RU2299207C2 - Cyclic amine compounds - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1):

, their pharmaceutically acceptable salts or hydrates wherein each among R¹, R² and R³ represents independently hydrogen atom, halogen atom, hydroxy-group, (C₁-C₈)-alkoxy-group; each among W¹ and W² represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR⁴, -COONR⁴ or -NR⁴CO; R⁴ represents hydrogen atom, (C₁-C₈)-alkyl, (C₃-C₆)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy-group, (C₁-C₈)-alkoxy-group substituted with 1-3 halogen atoms, (C₁-C₈)-alkylthio-group, (C₁-C₈)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C₁-C₃)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

Description

The present invention relates to new cyclic amine compounds that have an inhibitory effect on both cell adhesion and cell infiltration, and are useful as anti-asthma agents, anti-allergic drugs, anti-rheumatic drugs, anti-arteriosclerotic drugs, anti-inflammatory drugs, anti-Sjogren's syndrome drugs, etc. item, and to medicines containing such compounds.

Description of the Related Art

With various inflammatory diseases, leukocyte infiltration into the inflamed areas is observed. For example, bronchial eosinophil infiltration in asthma has been described (Ohkawara Y. et al., Am. J. Respir. Cell Mol. Biol., 12 , 4-12 (1995)), macrophage and T cell infiltration in arteriosclerosis ( Sakai A. et al., Arterioscler. Thromb. Vasc. Biol., 17 , 310-316 (1997)), infiltration of T cells and eosinophils into the skin with atopic dermatitis (Wakita H. et al., J. Cutan. Pathol ., 21 , 33-39 (1994)) or contact dermatitis (Satoh T. et al., Eur. J. Immunol., 27 , 85-91 (1997)), as well as the infiltration of various white blood cells into rheumatoid synovial tissue (Tak PP. Et al., Clin. Immunol. Immunopathol., 77 , 236-242 (1995)).

Sjögren’s syndrome in humans is an organ-specific autoimmune disease characterized by leukocyte infiltration into the salivary and lacrimal glands, which causes the destruction of the glandular system and the appearance of symptoms such as dry mouth and dry eyes due to insufficient secretion of glands (Fox RI. Et al. "Sjogren's syndrome: proposed criteria for classification ", Arthritis Rheum., 1986, 29: 577-585).

The leukocyte infiltration is caused by cytokines, chemokines, lipids and complements produced in the inflamed areas (Albeda SM. Et al., FASEB J., 8 , 504-512 (1994)). Activated white blood cells adhere to vascular endothelial cells as a result of an interaction called "rotation" or "binding" to endothelial cells activated in this way. White blood cells then transmigrate through the endothelium, penetrating into the inflamed areas (Springer TA., Annu. Rev. Physiol., 57 , 827-872 (1995)). When leukocytes adhere to vascular endothelial cells, various cellular adhesion molecules, such as the superfamily of immunoglobulins (ICAM-1, VCAM-1, etc.), the family of selectins (E-selectin, etc.) play an important role during this process. , a family of integrins (LFA-1, VLA-4, etc.) and CD44, induced on the surface of cells as a result of stimulation by cytokines, etc. ("Rinsho Meneki (Clinical Immune)", 30 , Supple. 18 (1998)), while there is a connection between the impaired state and aberrant expression of cell adhesion molecules.

Accordingly, an agent capable of inhibiting cell adhesion or cell infiltration may be useful as an agent for the prevention and treatment of allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, Sjogren's syndrome, inflammatory bowel disease, diabetes and arteriosclerosis, as well as chronic inflammatory diseases. In fact, there are reports that antibodies against cell adhesion molecules on white blood cells such as LFA-1, Mac-1 and VLA-4, or antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin, etc. .P. on vascular endothelial cells, which become their ligands, inhibit leukocyte infiltration into inflammatory regions in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, which are their reading receptors, can slow the development of diabetes in the mouse model of NOD, spontaneously causing diabetes (Michie SA. Et al., Curr. Top. Microbiol. Immunol., 231 , 65-83 (1998)). It has also been found that an anti-VLA-4 or ICAM-1 antibody and its reading receptor LFA-1 inhibits eosinophil infiltration in a model of allergic conjunctivitis in guinea pigs and mice (Ebihara et al., Current Eye Res., 19 , 20-25 ( 1999); Whitcup, SM. Et al., Clin. Immuniol., 93 , 107-113 (1999)), and the monoclonal body against VCAM-1 inhibits leukocyte infiltration in a model of DSS-induced colitis in mice, weakening it (Soriano A . et al., Lab. Invest., 80 , 1541-1551 (2000)). In addition, the anti-VLA-4 antibody and anti-CD44 antibody reduce the incidence of disease symptoms in a model of collagen-induced arthritis in mice (Zeidler A. et al., Autoimmunity, 21 , 245-252 (1995)). Even in mice deficient in cell adhesion molecules, inhibition of leukocyte infiltration into inflamed tissues is observed, similarly to models of inflammation (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, the development of antibody-based drugs is difficult because they are polypeptides and their oral administration is difficult. Moreover, a possible side effect caused by antigenicity and allergic reactions is also a problem.

On the other hand, various studies of low molecular weight compounds that have an inhibitory effect on cell adhesion have been conducted in order to enable oral administration. Such compounds include benzothiophene derivatives (Boschelli DH. Et al., J. Med. Chem., 38 , 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Application Laid-Open No. 10-147568), hydroxybenzoic acid derivatives (Patent Application Laid-open) Japan No. 10-182550), lignans (Japanese Patent Laid-Open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese Patent Laid-Open No. 2000-086641), fused pyrazine compounds (Japanese Laid-open Patent Application No. 2000-319277, filed as PCT), 2,6-dialkyl-4-silylphenol (Japanese Patent Application Laid-Open No. 2000 -509070), etc. However, in these cases, the goal was often not achieved. The cyclic diamine compounds described in Japanese Patent Laid-open No. 9-143075, 11-92382 and WO 02/20477 do not have a sufficient inhibitory effect on cell adhesion, therefore, further enhancement of their activity is necessary.

The aim of the present invention is to develop a substance that has an inhibitory effect on both cell adhesion and cell infiltration, plus a strong anti-asthma effect, anti-allergic effect, anti-rheumatic effect, anti-arteriosclerotic effect, anti-inflammatory effect and action against Sjogren's syndrome.

SUMMARY OF THE INVENTION

Given the above circumstances, the authors of this invention conducted extensive research on the development of substances that inhibit cell adhesion and cell infiltration. As a result, it was found that the compounds represented by general formula (1) having phenylpyridyl or biphenyl groups at both ends of the cyclic amine have a strong effect on the inhibition of cell adhesion and cell infiltration and are useful as anti-allergic drugs, anti-asthma drugs, anti-rheumatic drugs, anti-arteriosclerotic drugs funds, anti-inflammatory drugs or anti-Sjogren's agents.

The present invention provides a cyclic amine compound represented by the following general formula (1):

where each of R ¹ , R ² and R ³ independently represents a hydrogen atom, a halogen atom or hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl;

each of W ¹ and W ² independently represents N or CH;

X represents O, NR ⁴ , CONR ⁴ or NR ⁴ CO;

each of R ⁴ independently represents a hydrogen atom or alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl and each of l, m and n represents the number 0 or 1,

or an acid addition salt thereof or a hydrate thereof.

In accordance with the present invention, there is also provided a medicament containing, as an active ingredient, the above cyclic amine compound, an acid addition salt thereof or a hydrate thereof.

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

The use of the aforementioned cyclic amine compound, its acid addition salt or its hydrate for the manufacture of a medicament is also contemplated by the present invention.

The present invention also provides a method of treating a disease caused by cell adhesion and / or cell infiltration, comprising administering an effective amount of the aforementioned cyclic amine compound, a salt thereof or a hydrate thereof to a patient in need of such treatment.

Preferred Embodiments

The compound of the present invention is characterized in that the cyclic amine has at its two ends two phenylpyridyl or biphenyl groups. Until now, it was not known that compounds having such a structure have a potent effect on the inhibition of both cell adhesion and cell infiltration.

In the general formula (1), halogen atoms for R ¹ , R ^2, and R ³ include fluorine, chlorine, bromine, and iodine atoms.

The alkyl group for R ¹ , R ² , R ³ and R ⁴ typically includes straight, branched or cyclic C ₁ -C ₈ alkyl groups, such as straight, branched or cyclic C ₁ -C ₈ alkyl groups, for example methyl, ethyl, propyl , butyl, pentyl, hexyl, heptyl and octyl groups, and C ₃ -C ₈ cycloalkyl groups, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl. Among them, C ₁ -C ₆ alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like are particularly preferred.

The halogen-substituted alkyl group for R ¹ , R ² and R ³ typically includes C ₁ -C ₈ alkyl groups substituted with 1 to 3 halogen atoms. Among them, C ₁ -C ₆ alkyl groups substituted with 1 to 3 halogen atoms such as trifluoromethyl, 2,2,2-trifluoroethyl, etc. are particularly preferred.

The alkoxy group typically includes straight, branched or cyclic C ₁ -C ₈ alkoxy groups, such as straight, branched or cyclic C ₁ -C ₈ alkoxy groups, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups, as well as C _{3 -C 8} cycloalkyloxy groups, for example cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclohexylmethyloxy and cyclohexylethyloxy. Among them, C ₁ -C ₆ alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butyloxy groups are particularly preferred.

The alkylthio group typically includes C ₁ -C ₈ alkylthio groups and is preferably a C ₁ -C ₆ alkylthio group, such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio and the like.

Alkoxycarbonyl group typically includes C _1- C ₆ alkoxycarbonyl group, and preferably represents a C ₁ -C ₄ alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.

An alkanoyl group typically includes C ₁ -C ₆ alkanoyl groups and is preferably a C ₁ -C ₄ alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl and the like.

The alkenyl group for R ⁴ typically includes C ₃ -C ₈ alkenyl groups and is preferably a C ₃ -C ₆ alkenyl group such as 2-propenyl, 3-butenyl and the like. The alkynyl group typically includes C ₃ -C ₈ alkynyl groups and is preferably a C ₃ -C ₆ alkynyl group such as 2-propynyl, 3-butynyl and the like.

The aryl group for R ⁴ typically includes C ₆ -C ₁₄ aryl groups and is preferably phenyl, naphthyl, antryl, indenyl, indanyl, 5,6,7,8-tetrahydronaphthyl and the like.

The heteroaryl group for R ⁴ typically includes 5- or 6-membered ring heteroaryl groups containing 1-4 nitrogen atoms in the ring, and is preferably imidazolyl, pyridyl, pyrimidinyl, and the like.

The aralkyl group typically includes C ₆ -C ₁₄ arylC ₁ -C ₆ alkyl groups such as a phenyl C ₁ -C ₆ alkyl groups and naftilS _1- C ₆ alkyl groups such as benzyl, naphthylmethyl, phenylethyl, phenylpropyl, etc. The heteroalkyl group for R ⁴ typically includes heteroaryl C ₁ -C ₆ alkyl groups with a 5- or 6-membered ring containing 1-4 ring nitrogen atoms, such as imidazolyl-C ₁ -C ₆ alkyl, pyridylC ₁ -C ₆ alkyl, pyrimidinyl C ₁ -C ₆ alkyl, etc.

Groups which may replace the above aryl, heteroaryl, aralkyl or heteroaralkyl include 1-3 groups or atoms selected from alkyl, alkoxy, halogen-substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, nitro, amino, acetylamino, trifluoromethyl and alkylene said alkyl, alkoxy and alkylthio include the values illustrated for R ¹ ~ R ³ . The alkyl group contained in the alkylsulfinyl and alkylsulfonyl groups includes C ₁ -C ₃ alkyl groups such as methyl, ethyl, n-propyl and isopropyl groups. The halogen-substituted alkoxy includes C ₁ -C ₈ alkoxy groups substituted by 1-3 halogen atoms, and preferably represents a C ₁ -C ₄ alkoxy group substituted by 1-3 halogen atoms such as trifluoromethoxy or 2,2,2-trifluoroethoxy. The alkylenedioxy group typically includes C ₁ -C ₃ alkylenedioxy groups, such as methylenedioxy, ethylenedioxy and propylenedioxy groups.

X is preferably NR ⁴ . More preferably, X is NR ⁴ , where R ⁴ is a substituted or unsubstituted C ₆ -C ₁₄ aryl group or a substituted or unsubstituted heteroaryl group with a 5- or 6-membered ring containing 1-4 nitrogen atoms in the ring. As shown in Test Example 1 below, the compounds of formula (1) in which X is NR ⁴ have a particularly potent effect on the inhibition of cell adhesion.

R ¹ , R ^2, and R ^{3 are} preferably attached to the phenyl group at positions 3, 4, and 5. In this case, it is particularly preferred that R ¹ and R ³ (at positions 3 and 5 of the phenyl ring) are alkoxy or halogen. It is also preferred that R ² (at position 4 of the phenyl ring) is a hydrogen atom, a halogen atom or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl or alkanoyl group.

l is 0 or 1, preferably 1.

W ¹ preferably represents N.

W ^{2 is} preferably N.

Preferred compounds include compounds of formula (1) in which X represents NR ⁴ , where R ⁴ represents a substituted or unsubstituted C ₆ -C ₁₄ aryl group or a substituted or unsubstituted heteroaryl group with a 5- or 6-membered ring containing 1-4 nitrogen atom in the ring. Particularly preferably, R ⁴ represents a phenyl or pyridyl group which may be substituted with one or two groups or one or two atoms selected from halogen, alkyl, alkoxy, alkylthio, trifluoromethyl and alkylenedioxy.

The acid addition salts of the compounds (1) in accordance with this invention are not particularly limited so long as they are pharmaceutically acceptable salts. Examples of such salts include acid addition salts of mineral acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, as well as acid addition salts of organic acids such as benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates and acetates.

The compounds of formula (1) may be present in the form of solvates, for example hydrates, such solvates being included in the scope of the present invention.

The compounds of formula (1) can be obtained in accordance with the following methods A ~ L.

Method A : obtaining a compound of formula (1) in which l = 1, m = 0, n = 1 and X = CONR ⁴

where W ¹ , W ² , R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above, W ³ has the same meanings as W ¹ or W ² , and B means a leaving group such as a halogen atom, or methanesulfonyloxy or p-toluenesulfonyloxy group.

Compound (2) and the N- (2-nitrobenzenesulfonylamine derivative (3) are reacted to give compound (4). The resulting compound (4) is treated with thiophenol in the presence of a base such as potassium carbonate to remove the 2-nitrobenzenesulfonyl group, resulting in amine compound (5) Alternatively, if R ⁴ is H, then compound (2) can be reacted with potassium phthalimide and then the resulting phthalimide derivative (6) can be treated with hydrazine to give the corresponding soy distinction of amine (5).

On the other hand, the compound (2) is reacted with ethyl isonipecotate (7) in a solvent such as acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, toluene, benzene, etc. ., in the presence of a base such as potassium carbonate and the like, at a temperature of from 0 ° C to a reflux temperature over a period of several hours to several days, preferably at room temperature overnight, to give compound (8) . Compound (8) is subjected to ordinary alkaline hydrolysis to obtain the corresponding carboxylic acid compound (9).

The carboxylic acid compound (9) is reacted with the amine compound (5) using a dehydrating condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2- (1H-benzotriazole-1 hexafluorophosphate) -yl) -1,1,3,3-tetramethyluronium (HBTU) and the like, in a solvent such as chloroform, dichloroethane, THF, dioxane, acetonitrile, etc., at a temperature of from 0 ° C to a temperature the formation of phlegm over a period of time from several hours to several days, preferably at room temperature ur for 12 hours, obtaining the final product (1A).

Method B : preparing a compound of formula (1) in which l = 1, m = 0, n = 1, and X = O

where B, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above, and J is a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, or benzyl.

