s，3H)，3.05(br，2H)，3.50-3.70(br，3H)，3.86(s，3H)，3.87(s，3H)，3.92(s，6H)，3.95(s，6H)，4.52(s，2H)，6.49(d，1H，J＝8.3Hz)，6.62(br，2H)，7.09(t，1H，J＝8.2Hz)，7.18-7.30(m，6H)，7.58(s，2H)，8.54(br，1H)，8.60(br，1H)。

Example 50

Synthesis of 4- [ N- (3-methylthiophenyl) -N- [4- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (3-Methylthioanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 57mg (22%).

¹H-NMR (400MHz, in order ofDetermination of free base, CDCl₃)δ：1.58-1.83(m，4H)，2.20(t，2H，J＝11.3Hz)，2.39(s，3H)，2.98(d，2H，J＝11.1Hz)，3.58(s，2H)，3.88(s，3H)，3.90(s，3H)，3.91(s，6H)，3.96(s，6H)，4.53(s，2H)，6.51(dd，1H，J＝8.4Hz，2.4Hz)，6.60(d，1H，J＝8.0Hz)，6.64(s，1H)，6.75(s，2H)，7.10(t，1H，J＝8.1Hz)，7.24-7.33(m，4H)，7.47(d，2H，J＝8.0Hz)，7.61(s，1H)，8.59(d，1H，J＝5.0Hz)。

Preparation example 87

Synthesis of 4-propargylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (400mg) and propargylamine (80mg) were treated in the same manner as described in preparation example 25 to give the title compound.

Yield: 227mg (63%).

¹H-NMR(400MHz，CDCl₃)δ：1.38-1.51(m，2H)，1.83-1.86(m，3H)，2.10-2.15(m，2H)，2.21(s，1H)，2.74(br，1H)，2.83-2.87(m，2H)，3.45(s，2H)，3.56(s，2H)，3.89(s，3H)，3.96(s，6H)，7.19(d，1H，J＝4.9Hz)，7.24(s，2H)，7.65(s，1H)，8.58(d，1H，J＝4.9Hz)。

Example 51

Synthesis of 4- [ N-propargyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine tetrahydrate hydrochloride:

4-propargylamino-1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (227mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (226mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the tetrahydrochloride salt.

Yield: 128mg (23%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.48-2.40(m，7H)，2.72(br，1H)，3.02(br，2H)，3.39(s，2H)，3.64(br，2H)，3.84(s，2H)，3.91(s，6H)，3.98(s，6H)，3.99(s，6H)，7.22-7.29(m，6H)，7.66(br，2H)，8.60(d，1H，J＝4.9Hz)，8.62(d，1H，J＝4.9Hz)。

Preparation example 88

Synthesis of 4- (5-dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (1.40g) and 5-aminoindan (680mg) were treated in the same manner as described in preparation example 37 to give the title compound.

Yield: 1.22g (59%).

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.57(m，2H)，2.00-2.15(m，5H)，2.19-2.25(m，2H)，2.77-2.93(m，6H)，3.30(br，1H)，3.58(s，2H)，3.91(s，3H)，3.97(s，6H)，6.41(d，1H，J＝8.0Hz)，6.52(s，1H)，7.01(d，1H，J＝8.0Hz)，7.21-7.26(m，3H)，7.64(s，1H)，8.60(d，1H，J＝4.9Hz)。

Example 52

Synthesis of 4- [ N- (indan-5-yl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (142mg) was reacted with 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the trihydrochloride salt.

Yield: 90mg (41%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.54-1.67(m，2H)，1.74-1.83(m，2H)，1.98-2.07(m，2H)，2.09-2.98(m，2H)，3.55(s，2H)，3.64-3.74(m，1H)，3.90(s，3H)，3.91(s，6H)，3.92(s，3H)，3.96(s，6H)，4.41(s，2H)，6.49(dd，1H，J＝8.2Hz，2.4Hz)，6.59(s，1H)，6.74(s，2H)，7.04(d，1H，J＝8.2Hz)，7.15-7.20(m，2H)，7.22(s，2H)，7.54(s，1H)，7.77(dd，1H，J＝7.8Hz，1.4Hz)，8.52(dd，1H，J＝4.7Hz，1.8Hz)，8.59(d，1H，J＝5.1Hz)。

Example 53

Synthesis of 4- [ N- (indan-5-yl) -N- [2- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (142mg) was reacted with 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 115mg (47%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.56-1.66(m，2H)，1.80-1.83(m，2H)，2.00-2.05(m，2H)，2.11-2.18(m，2H)，2.77-2.83(m，4H)，2.92-2.95(m，2H)，3.55(s，2H)，3.72(br，1H)，3.87(s，6H)，3.90(s，3H)，3.92(s，3H)，3.96(s，6H)，4.34(s，2H)，6.49(d，1H，J＝8.3Hz)，6.56(s，2H)，6.60(s，1H)，7.02(d，1H，J＝8.3Hz)，7.17-7.27(m，5H)，7.42-7.45(m，1H)，7.54(s，1H)，8.58(d，1H，J＝4.9Hz)。

Example 54

Synthesis of 4- [ N- (indan-5-yl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (142mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a white powder after conversion of the product to the trihydrochloride salt.

Yield: 23mg (9%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.95(m，4H)，2.00(quint，2H，J＝7.3Hz)，2.20(br，2H)，2.75-2.81(m，4H)，2.99(br，2H)，3.58(br，2H)，3.77(s，1H)，3.86(s，3H)，3.87(s，3H)，3.91(s，6H)，3.94(s，6H)，4.49(s，2H)，6.51(d，1H，J＝8.3Hz)，6.62(s，1H)，7.02(d，1H，J＝8.0Hz)，7.16(s，2H)，7.18-7.22(m，4H)，7.57(br，2H)，8.52(d，1H，J＝4.9Hz)，8.57(d，1H，J＝4.9Hz)。

Example 55

Synthesis of 4- [ N- (indan-5-yl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (60mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. After conversion of the product to the dihydrochloride salt, the title compound was obtained as a yellow powder.

Yield: 18mg (19%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.60-1.95(m，4H)，2.00(quint，2H，J＝7.2Hz)，2.20(br，2H)，2.75-2.81(m，4H)，2.95(br，2H)，3.60(br，2H)，3.85(br，1H)，3.86(s，3H)，3.87(s，6H)，3.88(s，3H)，3.94(s，6H)，4.51(s，2H)，6.54(d，1H，J＝8.2Hz)，6.66(s，1H)，6.70(s，2H)，7.01(d，1H，J＝8.4Hz)，7.19(d，1H，J＝4.9Hz)，7.19-7.42(m，6H)，7.60(br，1H)，8.59(br，1H)。

Example 56

Synthesis of 4- [ N- (indan-5-yl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. After conversion of the product to the trihydrochloride salt, the title compound was obtained as a yellow powder.

Yield: 138mg (63%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.71-1.91(m，4H)，1.98-2.06(m，2H)，2.13-2.22(m，2H)，2.76-2.84(m，4H)，2.94-3.05(m，2H)，3.57(s，2H)，3.69-3.78(m，1H)，3.89(s，3H)，3.90(s，3H)，3.94(s，6H)，3.96(s，6H)，4.50(s，2H)，6.57(dd，1H，J＝8.2Hz，2.3Hz)，6.67(s，1H)，7.04(d，1H，J＝8.4Hz)，7.20-7.22(m，1H)，7.22(s，2H)，7.23(s，2H)，7.57-7.62(m，1H)，7.60(s，1H)，7.65(dd，1H，J＝8.2Hz，2.2Hz)，8.58-8.62(m，2H)。.

Example 57

Synthesis of 4- [ N- (indan-5-yl) -N- [4- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (5-Dihydroindenylamino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (143mg) was reacted with 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. After conversion of the product to the dihydrochloride salt, the title compound was obtained as a yellow powder.

Yield: 95mg (39%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.74-1.90(m，4H)，2.01-2.06(m，2H)，2.16-2.22(m，2H)，2.78-2.84(m，4H)，2.96-2.99(m，2H)，3.58(s，2H)，3.72(br，1H)，3.88(s，3H)，3.90(s，3H)，3.91(s，6H)，3.96(s，6H)，4.51(s，2H)，6.55(d，1H，J＝8.3Hz)，6.67(s，1H)，6.72(s，2H)，7.04(d，1H，J＝8.3Hz)，7.20(d，1H，J＝5.1Hz)，7.23(s，2H)，7.35(d，2H，J＝8.1Hz)，7.47(d，2H，J＝8.1Hz)，7.61(s，1H)，8.59(d，1H，J＝4.9Hz)。

Preparation example 89

Synthesis of 4- (4-butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] -4-piperidone (1.24g) and 4-butylaniline (149mg) were treated in the same manner as described in preparation example 37 to give the title compound.

Yield: 1.23g (72%).

¹H-NMR (400MHz，CDCl₃)δ：0.82(t，3H，J＝7.3Hz)，1.20-1.30(m，2H)，1.38-1.50(m，4H)，1.92-2.25(m，4H)，2.40(t，2H，J＝7.7Hz)，2.77(br，2H)，3.21(br，1H)，3.50(s，2H)，3.82(s，3H)，3.89(s，6H)，6.45(d，2H，J＝7.8Hz)，6.89(d，2H，J＝8.0Hz)，7.13(d，1H，J＝4.9Hz)，7.18(s，2H)，7.58(s，1H)，8.52(d，1H，J＝4.9Hz)。

Example 58

Synthesis of 4- [ N- (4-butylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-3-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (147mg) was reacted with 3-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9 to obtain the title compound as a yellow powder after conversion of the product to the trihydrochloride.

Yield: 58mg (27%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.91(t，3H，J＝7.3Hz)，1.32-1.35(m，2H)，1.50-1.70(m，4H)，1.75(br，2H)，2.10-2.20(m，2H)，2.49(t，2H，J＝7.6Hz)，2.95(br，2H)，3.55(s，2H)，3.70(br，1H)，3.90(s，3H)，3.91(s，6H)，3.92(s，3H)，3.96(s，6H)，4.41(s，2H)，6.59(d，2H，J＝8.8Hz)，6.74(s，2H)，7.00(d，2H，J＝8.6Hz)，7.16-7.17(m，1H)，7.19(d，1H，J＝4.9Hz)，7.22(s，2H)，7.54(s，1H)，8.59(d，1H，J＝7.5Hz)，8.52(br，1H)，8.59(d，1H，J＝4.9Hz)。

Example 59

Synthesis of 4- [ N- (4-butylphenyl) -N- [2- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (147mg) was reacted with 2- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 59mg (24%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.90(t，3H，J＝7.4Hz)，1.25-1.41(m，2H)，1.48-1.75(m，4H)，1.81(d，2H，J＝11.7Hz)，2.13(t，2H，J＝11.2Hz)，2.48(t，2H，J＝7.5Hz)，2.93(d，2H，J＝11.2Hz)，3.55(s，2H)，3.65-3.80(m，1H)，3.87(s，6H)，3.90(s，3H)，3.92(s，1H)，3.96(s，6H)，4.33(s，2H)，6.56(s，2H)，6.60(d，2H，J＝8.5Hz)，6.98(d，2H，J＝8.5Hz)，7.18(d，1H，J＝4.9Hz)，7.21(s，2H)，7.20-7.37(m，3H)，7.41(br，1H)，7.54(s，1H)，8.58(d，1H，J＝4.9Hz)。

Example 60

Synthesis of 4- [ N- (4-butylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (196mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (129mg) in the same manner as described in example 9. The title compound was obtained as a white powder after conversion of the product to the trihydrochloride salt.

Yield: 20mg (6%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.88(t，3H，J＝7.3Hz)，1.20-1.35(m，2H)，1.49-1.60(m，2H)，1.62-2.02(m，4H)，2.20(br，2H)，2.46(t，2H，J＝7.3Hz)，3.05(br，2H)，3.60(br，3H)，3.87(s，3H)，3.88(s，3H)，3.90(s，6H)，3.94(s，6H)，4.49(s，2H)，6.62(d，2H，J＝8.3Hz)，6.98(d，2H，J＝8.3Hz)，7.13(s，2H)，7.15-7.40(m，4H)，7.55(br，2H)，8.52(d，1H，J＝4.9Hz)，8.60(br，1H)。

Example 61

Synthesis of 4- [ N- (4-butylphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (147mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 102mg (42%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.90(t，3H，J＝7.4Hz)，1.30-1.36(m，2H)，1.48-1.56(m，2H)，1.76-1.89(m，4H)，2.19(br，2H)，2.48(t，2H，J＝7.8Hz)，2.97(br，2H)，3.58(s，2H)，3.86(br，1H)，3.88(s，3H)，3.58(s，2H)，3.86(br，1H)，3.88(s，3H)，3.90(s，3H)，3.95(s，6H)，4.54(s，2H)，6.68(d，2H，J＝8.6Hz)，6.72(s，2H)，7.00(d，2H，J＝8.6Hz)，7.20-7.27(m，2H)，7.23(s，2H)，7.32-7.40(m，2H)，7.44(s，1H)，7.62(s，1H)，8.59(d，1H，J＝5.1Hz)。

Example 62

Synthesis of 4- [ N- (4-butylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (147mg) was reacted with 5-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the trihydrochloride salt.

Yield: 65mg (21%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.90(t，3H，J＝7.3Hz)，1.32-1.36(m，2H)，1.50-1.54(m，2H)，1.70-1.95(m，4H)，2.17(br，2H)，2.49(t，2H，J＝7.7Hz)，2.96(br，2H)，3.58(s，2H)，3.75(br，1H)，3.89(s，3H)，3.90(s，3H)，3.94(s，6H)，3.96(s，6H)，4.50(s，2H)，6.68(d，2H，J＝8.6Hz)，7.00(d，2H，J＝8.6Hz)，7.20-7.22(m，3H)，7.23(s，2H)，7.58-7.66(m，3H)，8.59(br，1H)，8.60(br，1H)。

Example 63

Synthesis of 4- [ N- (4-butylphenyl) -N- [4- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

4- (4-Butylanilino) -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine (147mg) was reacted with 4- (3, 4, 5-trimethoxyphenyl) benzyl chloride (114mg) in the same manner as described in example 9. The title compound was obtained as a yellow powder after conversion of the product to the dihydrochloride salt.

Yield: 82mg (33%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：0.90(t，3H，J＝7.3Hz)，1.30-1.36(m，2H)，1.51-1.55(m，2H)，1.79-1.90(m，4H)，2.18(br，2H)，2.48(t，2H，J＝7.7Hz)，2.98(d，2H，J＝10.7Hz)，3.57(s，2H)，3.72-3.85(m，1H)，3.88(s，3H)，3.90(s，3H)，3.91(s，6H)，3.96(s，6H)，4.50(s，2H)，6.66(d，2H，J＝8.8Hz)，6.75(s，2H)，7.00(d，2H，J＝8.8Hz)，7.20(d，1H，J＝4.9Hz)，7.22(s，2H)，7.33(d，2H，J＝8.2Hz)，7.47(d，2H，J＝8.2Hz)，7.61(s，1H)，8.59(d，1H，J＝5.1Hz)。

Preparation example 90

Synthesis of 1- (4-picolyl) -4-piperidone:

4-Piperidinone hydrochloride monohydrate (922mg) and 4-picolyl chloride hydrochloride (820mg) were reacted by the same way with the example 2 to obtain the titled compound.

Yield: 870mg (92%).

¹H-NMR(400MHz，CDCl₃)δ：2.46(t，4H，J＝5.9Hz)，2.74(t，4H，J＝6.2Hz)，3.61(s，2H)，7.29(d，2H，J＝6.2Hz)，8.55(dd，2H，J＝6.2Hz，1.1Hz)。

Preparation example 91

Synthesis of 1- (4-picolyl) -4- (4-picolylamino) piperidine tetrahydrate salt:

1- (4-picolyl) -4-piperidone (870mg) and 4-picolylamine (497mg) were reacted by the same way as described in preparation 37. The title compound was obtained as light brown tetrahydrate salt.

Yield: 363mg (19%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.37-1.51(m，2H)，1.82-1.90(m，2H)，2.04(dt，2H，J＝11.6Hz，2.7Hz)，2.44-2.55(m，1H)，2.76-2.82(m，2H)，3.47(s，2H)，3.82(s，2H)，7.23-7.26(m，4H)，8.50-8.53(m，4H)。

Preparation example 92

Synthesis of 4- (p-methoxybenzylamino) -1- (tert-butoxycarbonyl) piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (116g) and p-anisidine (68.3g) were reacted by the same way with the preparation example 37 to give the title compound.

Yield: 125g (74%).

¹H-NMR(400MHz，CDCl₃)δ：1.23-1.35(m，2H)，1.46(s，9H)，1.96-2.06(m，2H)，2.83-2.96(m，2H)，3.27-3.38(m，1H)，3.74(s，9H)，3.94-4.12(m，2H)，6.58(d，2H，J＝9.0Hz)，6.77(d，2H，J＝9.0Hz)。

Preparation example 93

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzoylamino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzoic acid (577mg) in the same manner as described in example 1 to give the title compound.

Yield: 416mg (36%).

Preparation 94

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzoyl ] amino ] piperidine hydrochloride:

to a solution of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzoylamino ] piperidine (416mg) in ethyl acetate (5mL) was added a 4M solution of hydrogen chloride in ethyl acetate (5 mL). The mixture was stirred at room temperature for 4 hours, and the resulting precipitate was filtered, washed on the funnel with ethyl acetate, and then dried to give the title compound.

Yield: 315mg (85%)

Examples 64 to 66

These compounds were prepared by reacting 4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzoyl ] amino ] piperidine hydrochloride with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is converted into the corresponding hydrochloride. The yield of the free base and the NMR data are given in the table below.

Preparation example 95

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (2.21g) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (2.12g) in the same manner as described in example 9 to give the title compound.

Yield: 3.76g (93%)

¹H-NMR(400MHz，CDCl₃)δ：1.40-1.64(m，2H)，1.44(s，9H)，1.82-1.91(m，2H)，2.71-2.84(m，2H)，3.62-3.73(m，1H)，3.74(s，3H)，3.89(s，3H)，3.94(s，6H)，4.10-4.30(m，2H)，4.40(s，2H)，6.76(d，2H，J＝9.4Hz)，6.79(d，2H，J＝9.8Hz)，7.14-7.19(m，3H)，7.56(s，1H)，8.55(d，1H，J＝5.1Hz)。

Preparation example 96

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (3.76g) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 3.77g (theoretical yield).

Preparation example 97

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in preparation example 9 to give the title compound as a yellow amorphous substance.

Yield: 159mg (14%).

¹H-NMR(400_MHz，CDCl₃)δ：1.44(s，9H)，1.50-1.65(m，2H)，1.83-1.91(m，2H)，2.70-2.84(m，2H)，3.53-3.62(m，1H)，3.73(s，3H)，3.89(s，3H)，3.91(s，6H)，4.10-4.29(m，2H)，4.41(s，2H)，6.66(s，2H)，6.76-6.84(m，4H)，7.70(s，1H)，8.49(s，1H)，8.63(d，1H，J＝2.1Hz)。

Preparation example 98

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (159mg) was treated in the same manner as described in preparation 94 to give the title compound as a yellow powder.

Yield: 142mg (94%).

Preparation example 99

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were treated in the same manner as described in example 9 to obtain the title compound as a yellow amorphous substance.

Yield: 1.12g (90%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.50-1.63(m，2H)，1.82-1.91(m，2H)，2.71-2.83(m，2H)，3.69(tt，1H，J＝11.5Hz，3.5Hz)，3.73(s，3H)，3.88(s，3H)，3.90(s，6H)，4.10-4.28(m，2H)，4.42(s，2H)，6.71(s，2H)，6.78(s，4H)，7.24-7.28(m，1H)，7.31-7.40(m，2H)，7.42(s，1H)。

Preparation example 100

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.12g) was treated in the same manner as described in preparation 94 to obtain the title compound as a yellow powder.