Incidentally, in the reaction schemes presented above and below, the expression "(W ² → W ¹ )" means that W ² in the formula representing compound (2) is replaced by W ¹ . The same goes for the reaction schemes presented below.

The protected amino group 4-hydroxypiperidine compound (10) is reacted with compound (2) in the presence of sodium hydride or potassium iodide in a solvent such as DMF, DMSO, etc., at a temperature of from 0 ° C. to reflux during a period of time from several hours to several days, preferably at room temperature for 2 days, obtaining the compound (11). The protective group in compound (11) is removed in a known manner. The obtained compound (12) is reacted with a compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at a temperature of from 0 ° C to the temperature of formation reflux for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1B).

Method C : obtaining a compound of formula (1) in which l = 1, m = 0, n = 0, X = NR ⁴ CO, where R ⁴ = H or Me

where B, W ¹ , W ² , R ¹ , R ² and R ³ are as defined above, and R ⁴ is a hydrogen atom or methyl.

Isonipecotamide (13) is reacted with compound (2) in the presence of a base such as potassium carbonate, sodium carbonate and the like, in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at a temperature from 0 ° C. to a reflux temperature over a period of several hours to several days, preferably at room temperature for 4 hours, to obtain compound (14). Compound (14) is subjected to a Hoffmann rearrangement reaction to give an amine compound (15).

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

As a result of the interaction of the carboxylic acid compound (18) with the amine compound (15) or the methylamine compound (17), like the condensation reaction in Method A, the final compound (1C) is obtained.

Method D : obtaining a compound of formula (1) in which l = 1, m = 0, n = 1 and X = NR ⁴

where B, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above and R ⁴ is alkyl, alkenyl, alkynyl, aralkyl, or heteroaralkyl.

The above amine compound (15) is reacted with 2-nitrobenzenesulfonyl chloride (19) in accordance with a known method to give compound (20). Compound (20) 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 a temperature of from 0 ° C to a reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (21). The benzenesulfonyl group of compound (21) is removed according to the procedure used for compound (4) in Method A to give the final compound (1D) (R ⁴ = H). Compound (1D) is reacted with R ⁴ -B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and the like, in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF , DMSO, etc., at a temperature from 0 ° C. to reflux during a period of several hours to several days, preferably at 80 ° C. for 12 hours, to obtain compound (1D ′).

On the other hand, the methylamine compound (17) is reacted with the compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc., at a temperature of from 0 ° C to a reflux temperature over a period of several hours to several days, preferably at room temperature for 4 hours, to give compound (1D ") (R ⁴ = Me).

Method E : obtaining a compound of formula (1) in which l = 1, m = 0 or 1, n = 1 and X = NR ⁴

where B, J, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above, and R ⁴ is alkyl, alkenyl, alkynyl, aralkyl, or heteroaralkyl.

An aminopiperidine derivative of formula (22) wherein the amino group in the ring is protected 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 a temperature of from 0 ° C. to a reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, to obtain compound (23). Compound (23) is reacted with R ⁴ -B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and the like, in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF , DMSO, etc., at a temperature of from 0 ° C to a reflux temperature for a period of time from several hours to several days, preferably at 80 ° C for 12 hours, obtaining the compound (24). After removal of the protecting group in compound (24), the resulting compound 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 a temperature of 0 ° C. to a reflux temperature over a period of several hours to several days, preferably at room temperature for 4 hours, to give compound (1E).

Method F : obtaining a compound of formula (1) in which l = 1, m = 0, n = 1 and X = NR ⁴

where B, J, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above, and R ⁴ is alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, or heteroaryl.

4-Piperidoneethyl ketal (26) 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 a temperature of from 0 ° C to a temperature the formation of reflux over a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (27), which, in turn, is subjected to decetalization using acid to obtain the ketone compound (28).

On the other hand, 4-piperidone (29) 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 and the like, at a temperature of from 0 ° C to a reflux temperature over a period of several hours to several days, preferably at room temperature for 4 hours, to obtain compound (28). By using compound (28) in accordance with any of the following two synthetic methods, an amine compound (30) can be obtained.

Synthesis Method 1: Compound (28) is reacted with an amine compound of the formula R ⁴ —NH ₂ in the presence of molecular sieves in toluene or benzene at a temperature of from 0 ° C. to a reflux temperature over a period of several hours to several days, preferably at the temperature of the formation of phlegmy for 12 hours, followed by interaction with a reducing agent, such as sodium borohydride or sodium cyanoborohydride, at a temperature of from 0 ° C to the temperature of the formation of phlegmy over a period of time from a few chickpeas for several days, preferably at room temperature for 1 hour, to obtain the amine compound (30).

Synthesis Method 2: Compound (28) is reacted with an amine compound of the formula R ⁴ —NH ₂ in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent such as dichloromethane, 1,2-dichloroethane, methanol, ethanol, etc., at a temperature of from 0 ° C to a reflux temperature for a period of time from several minutes to several days, preferably at room temperature for 4 hours, to obtain an amine compound (30).

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

Method G : obtaining a compound of formula (1) in which l = 1, m = 0, n = 1 and X = NR ⁴

where B, J, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above, and R ⁴ is alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, or heteroaryl.

A 4-piperidone derivative of the formula (31) in which the amino group is protected is reacted with an amine compound R ⁴ —NH ₂ , similarly to the procedure for preparing the compound (30) of Method F, to obtain the compound (32). Compound (32) 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 a temperature of from 0 ° C to reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (33). After removing the protecting group from compound (33), the obtained compound (34) 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 and the like, at a temperature of from 0 ° C to a reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1G).

Method H : obtaining a compound of formula (1) in which l = 0, m = 0, n = 1 and X = NH

where B, J, W ¹ , W ² , R ¹ , R ² and R ³ have the meanings indicated above.

The 3-aminopyrrolidine derivative (35) with a protected amino group in the ring is reacted with 2-nitrobenzenesulfonyl chloride (19) under ordinary conditions to obtain a benzenesulfonyl derivative (36). Derivative (36) 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 a temperature of from 0 ° C to reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the compound (37). The amino group protecting group is removed from compound (37) to give compound (38), which, in turn, 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 and the like, at a temperature of from 0 ° C to a reflux temperature for a period of time from several hours to several days, preferably at room temperature for 4 hours, to obtain compound (39). Subjecting the compound (39) to interaction, similarly to the preparation of the compound (5) described in Method A, the final product (1H) is obtained.

Method I : obtaining a compound of formula (1) in which l = 0, m = 0, n = 1 and X = NR ⁴

where B, J, W ¹ , W ² , R ¹ , R ² and R ³ are as defined above, and R ⁴ is alkyl, alkenyl, alkynyl or aralkyl.

Compound (36) is reacted with R ⁴ -B in the presence of a base such as sodium carbonate, potassium carbonate, etc., in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. ., at a temperature of from 0 ° C to the temperature of the formation of reflux over a period of time from several hours to several days, preferably at 80 ° C for 12 hours, obtaining the compound (40). An amino protecting group is removed from compound (40) and the resulting compound (41) 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 and the like, at a temperature of from 0 ° C to reflux for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (42). Subjecting the compound (42) to interaction, similar to the preparation of the compound (5) described in Method A, the compound (43) is obtained. Compound (43) 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 a temperature of from 0 ° C to reflux temperature over a period of time from several hours to several days, preferably at room temperature for 4 hours to obtain the final product (1I).

Method J : obtaining a compound of formula (1) in which R ² = OH

where X, W ¹ , W ² , R ¹ , R ³ , l, m and n are as defined above.

As a result of the interaction of the methoxy compound (1J) with iodotrimethylsilane in a solvent such as toluene, chloroform, dichloromethane, etc., at a temperature of from -25 ° C to a temperature of reflux for a period of time from several hours to several days, preferably at 0 ° C for 2 hours, the final product (1J ′) can be obtained.

Method K : obtaining a compound of formula (1) in which l = 1, m = 0, n = 0 and X = NR ⁴ CO

where B, J, W ¹ , W ² , R ¹ , R ^2, and R ³ are as defined above, and R ⁴ is alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl, or heteroaryl.

Compound (32) described in Method G is reacted with compound (18) in accordance with the method for producing compound (1A) described in Method A to obtain compound (44). After removing the protecting group from 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 a temperature of from 0 ° C to the temperature of the formation of reflux for a period of time from several hours to several days, preferably at room temperature for 4 hours, obtaining the final product (1K).

Method L : obtaining a compound of formula (1) in which l = 1, m = 0, n = 1 and X = alkylsulfonylphenylamino group

where B, W ¹ , W ² , R ¹ , R ² and R ³ have the meanings indicated above.

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

Compounds (1) in accordance with the present invention can be obtained by any of the methods described above and, if necessary, subjected to further purification using conventional purification methods, such as recrystallization or column chromatography. If necessary, the obtained compounds can also be converted into the desired salts or solvates by a method known in the art per se.

In the case where the compounds (1) include an asymmetric carbon atom, the present invention includes any configuration of isomers.

The compounds (1) in accordance with the present invention, thus obtained, or their salts or solvates, as described below in test example 1, have a strong inhibitory effect on cell adhesion and are useful as drugs for the treatment and prevention of diseases of animals, including humans caused by cell adhesion or cell infiltration, such as asthma, allergies, rheumatism, arteriosclerosis, inflammation, Sjogren's syndrome, etc.

A medicament in accordance with the present invention includes a compound (1), a salt thereof or a solvate thereof as an active ingredient. The administration form can, if necessary, be appropriately selected for the intended therapeutic purpose without any specific restrictions, including oral preparations, injections, suppositories, ointments, inhalation dosage forms, eye drops, nasal drops and patches. A composition suitable for use in these administration forms may be prepared by admixing a pharmaceutically acceptable carrier in accordance with a conventional method of preparation well known to those skilled in the art.

When preparing a solid preparation for oral administration, an excipient and optionally a binder, disintegrant, lubricant, colorant, flavoring agent, flavoring agent, etc. are added to the compound (1), and the resulting composition can be formulated as tablets, granules, powders, capsules etc. in accordance with methods known in the art. As the additives described above, any additives commonly used in the pharmacological field can be used. 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, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceryl stearate and lactose; lubricants such as purified talc, stearic acid salts, sodium tetraborate and polyethylene glycol, as well as flavoring agents such as sucrose, orange peel, citric acid and tartaric acid.

Upon receipt of a liquid preparation for oral administration, a flavoring agent, a buffer, a stabilizer, a flavoring substance and / or the like are added to the compound (1), and the resulting composition can be prepared in the form of liquid preparations for internal use, syrups, elixirs, etc. .d. in accordance with methods known in the art. In this case, vanillin can be used as a flavoring substance in accordance with the above description. Sodium citrate may be used as a buffer. As examples of the stabilizer can be given tragacanth, gum arabic and gelatin.

In preparing an injection solution, a pH regulator, a buffer, a stabilizer, an isotonic agent, a local anesthetic and the like can be added to the compound (1) in accordance with the present invention, and the resulting composition can be prepared in the form of solutions for subcutaneous, intramuscular and intravenous injection in accordance with methods known in the art. Examples of a pH adjuster and buffer in this case include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. Examples of a local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride and glucose.

In preparing a suppository, a suitable carrier known in the art is added to compound (1), for example polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and optionally a surfactant such as “Tween” (registered trademark sign) and the like, while the resulting composition can be prepared in the form of suppositories in accordance with methods known in the art.

Upon receipt of the ointment, the commonly used base material, stabilizer, moisturizer, preservative, and the like. mixed with the compound (1) accordingly and the resulting mixture is stirred and prepared in the form of ointments in accordance with a known method. Examples of the base material include liquid paraffin, white petrolatum, bleached beeswax, octyldodecyl alcohol, and paraffin. Examples of preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.

In addition to the above preparations, inhalation dosage forms, eye drops and nasal drops can also be prepared in accordance with known methods.

The dose of the drug in accordance with the present invention varies in accordance with the age, weight and condition of the patient being treated, route of administration, number of administrations, and the like. However, in general, oral or parenteral administration of the drug is preferred one or more times in a dose of 1 to 1000 mg per day of the compound (1) for an adult.

Examples

The following is a more detailed description of the present invention using examples. However, the present invention is not limited to these examples.

Production Example 1

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

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

Yield 27.99 g (88%).

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

Production Example 2

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

Ethyl 2- (3,4,5-trimethoxyphenyl) isonicotinate (24.57 g) was dissolved in dry THF (200 ml) and lithium aluminum hydride (2.94 g) was added to the solution at 0 ° C. under argon atmosphere. In this state, the mixture is stirred at 0 ° C for one hour. A small amount of water and then sodium sulfate are added to the reaction mixture, after which insoluble matters are filtered off through celite. The filtrate was concentrated under reduced pressure, and the resulting untreated crystals were recrystallized from ethyl acetate / hexane to give the title compound.

Yield 17.53 g (82%).

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

Production Example 3

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

4-Hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (19.18 g) was dissolved in chloroform (100 ml) and chloride was slowly added to the solution at 0 ° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with aqueous saturated sodium bicarbonate and 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 18.24 g (89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.61 (s, 2H), 7.24 (s, 2H), 7 26 (d, 1H, J = 5.1 Hz), 7.68 (s, 1H), 8.67 (d, 1H, J = 5.1 Hz).

Production 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 (881 mg) in chloroform (10 ml) was added potassium phthalimide (556 mg). The mixture was stirred at room temperature overnight and water was added. After separation of 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 obtain the title compound as a white powder.

Yield 1.16 g (96%).

Production Example 5

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

To a suspension of N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] phthalimide (1.16 g) in ethanol (30 ml) was added hydrazine monohydrate (1 ml). The mixture was refluxed for 3 hours. After cooling, insoluble matters are filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow oil.

Yield 418 mg (53%).

Production Example 6

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

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

Yield 1.20 g (88%).

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

Production 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] piperidin-4-carboxylate (760 mg) in ethanol (10 ml) was added 1 M sodium hydroxide (10 ml). The mixture was stirred at room temperature for 4 hours and ethanol was distilled off under reduced pressure. Water (20 ml) was added to the residue, and then 5% aqueous potassium bisulfate was gradually added until the solution reached pH 7. Precipitated crystals were collected by filtration and the product was used in the next steps without further purification.

Yield 779 mg (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 (97 mg) and 4-aminomethyl-2- (3,4,5-trimethoxyphenyl ) pyridine (68 mg) in acetonitrile (5 ml) was added 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (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 saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a chloroform / methanol mixture (40: 1 ~ 20: 1). The title compound was obtained as the free base. Then, by adding maleic acid, the free base is converted to maleate.

Yield 93 mg (49%).

¹ H-NMR (400 MHz, defined 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 = 5.9 Hz), 6.16 (s, 2H), 7.16 (d, 1H, J = 5.9 Hz), 7.35 (s, 2H), 7.39 (d, 1H, J = 5.9 Hz), 7.39 (s, 2H), 7.73 (s, 1H), 7.95 (s, 1H), 8.15 (d, 1H, J = 5.9 Hz), 8.54 (d, 1H, J = 4.9 Hz), 8.68 (d, 1H, J = 4.9 Hz).

Production Example 8

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

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

Yield 213 mg (10%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.63 (broad, 2H), 1.89 (broad, 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 = 5.0 Hz).

Production Example 9

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

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

Yield 93 mg (60%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55-1.68 (m, 2H), 2.01 (broad, 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 = 4.3 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.63 (d, 1H, J = 5.1 Hz) .

Example 2

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

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

Yield 42 mg (39%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.53-2.42 (m, 6H), 2.80 (broad, 2H), 3.57 (broad, 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).

Production Example 10

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

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

Yield 597 mg (74%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 7.2 Hz), 7.77 (t, 2H, J = 4.4 Hz), 7.87-7.90 (m, 1H ), 8.17-8.19 (m, 1H).