Yield: 980mg (99%).

Examples 67 to 71

These compounds were prepared by reacting the amine compounds obtained in preparation examples 96, 98 and 100 with the chloride derivatives obtained in preparation examples 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 101

Synthesis of 1- (tert-butoxycarbonyl) -4- (4-ethoxyphenylamino) piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (5.00g) and p-aminophenethyl ether (3.28g) were reacted by the same way with the preparation example 37 to give the title compound as a brown powder.

Yield: 7.00g (91%).

¹H-NMR(400MHz，CDCl₃)δ：1.21-1.31(m，2H)，1.37(t，3H，J＝7.0Hz)，1.46(s，9H)，1.97-2.05(m，2H)，2.84-2.95(m，2H)，3.28-3.37(m，1H)，3.96(q，2H，J＝7.0Hz)，3.99-4.10(m，2H)，6.57(d，2H，J＝8.8Hz)，6.77(d，2H，J＝9.0Hz)。

Preparation example 102

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-ethoxyphenyl) amino ] piperidine (641mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to obtain the title compound as a yellow amorphous substance.

Yield: 2.08g (94%).

¹H-NMR(400MHz，CDCl₃)δ：1.36(t，3H，J＝7.9Hz)，1.44(s，9H)，1.49-1.58(m，2H)，1.82-1.92(m，2H)，2.70-2.85(m，2H)，3.62-3.72(m，1H)，3.89(s，3H)，3.94(s，6H)，4.12-4.29(m，2H)，4.39(s，2H)，6.75(d，2H，J＝9.2Hz)，6.78(d，2H，J＝9.6Hz)，7.14-7.18(m，3H)，7.55(s，1H)，8.54(d，1H，J＝5.1Hz)。

Preparation example 103

Synthesis of 4- [ N- (4-ethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (1.08g) was treated in the same manner as described in preparation 94 to obtain the title compound as a pale yellow powder.

Yield: 1.01g (98%).

Preparation example 104

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-ethoxyphenyl) amino ] piperidine (641mg) was reacted with 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 452mg (39%).

¹H-NMR(400MHz，CDCl₃)δ：1.36(t，3H，J＝6.8Hz)，1.44(s，9H)，1.50-1.60(m，2H)，1.82-1.90(m，1H)，2.68-2.82(m，2H)，3.52-3.61(m，1H)，3.88(s，3H)，3.90(s，6H)，3.94(q，2H，J＝7.0Hz)，4.10-4.25(m，2H)，4.40(s，2H)，6.66(s，2H)，6.77(d，2H，J＝9.2Hz)，6.81(d，2H，J＝9.2Hz)，7.67(s，1H)，8.49(d，1H，J＝2.0Hz)，8.62(d，1H，J＝2.1Hz)。

Preparation example 105

Synthesis of 4- [ N- (4-ethoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (452mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 380mg (88%).

Preparation example 106

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-ethoxyphenyl) amino ] piperidine (641mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.06g (92%).

¹H-NMR(400_MHz，CDCl₃)δ：1.36(t，3H，J＝7.0Hz)，1.44(s，9H)，1.53-1.59(m，2H)，1.83-1.91(m，2H)，2.70-2.83(m，2H)，3.64-3.73(m，1H)，3.88(s，3H)，3.90(s，6H)，3.94(q，2H，J＝7.0Hz)，4.10-4.29(m，2H)，4.41(s，2H)，6.71(s，2H)，6.76(s，4H)，7.26(d，1H，J＝7.9Hz)，7.33(dd，1H，J＝7.4Hz，7.4Hz)，7.38(d，1H，J＝7.6Hz)，7.42(s，1H)。

Preparation example 107

Synthesis of 4- [ N- (4-ethoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-ethoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.06g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 913mg (97%).

Examples 72 to 79

These compounds were prepared by reacting the amine compounds obtained in preparation examples 103, 105 and 107 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The free base is then converted to the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 108

Synthesis of 1- (tert-butoxycarbonyl) -4- (4-butoxyphenylamino) piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (5.00g) and 4-butoxyaniline (3.95g) were reacted by the same way with the preparation of example 37 to give the title compound as a brown powder.

Yield: 6.91g (83%).

¹H-NMR(400MHz，CDCl₃)δ：0.96(t，3H，J＝7.2Hz)，1.23-1.35(m，2H)，1.42-1.53(m，2H)，1.46(s，9H)，1.68-1.76(m，2H)，1.97-2.05(m，2H)，2.84-2.95(m，2H)，3.28-3.37(m，1H)，3.88(t，2H，J＝6.6Hz)，3.96-4.12(m，2H)，6.57(d，2H，J＝9.0Hz)，6.77(d，2H，J＝8.8Hz)。

Preparation example 109

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-butoxyphenyl) amino ] piperidine (696mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 980mg (81%).

¹H-NMR(400MHz，CDCl₃)δ：0.95(t，3H，J＝7.4Hz)，1.40-1.50(m，2H)，1.44(s，9H)，1.67-1.76(m，2H)，1.82-1.90(m，2H)，1.82-1.90(m，2H)，2.70-2.82(m，2H)，3.61-3.71(m，1H)，3.84-3.90(m，5H)，3.94(s，6H)，4.10-4.28(m，2H)，4.39(s，2H)，6.74(d，2H，J＝9.4Hz)，6.78(d，2H，J＝9.4Hz)，7.14-7.18(m，3H)，7.56(s，1H)，8.54(d，1H，J＝5.1Hz)。

Preparation example 110

Synthesis of 4- [ N- (4-butoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (980mg) was treated in the same manner as described in preparation 94 to obtain the title compound as a yellow powder.

Yield: 926mg (99%).

Preparation example 111

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-butoxyphenyl) amino ] piperidine (697mg) was reacted with 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 485mg (40%).

¹H-NMR(400MHz，CDCl₃)δ：0.95(t，3H，J＝7.4Hz)，1.40-1.57(m，2H)，1.44(s，9H)，1.67-1.75(m，2H)，1.82-1.90(m，2H)，2.69-2.81(m，2H)，3.51-3.60(m，1H)，3.87(q，2H，J＝6.6Hz)，3.88(s，3H)，3.90(s，6H)，4.06-4.23(m，2H)，4.39(s，2H)，6.66(s，2H)，6.77(d，2H，J＝9.2Hz)，6.81(d，2H，J＝9.2Hz)，6.81(d，2H，J＝9.4Hz)，7.67(s，1H)，8.49(d，1H，J＝1.8Hz)，8.62(d，1H，J＝2.2Hz)。

Preparation example 112

Synthesis of 4- [ N- (4-butoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (485mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 456mg (98%).

Preparation example 113

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-butoxycarbonyl) -4- [ (4-butoxyphenyl) amino ] piperidine (697mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.17g (97%).

¹H-NMR(400MHz，CDCl₃)δ：0.95(t，3H，J＝7.3Hz)，1.40-1.61(m，4H)，1.44(s，9H)，1.67-1.75(m，2H)，1.83-1.90(m，2H)，2.70-2.83(m，2H)，3.63-3.72(m，2H)，3.87(q，2H，J＝6.6Hz)，3.88(s，3H)，3.90(s，6H)，4.09-4.28(m，2H)，4.41(s，2H)，6.70(s，2H)，6.76(s，4H)，7.26(d，2H，J＝8.0Hz)，7.33(t，1H，J＝7.6Hz)，7.38(d，1H，J＝7.3Hz)，7.42(s，1H)。

Preparation example 114

Synthesis of 4- [ N- (4-butoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-butoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.17g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 1.02g (98%).

Examples 80 to 87

These compounds were prepared by reacting the amine compounds obtained in preparation examples 110, 112 and 114 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 115

Synthesis of 4- (m-methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (4.78g) and m-anisidine (2.96g) were reacted by the same way with the preparation example 37 to give the title compound.

Yield: 4.83g (66%).

¹H-NMR(400MHz，CDCl₃)δ：1.20-1.39(m，2H)，1.44(s，9H)，1.99-2.05(m，2H)，2.89(dt，2H，J＝13.5Hz，2.2Hz)，3.33-3.44(m，1H)，3.75(s，3H)，3.96-4.07(m，2H)，6.14(t，1H，J＝2.2Hz)，6.18-6.29(m，2H)，7.05(t，1H，J＝8.1Hz)。

Preparation example 116

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

4- (m-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 789mg (70%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.50-1.67(m，2H)，1.82-1.91(m，2H)，2.74-2.87(m，2H)，3.74(s，3H)，3.88-3.98(m，1H)，3.89(s，3H)，3.94(s，6H)，4.14-4.32(m，2H)，4.48(s，2H)，6.28(dd，1H，J＝2.2Hz，2.2Hz)，6.31-6.37(m，2H)，7.10-7.15(m，2H)，7.16(s，2H)，7.55(s，1H)，8.56(d，1H，J＝5.1Hz)。

Preparation example 117

Synthesis of 4- [ N- (3-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (789mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 710mg (95%).

Preparation example 118

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

4- (m-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 396mg (35%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.54-1.66(m，2H)，1.81-1.91(m，2H)，2.73-2.87(m，2H)，3.74(s，3H)，3.87-3.93(m，1H)，3.88(s，3H)，3.90(s，6H)，4.14-4.29(m，2H)，4.51(s，2H)，6.30-6.35(m，2H)，6.38(d，1H，J＝7.2Hz)，6.68(s，2H)，7.12(dd，1H，J＝8.8Hz，8.88Hz)，7.66(s，1H)，8.49(d，1H，J＝2.0Hz)，8.66(d，1H，J＝2.2Hz)。

Preparation example 119

Synthesis of 4- [ N- (3-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (396mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 348mg (92%).