Production 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-nitrobenzene) sulfonylamino] pyrrolidine (371 mg) and potassium carbonate (138 mg) in acetonitrile (10 ml) was added methyl iodide (141 mg). The mixture was stirred at 60 ° C for 2 hours and concentrated under reduced pressure. Ethyl acetate was added to the mixture. The solution was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used for silica gel column chromatography using hexane / ethyl acetate (2: 1) as an eluent for purification, to give the title compound as a yellow oil.

Yield 365 mg (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 (s, 9H), 1.95 (broad, 1H), 2.09 (broad, 1H), 2.87 (s, 3H), 3 , 20-3.31 (m, 2H), 3.53 (broad, 2H), 4.58 (broad, 1H), 7.65 (broad, 1H), 7.71 (broad, 2H), 8, 04 (broad, 1H).

Production Example 12

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

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

Yield 135 mg (50%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.69-1.74 (m, 1H), 1.87 (broad, 1H), 1.95-2.02 (m, 1H), 2, 80 (dd, 1H, J = 11.7 Hz, 5.7 Hz), 2.84-2.91 (m, 4H), 2.96-3.05 (m, 1H), 3.10 (dd , 1H, J = 11.7 Hz, 8.2 Hz), 4.48-4.56 (m, 1H), 7.61-7.63 (m, 1H), 7.66-7.73 ( m, 2H), 8.01-8.04 (m, 1H).

Production 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 (135 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (139 mg) are treated according to the procedure, similar to that described in example 2, getting mentioned in the title compound as a yellow amorphous substance.

Yield 247 mg (96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.80-1.87 (m, 1H), 2.15-2.30 (m, 2H), 2.52 (dd, 1H, J = 10 5 Hz, 8.2 Hz), 2.71 (dd, 1H, J = 10.5 Hz, 8.2 Hz), 2.90 (dt, 1H, J = 8.8 Hz, 2.9 Hz ), 2.96 (s, 3H), 3.53 (d, 1H, J = 13.9 Hz), 3.68 (d, 1H, J = 13.9 Hz), 3.90 (s, 3H ), 3.96 (s, 6H), 4.61-4.68 (m, 1H), 7.16 (dd, 1H, J = 4.9 Hz, 1.2 Hz), 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 = 4.9 Hz).

Production 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] pyrrolidine (242 mg) in acetonitrile (5 ml) potassium carbonate (94 mg) and thiophenol (75 mg) are added. The mixture was stirred at 80 ° C for one hour. After cooling, ethyl acetate was added to the mixture, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC using a chloroform / methanol solution (20: 1) as an eluent to give the title compound as a yellow oil.

Yield 104 mg (64%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (broad, 1H), 1.56-1.64 (m, 1H), 2.11-2.17 (m, 1H), 2, 38 (s, 3H), 2.44 (dd, 1H, J = 7.4 Hz, 4.5 Hz), 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 = 4.1 Hz), 7.25 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz).

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

(3S) -3-Methylamino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine (104 mg) and 4-chloromethyl-2- (3,4,5- trimethoxyphenyl) pyridine (85 mg) was reacted according to the procedure similar to that described in Example 2. The resulting product was converted to tetrahydrochloride to give the title compound as a yellow powder.

Yield 151 mg (68%).

¹ H-NMR (400 MHz, defined 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 = 14.3 Hz), 3.62 (d , 1H, J = 14.3 Hz), 3.64 (d, 1H, J = 13.9 Hz), 3.73 (d, 1H, J = 13.9 Hz), 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 = 5.7 Hz), 8.60 (d, 1H, J = 5.3 Hz) .

Production Example 15

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

Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (881 mg) were reacted according to the procedure similar to that described in Example 2 to give the title compound as white needles .

Yield 1.01 g (87%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.70-1.88 (m, 4H), 2.01-2.23 (m, 3H), 2.95 (d, 2H, J = 11 , 0 Hz), 3.56 (s, 2H), 3.90 (s, 3H), 3.98 (s, 6H), 5.46 (d, 2H, J = 16.3 Hz), 7, 21 (d, 1H, J = 5.0 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J = 5.0 Hz).

Production Example 16

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

To a solution of 1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidin-4-carboxamide (192 mg) in a mixed solvent of water (50 ml) and acetonitrile (50 ml) [bis (trifluoroacetoxy) iodine] benzene (323 mg). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue to alkalize, and the residue was extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The yellow oil thus obtained is then converted into hydrochloride, which gives a yellow powder. The title compound was used in the next step without further purification.

Yield 201 mg (theoretical amount).

Production Example 17

Synthesis of 2- (3,4,5-trimethoxyphenyl) isonicotinic acid

To a solution of ethyl 2- (3,4,5-trimethoxyphenyl) isonicotinate (3.17 g) in ethanol (40 ml) 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 obtained title compound was used in the following steps without further purification.

Yield 2.60 g (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) pyridin-4-carboxylic acid (72 mg) and 4-amino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (117 mg) were reacted in the same manner as described in Example 1. The resulting product was converted to maleate to give the title compound.

Yield 173 mg (93%).

¹ H-NMR (400 MHz, defined 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 = 4.9 Hz), 8.74 (d, 1H, J = 5.1 Hz).

Production 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 (467 mg) and 2-nitrobenzenesulfonyl chloride (244 mg) are reacted according to the procedure similar to that described in the preparation example 10, obtaining the title compound.

Yield 494 mg (91%).

Production 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 (494 mg) and 4-chloromethyl-2- (3.4 , 5-trimethoxyphenyl) pyridine (267 mg) was reacted according to the procedure similar to that described in Production Example 2 to afford the title compound.

Yield 443 mg (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 Difumalate

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 (443 mg) was worked up as described in Production Example 14. The title compound was obtained as difumalate.

Yield 103 mg (24%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.44-1.53 (m, 2H), 1.87-1.91 (m, 2H), 2.15 (t, 2H, J = 1.1 Hz), 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 = 4.9 Hz), 7.29 (d, 1H, J = 4.9 Hz), 7.35 (s, 2H), 7.37 (s, 2H), 7.76 (s, 1H), 7.85 (s, 1H), 8 53-8.56 (m, 2H).

Production Example 20

Synthesis of 4- (ethoxycarbonylamino) -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] piperidin-4-carboxamide (528 mg) in a mixed solvent of ethanol (10 ml) and acetonitrile (10 ml) [bis (trifluoroacetoxy) iodine] benzene (884 mg). The mixture was stirred at room temperature overnight. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the mixture and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (20: 1) as an eluent to obtain the title compound.

Yield 566 mg (96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (t, 3H, J = 7.0 Hz), 1.40-1.51 (m, 2H), 1.92 (d, 2H, J = 10.9 Hz), 2.15 (t, 2H, J = 10.9 Hz), 2.78 (d, 2H, J = 11.6 Hz), 3.52 (br, 3H), 3 87 (s, 3H), 3.94 (s, 6H), 4.07 (q, 2H, J = 7.0 Hz), 4.56 (br, 1H), 7.17 (d, 1H, J = 4.9 Hz), 7.21 (s, 2H), 7.59 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz).

Production Example 21

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

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

Yield 379 mg (78%).

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

Production Example 22

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

4-Piperidoneethylene ketal (12.0 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (12.3 g) were reacted according to the procedure similar to that described in Example 2 to give the title compound.

Yield 19.0 g (theoretical amount).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.68 (t, 4H, J = 5.6 Hz), 2.48 (broad, 4H), 3.50 (s, 2H), 3.82 (s, 3H), 3.86 (s, 4H), 3.88 (s, 6H), 7.13 (d, 1H, J = 4.9 Hz), 7.17 (s, 2H), 7 57 (s, 1H); 8.51 (d, 1H, J = 4.9 Hz).

Production Example 23

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

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

Yield 15.0 g (75%).

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

Production Example 24

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

4-piperidone hydrochloride monohydrate (3.07 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (2.94 g) were reacted according to the procedure similar to that described in example 2, to obtain the title compound .

Yield 3.55 g (99%).

Production 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 (1.00 g) in 1,2-dichloroethane (60 ml) was added a 30% methylamine solution in ethanol (750 g) 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 adding water, the residue was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (40: 1) as an eluent to obtain the title compound.

Yield 640 mg (62%).

Production Example 26

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

3,4,5-Trimethoxyphenylboronic acid (3.7 g) and ethyl 3-bromobenzoate (4.02 g) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 5.09 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (t, 3H, J = 7.1 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.41 (q, 2H, J = 7.1 Hz), 6.79 (s, 2H), 7.50 (t, 1H, J = 7.8 Hz), 7.73 (dt, 1H, J = 7, 1 Hz, 1.5 Hz), 8.01 (dt, 1H, J = 7.8 Hz, 1.4 Hz), 8.23 (t, 1H, J = 1.8 Hz).

Production Example 27

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

Ethyl 3- (3,4,5-trimethoxyphenyl) benzoate (1.19 g) was treated according to the procedure similar to that described in Production Example 17 to obtain the title compound.

Yield 986 mg (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 dihydrochloride ] piperidine

3- (3,4,5-trimethoxyphenyl) benzoic acid (1.03 g) and 4- (methylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (1.32 g) was reacted according to the procedure similar to that described in Example 1 to afford the title compound as dihydrochloride.

Yield 1.44 g (57%).

¹ H-NMR (400 MHz, defined as dihydrochloride, DMSO-d ₆ ) δ: 1.89 (d, 2H, J = 11.7 Hz), 2.54-2.62 (m, 2H), 2, 89 (s, 3H), 3.09 (t, 2H, J = 12.7 Hz), 3.43 (d, 2H, J = 14.4 Hz), 3.76 (s, 3H), 3, 78 (s, 3H), 3.88 (s, 6H), 3.91 (s, 6H), 4.34 (broad, 3H), 6.91 (s, 2H), 7.33 (d, 1H , J = 7.6 Hz), 7.47-7.51 (m, 2H), 7.54 (s, 2H), 7.60 (s, 1H), 7.71 (d, 1H, J = 7.8 Hz), 8.55 (s, 1H), 8.68 (d, 1H, J = 5.1 Hz).

Example 7

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

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

Yield 180 mg (58%).

¹ H-NMR (400 MHz, defined 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 = 5.1 Hz), 7.24 (s, 2H), 7.62 (s, 1H), 7.80 (s, 1H), 8, 50 (d, 1H, J = 2.0 Hz), 8.60 (d, 1H, J = 4.3 Hz), 8.69 (d, 1H, J = 5.1 Hz).

Production Example 28

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

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

Yield 230 mg (92%).

Production Example 29

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

Under argon, a 1.57 M solution of n-butyllithium in hexane (0.8 ml) was gradually added to dry THF (2 ml), cooled in a dry ice / methanol bath, followed by a dropwise solution of 1-bromo-4-chlorine -3,5-dimethoxybenzene (160 mg) in dry THF (2 ml). After the mixture was stirred for 20 minutes in a dry ice / methanol bath, triisopropyl borate (0.18 ml) was added and the mixture was further stirred for another 20 minutes. The reaction mixture was then stirred at room temperature for one hour, and the pH of the mixture was adjusted to 3 using 4 M hydrochloric acid. The mixture was stirred at 0 ° C. for one hour and extracted with ethyl acetate. The organic layer was washed with 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 90 mg (66%).

Production Example 30

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

4-Chloro-3,5-dimethoxyphenylboronic acid (7.45 g) and ethyl 2-chloroisonicotinate (6.39 g) were treated according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 8.55 g (77%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45 (t, 3H, J = 7.3 Hz), 4.03 (s, 6H), 4.45 (q, 2H, J = 7, 3 Hz), 7.32 (s, 2H), 7.80 (d, 1H, J = 5.1 Hz), 8.27 (s, 1H), 8.83 (d, 1H, J = 5, 0 Hz).

Production Example 31

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

To a solution of ethyl 2- (4-chloro-3,5-dimethoxyphenyl) isonicotinate (8.55 g) in ethanol (80 ml) was added 2 M sodium hydroxide (100 ml). The mixture was stirred at reflux for 30 minutes and ethanol was distilled off under reduced pressure. The mixture was neutralized by the addition of 1 M 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 obtain the title compound.

Yield 7.20 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.02 (s, 6H), 7.34 (s, 2H), 7.83 (d, 1H, J = 4.9 Hz), 7.84 (s, 1H), 8.82 (d, 1H, J = 4.9 Hz).

Production Example 32

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

Ethyl chloroformate (2.8 ml) was added to a solution of 2- (4-chloro-3,5-dimethoxyphenyl) isonicotinic acid (7.20 g) and triethylamine (5.6 ml) in THF (70 ml) at 0 ° C. The mixture was stirred at room temperature for one hour and insoluble matters were filtered off. A solution of sodium borohydride (1.25 g) in water (4 ml) was then added to the filtrate. The mixture was stirred at room temperature for another hour and concentrated under reduced pressure. After adding water, the residue was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (20: 1 ~ 15: 1) to obtain the title compound.

Yield 4.10 g (60%).

¹ H-NMR (400 MHz, CDCl ₃ + DMSO-d ₆ ) δ: 4.01 (s, 6H), 4.76 (s, 2H), 7.20-7.35 (m, 3H), 7 78 (s, 1H); 8.62 (s, 1H).

Production Example 33

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

2- (4-Chloro-3,5-dimethoxyphenyl) -4-hydromethylpyridine (4.10 g) was dissolved in chloroform (20 ml), thionyl chloride (5.2 ml) was added and stirred at 70 ° C for one hour. After concentrating the mixture under reduced pressure, the resulting residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.

Yield 4.20 g (96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.02 (s, 6H), 4.63 (s, 2H), 7.26 (s, 2H), 7.29 (d, 1H, J = 4.9 Hz), 7.72 (s, 1H), 8.69 (d, 1H, J = 4.9 Hz).

Production Example 34

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

Piperidine-4-carboxamide (301 mg) and 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethylpyridine (600 mg) were reacted in the same manner as described in Example 2 to give the title compound.

Yield 743 mg (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.75-1.90 (m, 4H), 2.07-2.25 (m, 3H), 2.94 (d, 2H, J = 11 , 6 Hz), 3.57 (s, 2H), 4.02 (s, 6H), 7.24-7.31 (m, 3H), 7.67 (s, 1H), 8.61 (d , 1H, J = 5.1 Hz).

Production 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] piperidin-4-carboxamide (743 mg) was treated according to the procedure similar to that described in Production Example 20 to obtain the title compound .

Yield 887 mg (theoretical amount).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.24 (t, 3H, J = 7.1 Hz), 1.43-1.59 (m, 2H), 1.96 (d, 2H, J = 11.4 Hz), 2.19 (t, 2H, J = 11.0 Hz), 2.82 (d, 2H, J = 11.5 Hz), 3.56 (s, 2H), 4 02 (s, 6H), 4.10 (q, 2H, J = 7.1 Hz), 7.26 (s, 2H), 7.66 (s, 1H), 7.71 (dd, 1H, J = 5.6 Hz, 1.0 Hz), 8.6 (dd, 1H, J = 4.9 Hz, 0.5 Hz).

Production 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-ethoxycarbonylamino) piperidine (887 mg) was treated in the same manner as described in Production Example 21 to give the title compound.

Yield 195 mg (27%).

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

Example 8

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

1 - [[2- (4-Chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-methylaminopiperidine (195 mg) and 2- (4-chloro-3,5-dimethoxyphenyl) -4- chloromethylpyridine (152 mg) was reacted according to the procedure similar to that described in Example 2. The free base thus obtained was converted to tetrahydrochloride to give the title compound as a yellow powder.

Yield 300 mg (75%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.90 (m, 4H), 2.06 (t, 2H, J = 11.7 Hz), 2.26 (s, 3H), 2.45-2.55 (m, 1H), 2.97 (d, 2H, J = 11.3 Hz), 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 = 5.4 Hz), 8.62 (d, 1H, J = 5.4 Hz).

Production Example 37

Synthesis of 4- (p-anisidino) -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 (2.17 g) in toluene (40 ml) was added p-anisidine (900 mg) and 4Å molecular sieves (6.0 g). The mixture was refluxed overnight, then the molecular sieves were filtered off and the filtrate was evaporated. The residue was dissolved in ethanol (40 ml) and sodium borohydride (276 mg) was added. The mixture was stirred at room temperature for 2 hours before concentration in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (50: 1) to obtain the title compound.