Preparation example 120

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

4- (m-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) in the same manner as described in preparation example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.01g (90%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.56-1.67(m，2H)，1.83-1.91(m，2H)，2.72-2.86(m，2H)，3.73(s，3H)，3.85-3.98(m，1H)，3.88(s，3H)，3.90(s，6H)，4.12-4.30(m，2H)，4.50(s，2H)，6.27-6.34(m，2H)，6.38(dd，1H，J＝8.2Hz，2.4Hz)，6.72(s，2H)，7.10(dd，1H，J＝8.2Hz，8.2Hz)，7.21-7.27(m，1H)，7.32-7.43(m，3H)。

Preparation example 121

Synthesis of 4- [ N- (3-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (3-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.01g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 820mg (92%).

Examples 88 to 95

These compounds were prepared by reacting the amine compounds obtained in preparation examples 117, 119 and 121 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base was then converted into the corresponding hydrochloride salt-the yield of their free base and NMR data are listed in the table below.

Preparation example 122

Synthesis of 4- (o-methoxybenzylamino) -1- (tert-butoxycarbonyl) piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (4.78g) and o-anisidine (2.96g) were reacted by the same way with the preparation example 37 to give the title compound.

Yield: 2.61g (36%).

¹H-NMR(400MHz，CDCl₃)δ：1.31-1.41(m，2H)，1.47(s，9H)，2.00-2.08(m，2H)，2.90-3.01(m，2H)，3.38-3.47(m，1H)，3.83(s，3H)，4.00-4.21(m，2H)，6.60-6.69(m，2H)，6.76-6.89(m，2H)。

Preparation example 123

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

4- (o-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 763mg (68%).

¹H-NMR(400MHz，CDCl₃)δ：1.41-1.58(m，2H)，1.44(s，9H)，1.81-1.91(m，2H)，2.62-2.78(m，2H)，3.29(tt，1H，J＝7.6Hz，3.7Hz)，3.86(s，3H)，3.89(s，3H)，3.95(s，6H)，4.06-4.16(m，2H)，4.37(s，2H)，6.80(ddd，1H，J＝7.6Hz，7.6Hz，1.2Hz)，6.87(dd，1H，J＝8.5Hz，1.0Hz)，7.00-7.06(m，2H)，7.14(s，2H)，7.20(dd，1H，J＝4.9Hz，1.0Hz)，7.61(s，1H)，8.49(d，1H，J＝4.9Hz)。

Preparation example 124

Synthesis of 4- [ N- (2-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (763mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 701mg (97%).

Preparation example 125

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] -methyl ] amino ] piperidine:

4- (o-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 353mg (31%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.46-1.53(m，2H)，1.82-1.91(m，2H)，2.62-2.78(m，2H)，3.24-3.33(m，1H)，3.83(s，3H)，3.89(s，3H)，3.91(s，6H)，4.03-4.16(m，2H)，4.37(s，2H)，6.64(s，2H)，6.79(ddd，1H，J＝7.6Hz，7.6Hz，1.2Hz)，6.84(dd，1H，J＝7.0Hz，1.2Hz)，6.97-7.06(m，2H)，7.68(dd，1H，J＝1.3Hz，1.3Hz)，8.49(d，1H，J＝2.0Hz)，8.56(d，1H，J＝2.2Hz)。

Preparation example 126

Synthesis of 4- [ N- (2-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (353mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 312mg (93%).

Preparation example 127

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -piperidine:

4- (o-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (613mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.12g (100%).

¹H-NMR(400MHz，CDCl₃)δ：1.43(s，9H)，1.46-1.57(m，2H)，1.81-1.90(m，2H)，2.62-2.76(m，2H)，3.31(tt，1H，J＝11.1Hz，3.3Hz)，3.84(s，3H)，3.88(s，3H)，3.91(s，6H)，4.00-4.16(m，2H)，4.36(s，2H)，6.67(s，2H)，6.78(t，1H，J＝7.3Hz)，6.85(d，1H，J＝7.9Hz)，6.96-7.03(m，2H)，7.24-7.34(m，3H)，7.43(s，1H)。

Preparation example 128

Synthesis of 4- [ N- (2-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (2-methoxyphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.12g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 987mg (99%).

Examples 96 to 101

These compounds were prepared by reacting the amine compounds obtained in preparation examples 124, 126 and 128 with the chloride derivatives obtained in preparation examples 3 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 129

Synthesis of 1- (tert-butoxycarbonyl) -4- (2, 3-dimethoxyphenylamino) piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (4.78g) and 2, 3-dimethoxyaniline (3.68g) were reacted in the same manner as described in preparation example 37 to give the title compound.

Yield: 3.18g (39%).

¹H-NMR(400MHz，CDCl₃)δ：1.29-1.42(m，2H)，1.45(s，9H)，1.97-2.03(m，2H)，2.92(dt，2H，J＝13.5Hz，2.2Hz)，3.38(dt，1H，J＝13.8Hz，4.1Hz)，3.77(s，3H)，3.82(s，3H)，3.99-4.03(m，2H)，4.17(m，1H)，6.27-6.32(m，2H)，6.88(t，1H，J＝8.4Hz)。

Preparation example 130

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (2, 3-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- (2, 3-dimethoxyphenylamino) piperidine (673mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 613mg (52%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.56-1.70(m，2H)，1.84-1.91(m，2H)，2.62-2.76(m，2H)，3.58(tt，1H，J＝11.8Hz，3.6Hz)，3.83(s，3H)，3.89(s，6H)，3.93(s，6H)，4.08-4.25(m，2H)，4.35(s，2H)，6.56-6.63(m，2H)，6.86(t，1H，J＝8.3Hz)，7.14(s，2H)，7.17(dd，1H，J＝5.1Hz，1.2Hz)，7.62(s，1H)，8.50(d，1H，J＝5.1Hz)。

Preparation example 131

Synthesis of 4- [ N- (2, 3-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methan-e ] aminopiperidine dihydrochloride.

1- (tert-Butoxycarbonyl) -4- [ N- (2, 3-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (613mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 512mg (88%).

Example 102

Synthesis of 4- [ N- (2, 3-dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -1- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- [ N- (2, 3-Dimethoxyphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] ] piperidine dihydrochloride (113mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (59mg) in the same manner as described in example 2. The title compound was obtained as a yellow powder after conversion of the product to the hydrochloride salt.

Yield: 21mg (12%).

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.76-1.96(m，4H)，2.00-2.13(m，2H)，2.86-3.00(m，2H)，3.42-3.60(m，1H)，3.54(s，2H)，3.82(s，3H)，3.88(s，3H)，3.90(s，3H)，3.97(s，6H)，4.41(s，2H)，6.57(d，1H，J＝8.0Hz)，6.62(d，1H，J＝8.2Hz)，6.85(dd，1H，J＝8.4Hz，8.4Hz)，7.11-7.29(m，6H)，7.59(s，1H)，7.63(s，1H)，8.50(d，1H，J＝4.9Hz)，8.59(d，1H，J＝4.9Hz)。

Preparation 132

Synthesis of 1- (tert-butoxycarbonyl) -4- [4- [ (trifluoromethoxy) phenyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and 4- (trifluoromethoxy) aniline (4.23g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 5.22g (60%).

¹H-NMR(400MHz，CDCl₃)δ：1.25-1.40(m，2H)，1.47(s，9H)，1.98-2.08(m，2H)，2.83-2.98(m，2H)，3.34-3.43(m，1H)，3.97-4.12(m，2H)，6.58(d，2H，J＝8.8Hz)，7.03(d，2H，J＝8.8Hz)。

Preparation example 133

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [4- [ (trifluoromethoxy) phenyl ] amino ] piperidine (721mg) was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 543mg (44%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.66(m，2H)，1.81-1.91(m，2H)，2.73-2.88(m，2H)，3.88-3.99(m，1H)，3.89(s，3H)，3.93(s，6H)，4.15-4.34(m，2H)，4.48(s，2H)，6.68(d，2H，J＝9.2Hz)，7.07(d，2H，J＝8.6Hz)，7.12(dd，1H，J＝5.2Hz，1.3Hz)，7.15(s，2H)，7.52(s，1H)，8.58(d，1H，J＝5.2Hz)。

Preparation example 134

Synthesis of 4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-butoxycarbonyl) -4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [2- (3, 4, 5-trifluoromethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (543mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 481mg (93%).

Preparation example 135

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [4- [ (trifluoromethoxy) phenyl ] amino ] piperidine (721mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 201mg (16%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.54-1.67(m，2H)，1.82-1.90(m，2H)，2.74-2.86(m，2H)，3.84-3.91(m，1H)，3.88(s，3H)，3.89(s，6H)，4.16-4.30(m，2H)，4.52(s，2H)，6.67(s，2H)，6.72(d，2H，J＝9.4Hz)，7.06(d，2H，J＝8.4Hz)，7.64(t，1H，J＝2.1Hz)，8.49(d，1H，J＝2.2Hz)，8.68(d，1H，J＝2.1Hz)。

Preparation example 136

Synthesis of 4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (201mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 185mg (96%).

Preparation example 137

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ (4-trifluoromethoxy) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [4- [ (trifluoromethoxy) phenyl ] amino ] piperidine (721mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.06mg (86%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.56-1.68(m，2H)，1.83-1.90(m，2H)，2.71-2.86(m，2H)，3.87-3.90(m，1H)，3.88(s，3H)，3.89(s，6H)，4.16-4.29(m，2H)，4.51(s，2H)，6.70(d，2H，J＝9.3Hz)，6.70(s，2H)，7.04(d，2H，J＝8.5Hz)，7.22(d，1H，J＝7.8Hz)，7.34-7.44(m，3H)。

Preparation example 138

Synthesis of 4- [ N- [4- (trifluoromethoxy) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ (4-trifluoromethoxy) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.06g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 795mg (84%).

Example 103-110

These compounds were prepared by reacting the amine compounds obtained in preparation examples 134, 136 and 138 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 139

Synthesis of 1- (tert-butoxycarbonyl) -4- [ [4- (methylthio) phenyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and 4- (methylthio) aniline (3.33g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 3.80g (49%).