Yield 1.56 g (55%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (broad, 2H), 2.05 (broad, 2H), 2.20 (broad, 2H), 2.86 (broad, 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 = 8.8 Hz), 6.77 (d, 2H, J = 9.0 Hz), 7.22 (d, 1H, J = 5.1 Hz), 7.26 (s, 2H) 7.64 (s, 1H); 8.59 (d, 1H, J = 4.9 Hz).

Production Example 38

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

3,4,5-Trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as described in Production Example 1 to obtain the title compound.

Yield 799 mg (77%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.10 (t, 3H, J = 7.2 Hz), 3.89 (s, 9H), 4.19 (q, 2H, J = 7, 2 Hz), 6.79 (s, 2H), 7.34 (dd, 1H, J = 7.8 Hz, 4.8 Hz), 8.06 (dd, 1H, J = 7.8 Hz, 1 , 7 Hz), 8.75 (dd, 1H, J = 4.8 Hz, 1.7 Hz).

Production Example 39

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

Ethyl 2- (3,4,5-trimethoxyphenyl) nicotinate (468 mg) was worked up as described in Production Example 2 to afford the title compound.

Yield 293 mg (72%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 9H), 4.72 (s, 2H), 6.83 (s, 2H), 7.32 (dd, 1H, J = 7.9 Hz, 4.8 Hz), 7.92 (dd, 1H, J = 7.9 Hz, 1.7 Hz), 8.62 (dd, 1H, J = 4.8 Hz, 1.7 Hz).

Production Example 40

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

3-Hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (293 mg) was treated according to the procedure similar to that described in Production Example 3 to obtain the title compound.

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

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

Yield 16 mg (8%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60 (broad, 2H), 1.77 (broad, 2H), 2.09 (broad, 2H), 2.93 (broad) , 2H), 3.45 (s, 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 = 9.0 Hz), 6.71 (s, 2H), 6.74 (d, 2H, J = 9.0 Hz), 7.16-7.19 (m, 2H), 7.22 (s, 2H), 7.55 (s, 1H), 7.79 (d, 1H, J = 7 , 0 Hz), 8.50 (br, 1H), 8.58 (d, 1H, J = 4.9 Hz).

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

4- (p-Anisidino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (1.56 g) and 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (1.08 g) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 1.17 g (40%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.68-1.97 (m, 4H), 2.09-2.23 (m, 2H), 2.98 (broad, 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 = 9.2 Hz), 6.79 (d, 2H, J = 9.2 Hz) 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 = 5.1 Hz); 8.59 (d, 1H, J = 4.9 Hz).

Production Example 41

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

Ethyl 3- (3,4,5-trimethoxyphenyl) benzoate (5.09 g) was treated according to the procedure similar to that described in Production Example 2 to obtain the title compound.

Yield 4.25 g (97%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.87 (t, 1H, J = 6 0 Hz), 3.89 (s, 3H), 3.92 (s, 6H), 4.76 ( d, 1H, J = 5.6 Hz), 6.77 (s, 2H), 7.34 (d, 1H, J = 7.4 Hz), 7.42 (t, 1H, J = 7.5 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.55 (s, 1H).

Production Example 42

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

3- (3,4,5-Trimethoxyphenyl) benzyl alcohol (1.21 g) was worked up as described in Production Example 3 to afford the title compound.

Yield 893 mg (69%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.87 (s, 3H), 3.90 (s, 6H), 4.62 (s, 2H), 6.75 (s, 2H), 7 33 (d, 1H, J = 7.6 Hz), 7.39 (t, 1H, J = 7.7 Hz), 7.48 (d, 1H, J = 7.6 Hz), 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 dihydrochloride -yl] methyl] piperidine

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

Yield 52 mg (22%).

¹ H-NMR (400 MHz, defined 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 = 7.4 Hz), 7.23 (s, 2H), 7.25-7.27 (m, 1H), 7.33 (t, 1H, J = 7.4 Hz), 7.38 (d, 1H, J = 8.7 Hz), 7.43 (s, 1H), 7.62 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz).

Production Example 43

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

3,4,5-Trimethoxyphenylboronic acid (1.16 g) and ethyl 6-chloronicotinate (1.02 g) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 1.42 g (82%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (t, 3H, J = 7.2 Hz), 3.92 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H, J = 7.2 Hz), 7.32 (s, 2H), 7.76 (d, 1H, J = 8.3 Hz), 8.33 (dd, 1H, J = 8, 2 Hz, 2.2 Hz), 9.26 (d, 1H, J = 2.2 Hz).

Production Example 44

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

Ethyl 6- (3,4,5-trimethoxyphenyl) nicotinate (658 mg) was treated according to the procedure similar to that described in Production Example 2 to obtain the title compound.

Yield 482 mg (85%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.76 (s, 2H), 7.23 (s, 2H), 7 68 (d, 1H, J = 7.4 Hz), 7.78 (dd, 1H, J = 7.4 Hz, 2.3 Hz), 8.63 (d, 1H, J = 2.3 Hz )

Production Example 45

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

5-Hydroxymethyl-2- (3,4,5-trimethoxyphenyl) pyridine (685 mg) was treated according to the procedure similar to that described in Production Example 3 to obtain the title compound.

Yield 717 mg (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

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

Yield 13 mg (5%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.76 (broad, 2H), 1.88 (broad, 2H), 2.14 (broad, 2H), 2.97 (broad , 2H), 3.51 (s, 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 (broad, 4H), 7.20 (broad, 3H), 7.23 (s, 2H), 7.57-7.70 (m, 3H), 8.58-8.60 (m, 2H).

Production Example 46

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

3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 7.19 g (76%).

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

Production Example 47

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

Ethyl 5- (3,4,5-trimethoxyphenyl) nicotinate (7.19 g) was treated according to the procedure similar to that described in Production Example 2 to obtain the title compound.

Yield 3.83 g (61%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.88 (s, 3H), 3.89 (s, 6H), 4.39 (broad, 1H), 4.80 (s, 2H), 6 72 (s, 2H), 7.89 (t, 1H, J = 1.2 Hz), 8.47 (d, 1H, J = 2.1 Hz), 8.63 (d, 1H, J = 2.2 Hz).

Production Example 48

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

3-Hydroxymethyl-5- (3,4,5-trimethoxyphenyl) pyridine (2.85 g) was processed according to the procedure similar to that described in Production Example 3 to obtain the title compound.

Yield 1.97 g (65%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.94 (s, 6H), 4.67 (s, 2H), 6.75 (s, 2H), 7 87 (t, 1H, J = 2.1 Hz), 8.59 (d, 1H, J = 2.0 Hz), 8.76 (d, 1H, J = 2.1 Hz).

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

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

Yield 14 mg (5%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.73-1.75 (m, 2H), 1.88 (d, 2H, J = 11.3 Hz), 2.13 (t, 2H, J = 11.3 Hz), 2.96 (d, 2H, J = 11.5 Hz), 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 = 9.6 Hz), 6.80 (d, 2H, J = 9.4 Hz), 7.20 (d, 1H, J = 5.3 Hz), 7 22 (s, 2H), 7.59 (s, 1H), 7.67 (s, 1H), 8.50 (s, 1H), 8.59 (d, 1H, J = 4.7 Hz) 8.62 (s, 1H).

Production Example 49

Synthesis of 4-iodine-2,6-dimethoxyphenol

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

Yield 1.0 g (31%).

Production Example 50

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

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

Yield 788 mg (72%).

Production Example 51

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

1,3-Dimethoxy-5-iodo-2-isopropoxybenzene (2.25 g) was treated according to the procedure similar to that described in Production Example 29 to obtain the title compound.

Yield 1.23 g (74%).

Production Example 52

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

3,5-Dimethoxy-4-isopropoxyphenylboronic acid (1.23 g) and ethyl 2-chloroisonicotinate (0.95 g) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 1.57 g (89%).

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

Production Example 53

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

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

Yield 1.31 g (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (d, 6H, J = 6.1 Hz), 3.93 (s, 6H), 4.45 (quintet, 1H, J = 6, 1 Hz), 4.81 (s, 2H), 7.20 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.68 (s, 1H), 8.62 (d, 1H, J = 5.1 Hz).

Production Example 54

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

2- (3,5-Dimethoxy-4-isopropoxyphenyl) -4-hydroxymethylpyridine (1.49 g) was processed according to the procedure similar to that described in Production Example 3 to obtain the title compound.

Yield 1.33 g (84%).

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

Production Example 55

Synthesis of Ethylene Ketal 1 - [[2- (3,5-Dimethoxy-4-isopropoxyphenyl) pyridin-4-yl] methyl] -4-piperidone

4-Chloromethyl-2- (3,5-dimethoxy-4-isopropoxyphenyl) pyridine (643 mg) and 4-piperidone ethylene ketal (287 mg) were reacted in the same manner as described in Example 2 to give the title compound.

Yield 818 mg (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (d, 6H, J = 6.1 Hz), 1.78 (t, 4H, J = 5.7 Hz), 2.57 (broad , 4H), 3.49 (s, 4H), 3.59 (s, 2H), 3.94 (s, 6H), 4.44 (quintet, 1H, J = 6.1 Hz), 7.21 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.65 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz).

Production Example 56

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

Ethylene ketal 1 - [[2- (3,5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (818 mg) was treated according to the procedure similar to that described in Production Example 23 to obtain the title compound .

Yield 717 mg (98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32 (d, 6H, J = 6.2 Hz), 2.50 (t, 4H, J = 6.1 Hz), 2.81 (t , 4H, J = 6.1 Hz), 3.69 (s, 2H), 3.95 (s, 6H), 4.45 (quintet, 1H, J = 6.2 Hz), 7.24 (s , 2H), 7.25-7.27 (m, 1H), 7.68 (s, 1H), 8.63 (d, 1H, J = 5.1 Hz).

Production Example 57

Synthesis of 4- (p-anisidino) -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 (350 mg) and p-anisidine (123 mg) are processed according to the procedure similar to that described in the preparation example 37, obtaining the title compound.

Yield 307 mg (69%).

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

Example 14

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

4- (p-Anisidino) -1 - [[2- (3,5-dimethoxy-4-isopropoxyphenyl) pyridin-4-yl] methyl] piperidine (307 mg) and 4-chloromethyl-2- (3,5- dimethoxy-4-isopropoxyphenyl) pyridine (201 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 230 mg (46%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.31 (d, 6H, J = 3.3 Hz), 1.32 (d, 6H, J = 6.8 Hz), 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 = 4.8 Hz), 6.78 (d, 2H, J = 4.8 Hz), 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 = 5.1 Hz), 8, 58 (d, 1H, J = 5.1 Hz).

Production 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 (1.40 g) and benzylamine (0.51 g) are reacted according to the procedure similar to that described in the preparation example 37 to afford the title compound as a yellow amorphous substance.

Yield 1.20 g (68%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-1.60 (m, 2H), 1.88-2.09 (m, 5H), 2.54 (broad, 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 = 5.1 Hz).

Example 15

Synthesis of tetrahydrochloride 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

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

Yield 43 mg (17%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.63 (broad, 4H), 1.87 (broad, 2H), 2.39 (broad, 1H), 2.88 (broad) , 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 = 5.1 Hz), 7.22-7.29 ( m, 8H), 7.56 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 8.50 (d, 1H, J = 6.4 Hz), 8.58 ( d, 1H, J = 5.1 Hz).

Example 16

Synthesis of tetrahydrochloride 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

4-Benzylamino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (230 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine ( 158 mg) were reacted in a manner analogous to that described in Example 9. The resulting free base was converted to tetrahydrochloride to give the title compound as a yellow powder.

Yield 172 mg (47%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.69-1.85 (m, 4H), 1.93-1.99 (m, 2H), 2.56 (broad, 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 = 7.1 Hz), 7 59 (s, 1H), 7.68 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.1 Hz).

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 trihydrochloride ] piperidine

4-Benzylamino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (134 mg) and 3- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) interaction by the method similar to that described in example 9. The resulting free base is converted into trihydrochloride, obtaining mentioned in the title compound as a yellow powder.

Yield 47 mg (18%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.70-1.86 (m, 4H), 1.96 (broad, 2H), 2.59 (broad, 1H), 2 94 (broad, 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 = 5.1 Hz).

Example 18

Synthesis of tetrahydrochloride 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

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

Yield 44 mg (17%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.81 (broad, 4H), 1.96 (broad, 2H), 2.55 (broad, 1H), 2.96 (broad , 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), 7.36-7.38 (m, 2H), 7.61 (d, 2H, J = 7.6 Hz), 7.69-7.73 (m , 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.63 (s, 1H).

Example 19

Synthesis of tetrahydrochloride 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

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

Yield 26 mg (10%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.83 (broad, 4H), 1.97 (broad, 2H), 2.58 (broad, 1H), 2.95 (broad) , 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 = 6.8 Hz), 7.60 ( s, 1H), 7.79 (s, 1H), 8.54 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.64 (s, 1H).

Production Example 59

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

1- ( tert- Butoxycarbonyl) -4-aminomethylpiperidine (200 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (183 mg) were reacted according to the procedure similar to that described in example 2, obtaining as indicated in the title compound is a yellow oil.

Yield 264 mg (90%).

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

Production 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 - [[3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminoethyl] piperidine (264 mg) was processed according to the procedure similar to that described in Production Example 11 to obtain the title compound as a yellow oil.

Yield 157 mg (58%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.00-1.09 (m, 2H), 1.43 (s, 9H), 1.65-1.70 (m, 1H), 1, 79 (d, 2H, J = 12.7 Hz), 2.21 (d, 2H, J = 7.4 Hz), 2.23 (s, 3H), 2.69 (broad, 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, 9 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz).

Production 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 (152 mg) is treated in a similar manner to described in Production Example 12 to obtain the title compound as yellow crystals.

Yield 105 mg (88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.00-1.10 (m, 2H), 1.60-1.68 (m, 1H), 1.80 (d, 2H, J = 12 5 Hz), 2.03 (br, 1H), 2.20 (d, 2H, J = 8.4 Hz), 2.21 (s, 3H), 2.58 (dt, 2H, J = 12 , 1 Hz, 2.1 Hz), 3.05 (d, 2H, J = 12.1 Hz), 3.51 (s, 2H), 3.89 (s, 3H), 3.95 (s, 6H), 7.20 (d, 1H, J = 5.1 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.57 (d, 1H, J = 5.9 Hz).

Example 20

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

4- [N-Methyl-N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] aminomethyl] piperidine (96 mg) and 4-chloromethyl-2- (3,4,5 β-trimethoxyphenyl) pyridine (73 mg) was reacted according to the procedure similar to that described in Example 2. After the obtained product was converted to dioxalate, the title compound was obtained in the form of a white powder.

Yield 109 mg (40%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.19-1.27 (m, 2H), 1.56 (broad, 1H), 1.81 (d, 2H, J = 11.1 Hz), 1.99-2.04 (m, 2H), 2.23 (s, 5H), 2.88 (d, 2H, J = 11.1 Hz), 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 = 4.9 Hz).

Production 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 (1.40 g) and 3,5-dimethoxyaniline (722 mg) are reacted in a similar manner to that described in Production Example 37, obtaining the title compound.

Yield 800 mg (41%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-1.90 (m, 2H), 1.95-2.50 (m, 4H), 2.93 (broad, 2H), 3, 31 (broad, 1H), 3.65 (broad, 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 = 4.9 Hz).

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

4- (3,5-dimethoxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 3-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 29 mg (11%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.63 (m, 2H), 1.79 (d, 2H, J = 11.7 Hz), 2.13 (t, 2H, J = 11.4 Hz), 2.94 (d, 2H, J = 11.3 Hz), 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 = 6.6 Hz), 8.51 (dd, 1H, J = 4.7 Hz, 1.6 Hz), 8.59 (d, 1H, J = 4.9 Hz).