¹H-NMR(400MHz，CDCl₃)δ：1.26-1.38(m，2H)，1.46(s，9H)，1.98-2.06(m，2H)，2.41(s，3H)，2.88-2.97(m，2H)，3.36-3.45(m，2H)，3.48-3.56(br，1H)，3.96-4.12(m，2H)，6.55(d，2H，J＝8.8Hz)，7.21(d，2H，J＝8.8Hz)。

Preparation example 140

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [4- (methylthio) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ [4- (methylthio) phenyl ] amino ] piperidine (644mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 671mg (58%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.50-1.66(m，2H)，1.81-1.89(m，2H)，2.40(s，3H)，2.74-2.87(m，2H)，3.88-3.94(m，1H)，3.90(s，3H)，3.94(s，6H)，4.15-4.29(m，2H)，4.48(s，2H)，6.67(d，2H，J＝9.0Hz)，7.11-7.18(m，1H)，7.16(s，2H)，7.22(d，2H，J＝6.6Hz)，7.54(s，1H)，8.57(d，1H，J＝5.1Hz)。

Preparation example 141

Synthesis of 4- [ N- [4- (methylthio) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (methylthio) phenyl ] -N- [ [2- (3, 4, 5-trifluoromethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (671mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 602mg (94%).

Preparation example 142

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [4- (methylthio) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ [4- (methylthio) phenyl ] amino ] piperidine (645mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 312mg (27%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.53-1.63(m，2H)，1.83-1.89(m，2H)，2.40(s，3H)，2.73-2.85(m，2H)，3.87-3.91(m，1H)，3.88(s，3H)，3.90(s，6H)，4.16-4.30(m，2H)，4.50(s，2H)，6.67(s，2H)，6.71(d，2H，J＝9.0Hz)，7.21(d，2H，J＝9.0Hz)，7.64(s，1H)，8.48(d，1H，J＝2.2Hz)，8.66(d，1H，J＝2.1Hz)。

Preparation example 143

Synthesis of 4- [ N- [4- (methylthio) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (methylthio) phenyl ] -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (312mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 251mg (84%).

Preparation example 144

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ (4-methylthio) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ N- [ (methylthio) phenyl ] amino ] piperidine (645mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.10g (95%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.55-1.68(m，2H)，1.81-1.90(m，2H)，2.39(s，3H)，2.73-2.86(m，2H)，3.87-3.91(m，1H)，3.88(s，3H)，3.89(s，6H)，4.15-4.29(m，2H)，4.50(s，2H)，6.68-6.73(m，4H)，7.19-7.24(m，3H)，7.33-7.43(m，3H)。

Preparation example 145

Synthesis of 4- [ N- [4- (methylthio) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (methylthio) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.10g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 866mg (89%).

Example 111-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 141, 143 and 145 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 146

Synthesis of 1- (tert-butoxycarbonyl) -4- [ (4-methylphenyl) amino ] piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (5.00g) and p-toluidine (2.56g) were treated in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 5.79g (83%).

¹H-NMR(400MHz，CDCl₃)δ：1.25-1.36(m，2H)，1.46(s，9H)，1.99-2.06(m，2H)，2.23(s，3H)，2.86-2.96(m，2H)，3.30-3.43(m，2H)，3.96-4.10(m，2H)，6.53(d，2H，J＝8.4Hz)，6.98(d，2H，J＝8.0Hz)。

Preparation example 147

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methylphenyl) amino ] piperidine (581mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.00g (91%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.55-1.59(m，2H)，1.81-1.90(m，2H)，2.23(s，3H)，2.72-2.86(m，2H)，3.81-3.94(m，1H)，3.89(s，3H)，3.93(s，6H)，4.14-4.30(m，2H)，4.45(s，2H)，6.66(d，2H，J＝8.6Hz)，7.02(d，2H，J＝8.2Hz)，7.13-7.16(m，3H)，7.55(s，1H)，8.55(d，1H，J＝8.1Hz)。

Preparation example 148

Synthesis of 4- [ N- (4-methylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (1.00g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 924mg (97%).

Preparation example 149

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-methylphenyl) amino ] piperidine (581mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 426mg (39%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.70(m，2H)，1.82-1.90(m，2H)，2.23(s，3H)，2.72-2.86(m，2H)，3.77-3.86(m，1H)，3.88(s，3H)，3.90(s，6H)，4.10-4.28(m，2H)，4.47(s，2H)，6.67(s，2H)，6.70(d，2H，J＝8.6Hz)，7.01(d，2H，J＝8.2Hz)，7.67(dd，1H，J＝2.1Hz，2.1Hz)，8.50(d，1H，J＝2.0Hz)，8.64(d，1H，J＝2.2Hz)。

Preparation example 150

Synthesis of 4- [ N- (4-methylphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (426mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 400mg (99%).

Preparation example 151

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-methylphenyl) amino ] piperidine (581mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.03g (94%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.50-1.66(m，2H)，1.83-1.90(m，2H)，2.23(s，3H)，2.72-2.85(m，2H)，3.82-3.92(m，1H)，3.88(s，3H)，3.89(s，6H)，4.11-4.30(m，2H)，4.47(s，2H)，6.68(d，2H，J＝8.6Hz)，6.71(s，2H)，7.00(d，2H，J＝8.8Hz)，7.23-7.27(m，1H)，7.32-7.44(m，3H)。

Preparation 152

Synthesis of 4- [ N- (4-methylphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methylphenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.03g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 882mg (97%).

Example 119-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 148, 150 and 152 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. Their yield between the free radicals and the NMR data are given in the table below.

Preparation example 153

Synthesis of 1- (tert-butoxycarbonyl) -4- [ [4- (trifluoromethyl) phenyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and 4- (trifluoromethyl) aniline (3.85g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 3.30g (40%).

¹H-NMR(400MHz，CDCl₃)δ：1.30-1.41(m，2H)，1.47(s，9H)，2.00-2.07(m，2H)，2.88-2.99(m，2H)，3.32-3.52(m，1H)，3.83-3.89(m，1H)，4.00-4.14(m，2H)，6.59(d，2H，J＝8.4Hz)，7.39(d，2H，J＝8.4Hz)。

Preparation example 154

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [4- (trifluoromethyl) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-butoxycarbonyl) -4- [ [4- (trifluoromethyl) phenyl ] amino ] piperidine (688mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 412mg (34%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.54-1.68(m，2H)，1.81-1.90(m，2H)，2.77-2.90(m，2H)，3.89(s，3H)，3.92(s，6H)，3.98-4.07(m，1H)，4.18-4.33(m，2H)，4.55(s，2H)，6.73(d，2H，J＝8.8Hz)，7.09(d，1H，J＝3.7Hz)，7.13(s，2H)，7.44(d，2H，J＝8.8Hz)，7.49(s，1H)，8.58(d，1H，J＝5.1Hz)。

Preparation example 155

Synthesis of 4- [ N- [4- (trifluoromethyl) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (trifluoromethyl) phenyl ] -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (412mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 359mg (91%).

Preparation example 156

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ (4-trifluoromethyl) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ [4- (trifluoromethyl) phenyl ] amino ] piperidine (689mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 522mg (44%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.58-1.70(m，2H)，1.83-1.90(m，2H)，2.76-2.87(m，2H)，3.87(s，6H)，3.88(s，3H)，3.96-4.06(m，1H)，4.15-4.30(m，2H)，4.58(s，2H)，6.68(s，2H)，6.76(d，2H，J＝8.8Hz)，7.19(s，1H，J＝7.4Hz)，7.33-7.44(m，5H)。

Preparation 157

Synthesis of 4- [ N- [4- (trifluoromethyl) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [4- (trifluoromethyl) phenyl ] -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (522mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 460mg (99%).

Example 127-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 155 and 157 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 158

Synthesis of 1- (tert-butoxycarbonyl) -4- (4-bromophenyl) amino-piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (5.00g) and 4-bromoaniline (4.11g) were reacted by the same way with the example 37 to obtain the title compound as a white powder.

Yield: 3.09g (36%).

¹H-NMR(400MHz，CDCl₃)δ：1.25-1.37(m，2H)，1.46(s，9H)，1.97-2.05(m，2H)，2.86-2.96(m，2H)，3.33-3.42(m，2H)，3.47-3.57(m，1H)，3.96-4.12(m，2H)，6.47(d，2H，J＝8.8Hz)，7.24(d，2H，J＝9.0Hz)。

Preparation example 159

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -piperidine:

1- (tert-Butoxycarbonyl) -4- (4-bromophenyl) amino-piperidine (711mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 607mg (50%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.50-1.64(m，2H)，1.81-1.88(m，2H)，2.74-2.88(m，2H)，3.86-3.94(m，1H)，3.89(s，3H)，3.93(s，6H)，4.14-4.32(m，2H)，4.46(s，2H)，6.59(d，2H，J＝9.1Hz)，7.10(d，1H，J＝5.2Hz)，7.14(s，2H)，7.28(d，2H，J＝9.1Hz)，7.50(s，1H)，8.57(d，1H，J＝5.0Hz)。

Preparation example 160

Synthesis of 4- [ N- (4-bromophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] -piperidine (607mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 541mg (93%).

Preparation 161

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -piperidine:

1- (tert-Butoxycarbonyl) -4- (4-bromophenyl) amino-piperidine (711mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 347mg (28%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.67(m，2H)，1.80-1.89(m，2H)，2.72-2.87(m，2H)，3.82-3.92(m，1H)，3.89(s，3H)，3.90(s，6H)，4.14-4.33(m，2H)，4.50(s，2H)，6.63(d，2H，J＝9.2Hz)，6.65(s，2H)，7.28(d，2H，J＝9.4Hz)，7.61(s，1H)，8.47(d，1H，J＝2.0Hz)，8.67(d，1H，J＝2.2Hz)。

Preparation 162

Synthesis of 4- [ N- (4-bromophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -piperidine (347mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 302mg (91%).