Production Example 63

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

3,4,5-Trimethoxyphenylboronic acid (649 mg) and ethyl 2-bromobenzoate (479 mg) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 655 mg (69%).

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

Production Example 64

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

Ethyl 2- (3,4,5-trimethoxyphenyl) benzoate (655 mg) was treated according to the procedure similar to that described in Production Example 2 to obtain the title compound.

Yield 630 mg (theoretical amount).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 6.8 Hz).

Production Example 65

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

2- (3,4,5-Trimethoxyphenyl) benzyl alcohol (630 mg) was treated according to the procedure similar to that described in Production Example 3 to obtain the title compound.

Yield 615 mg (theoretical amount).

¹ H-NMR (400 MHz, CDCl ₃ ) 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) pyridine dihydrochloride -4-yl] methyl] piperidine

4- (3,5-Dimethoxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 2- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 20 mg (8%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.50-1.90 (m, 4H), 2.05-2.20 (m, 2H), 2.92 (broad, 2H), 3.52 (s, 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

4- (3,5-dimethoxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 40 mg (18%).

¹ H-NMR (400 MHz, defined 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 = 5.3 Hz), 7.16 (s, 2H), 7.20 (d, 1H, J = 3.7 Hz), 7.22 (s, 2H), 7.54- 7.60 (m, 2H), 8.55 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz).

Example 24

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

4- (3,5-Dimethoxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 3- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 41 mg (16%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.78-1.88 (m, 4H), 2.16 (t, 2H, J = 10.7 Hz), 2.96 (d, 2H, J = 11.3 Hz), 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 = 4.9 Hz).

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

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

Yield 23 mg (10%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.64 (broad, 2H), 1.82 (broad, 2H), 2.10 (broad, 2H), 2.94 (broad , 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 (broad, 1H).

Production Example 66

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

3,4,5-Trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were reacted according to the procedure similar to that described in Production Example 1 to obtain the title compound.

Yield 2.99 g (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42 (t, 3H, J = 7.2 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.38 (q, 2H, J = 7.2 Hz), 6.81 (s, 2H), 7.62 (d, 2H, J = 8.2 Hz), 8.10 (d, 2H, J = 8, 2 Hz).

Production Example 67

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

Ethyl 4- (3,4,5-trimethoxyphenyl) benzoate (2.99 g) was treated according to the procedure similar to that described in Production Example 2 to obtain the title compound.

Yield 1.83 g (71%).

Production Example 68

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

4- (3,4,5-Trimethoxyphenyl) benzyl alcohol (1.83 g) was worked up as described in Production Example 3 to afford the title compound.

Yield 1.65 g (84%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.93 (s, 6H), 4.65 (s, 2H), 6.77 (s, 2H), 7 46 (d, 2H, J = 8.0 Hz); 7.55 (d, 2H, J = 8.0 Hz).

Example 26

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

4- (3,5-Dimethoxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (148 mg) and 4- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 35 mg (14%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.80-1.89 (m, 4H), 2.17 (broad, 2H), 2.97 (d, 2H, J = 10.5 Hz), 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 = 8.2 Hz), 7.46 (d, 2H, J = 8.2 Hz), 7.60 (s , 1H), 8.59 (d, 1H, J = 5.1 Hz).

Production Example 69

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

1 - [[2- (3,4,5-Trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) are reacted in a similar manner to that described in Production Example 37, obtaining the title compound.

Yield 810 mg (43%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.63 (broad, 2H), 2.02-2.60 (m, 4H), 2.80-3.15 (m, 2H), 3, 25 (broad, 1H), 3.70 (broad, 2H), 3.88 (s, 3H), 3.96 (s, 6H), 5.83 (s, 2H), 6.02 (d, 1H , J = 8.3 Hz), 6.22 (s, 1H), 6.61 (d, 1H, J = 8.3 Hz), 7.18-7.28 (m, 3H), 7.64 (broad, 1H), 8.60 (d, 1H, J = 4.9 Hz).

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 3-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 30 mg (14%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.45-2.25 (m, 6H), 2.90 (broad, 2H), 3.40 (broad, 1H), 3 55 (broad, 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 = 8.4 Hz), 6.67 (s, 2H), 7.12- 7.30 (m, 4H), 7.52 (broad, 1H), 7.75 (broad, 1H), 8.51 (broad, 1H), 8.57 (broad, 1H).

Example 28

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 2- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 13 mg (6%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.61 (broad, 2H), 1.78 (broad, 2H), 2.10 (broad, 2H), 2.91 (broad) , 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 = 8.6 Hz), 6.32 (s, 1H), 6.53 ( s, 2H), 6.62 (d, 1H, J = 8.6 Hz), 7.17-7.26 (m, 6H), 7.42 (br, 1H), 7.55 (s, 1H ), 8.58 (d, 1H, J = 4.9 Hz).

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 52 mg (25%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.95 (m, 4H), 2.20 (broad, 2H), 3.00 (broad, 2H), 3 58 (broad, 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 = 8.4 Hz), 6.39 (s, 1H), 6.62 (d, 1H, J = 8.4 Hz), 7.12-7.13 (m, 3H), 7.18 (d, 1H, J = 4.1 Hz), 7.23 (br, 2H), 7.54 (br, 2H), 8.51 (d, 1H, J = 5.1 Hz); 8.57 (d, 1H, J = 4.9 Hz).

Example 30

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 3- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 58 mg (29%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.97 (m, 4H), 2.15 (broad, 2H), 3.00 (broad, 2H), 3 58 (broad, 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 = 8.4 Hz), 6.69 (s, 2H), 7.18 ( d, 1H, J = 4.9 Hz), 7.22-7.39 (m, 6H), 7.60 (br, 1H), 8.57 (d, 1H, J = 4.9 Hz).

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 5-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to trihydrochloride to give the title compound as a yellow powder.

Yield 69 mg (27%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.71-1.88 (m, 4H), 2.14 (d, 2H, J = 11.2 Hz), 2.97 (d, 2H, J = 11.5 Hz), 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 5 Hz, 2.5 Hz), 6.45 (d, 1H, J = 2.4 Hz), 6.64 (d, 1H, J = 8.5 Hz), 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 = 1.5 Hz ), 8.59 (d, 1H, J = 4.9 Hz).

Example 32

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

4- (3,4-Methylenedioxyphenylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (119 mg) and 4- (3,4,5-trimethoxyphenyl) Benzyl chloride (114 mg) was reacted according to the procedure similar to that described in Example 9. The resulting free base was converted to dihydrochloride to give the title compound as a yellow powder.

Yield 29 mg (14%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.62-2.00 (m, 4H), 2.20 (broad, 2H), 2.99 (broad, 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 = 8.6 Hz), 6.39 (s, 1H), 6.63 (d, 1H, J = 8.4 Hz), 6.72 (s, 2H), 7.18 (d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.29 (d, 2H, J = 8.0 Hz), 7.43 (d, 2H, J = 8.2 Hz), 7.60 (br, 1H), 8.57 (d, 1H, J = 4.9 Hz).

Production Example 70

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

4-Chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (232 mg), N-methyl-2-nitrobenzenesulfonamide (171 mg) and potassium carbonate (138 mg) are 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 saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.

Yield 362 mg (97.0%).

Production Example 71

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

To a suspension of 4- [N-methyl-N - [(2-nitrobenzene) sulfonyl] aminomethyl] -2- (3,4,5-trimethoxyphenyl) pyridine (691 mg) and potassium carbonate (203 mg) in acetonitrile (20 ml ) thiophenol (228 μl) is added. The mixture was stirred at 50 ° C. overnight and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (40: 1 ~ 10: 1) as eluents to obtain the title compound.

Yield 356 mg (84%).

Example 33

Synthesis of Maleate 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

1 - [[2- (3,4,5-Trimethoxyphenyl) pyridin-4-yl] methyl] piperidin-4-carboxylic acid (98 mg) and 4- (methylaminomethyl) -2- (3,4,5-trimethoxyphenyl ) pyridine (73 mg) was treated according to a procedure similar to that described in Example 1, to give the maleate of the title compound.

Yield 145 mg (75%).

¹ H-NMR (400 MHz, defined 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 = 12.0 Hz), 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 = 5.0 Hz), 7 , 33 (s, 2H), 7.37 (d, 1H, J = 5.0 Hz), 7.38 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H) 8.57 (d, 1H, J = 5.0 Hz); 8.67 (d, 1H, J = 5.0 Hz).

Production Example 72

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

(3S) -1- (tert-Butoxycarbonyl) -3 - [(2-nitrobenzene) sulfonylamino] pyrrolidine (72 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (57 mg) according to the method similar to that described in Production Example 2, to obtain the title compound as a colorless amorphous substance.

Yield 103 mg (85%).

Production Example 73

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

(3S) -1- (tert-butoxycarbonyl) -3- [N - [(2-nitrobenzene) sulfonyl] -N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino ] pyrrolidine (103 mg) was processed according to the procedure similar to that described in Production Example 12 to obtain the title compound as a yellow amorphous substance.

Yield 72 mg (84%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad, 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 = 7.9 Hz, 1.1 Hz); 8.52 (d, 1H, J = 5.1 Hz).

Production Example 74

Synthesis of (3S) -3- [N - [(2-nitrobenzene) 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 (72 mg) and 4 -chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (40 mg) was reacted according to the procedure similar to that described in example 2, to obtain the title compound as a yellow amorphous substance.

Yield 97 mg (91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.59 (broad, 1H), 1.80-1.90 (m, 1H), 2.20-2.30 (m, 2H), 2, 55 (dd, 1H, J = 10.5 Hz, 8.2 Hz), 2.78 (dd, 1H, J = 10.6 Hz, 3.2 Hz), 2.87 (t, 1H, J = 7.2 Hz), 3.50 (d, 1H, J = 13.7 Hz), 3.64 (d, 1H, J = 13.7 Hz), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.83 (d, 2H, J = 4.5 Hz), 7.07 (d, 1H, J = 5.1 Hz), 7.10 (d, 1H, J = 4.9 Hz), 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 = 7.4 Hz), 8.45 (d, 1H, J = 4.9 Hz), 8.51 (d, 1H, J = 5.1 Hz).

Example 34

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

(3S) -3- [N - [(2-Nitrobenzenesulfonyl] -N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] -1 - [[2- (3 , 4,5-trimethoxyphenyl) pyridin-4-yl] methyl] pyrrolidine (97 mg) was worked up as described in Production Example 14. The product was converted into trihydrochloride according to a known method to give the title compound as a yellow powder .

Yield 80 mg (89%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.71 (broad, 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 = 13.7 Hz), 3.71 (d, 1H, J = 13.7 Hz), 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 = 4.3 Hz), 8.60 (d, 1H, J = 4.3 Hz).

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 (69 mg) and 4-amino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (114 mg) subjected to interaction by the method similar to that described in example 1. After the conversion of the product to maleate, the title compound is obtained.

Yield 100 mg (56%).

¹ H-NMR (400 MHz, defined 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 tetrahydrochloride 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

4- (Methylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (2.67 g) and 4-chloromethyl-2- (3,4,5- trimethoxyphenyl) pyridine (2.12 g) was reacted according to the procedure similar to that described in Example 2. After converting the product to tetrahydrochloride, the title compound was obtained.

Yield 2.55 g (46%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.66-1.74 (m, 2H), 1.82 (d, 2H, J = 10.7 Hz), 2.04 (t, 2H, J = 11.0 Hz), 2.25 (s, 3H), 2.45-2.51 (m, 1H), 2.98 (d, 2H, J = 11.7 Hz) 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 = 5.1 Hz), 8.60 (d, 1H, J = 5.3 Hz).

Production Example 75

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

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

Yield 438 mg (theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (t, 3H, J = 7.1 Hz), 1.27-1.34 (m, 2H), 1.60 (broad, 1H) 1.90 (d, 2H, J = 10.9 Hz), 2.67-2.72 (m, 1H), 2.87 (t, 2H, J = 11.5 Hz), 3.90 ( s, 3H), 3.91 (br, 2H), 3.96 (s, 6H), 4.09 (br, 2H), 4.12 (q, 2H, J = 7.0 Hz), 7, 21 (d, 1H, J = 3.5 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz).

Production 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 (438 mg) was treated according to the procedure similar to that described in Production Example 11 to obtain the title compound in the form of a yellow oil.

Yield 235 mg (52%).

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

Production 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 (100 mg) in ethanol (2 ml ) add 4 M sodium hydroxide (8 ml). The mixture was stirred overnight and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a chloroform / methanol mixture (20: 1) to obtain the title compound as a yellow oil.

Yield 73 mg (88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.55 (m, 2H), 1.84 (d, 2H, J = 12.0 Hz), 1.99 (br, 1H) 2.25 (s, 3H), 2.55-2.63 (m, 3H), 3.16 (d, 2H, J = 12.2 Hz), 3.65 (s, 2H), 3, 90 (s, 3H), 3.97 (s, 6H), 7.22 (d, 1H, J = 6.1 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz).

Example 37

Synthesis of tetrahydrochloride 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

4- [N-Methyl-N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (73 mg) and 4-chloromethyl-2- (3,4,5 β-trimethoxyphenyl) pyridine (58 mg) was reacted according to the procedure similar to that described in Example 2. After converting the product to tetrahydrochloride, the title compound was obtained.

Yield 126 mg (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 difumarate ] piperidine

4- (Methylamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (111 mg) and 3- (3,4,5-trimethoxyphenyl) benzyl chloride (88 mg ) are reacted in a manner analogous to that described in Example 2. After the product is converted to difumarate, the title compound is obtained in the form of a white powder.

Yield 59 mg (23%).

¹ H-NMR (400 MHz, defined 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 = 11.3 Hz), 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 = 4.9 Hz), 7.28 (s, 2H), 7.31 (d, 1H, J = 7.6 Hz), 7 , 38 (t, 1H, J = 7.4 Hz), 7.45 (d, 1H, J = 7.6 Hz), 7.51 (s, 1H), 7.63 (s, 1H), 8 60 (d, 1H, J = 5.1 Hz).

Example 39

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

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 (100 mg) in dichloromethane (5 ml) at 0 ° C, iodotrimethylsilane (173 μl) was added. The mixture was stirred at 0 ° C. for 2 hours and then at room temperature overnight. A small amount of water, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the mixture at 0 ° C., after which the organic layer was separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel using a mixture of chloroform / methanol saturated with ammonia (15: 1) and converted into tetrahydrochloride in a known manner to give the title compound.

Yield 50 mg (52.3%).

¹ H-NMR (400 MHz, defined 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 = 5.3 Hz), 8.58 (d, 1H, J = 5.2 Hz).

Production 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 (400 mg) in acetonitrile (5 ml) was added potassium carbonate (13 mg) and iodoethane (145 mg). The mixture was placed in a sealed vessel and stirred at 80 ° C for 2 hours. After the reaction liquid was concentrated in vacuo, ethyl acetate was added to the residue, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using a chloroform / methanol mixture (30: 1) as an eluent to obtain the title compound as a yellow oil.

Yield 242 mg (57%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.04 (t, 3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.43-1 52 (m, 2H), 1.79 (d, 2H, J = 11.5 Hz), 2.60 (q, 2H, J = 7.0 Hz), 2.66-2.76 (m, 3H), 3.70 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.12 (q, 2H, J = 7.0 Hz), 4.20 ( broad, 2H), 7.23 (s, 2H), 7.26 (d, 1H, J = 5.7 Hz), 7.67 (s, 1H), 8.58 (d, 1H, J = 4 9 Hz).

Production 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 (242 mg) was processed according to the procedure similar to that described in Production Example 77 to afford the title compound as a yellow oil.

Yield 150 mg (74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.03 (t, 3H, J = 7.0 Hz), 1.43-1.52 (m, 2H), 1.70 (broad, 1H) 1.79 (d, 2H, J = 12.3 Hz), 2.53-2.67 (m, 5H), 3.13 (d, 2H, J = 11.9 Hz), 3.71 ( s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.24 (s, 2H), 7.27 (d, 1H, J = 5.1 Hz), 7, 68 (s, 1H); 8.57 (d, 1H, J = 4.3 Hz).

Example 40

Synthesis of tetrahydrochloride 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

4- [N-Ethyl-N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (65 mg) is reacted with 4-chloromethyl-2- (3,4 , 5-trimethoxyphenyl) pyridine (50 mg) according to the procedure similar to that described in example 2. After converting the product to tetrahydrochloride, the title compound is obtained.

Yield 121 mg (90%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.03 (t, 3H, J = 7.1 Hz), 1.64-1.69 (m, 2H), 1.77 (d, 2H, J = 10.7 Hz), 2.01 (t, 2H, J = 10.8 Hz), 2.55-2.64 (m, 3H), 2.95 (d, 2H, J = 11.1 Hz), 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 = 4.9 Hz), 8.59 (d, 1H, J = 5.1 Hz).

Production 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 (400 mg) and cyclohexylamine (134 mg) are reacted according to the procedure similar to that described in Production Example 37 to obtain specified in the connection header.

Yield 342 mg (69%).

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

Example 41

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

4- (Cyclohexylamine) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (342 mg) is reacted with 4-chloromethyl-2- (3,4,5- trimethoxyphenyl) pyridine (252 mg) according to the procedure similar to that described in Production Example 9. After converting the product to tetrahydrochloride, the title compound is obtained.

Yield 55 mg (8%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.00-1.39 (m, 6H), 1.58-1.88 (m, 8H), 2.07 (broad, 2H), 2.61 (broad, 2H), 2.96 (broad, 2H), 3.57 (broad, 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, 1 Hz), 8.60 (d, 1H, J = 5.1 Hz).

Production 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 (1.1 g) and aniline (344 mg) are reacted according to the procedure similar to that described in Production Example 37 receiving the title compound.

Yield 1.09 g (81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.53 (broad, 2H), 2.02-2.13 (m, 2H), 2.16-2.32 (m, 2H), 2, 86 (broad, 2H), 3.32 (broad, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H), 6.57 (d, 2H) , J = 8.6 Hz), 6.66 (t, 1H, J = 7.3 Hz), 7.14 (t, 2H, J = 7.9 Hz), 7.20-7.24 (m 5H), 7.65 (br, 1H), 8.59 (d, 1H, J = 5.1 Hz).

Example 42

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

4-Anilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (1.64 g) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (1.33 g) was reacted according to the procedure similar to that described in Production Example 9. After converting the product to trihydrochloride, the title compound was obtained.

Yield 635 mg (20%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-2.00 (m, 4H), 2.10-2.35 (m, 2H), 2.99 (broad, 2H), 3.58 (s, 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 (broad, 2H), 8.53 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 4.9 Hz).

Production Example 82

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

4-piperidone ethylene ketal (573 mg) was reacted with 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethylpyridine (1.19 g) according to a similar manner to that described in Example 2 to give the title compound.

Yield 1.67 g (theoretical amount).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78 (t, 4H, J = 5.6 Hz), 2.58 (broad, 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 = 4.9 Hz).

Production Example 83

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

Ethylene ketal 1 - [[2- (4-Chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.67 g) is processed according to the procedure similar to that described in Production Example 23, obtaining as indicated in connection header.

Yield 1.29 g (89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.50 (t, 4H, J = 5.8 Hz), 2.81 (t, 4H, J = 5.8 Hz), 3.71 (s , 2H), 4.02 (s, 6H), 7.26 (s, 2H), 7.33 (d, 1H, J = 4.3 Hz), 7.70 (s, 1H), 8.66 (d, 1H, J = 4.9 Hz).

Production 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 (600 mg) and aniline (0.18 ml) are processed according to the procedure similar to that described in the preparation example 37, obtaining the title compound.

Yield 465 mg (63%).

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

Example 43

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

4-Anilino-1 - [[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine (230 mg) is reacted with 2- (4-chloro-3,5-dimethoxyphenyl) -4-chloromethylpyridine (157 mg) according to the procedure similar to that described in example 9. After converting the product to trihydrochloride, the title compound is obtained as a yellow powder.

Yield 104 mg (24%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.70-1.85 (m, 4H), 2.20 (t, 2H, J = 2.3 Hz), 3.00 (d, 2H, J = 1.3 Hz), 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 = 5.1 Hz), 8.57 (d, 1H, J = 4.8 Hz).

Production Example 85

Synthesis of 4- (p-anisidino) -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 (690 mg) and p-anisidine (283 mg) are processed according to the procedure similar to that described in the preparation example 37, obtaining the title compound.

Yield 646 mg (72%).

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

Example 44

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

4- (p-Anisidino-1 - [[2- (4-chloro-3,5-dimethoxyphenyl) pyridin-4-yl] methyl] piperidine (271 mg) is reacted with 2- (4-chloro-3,5 -dimethoxyphenyl) -4-chloromethylpyridine (173 mg) according to the procedure similar to that described in example 9. After converting the product to trihydrochloride, the title compound is obtained as a yellow powder.

Yield 324 mg (67%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.65-1.90 (m, 4H), 2.16 (t, 2H, J = 10.4 Hz), 2.97 (d, 2H, J = 7.5 Hz), 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 = 9.4 Hz), 6.79 (d, 2H, J = 9.4 Hz), 7.16 (s, 2H), 7.20-7.29 (m, 4H), 7.59 (s, 1H), 7.62 (s, 1H), 8.56 (d, 1H , J = 4.8 Hz), 8.60 (d, 1H, J = 4.8 Hz).

Production Example 86

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

1 - [[2- (3,4,5-Trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 3-methylthioaniline (655 mg) are processed according to the procedure similar to that described in the preparation example 37, obtaining the title compound.

Yield 1.01 g (54%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.60 (m, 2H), 1.98-2.10 (m, 2H), 2.23 (broad, 2H), 2, 42 (s, 3H), 2.88 (broad, 2H), 3.30 (broad, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H ), 6.35 (d, 1H, J = 7.6 Hz), 6.47 (s, 1H), 6.55 (d, 1H, J = 8.6 Hz), 7.05 (t, 1H , J = 7.9 Hz), 7.20 (d, 1H, J = 4.9 Hz), 7.24 (s, 2H), 7.68 (br, 1H), 8.58 (d, 1H , J = 4.9 Hz).

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

4- (3-Methylthioanilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 3-chloromethyl-2- (3,4,5 -trimethoxyphenyl) pyridine (114 mg) according to the procedure similarly to that described in Example 9. After converting the product to trihydrochloride, the title compound is obtained as a yellow powder.

Yield 45 mg (18%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.58-1.71 (s, 2H), 1.79 (d, 2H, J = 10.7 Hz), 2.16 (t, 2H, J = 11.2 Hz), 2.38 (s, 3H), 2.96 (d, 2H, J = 11.2 Hz), 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 = 8.3 Hz), 6.52 (s, 1H), 6.61 (d, 1H, J = 7.3 Hz), 6.74 (s, 2H), 7.11 ( t, 1H, J = 8.1 Hz), 7.15-7.26 (m, 4H), 7.54 (s, 1H), 7.68 (d, 1H, J = 7.8 Hz), 8.53 (d, 1H, J = 3.2 Hz); 8.59 (d, 1H, J = 4.8 Hz).

Example 46

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

4- (3-Methylthioanilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 2- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After the conversion of the product to dihydrochloride, the title compound is obtained in the form of a yellow powder.

Yield 51 mg (23%).

¹ H-NMR (400 MHz, defined 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 = 8.2 Hz), 6.53-6.62 (m, 5H), 7.09 (t, 1H, J = 8.0 Hz), 7.18-7.40 (m 6H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4.7 Hz).

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

4- (3-Methylthioanilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 4-chloromethyl-2- (3,4,5 -trimethoxyphenyl) pyridine (114 mg) according to the procedure similar to that described in example 9. After converting the product to fumarate, the title compound is obtained in the form of a white powder.

Yield 14 mg (5%).

¹ H-NMR (400 MHz, defined 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 = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz).

Example 48

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

4- (3-Methylthioanilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After the conversion of the product to dihydrochloride, the title compound is obtained in the form of a yellow powder.

Yield 60 mg (24%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.65-1.91 (m, 4H), 2.18 (t, 2H, J = 10.5 Hz), 2.33 (s, 3H), 2.97 (d, 2H, J = 10.9 Hz), 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 4 Hz), 6.59 (d, 1H, J = 7.6 Hz), 6.65 (s, 1H), 6.72 (s, 2H), 7.10 (t, 2H, J = 8 , 0 Hz), 7.19-7.25 (m, 4H), 7.31-7.42 (m, 3H), 7.60 (s, 1H), 8.59 (d, 1H, J = 7.8 Hz).

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

4- (3-Methylthioanilino-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 5-chloromethyl-2- (3,4,5 -trimethoxyphenyl) pyridine (114 mg) according to the procedure similarly to that described in Example 9. After converting the product to trihydrochloride, the title compound is obtained as a yellow powder.

Yield 22 mg (9%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.50-2.05 (m, 4H), 2.20 (broad, 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 = 8.3 Hz), 6.62 (br, 2H), 7.09 (t, 1H, J = 8.2 Hz), 7.18-7.30 (m, 6H), 7.58 (s, 2H), 8.54 (br, 1H), 8.60 (br, 1H).

Example 50

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

4- (3-Methylthioanilin-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 4- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After the conversion of the product to dihydrochloride, the title compound is obtained in the form of a yellow powder.

Yield 57 mg (22%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.58-1.83 (m, 4H), 2.20 (t, 2H, J = 11.3 Hz), 2.39 (s, 3H), 2.98 (d, 2H, J = 11.1 Hz), 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 = 8.4 Hz, 2.4 Hz), 6.60 (d, 1H, J = 8.0 Hz), 6.64 (s, 1H), 6.75 (s, 2H), 7.10 (t, 1H, J = 8.1 Hz), 7.24 -7.33 (m, 4H), 7.47 (d, 2H, J = 8.0 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 5.0 Hz) .

Production 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 (400 mg) and propargylamine (80 mg) are treated in a similar manner to that described in Production Example 25 to obtain the above in the connection header.

Yield 227 mg (63%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad, 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 = 4.9 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz).

Example 51

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

4-Propargylamin-1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (227 mg) is reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (226 mg) according to the procedure similar to that described in example 9. After converting the product to tetrahydrochloride, the title compound is obtained as a yellow powder.

Yield 128 mg (23%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.48-2.40 (m, 7H), 2.72 (broad, 1H), 3.02 (broad, 2H), 3 39 (s, 2H), 3.64 (s, 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 = 4.9 Hz), 8.62 (d, 1H, J = 4.9 Hz).

Production Example 88

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

1 - [[2- (3,4,5-Trimethoxyphenyl) pyridin-4-yl] methyl] -4-piperidone (1.40 g) and 5-aminoindan (680 mg) are processed according to the procedure similar to that described in the preparation example 37, obtaining the title compound.

Yield 1.22 g (59%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.0 Hz), 6.52 (s, 1H), 7.01 (d, 1H, J = 8.0 Hz), 7.21-7.26 ( m, 3H), 7.64 (s, 1H), 8.60 (d, 1H, J = 4.9 Hz).

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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) is reacted with 3-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) according to the procedure similarly to that described in Example 9. After converting the product to trihydrochloride, the title compound is obtained as a yellow powder.

Yield 90 mg (41%).

¹ H-NMR (400 MHz, defined 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 = 8.2 Hz, 2.4 Hz), 6.59 (s, 1H), 6.74 (s, 2H), 7.04 (d, 1H, J = 8.2 Hz), 7.15-7.20 ( m, 2H), 7.22 (s, 2H), 7.54 (s, 1H), 7.77 (dd, 1H, J = 7.8 Hz, 1.4 Hz), 8.52 (dd, 1H, J = 4.7 Hz, 1.8 Hz), 8.59 (d, 1H, J = 5.1 Hz).

Example 53

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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) is reacted with 2- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 115 mg (47%).

¹ H-NMR (400 MHz, defined 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 (s, 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 = 8.3 Hz), 6.56 (s, 2H), 6.60 (s, 1H), 7.02 (d, 1H , J = 8.3 Hz), 7.17-7.27 (m, 5H), 7.42-7.45 (m, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz).

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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (142 mg) is reacted with 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) according to the procedure similar to that described in example 9. After converting the product to trihydrochloride, the title compound is obtained in the form of a white powder.

Yield 23 mg (9%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.95 (m, 4H), 2.00 (quintet, 2H, J = 7.3 Hz), 2.20 (broad, 2H), 2.75-2.81 (m, 4H), 2.99 (broad, 2H), 3.58 (broad, 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 = 8.3 Hz), 6.62 (s, 1H), 7.02 (d, 1H, J = 8.0 Hz), 7.16 (s, 2H), 7.18-7.22 (m , 4H), 7.57 (br, 2H), 8.52 (d, 1H, J = 4.9 Hz), 8.57 (d, 1H, J = 4.9 Hz).

Example 55

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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (60 mg) is reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 18 mg (19%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.60-1.95 (m, 4H), 2.00 (quintet, 2H, J = 7.2 Hz), 2.20 (broad, 2H), 2.75-2.81 (m, 4H), 2.95 (broad, 2H), 3.60 (broad, 2H), 3.85 (broad, 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 = 8.2 Hz), 6.66 (s, 1H), 6.70 (s, 2H), 7.01 (d, 1H, J = 8.4 Hz), 7.19 (d, 1H, J = 4.9 Hz), 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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 5-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) according to the procedure similar to that described in example 9. After converting the product to trihydrochloride, the title compound is obtained in the form of a white powder.

Yield 138 mg (63%).

¹ H-NMR (400 MHz, defined 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 = 8.2 Hz, 2.3 Hz), 6.67 (s, 1H), 7.04 (d, 1H, J = 8.4 Hz), 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 = 8.2 Hz, 2.2 Hz); 8.58-8.62 (m, 2H).

Example 57

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

4- (5-Indanilamino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (143 mg) is reacted with 4- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 95 mg (39%).

¹ H-NMR (400 MHz, defined 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 (broad, 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 = 8.3 Hz), 6.67 (s, 1H), 6.72 (s, 2H), 7.04 (d, 1H, J = 8.3 Hz), 7.20 ( d, 1H, J = 5.1 Hz), 7.23 (s, 2H), 7.35 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz).

Production 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 (1.24 g) and 4-butylaniline (149 mg) are treated according to the method described in the example obtain 37, obtaining the title compound.

Yield 1.23 g (72%).

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

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

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) is reacted with 3-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) according to a similar manner to that described in Example 9. After the product was converted to the trihydrochloride, the title compound was obtained as a yellow powder.

Yield 58 mg (27%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.91 (t, 3H, J = 7.3 Hz), 1.32-1.35 (m, 2H), 1.50 -1.70 (m, 4H), 1.75 (broad, 2H), 2.10-2.20 (m, 2H), 2.49 (t, 2H, J = 7.6 Hz), 2, 95 (broad, 2H), 3.55 (s, 2H), 3.70 (broad, 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 = 8.8 Hz), 6.74 (s, 2H), 7.00 (d , 2H, J = 8.6 Hz), 7.16-7.17 (m, 1H), 7.19 (d, 1H, J = 4.9 Hz), 7.22 (s, 2H), 7 54 (s, 1H), 8.59 (d, 1H, J = 7.5 Hz), 8.52 (br, 1H), 8.59 (d, 1H, J = 4.9 Hz).