Preparation example 163

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -piperidine:

1- (tert-Butoxycarbonyl) -4- (4-bromophenyl) amino-piperidine (711mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.14g (93%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.67(m，2H)，1.80-1.89(m，2H)，2.72-2.86(m，2H)，3.84-3.91(m，1H)，3.88(s，3H)，3.89(s，6H)，4.11-4.32(m，2H)，4.49(s，2H)，6.62(d，2H，J＝9.2Hz)，6.69(s，2H)，7.19(d，1H，J＝7.6Hz)，7.25(d，2H，J＝5.5Hz)，7.32-7.42(m，3H)。

Preparation example 164

Synthesis of 4- [ N- (4-bromophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-bromophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] -piperidine (1.03g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 973mg (84%).

Example 133-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 160, 162 and 164 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 165

Synthesis of 1- (tert-butoxycarbonyl) -4- [ (4-chlorophenyl) amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and 4-chloroaniline (3.05g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 3.80g (49%).

¹H-NMR(400MHz，CDCl₃)δ：1.24-1.38(m，2H)，1.46(s，9H)，1.97-2.05(m，2H)，2.86-2.96(m，2H)，3.32-3.42(m，2H)，3.51(br，1H)，6.52(d，2H，J＝9.0Hz)，7.11(d，2H，J＝9.0Hz)。

Preparation 166

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-chlorophenyl) amino ] piperidine (621mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 789mg (69%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.51-1.68(m，2H)，1.80-1.89(m，2H)，2.72-2.86(m，2H)，3.87-3.90(m，1H)，3.89(s，3H)，3.93(s，6H)，4.64(s，2H)，6.64(d，2H，J＝9.0Hz)，7.14(d，1H，J＝5.3Hz)，7.15(d，2H，J＝9.0Hz)，7.51(s，2H)，8.57(d，2H，J＝5.1Hz)。

Preparation example 167

Synthesis of 4- [ N- (4-chlorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (789mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 673mg (90%).

Preparation example 168

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-chlorophenyl) amino ] piperidine (621mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 268mg (24%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.56-1.76(m，2H)，1.80-1.90(m，2H)，2.76-2.83(m，2H)，3.86-3.90(m，1H)，3.89(s，3H)，3.90(s，6H)，4.15-4.30(m，2H)，4.50(s，2H)，6.66(s，2H)，6.68(d，2H，J＝9.2Hz)，7.15(d，2H，J＝9.0Hz)，7.63(s，1H)，8.47(d，1H，J＝2.0Hz)，8.66(d，1H，J＝2.0Hz)。

Preparation example 169

Synthesis of 4- [ N- (4-chlorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (268mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 233mg (91%).

Preparation example 170

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [4- (chlorophenyl) amino ] piperidine (622mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted by the same way with the method described in example 9 to obtain the title compound as a pale yellow amorphous substance.

Yield: 1.04g (92%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.58-1.67(m，2H)，1.82-1.91(m，2H)，2.74-2.86(m，2H)，3.85-3.92(m，1H)，3.88(s，3H)，3.89(s，6H)，4.35-4.31(m，2H)，4.49(s，2H)，6.66(d，2H，J＝9.2Hz)，6.70(s，2H)，7.12(d，2H，J＝9.0Hz)，7.20(d，2H，J＝7.3Hz)，7.33-7.43(m，3H)。

Preparation example 171

Synthesis of 4- [ N- (4-chlorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-chlorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.04g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 899mg (97%).

Examples 14l to 148

These compounds were prepared by reacting the amine compounds obtained in preparation examples 167, 169 and 171 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 172

Synthesis of 1- (tert-butoxycarbonyl) -4- [ (3, 4-difluorophenyl) amino ] piperidine:

1- (tert-butoxycarbonyl) -4-piperidone (5.00g) and 3, 4-difluoroaniline (3.09g) were reacted in the same manner as described in preparation 37 to give the title compound as a white powder.

Yield: 4.66g (62%).

¹H-NMR(400MHz，CDCl₃)δ：1.24-1.37(m，2H)，1.46(s，9H)，1.97-2.05(m，2H)，2.85-2.96(m，2H)，3.26-3.36(m，1H)，3.38-3.52(m，1H)，3.96-4.14(m，2H)，6.22-6.28(m，1H)，6.38(ddd，1H，J＝12.7Hz，6.6Hz，2.9Hz)，6.94(dd，1H，J＝19.1Hz，9.0Hz)。

Preparation example 173

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3, 4-difluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (3, 4-difluorophenyl) amino ] piperidone (625mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 534mg (47%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.50-1.70(m，2H)，1.82-1.90(m，2H)，2.73-2.88(m，2H)，3.90(s，3H)，3.94(s，6H)，4.15-4.30(m，2H)，4.43(s，2H)，6.33-6.39(m，1H)，6.52(ddd，1H，J＝13.6Hz，6.4Hz，3.1Hz)，6.98(dd，1H，J＝19.1Hz，9.2Hz)，7.11(dd，1H，J＝5.0Hz，1.3Hz)，7.16(s，2H)，7.51(s，1H)，8.58(d，1H，J＝5.1Hz)。

Preparation example 174

Synthesis of 4- [ N- (3, 4-difluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (3, 4-difluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (534mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 442mg (87%).

Preparation 175

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3, 4-difluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (3, 4-difluorophenyl) amino ] piperidine (625mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 350mg (31%).

Preparation example 176

Synthesis of 4- [ N- (3, 4-difluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (3, 4-difluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (350mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 305mg (92%).

Preparation example 177

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (3, 4-difluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (3, 4-difluorophenyl) amino ] piperidine (625mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.04g (92%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.66(m，2H)，1.81-1.89(m，2H)，2.72-2.85(m，2H)，3.78(tt，1H，J＝11.8Hz，3.8Hz)，3.88(s，3H)，3.90(s，6H)，4.12-4.30(m，2H)，4.45(s，2H)，6.36-6.42(m，1H)，6.54(ddd，1H，J＝13.9Hz，6.8Hz，2.9Hz)，6.71(s，2H)，6.95(dd，1H，J＝19.2Hz，9.2Hz)，7.20(d，1H，J＝7.4Hz)，7.36-7.43(m，3H)。

Preparation example 178

Synthesis of 4- [ N- (3, 4-difluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ (3, 4-difluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (980mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 819mg (94%).

Example 149-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 174, 176 and 178 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 179

Synthesis of 1- (tert-butoxycarbonyl) -4- [ (4-fluorophenyl) amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and 4-fluoroaniline (2.66g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 4.99g (71%).

¹H-NMR(400MHz，CDCl₃)δ：1.23-1.36(m，2H)，1.46(s，9H)，1.97-2.05(m，2H)，2.84-2.96(m，2H)，3.30-3.39(m，2H)，3.96-4.14(m，2H)，6.51-6.57(m，2H)，6.84-6.91(m，2H)。

Preparation example 180

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-fluorophenyl) amino ] piperidine (589mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 702mg (64%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.48-1.64(m，2H)，1.81-1.90(m，2H)，2.72-2.85(m，2H)，3.69-3.98(m，1H)，3.89(m，3H)，3.94(m，6H)，4.16-4.28(m，2H)，4.43(s，2H)，6.66-6.73(m，2H)，6.91(dd，2H，J＝9.2Hz，9.2Hz)，7.12-7.16(m，3H)，7.53(s，1H)。

Preparation example 181

Synthesis of 4- [ N- (4-fluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (702mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 561mg (84%).

Preparation example 182

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-fluorophenyl) amino ] piperidine (589mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 190mg (17%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.50-1.73(m，2H)，1.82-1.90(m，2H)，2.71-2.85(m，2H)，3.71(tt，1H，J＝11.7Hz，3.1Hz)，3.89(s，3H)，3.90(s，6H)，4.12-4.30(m，2H)，4.45(s，2H)，6.66(s，2H)，6.73-6.78(m，2H)，6.91(dd，2H，J＝9.2Hz，8.2Hz)，7.65(s，1H)，8.49(d，1H，J＝2.0Hz)，8.65(d，1H，J＝2.0Hz)。

Preparation example 183

Synthesis of 4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (190mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 165mg (91%).

Preparation example 184

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4- [ (4-fluorophenyl) amino ] piperidine (589mg) and 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) were reacted in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.01g (92%).

¹H-NMR(400MHz，CDCl₃)δ：1.44(s，9H)，1.51-1.65(m，2H)，1.82-1.90(m，2H)，2.82-2.84(m，2H)，3.78(tt，1H，J＝11.7Hz，3.5Hz)，3.88(s，3H)，3.90(s，6H)，4.10-4.30(m，2H)，4.45(s，2H)，6.68-6.73(m，4H)，6.89(dd，2H，J＝9.2Hz，8.2Hz)，7.21-7.25(m，1H)，7.32-7.41(m，3H)。

Preparation example 185

Synthesis of 4- [ N- (4-fluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-fluorophenyl) -N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.01g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 790mg (88%).

Example 157-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 181, 183 and 185 with the chloride derivatives obtained in preparation examples 3, 42 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 186

Synthesis of 1- (tert-butoxycarbonyl) -4-phenylaminopiperidine:

1- (tert-Butoxycarbonyl) -4-piperidone (5.00g) and aniline (2.23g) were reacted in the same manner as described in preparation example 37 to give the title compound as a white powder.

Yield: 3.77g (57%).

¹H-NMR(400MHz，CDCl₃)δ：1.25-1.38(m，2H)，1.47(s，9H)，2.00-2.07(m，2H)，2.87-2.97(m，2H)，3.38-3.53(m，2H)，3.96-4.14(m，2H)，6.57-6.52(m，2H)，6.70(tt，1H，J＝6.2Hz，1.0Hz)，7.17(dd，2H，J＝8.6Hz，7.2Hz)。

Preparation example 187

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N-phenyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-phenylaminopiperidine (553mg) and 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 760mg (71%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.53-1.63(m，2H)，1.83-1.91(m，2H)，2.76-2.90(m，2H)，3.86-3.97(m，1H)，3.89(s，3H)，3.93(s，6H)，4.14-4.32(m，2H)，4.49(s，2H)，6.71-6.78(m，3H)，7.14(s，1H)，7.15(s，2H)，7.21(dd，2H，J＝8.8Hz，7.4Hz)，7.55(s，1H)，8.56(d，1H，J＝5.1Hz)。

Preparation example 188

Synthesis of 4- [ N-phenyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N-phenyl-N- [ [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (760mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 652mg (90%).