Example 59

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

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) is reacted with 2- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 59 mg (24%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.90 (t, 3H, J = 7.4 Hz), 1.25-1.41 (m, 2H), 1.48 -1.75 (m, 4H), 1.81 (d, 2H, J = 11.7 Hz), 2.13 (t, 2H, J = 11.2 Hz), 2.48 (t, 2H, J = 7.5 Hz), 2.93 (d, 2H, J = 11.2 Hz), 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 = 8.5 Hz), 6.98 (d, 2H, J = 8.5 Hz), 7.18 (d, 1H, J = 4.9 Hz), 7, 21 (s, 2H), 7.20-7.37 (m, 3H), 7.41 (br, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J = 4, 9 Hz).

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

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (196 mg) is reacted with 4-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (129 mg) according to the procedure similar to that described in Example 9. After converting the product to trihydrochloride, the title compound is obtained in the form of a white powder.

Yield 20 mg (6%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.88 (t, 3H, J = 7.3 Hz), 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 = 7.3 Hz), 3, 05 (broad, 2H), 3.60 (broad, 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 = 8.3 Hz), 6.98 (d, 2H, J = 8.3 Hz), 7.13 (s, 2H ), 7.15-7.40 (m, 4H), 7.55 (br, 2H), 8.52 (d, 1H, J = 4.9 Hz), 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 dihydrochloride -yl] methyl] piperidine

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) is reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 102 mg (42%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.90 (t, 3H, J = 7.4 Hz), 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 = 7.8 Hz), 2, 97 (broad, 2H), 3.58 (s, 2H), 3.86 (broad, 1H), 3.88 (s, 3H), 3.58 (s, 2H), 3.86 (broad, 1H ), 3.88 (s, 3H), 3.90 (s, 3H), 3.95 (s, 6H), 4.54 (s, 2H), 6.68 (d, 2H, J = 8, 6 Hz), 6.72 (s, 2H), 7.00 (d, 2H, J = 8.6 Hz), 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 = 5.1 Hz).

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

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) is reacted with 5-chloromethyl-2- (3,4, 5-trimethoxyphenyl) pyridine (114 mg) according to the procedure similarly to that described in Example 9. After converting the product to trihydrochloride, the title compound is obtained in the form of a white powder.

Yield 65 mg (21%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.90 (t, 3H, J = 7.3 Hz), 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 = 7.7 Hz), 2, 96 (broad, 2H), 3.58 (s, 2H), 3.75 (broad, 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 = 8.6 Hz), 7.00 (d, 2H, J = 8.6 Hz ), 7.20-7.22 (m, 3H), 7.23 (s, 2H), 7.58-7.66 (m, 3H), 8.59 (br, 1H), 8.60 ( broad, 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 dihydrochloride -yl] methyl] piperidine

4- (4-Butylanilino) -1 - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine (147 mg) is reacted with 4- (3,4,5-trimethoxyphenyl) benzyl chloride (114 mg) according to the procedure similar to that described in example 9. After converting the product to dihydrochloride, the title compound is obtained as a yellow powder.

Yield 82 mg (33%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 0.90 (t, 3H, J = 7.3 Hz), 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 = 7.7 Hz), 2, 98 (d, 2H, J = 10.7 Hz), 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 = 8.8 Hz), 6.75 (s, 2H), 7.00 (d, 2H, J = 8.8 Hz), 7.20 (d, 1H, J = 4.9 Hz), 7.22 (s, 2H), 7.33 (d, 2H, J = 8.2 Hz), 7.47 (d, 2H, J = 8.2 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J = 5, 1 Hz).

Production Example 90

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

4-piperidone hydrochloride monohydrate (922 mg) and 4-picolyl chloride hydrochloride (820 mg) were reacted in accordance with the method described in example 2 to obtain the title compound.

Yield 870 mg (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.46 (t, 4H, J = 5.9 Hz), 2.74 (t, 4H, J = 6.2 Hz), 3.61 (s , 2H), 7.29 (d, 2H, J = 6.2 Hz), 8.55 (dd, 2H, J = 6.2 Hz, 1.1 Hz).

Production Example 91

Synthesis of 1- (4-picolyl) -4- (4-picolylamino) piperidine tetrahydrochloride

1- (4-Picolyl) -4-piperidone (870 mg) was reacted with 4-picolylamine (497 mg) according to the procedure similar to that described in Production Example 37. The target compound was obtained as pale brown tetrahydrochloride.

Yield 363 mg (19%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) δ: 1.37-1.51 (m, 2H), 1.82-1.90 (m, 2H), 2.04 (dt, 2H, J = 11.6 Hz, 2.7 Hz), 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).

Production Example 92

Synthesis of 4- (p-anisidino) -1- (tert-butoxycarbonyl) piperidine

1- (tert-Butoxycarbonyl) -4-piperidone (116 g) was reacted with p-anisidine (68.3 g) according to the procedure similar to that described in Production Example 37 to afford the title compound.

Yield 125 g (74%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.0 Hz), 6.77 (d, 2H, J = 9.0 Hz).

Production Example 93

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzoic acid (577 mg) according to the procedure similar to that described in example 1, obtaining specified in the connection header.

Yield 416 mg (36%).

Production Example 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 (416 mg) in ethyl acetate (5 ml) was added 4 M solution of hydrogen chloride in ethyl acetate (5 ml). The mixture was stirred at room temperature for 4 hours, the resulting precipitates were filtered, washed with ethyl acetate using a funnel, and dried to obtain the title compound.

Yield 315 mg (85%).

Examples 64-66

These compounds are prepared by reacting 4- [N- (4-methoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzoyl] amino] piperidine hydrochloride with the chloride derivatives obtained in Production Examples 3, 42 and 48. Obtained the free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 64

68% 1.53-1.55 (m, 2H), 1.89 (d, 2H, J = 12.0 Hz), 2.23 (t, 2H, J = 12.0 Hz), 2.91 (d , 2H, J = 11.0 Hz), 3.51 (s, 2H), 3.70 (s, 3H), 3.84 (s, 3H), 3.87 (s, 9H), 3.92 (s, 6H), 4.78 (broad, 1H), 6.54 (s, 2H), 6.72 (d, 2H, J = 8.5 Hz), 6.94 (d, 2H, J = 8.5 Hz), 7.13-7.20 (m, 4H), 7.18 (s, 2H), 7.32 (d, 1H, J = 5.3 Hz), 7.45 (s, 1H), 8.19 (d, 1H, J = 4.9 Hz). 65

52% 1.66-1.89 (m, 4H), 2.05-2.17 (m, 2H), 2.97 (d, 2H, J = 10.3 Hz), 3.43-3.60 ( m, 1H), 3.57 (s, 2H), 3.86 (s, 3H), 3.87 (s, 6H), 3.87 (s, 6H), 3.91 (s, 6H), 4.42 (s, 2H), 6.63 (s, 2H), 6.72-6.79 (m, 6H), 7.64 (s, 1H), 7.78 (broad, 1H), 8 46 (d, 2H, J = 1.6 Hz), 8.59 (d, 1H, J = 2.4 Hz), 8.68 (d, 1H, J = 2.2 Hz). 66

75% 1.42-1.58 (m, 2H), 1.85-1.92 (m, 2H), 2.14-2.23 (m, 2H), 2.93-3.03 (m, 2H) ), 3.56 (s, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.79 (broad, 1H), 6.54 (s, 2H), 6.70 (d, 2H, J = 8.9 Hz), 6.74 (s, 2H), 6 93 (d, 2H, J = 8.9 Hz), 7.17-7.23 (m, 3H), 7.31-7.43 (m, 5H).

Production 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-Anisidino) -1- (tert-butoxycarbonyl) piperidine (2.21 g) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (2.12 g) according to the procedure, similar to that described in example 9, getting mentioned in the title compound.

Yield 3.76 g (93%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.4 Hz), 6.79 (d, 2H, J = 9 8 Hz), 7.14-7.19 (m, 3H), 7.56 (s, 1H), 8.55 (d, 1H, J = 5.1 Hz).

Production 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 (3.76 g ) are processed according to a procedure similar to that described in Production Example 94 to give the title compound.

Yield 3.77 g (theoretical yield).

Production 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-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example obtain 9, obtaining the title compound as a yellow amorphous substance.

Yield 159 mg (14%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 2.1 Hz).

Production 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 (159 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a yellow powder.

Yield 142 mg (94%).

Production Example 99

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) and 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) are processed according to the procedure similar to that described in example 9, obtaining specified in the title compound as a yellow amorphous substance.

Yield 1.12 g (90%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.5 Hz, 3.5 Hz), 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).

Production 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 (1.12 g) is treated in a similar manner to that described in Production Example 94, obtaining the title compound as a yellow powder.

Yield 980 mg (99%).

Examples 67-71

These compounds are prepared by reacting the amines obtained in Production Examples 96, 98 and 100 with the chloride derivatives obtained in Production Examples 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 67

62% 1.60-1.92 (m, 4H), 2.08-2.22 (m, 2H), 2.92-3.06 (m, 2H), 3.54-3.64 (m, 3H) ), 3.73 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 12H), 4.43 (s, 2H), 6.70 -6.81 (m, 6H), 7.12-7.17 (m, 3H), 7.56 (s, 1H), 7.76 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8.53 (d, 1H, J = 5.1 Hz), 8.70 (s, 1H). 68

54% 1.65-1.79 (m, 2H), 1.81-1.90 (m, 2H), 2.04-2.18 (m, 2H), 2.94-3.06 (m, 2H) ), 3.52-3.66 (m, 3H), 3.72 (s, 3H), 3.89 (s, 6H), 3.92 (s, 6H), 3.93 (s, 6H) 4.44 (s, 2H), 6.70-6.80 (m, 6H), 7.13-7.17 (m, 3H), 7.24-7.50 (m, 4H), 7 55 (s, 1H); 8.53 (d, 1H, J = 4.9 Hz). 69

52% 1.66-1.89 (m, 4H), 2.05-2.17 (m, 2H), 2.97 (d, 2H, J = 10.3 Hz), 3.43-3.60 ( m, 1H), 3.57 (s, 2H), 3.86 (s, 3H), 3.87 (s, 6H), 3.87 (s, 6H), 3.91 (s, 6H), 4.42 (s, 2H), 6.63 (s, 2H), 6.72-6.79 (m, 6H), 7.64 (s, 1H), 7.78 (broad, 1H), 8 46 (d, 2H, J = 1.6 Hz), 8.59 (d, 1H, J = 2.4 Hz), 8.68 (d, 1H, J = 2.2 Hz). 70

69% 1.55-1.97 (m, 4H), 2.06-2.21 (m, 2H), 2.92-3.07 (m, 2H), 3.53-3.68 (m, 3H) ), 3.72 (s, 3H), 3.87 (s, 3H), 3.89 (s, 6H), 3.89 (s, 3H), 3.94 (s, 3H), 4.46 (s, 2H), 6.69 (s, 2H), 6.73-6.82 (m, 6H), 7.22-7.29 (m, 1H), 7.32 (t, 1H, J = 7.4 Hz), 7.36 (d, 1H, J = 7.8 Hz), 7.41 (s, 1H), 7.79 (br, 1H), 8.48 (s, 1H), 8.71 (broad, 1H). 71

75% 1.69-1.89 (m, 4H), 2.06-2.15 (m, 2H), 2.96-3.04 (m, 2H), 3.56-3.66 (m, 1H ), 3.57 (s, 2H), 3.72 (s, 3H), 3.87 (s, 3H), 3.89 (s, 9H), 3.92 (s, 6H), 3.92 (s, 6H), 4.46 (s, 2H), 6.70 (s, 2H), 6.71-6.79 (m, 6H), 7.23-7.47 (m, 8H).

Production Example 101

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

1- (tert-Butoxycarbonyl) -4-piperidinone (5.00 g) was reacted with p-phenytidine (3.28 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a brown powder.

Yield 7.00 g (91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21-1.31 (m, 2H), 1.37 (t, 3H, J = 7.0 Hz), 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 = 7.0 Hz), 3.99-4.10 (m, 2H), 6.57 (d, 2H, J = 8.8 Hz), 6.77 (d, 2H, J = 9.0 Hz) .

Production 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 (641 mg) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure, similarly described in Example 9 to afford the title compound as a yellow amorphous substance.

Yield 2.08 g (94%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (t, 3H, J = 7.9 Hz), 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 = 9.2 Hz), 6.78 ( d, 2H, J = 9.6 Hz), 7.14-7.18 (m, 3H), 7.55 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz).

Production 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 (1.08 g ) are processed according to a procedure similar to that described in Production Example 94 to afford the title compound as a pale yellow powder.

Yield 1.01 g (98%).

Production 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 (641 mg) was reacted with 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure, similarly described in Example 9 to afford the title compound as a yellow amorphous substance.

Yield 452 mg (39%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (t, 3H, J = 6.8 Hz), 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 = 7.0 Hz), 4.10-4.25 (m, 2H), 4.40 (s, 2H), 6.66 (s , 2H), 6.77 (d, 2H, J = 9.2 Hz), 6.81 (d, 2H, J = 9.2 Hz), 7.67 (s, 1H), 8.49 (d , 1H, J = 2.0 Hz), 8.62 (d, 1H, J = 2.1 Hz).

Production 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 (452 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 380 mg (88%).

Production 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 (641 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9, receiving the title compound as a pale yellow amorphous substance.

Yield 1.06 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (t, 3H, J = 7.0 Hz), 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 = 7.0 Hz), 4.10-4.29 (m, 2H), 4.41 (s, 2H), 6.71 ( s, 2H), 6.76 (s, 4H), 7.26 (d, 1H, J = 7.9 Hz), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz) 7.38 (d, 1H, J = 7.6 Hz); 7.42 (s, 1H).

Production 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 (1.06 g) was processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 913 mg (97%).

Examples 72-79

These compounds are prepared by reacting the amines obtained in Production Examples 103, 105 and 107 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 72

49% 1.36 (t, 3H, J = 7.1 Hz), 1.68-1.94 (m, 4H), 2.10-2.24 (m, 2H), 2.93-3.04 ( m, 2H), 3.54-3.65 (m, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s 6H), 4.45 (s, 2H), 6.72 (d, 2H, J = 9.2 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.15 (s , 2H), 7.17 (d, 1H, J = 6.1 Hz), 7.20 (dd, 1H, J = 4.9 Hz, 1.0 Hz), 7.23 (s, 2H), 7.57 (s, 1H), 7.61 (br, 1H), 8.54 (d, 1H, J = 5.2 Hz), 8.59 (d, 1H, J = 4.9 Hz). 73

63% 1.36 (t, 3H, J = 7.0 Hz), 1.56-1.74 (m, 2H), 1.80-1.90 (m, 2H), 2.07-2.19 ( m, 2H), 2.92-3.02 (m, 2H), 3.58 (s, 2H), 3.88-3.95 (m, 2H), 3.89 (s, 3H), 3 93 (s, 12H), 4.43 (s, 2H), 6.69-6.79 (m, 6H), 7.12-7.17 (m, 3H), 7.55 (s, 1H ), 7.76 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8.53 (d, 1H, J = 5.1 Hz), 8.69 (s, 1H ) 74

65% 1.36 (t, 3H, J = 7.0 Hz), 1.58-1.78 (m, 2H), 1.80-1.89 (m, 2H), 2.04-2.16 ( m, 2H), 2.95-3.05 (m, 2H), 3.52-3.66 (m, 1H), 3.57 (s, 1H), 3.85-3.97 (m, 2H), 3.89 (s, 6H), 3.92 (s, 6H), 3.93 (s, 6H), 4.44 (s, 2H), 6.67-6.80 (m, 6H) ), 7.13-7.18 (m, 3H), 7.25-7.31 (m, 1H), 7.37 (dd, 1H, J = 7.6 Hz, 7.6 Hz), 7 41-7.48 (m, 2H); 7.55 (s, 1H); 8.53 (d, 1H; J = 4.9 Hz). 75