Preparation 189

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N-phenyl-N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-N-phenylaminopiperidine (553mg) and 5-chloromethyl-3- (3, 4, 5-trimethoxyphenyl) pyridine (588mg) were treated in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 222mg (21%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.67(m，2H)，1.82-1.91(m，2H)，2.74-2.87(m，2H)，3.88-3.90(m，1H)，3.88(s，3H)，3.89(s，6H)，4.14-4.31(m，2H)，4.53(s，2H)，6.67(s，2H)，6.74-6.80(m，3H)，7.21(dd，2H，J＝8.8Hz，7.2Hz)，7.67(s，1H)，8.50(d，1H，J＝5.3Hz，2.2Hz)，8.66(d，1H，J＝2.1Hz)。

Preparation example 190

Synthesis of 4- [ N-phenyl-N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N-phenyl-N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine (222mg) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 197mg (94%).

Preparation 191

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N-phenyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine:

1- (tert-Butoxycarbonyl) -4-phenylaminopiperidine (553mg) was reacted with 3- (3, 4, 5-trimethoxyphenyl) benzyl chloride (586mg) in the same manner as described in example 9 to give the title compound as a pale yellow amorphous substance.

Yield: 1.06g (100%).

¹H-NMR(400MHz，CDCl₃)δ：1.45(s，9H)，1.52-1.68(m，2H)，1.83-1.92(m，2H)，2.73-2.86(m，2H)，3.88(s，3H)，3.89(s，6H)，3.94(tt，1H，J＝11.7Hz，3.3Hz)，4.14-4.30(m，2H)，4.52(s，2H)，6.69-6.78(m，6H)，7.17-7.27(m，2H)，7.32-7.42(m，3H)。

Preparation example 192

Synthesis of 4- [ N-phenyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine hydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N-phenyl-N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] amino ] piperidine (1.06g) was treated in the same manner as described in preparation 94 to give the title compound as a pale yellow powder.

Yield: 909mg (97%).

Example 165-

These compounds were prepared by reacting the amine compounds obtained in preparation examples 188, 190 and 192 with the chloride derivatives obtained in preparation examples 3 and 48. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 193-

These compounds were prepared in the same manner as described in preparation examples 1 to 3. The structures and NMR data of these compounds are shown in the following table.

Preparation example 204

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ (2-phenylpyridin-4-yl) methyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (612mg) was reacted with 4-chloromethyl-2-phenylpyridine (204mg) in the same manner as described in example 9 to give the title compound.

Yield: 407mg (43%).

Preparation example 205

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ (2-phenylpyridin-4-yl) methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ (2-phenylpyridin-4-yl) methyl ] amino ] piperidine (407mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 365mg (95%).

Preparation example 206

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (2-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (2-methoxyphenyl) pyridine (234mg) in the same manner as described in example 9 to obtain the title compound.

Yield: 237mg (72%).

Preparation example 207

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (2-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (2-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (360mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 365mg (65%).

Preparation example 208

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reaction-condensed with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (234mg) in the same manner as described in example 9 to give the title compound.

Yield: 550mg (theoretical yield).

Preparation example 209

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- (4-methoxyphenyl) -N- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] amino ] piperidine (550mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 436mg (85%).

Preparation example 210

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (4-ethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl)) amino) piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (4-ethoxyphenyl) pyridine (248mg) in the same manner as described in example 9 to give the title compound.

Yield: 515mg (99%).

Preparation example 211

Synthesis of 4- [ N- [ [2- (4-ethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [2- (4-ethoxyphenyl) pyridin-4-yl ] methyl-N- (4-methoxyphenyl) amino ] piperidine (515mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 418mg (80%).

Preparation 212

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3, 4-dimethoxyphenyl) pyridin-4-yl ] methyl ] - [ N- (4-methoxyphenyl) amino ] piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (3, 4-dimethoxyphenyl) pyridine (264mg) in the same manner as described in example 9 to give the title compound.

Yield: 600mg (theoretical yield).

Preparation example 213

Synthesis of 4- [ N- [ [2- (3, 4-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ [2- (3, 4-dimethoxyphenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine (600mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 416mg (77%).

Preparation example 214

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (2-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) - (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (2-fluorophenyl) pyridine (222mg) in the same manner as described in example 9 to give the title compound.

Yield: 530mg (theoretical yield).

Preparation 215

Synthesis of 4- [ N- [ [2- (2-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ [2- (2-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine (530mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 423mg (85%).

Preparation example 216

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) - (tert-butoxycarbonyl) piperidine (153mg) was reacted with 4-chloromethyl-2- (3-fluorophenyl) pyridine (111mg) in the same manner as described in example 9 to give the title compound.

Yield: 270mg (theoretical yield).

Preparation 217

Synthesis of 4- [ N- [2- (3-fluorophenyl) pyridin-4-yl ] methyl-N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ [2- (3-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine (270mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 193mg (70%).

Preparation 218

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (4-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (4-fluorophenyl) pyridine (222mg) in the same manner as described in example 9 to obtain the title compound.

Yield: 550mg (theoretical yield).

Preparation example 219

Synthesis of 4- [ N- [ [2- (4-fluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ [2- (4-fluorophenyl) pyridin-4-yl ] methyl ] -1-N- (4-methoxyphenyl) amino ] piperidine (550mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 439mg (88%).

Preparation example 220

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3, 4-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (3, 4-difluorophenyl) pyridine (240mg) in the same manner as described in example 9 to give the title compound.

Yield: 590mg (theoretical yield).

Preparation example 221

Synthesis of 4- [ N- [ [2- (3, 4-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ -N- [ [2- (3, 4-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine (590mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 483mg (93%).

Preparation 222

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (3, 5-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (3, 5-difluorophenyl) pyridine (240mg) in the same manner as described in example 9 to give the title compound.

Yield: 530mg (theoretical yield).

Preparation example 223

Synthesis of 4- [ N- [ [2- (3, 5-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-Butoxycarbonyl) -4- [ N- [ [2- (3, 5-difluorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine (530mg) was treated in the same manner as described in preparation 94 to give the title compound.

Yield: 418mg (81%).

Preparation 224

Synthesis of 1- (tert-butoxycarbonyl) -4- [ N- [ [2- (4-chlorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino) piperidine:

4- (p-Methoxyphenylamino) -1- (tert-butoxycarbonyl) piperidine (306mg) was reacted with 4-chloromethyl-2- (4-chlorophenyl) pyridine (238mg) in the same manner as described in example 9 to obtain the title compound.

Yield: 600mg (theoretical yield).

Preparation example 225

Synthesis of 4- [ N- [ [2- (4-chlorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine dihydrochloride:

1- (tert-butoxycarbonyl) -4- [ N- [ [2- (4-chlorophenyl) pyridin-4-yl ] methyl ] -N- (4-methoxyphenyl) amino ] piperidine: (600mg) was treated in the same manner as described in preparation example 94 to give the title compound.

Yield: 447mg (86%).

Example 170-

These compounds are prepared by reacting the amine compounds obtained in preparation 96, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223 and 225 with the chloride derivatives obtained in preparation 3, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202 and 203. The obtained free base is then converted into the corresponding hydrochloride salt. The yields and NMR data of their free bases are given in the table below.

Preparation example 226

Synthesis of 4- [ N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] -N- [4- (methylsulfonyl) phenyl ] amino ] piperidine:

4- [ N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] -N- [4- (methylthio) phenyl ] amino ] -piperidine hydrochloride (52mg, prepared according to preparation example 145) was dissolved in methylene chloride (1mL), and 3-chloroperbenzoic acid (69mg) was added to the resultant solution at 0 ℃. After the mixture was cooled to room temperature, it was stirred for 3 hours, and then a saturated aqueous solution of sodium hydrogencarbonate was added thereto. After separating the organic layer, the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting pale yellow oil was used in the next reaction without purification.

Example 203

Synthesis of 4- [ N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] -N- [4- (methylsulfonyl) phenyl ] amino ] -1- [2- (3, 4, 5-trimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine dihydrochloride:

crude 4- [ N- [3- (3, 4, 5-trimethoxyphenyl) benzyl ] -N- [4- (methylsulfonyl) phenyl ] -amino ] piperidine obtained in preparation 226 was reacted with 4-chloromethyl-2- (3, 4, 5-trimethoxyphenyl) pyridine (29mg) in the same manner as described in example 2. The resulting free base was converted to the corresponding dihydrochloride salt to give the title compound as a pale yellow powder.

Yield: 23mg (26%, two steps)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.97(m，4H)，2.16-2.28(m，2H)，

2.95-3.04(m, 2H), 2.99(s, 3H), 3.59(s, 2H), 3.82(s, 3H), 3.87-3.97(m, 1H), 3.90(s, 3H), 3.91(s, 3H), 3.92(s, 3H), 3.96(s, 9H), 4.65(s, 2H), 6.59(s, 1H), 6.75(d, 2H, J ═ 9.3Hz), 7.19-7.30(m, 7H), 7.39(dd, 1H, J ═ 7.6Hz, 7.6Hz), 7.60(s, 1H), 7.68(d, 2H, J tris 9.0Hz), 8.60(d, 1H, J ═ 4.9Hz)

Example 204

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (139mg, see preparation 98) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70mg, see preparation 195) were reacted in the same manner as described in example 2 to obtain the title compound as a trihydrochloride salt.

Yield: 131mg (66%)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.95(m，4H)，2.05-2.25(m，2H)，2.90-3.08(m，2H)，3.45-3.68(m，3H)，3.72(s，3H)，3.88(s，3)，3.90(s，9H)，4.46(s，2H)，6.70-6.85(m，4H)，6.96(d，1H，J＝8.3Hz)，7.21(br，1H)，7.38(t，1H，J＝7.8Hz)，7.55(t，1H，J＝7.8Hz)，7.59(s，1H)，7.63-7.75(m，2H)，8.50(s，1H)，8.62(br，1H)

Example 205

Synthesis of 4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] amino ] -1- [ [2- (3, 4-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

4- [ N- (4-methoxyphenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (139mg, see preparation 98) was reacted with 4-chloromethyl-2- (3, 4-dimethoxyphenyl) pyridine (80mg, see preparation 197) in the same manner as described in example 2 to obtain the title compound as a trihydrochloride salt.

Yield: 139mg (67%)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.70-1.95(m，4H)，2.05-2.20(m，2H)，2.90-3.05(m，2H)，3.45-3.60(m，3H)，3.73(s，3H)，3.88(s，3H)，3.89(s，6H)，3.94(s，3H)，4.00(s，3H)，4.46(s，2H)，6.65(s，2H)，6.74-6.82(m，4H)，6.94(d，1H，J＝8.3Hz)，7.15(br，1H)，7.52(br，1H)，7.58-7.71(m，3H)，8.50(s，1H)，8.57(d，1H，J＝5.2Hz)，8.62(br，1H)

Example 206

Synthesis of 4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (135mg, see preparation 183) was reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70mg, see preparation 195) in the same manner as described in example 2 to obtain the title compound as a trihydrochloride salt.

Yield: 178mg (92%)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.73-1.95(m，4H)，2.10-2.25(m，2H)，2.93-3.05(m，2H)，3.57(s，2H)，3.64(br，1H)，3.88(s，3H)，3.89(s，9H)，4.51(s，2H)，6.66(s，2H)，6.70-6.76(m，2H)，6.90(t，2H，J＝8.3Hz)，6.96(d，1H，J＝8.3Hz)，7.21(br，1H)，7.38(t，1H，J＝8.0Hz)，7.54(d，1H，J＝7.8Hz)，7.58(s，1H)，7.65(s，1H)，7.74(br，1H)，8.50(s，1H)，8.61(d，1H，J＝5.1Hz)，8.65(br，1H)

Example 207

Synthesis of 4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3, 4-dimethoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- [ N- (4-fluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (135mg, see preparation 183) was reacted with 4-chloromethyl-2- (3, 4-dimethoxyphenyl) pyridine (80mg, see preparation 197) in the same manner as described in example 2 to obtain the title compound as a trihydrochloride salt.

Yield: 195mg (96%)

¹H-NMR(400MHz，Measured as free base, DCl₃)δ：1.70-1.95(m，4H)，2.10-2.24(m，2H)，2.94-3.09(m，2H)，3.57(s，2H)，3.64(br，1H)，3.88(s，3H)，3.89(s，6H)，3.94(s，3H)，4.00(s，3H)，4.51(s，2H)，6.65(s，2H)，6.69-6.78(m，2H)，6.86-6.97(m，3H)，7.16(d，1H，J＝4.9Hz)，7.51(d，1H，J＝8.5Hz)，7.60-7.70(m，3H)，8.50(s，1H)，8.58(d，1H，J＝4.9Hz)，8.65(s，1H)

Example 208

Synthesis of 4- [ N- (3, 4-difluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] piperidine trihydrochloride:

4- [ N- (3, 4-difluorophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (160mg, see preparation 176) and 4-chloromethyl-2- (3-methoxyphenyl) pyridine (80mg, see preparation 195) were reacted in the same manner as described in example 2 to obtain the title compound as a trihydrochloride salt.

Yield: 130mg (57%)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.73-1.90(m，4H)，2.01-2.24(m，2H)，2.92-3.05(m，2H)，3.57(s，2H)，3.67(br，1H)，3.88(s，3H)，3.89(s，3H)，3.90(s，6H)，4.52(s，2H)，6.36-6.42(m，1H)，6.50-6.58(m，1H)，6.67(s，2H)，6.93-7.01(m，2H)，7.20(br，1H)，7.38(t，1H，J＝7.8Hz)，7.52-7.62(m，2H)，7.62-7.72(m，2H)，8.48(br，1H)，8.61(br，1H)，

8.66(d，1H，J＝2.0Hz)

Example 209

Synthesis of 4- [ N- (4-methylthiophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] -1- [ [2- (3-methoxyphenyl) pyridin-4-yl ] methyl ] piperidine:

4- [ N- (4-methylthiophenyl) -N- [ [3- (3, 4, 5-trimethoxyphenyl) pyridin-5-yl ] methyl ] amino ] piperidine dihydrochloride (121mg, see preparation 143) was reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (55mg, see preparation 195) in the same manner as described in example 2 to obtain the title compound.

Yield: 71mg (44%)

¹H-NMR (400MHz, determined as free base, CDCl)₃)δ：1.72-1.83(m，4H)，2.12-2.20(m，2H)，2.37(s，3H)，2.97(d，2H，J＝10.8Hz)，3.56(s，2H)，3.75-3.81(m，1H)，3.86(s，3H)，3.87(s，6H)，4.54(s，2H)，6.64-6.69(m，3H)，6.94(dd，1H，J＝7.8Hz，1.9Hz)，7.17-7.26(m，4H)，7.35(t，1H，J＝7.8Hz)，7.51-7.66(m，4H)，8.47(s，1H)，8.59(d，1H，J＝4.6Hz)，8.63(s，1H)

Test example 1:

(inhibitory action on cell adhesion)

This assay was performed by reference to Ross et al (J.biol. chem.267, 8537-8543 (1992)). More specifically, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured in 48-well plates until after confluent growth, to which TNF α was added. After 5 hours of addition, at 1X 10⁶Cell/well ratio U937 cells, which are human monocytes/tissue cells fluorescently labeled with PKH2 (product of Sigma-Aldsi-ch co.ltd) were added. After the plate was allowed to stand at room temperature for 1 hour, non-adherent U937 cells were washed off and dissolved with 1% Triton X-100, and the residual fluorescence intensity (excitation wavelength: 480nm, measurement wavelength: 530nm) was measured. HUVEC and U937 were cultured in EGM-2(Sanko Junyaku K.K. product)Pin) and 10% RPMI1640 with FCS. Each test drug was added to HUVECs at the time of TNF α addition and to U937 24 hours prior to the cell adhesion assay. According to the equation [ (A-C)/(A-B)]×100(％)]The inhibition rate was calculated, where A is the number of U937 cells adhered to the TNF α -stimulated HUVEC without the addition of the test drug, B is the number of U937 cells adhered to the TNF α -stimulated HUVEC without the addition of the test drug, and C is the number of U937 cells adhered to the TNF α -stimulated HUVEC with the addition of the test drug. The results are shown in Table 1. As a control compound, test compound 1 described in Japanese patent application laid-open No.9-143075 and dela's test compound 11-92382(Dilazep) was also evaluated at the same time.

TABLE 1

As described above, the compound of the present invention is characterized in that the cyclic amine has a phenyl-pyridyl group or a biphenyl group at both molecular terminals.

The inhibition effect on cell adhesion of the cyclic amine compound having a vicinal pyridyl group at both ends of the molecule prepared in preparation example 91 was measured in a similar manner to the above. As a result, the compound showed no inhibitory effect on cell adhesion even at a concentration of up to 10. mu.M.

Specific formulation examples are described below.

Preparation example 1: (Capsule preparation)

Compound obtained in example 13	30mg
		Microcrystalline cellulose	30mg
Lactose	57mg
		Magnesium stearate	3mg
Total amount of	120mg

The above components are mixed according to a method known in the art, and then encapsulated in a gelatin capsule to obtain a capsule preparation.

Formulation example 2: (tablet)

Compound obtained in example 13	30mg
		Starch	44mg
Starch (for binding)	5.6mg
		Magnesium stearate	0.4mg
Calcium carboxymethylcellulose	20mg
		Total amount of	100mg

The above components are mixed according to methods known in the art to obtain tablets.

Formulation example 3: (injection)

The compound (100mg) obtained in example 13 and sodium chloride (900mg) were dissolved in distilled water for injection (about 80mL), and distilled water for injection was added to the resulting solution to a total amount of 100 mL. The diluted solution was sterilized by filtration, and then divided into 10 ampoules, which were sealed to prepare a preparation.

Industrial application:

as described above, the compound (1) of the present invention has an inhibitory effect on both cell adhesion and cell infiltration, and is useful as a medicament for preventing or treating allergy, asthma, rheumatism, arteriosclerosis, inflammation, Sjogren's syndrome and the like.

Claims (5)

1. A cyclic amine compound represented by the following general formula (1), or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

R¹，R²and R³Each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, or C₁-C₈An alkoxy group;

W¹and W²Each independently represents N;

x represents NR⁴；

R⁴Represents a hydrogen atom, or C₁-C₈Alkyl radical, C₃-C₈Alkynyl, substituted or unsubstituted C₆-C₁₄Aryl, or C₆-C₁₄aryl-C₁-C₆Alkyl, aryl substituents are 1-3 groups or atoms selected from: c₁-C₈Alkyl radical, C₁-C₈Alkoxy, C substituted by 1 to 3 halogen atoms₁-C₈Alkoxy radical, C₁-C₈Alkylthio radical, C₁-C₈Alkylsulfinyl, halogen, trifluoromethyl and C₁-C₃An alkylenedioxy group; and

l, m and n each represent 0 or 1.

2. A compound according to claim 1 wherein X represents NR⁴And R⁴Represents substituted or unsubstituted C₆-C₁₄And (4) an aryl group.

3. A pharmaceutical composition comprising a compound of any one of claims 1-2 and a pharmaceutically acceptable carrier.

4. Use of a compound according to any one of claims 1-2 in the manufacture of a medicament for the treatment of a disease caused by cell adhesion and/or cell infiltration.

5. Use according to claim 4, characterized in that said diseases are selected from: allergies, asthma, inflammation, rheumatism, arteriosclerosis and Sjogren's syndrome.