42% 1.36 (t, 3H, J = 7.0 Hz), 1.74-2.34 (m, 6H), 2.96-3.10 (m, 2H), 3.47-3.73 ( m, 3H), 3.87-3.98 (m, 2H), 3.88 (s, 3H), 3.90 (s, 9H), 3.97 (s, 6H), 4.44 (s , 2H), 6.65 (s, 2H), 6.74-6.82 (m, 4H), 7.18-7.32 (m, 4H), 7.67 (s, 1H), 8, 49 (d, 1H, J = 1.6 Hz), 8.57-8.65 (m, 2H). 76

43% 1.36 (t, 3H, J = 6.8 Hz), 1.63-1.96 (m, 4H), 2.00-2.26 (m, 2H), 2.92-3.03 ( m, 2H), 3.44-3.66 (m, 3H), 3.86-3.96 (m, 2H), 3.88 (s, 3H), 3.89 (s, 6H), 3 90 (s, 3H), 3.93 (s, 6H), 4.44 (s, 2H), 6.65 (s, 2H), 6.72-6.80 (m, 6H), 7, 67 (s, 1H), 7.77 (br, 1H), 8.47-8.53 (m, 2H), 8.62 (d, 1H, J = 1.9 Hz), 8.70 (s , 1H). 77

82% 1.35 (t, 3H, J = 6.8 Hz), 1.70-1.82 (m, 2H), 1.84-1.92 (m, 2H), 2.10-2.19 ( m, 2H), 2.92-3.00 (m, 2H), 3.52-3.65 (m, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3 90 (s, 3H), 3.93 (q, 2H, J = 7.1 Hz), 3.96 (s, 6H), 4.47 (s, 2H), 6.70 (s, 2H) 6.73 (d, 2H, J = 9.3 Hz), 6.77 (d, 2H, J = 9.3 Hz), 7.18-7.28 (m, 4H), 7.33 ( dd, 1H, J = 7.3 Hz, 7.3 Hz), 7.37 (d, 1H, J = 7.6 Hz), 7.43 (s, 1H), 7.59 (s, 1H) 8.58 (d, 1H, J = 4.9 Hz). 78

61% 1.35 (t, 3H, J = 6.9 Hz), 1.58-1.80 (m, 2H), 1.82-1.91 (m, 2H), 2.09-2.18 ( m, 2H), 2.93-3.20 (m, 2H), 3.56-3.65 (m, 1H), 3.58 (s, 2H), 3.87 (s, 3H), 3 89 (s, 6H), 3.89 (s, 3H), 3.91-3.94 (m, 2H), 3.93 (s, 6H), 4.45 (s, 2H), 6, 69 (s, 2H), 6.71-6.78 (m, 6H), 7.23-7.28 (m, 1H), 7.32 (t, 1H, J = 7.5 Hz), 7 36 (d, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.77 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8 69 (d, 1H, J = 1.8 Hz). 79

73% 1.35 (t, 3H, J = 6.8 Hz), 1.68-1.80 (m, 2H), 1.81-1.89 (m, 2H), 2.06-2.14 ( m, 2H), 2.96-3.03 (m, 2H), 3.57 (s, 2H), 3.57-3.65 (m, 1H), 3.87 (s, 3H), 3 89 (s, 9H), 3.91-3.96 (m, 2H), 3.92 (s, 6H), 4.46 (s, 2H), 6.69-6.79 (m, 9H) ), 7.23-7.47 (m, 7H).

Production Example 108

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

1- (tert-Butoxycarbonyl) -4-piperidinone (5.00 g) was reacted with 4-butoxyaniline (3.95 g) according to the method described in Production Example 37 to afford the title compound as a brown powder.

Yield 6.91 g (83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.96 (t, 3H, J = 7.2 Hz), 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 = 6.6 Hz), 3.96-4.12 (m, 2H), 6.57 (d , 2H, J = 9.0 Hz); 6.77 (d, 2H, J = 8.8 Hz).

Production 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 (696 mg) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure, similarly described in Example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 980 mg (81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.95 (t, 3H, J = 7.4 Hz), 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 = 9.4 Hz), 6.78 (d, 2H, J = 9.4 Hz), 7.14-7.18 ( m, 3H), 7.56 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz).

Production 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 (980 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a yellow powder.

Yield 926 mg (99%).

Production 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 (697 mg) was reacted with 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure, similarly described in Example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 485 mg (40%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.95 (t, 3H, J = 7.4 Hz), 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 = 6.6 Hz), 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 = 9.2 Hz), 6.81 (d, 2H, J = 9.2 Hz), 6.81 (d, 2H, J = 9.4 Hz), 7.67 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8.62 (d, 1H, J = 2.2 Hz).

Production 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 (485 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 456 mg (98%).

Production 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 (697 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9 obtaining the title compound as a pale yellow amorphous substance.

Yield 1.17 g (97%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.95 (t, 3H, J = 7.3 Hz), 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 = 6.6 Hz), 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 = 8.0 Hz), 7.33 (t, 1H , J = 7.6 Hz), 7.38 (d, 1H, J = 7.3 Hz), 7.42 (s, 1H).

Production Example 114

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

1- (tert-Butoxycarbonyl) -4- [N- (4-butoxyphenyl) -N- [3- (3,4,5-trimethoxyphenyl) benzyl] amino] piperidine (1.17 g) was treated in a similar manner to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 1.02 g (98%).

Examples 80-87

These compounds are prepared by reacting the amines obtained in Production Examples 110, 112 and 114 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 80

63% 0.95 (t, 3H, J = 7.3 Hz), 1.40-1.51 (m, 2H), 1.66-1, 79 (m, 2H), 1.83-1.92 ( m, 2H), 2.10-2.21 (m, 2H), 2.92-3.02 (m, 2H), 3.53-3.63 (m, 3H), 3.84-3, 90 (m, 2H), 3.89 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 6.72 (d, 2H, J = 9.3 Hz), 6.77 (d, 2H, J = 9.3 Hz), 7.15 (s, 2H), 7.17 (d, 1H, J = 5.1 Hz), 7.20 (d, 1H, J = 6.1 Hz), 7.22 (s, 2H), 7.57 (s, 1H), 7.59 (s, 1H), 8.54 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 5.1 Hz). 81

44% 0.95 (t, 3H, J = 7.4 Hz), 1.42-1.51 (m, 2H), 1.67-1.76 (m, 4H), 1.80-1.91 ( m, 2H), 2.08-2.20 (m, 2H), 2.92-3.03 (m, 2H), 3.84-3.96 (m, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 12H), 4.43 (s, 2H), 6.69-6.79 (m, 6H), 7.14 (s, 2H) ), 7.16 (d, 1H, J = 5.2 Hz), 7.55 (s, 1H), 7.76 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz ), 8.53 (d, 1H, J = 5.0 Hz), 8.69 (s, 1H). 82

53% 0.95 (t, 3H, J = 7.2 Hz), 1.40-1.51 (m, 2H), 1.65-1.78 (m, 4H), 1.81-1.89 ( m, 2H), 2.05-2.18 (m, 2H), 3.05-3.06 (m, 2H), 3.54-3.65 (m, 3H), 3.84-3, 96 (m, 20H), 4.44 (s, 2H), 6.70 (d, 2H, J = 9.2 Hz), 6.74-6.80 (m, 4H), 7.11-7 19 (m, 3H), 7.22-7.32 (m, 1H), 7.34-7.50 (m, 3H), 7.55 (s, 1H), 8.53 (d, 1H) , J = 5.1 Hz). 83

42% 0.95 (t, 3H, 7.4 Hz), 1.40-1.51 (m, 2H), 1.67-1.86 (m, 6H), 2.03-2.30 (m, 2H), 2.92-3.06 (m, 2H), 3.46-3.56 (m, 1H), 3.60 (s, 2H), 3.84-3.91 (m, 2H) 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.44 (s, 2H), 6.65 ( s, 2H), 6.74-6.81 (m, 4H), 7.20 (d, 1H, J = 4.9 Hz), 7.25 (s, 2H), 7.67 (br, 2H ), 8.50 (d, 1H, J = 1.6 Hz), 8.60 (d, 1H, J = 5.6 Hz). 84

36% 0.95 (t, 3H, J = 7.4 Hz), 1.40-1.51 (m, 2H), 1.66-1.79 (m, 4H), 1.82-1.92 ( m, 2H), 2.00-2.22 (m, 2H), 2.83-3.06 (m, 2H), 3.44-3.67 (m, 3H), 3.82-3, 97 (m, 2H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.44 (s, 2H ), 6.65 (s, 2H), 6.72-6.80 (m, 6H), 7.67 (s, 1H), 7.76 (br, 1H), 8.47-8.53 ( m, 2H), 8.62 (d, 1H, J = 2.2 Hz), 8.70 (s, 1H). 85

72% 0.95 (t, 3H, J = 7.3 Hz), 1.40-1.51 (m, 2H), 1.66-1.82 (m, 4H), 1.84-1.92 ( m, 2H), 2.10-2.20 (m, 2H), 2.92-3.00 (m, 2H), 3.53-3.66 (m, 3H), 3.83-3, 92 (m, 2H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.47 (s, 2H ), 6.67 (s, 2H), 6.73 (d, 2H, J = 9.2 Hz), 6.77 (d, 2H, J = 9.5 Hz), 7.18-7.29 (m, 4H), 7.33 (dd, 1H, J = 7.3 Hz, 7.3 Hz), 7.37 (d, 1H, J = 7.6 Hz), 7.43 (s, 1H ), 7.60 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz). 86

24% 0.94 (t, 3H, J = 7.4 Hz), 1.41-1.51 (m, 2H), 1.61-1.80 (m, 4H), 1.82-1.92 ( m, 2H), 2.08-2.19 (m, 2H), 2.92-3.02 (m, 2H), 3.55-3.65 (m, 1H), 3.57 (s, 2H), 3.84-3.91 (m, 2H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.93 (s, 6H ), 4.45 (s, 2H), 6.69 (s, 2H), 6.71-6.78 (m, 4H), 6.75 (s, 2H), 7.23-7.28 ( m, 1H), 7.32 (t, 1H, J = 7.4 Hz), 7.36 (d, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.77 ( s, 1H), 8.49 (d, 1H, J = 1.6 Hz), 8.69 (s, 1H). 87

78% 0.94 (t, 3H, J = 7.3 Hz), 1.40-1.50 (m, 2H), 1.66-1.88 (m, 4H), 1.82-1.89 ( m, 2H), 2.04-2.16 (m, 2H), 2.96-3.03 (m, 2H), 3.55-3.65 (m, 3H), 3.83-3, 90 (m, 2H), 3.87 (s, 3H), 3.89 (s, 9H), 3.92 (s, 6H), 4.46 (s, 2H), 6.69-6.79 (m, 9H); 7.23-7.48 (m, 7H).

Production Example 115

Synthesis of 4- (m-anisidino) -1- (tert-butoxycarbonyl) piperidine

1- (tert-Butoxycarbonyl) -4-piperidinone (4.78 g) was reacted with m-anisidine (2.96 g) in accordance with the method described in Production Example 37 to afford the title compound.

Yield 4.83 g (66%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.20-1.39 (m, 2H), 1.44 (s, 9H), 1.99-2.05 (m, 2H), 2, 89 (dt, 2H, J = 13.5 Hz, 2.2 Hz), 3.33-3.44 (m, 1H), 3.75 (s, 3H), 3.96-4.07 (m , 2H), 6.14 (t, 1H, J = 2.2 Hz), 6.18-6.29 (m, 2H), 7.05 (t, 1H, J = 8.1 Hz).

Production 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-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 789 mg (70%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 2.2 Hz, 2.2 Hz), 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, 1 Hz).

Production 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 (789 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 710 mg (95%).

Production 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-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) is reacted with 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 396 mg (35%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 7.2 Hz ), 6.68 (s, 2H), 7.12 (dd, 1H, J = 8.8 Hz, 8.88 Hz), 7.66 (s, 1H), 8.49 (d, 1H, J = 2.0 Hz), 8.66 (d, 1H, J = 2.2 Hz).

Production 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 (396 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 348 mg (92%).

Production Example 120

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

4- (m-Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9, to obtain the specified in the title compound as a pale yellow amorphous substance.

Yield 1.01 g (90%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.2 Hz , 2.4 Hz), 6.72 (s, 2H), 7.10 (dd, 1H, J = 8.2 Hz, 8.2 Hz), 7.21-7.27 (m, 1H), 7.32-7.43 (m, 3H).

Production 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 (1.01 g) is processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 820 mg (92%).

Examples 88-95

These compounds are prepared by reacting the amines obtained in Production Examples 117, 119 and 121 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 88

63% 1.70-1.82 (m, 2H), 1.83-1.90 (m, 2H), 2.14-2.23 (m, 2H), 2.94-3.01 (m, 2H) ), 3.57 (s, 2H), 3.73 (s, 3H), 3.76-3.88 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H) 3.93 (s, 6H), 3.96 (s, 6H), 4.53 (s, 2H), 6.26-6.35 (m, 3H), 7.11 (dd, 1H, J = 8.3 Hz, 8.3 Hz), 7.12-7.14 (m, 1H), 7.15 (s, 2H), 7.20 (d, 1H, J = 5.1 Hz), 7.22 (s, 2H), 7.55 (s, 1H), 7.58 (s, 1H), 8.55 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H , J = 4.9 Hz). 89

72% 1.67-1.90 (m, 4H), 2.13-2.22 (m, 2H), 2.94-3.04 (m, 2H), 3.59 (s, 2H), 3, 74 (s, 3H), 3.77-3.87 (m, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.52 (s, 2H), 6.27 (dd, 1H, J = 2.4 Hz, 2.4 Hz), 6.29-6.34 (m, 2H), 6 75 (s, 2H), 7.08-7.17 (m, 4H), 7.54 (s, 1H), 7.75 (s, 1H), 8.50 (d, 1H, J = 1 8 Hz), 8.54 (d, 1H, J = 5.1 Hz), 8.69 (d, 1H, J = 2.0 Hz). 90

60% 1.68-1.90 (m, 4H), 2.09-2.19 (m, 2H), 2.97-3.06 (m, 2H), 3.58 (s, 2H), 3, 73 (s, 3H), 3.76-3.87 (m, 1H), 3.89 (s, 6H), 3.92 (s, 6H), 3.92 (s, 6H), 4.52 (s, 2H), 6.25-6.35 (m, 3H), 6.76 (s, 2H), 6.78-7.17 (m, 4H), 7.25-7.32 (m , 1H), 7.37 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.41-7.47 (m, 2H), 7.54 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz). 91

fifty% 1.80-1.93 (m, 4H), 2.13-2.32 (m, 2H), 2.87-3.10 (m, 2H), 3.60 (s, 1H), 3, 69-3.85 (m, 1H), 3.73 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.57 (s, 2H), 6.29-6.34 (m, 2H), 6.37 (dd, 1H, J = 8.2 Hz, 8.1 Hz), 6 67 (s, 2H), 7.11 (dd, 1H, J = 8.6 Hz, 8.6 Hz), 7.20-7.28 (m, 3H), 7.58-7.72 ( m, 1H), 7.68 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.60 (d, 1H, J = 4.7 Hz), 8.65 ( d, 1H, J = 2.0 Hz). 92

35% 1.70-1.90 (m, 4H), 2.12-2.25 (m, 2H), 2.95-3.03 (m, 2H), 3.59 (s, 2H), 3, 72-3.97 (m, 1H), 3.73 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.54 (s, 2H), 6.25-6.38 (m, 2H), 6.36 (d, 1H, J = 8.4 Hz, 8.4 Hz), 6 67 (s, 2H), 6.75 (s, 2H), 7.11 (dd, 1H, J = 8.4 Hz), 7.66 (s, 1H), 8.49 (s, 1H) 8.50 (d, 1H, J = 1.8 Hz), 8.64 (d, 1H, J = 2.0 Hz), 8.70 (d, 1H, J = 1.9 Hz). 93

86% 1.73-1.93 (m, 4H), 2.13-2.23 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H), 3, 73 (s, 3H), 3.77-3.87 (m, 1H), 3.88 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.56 (s, 2H), 6.27 (dd, 1H, J = 8.0 Hz, 2.2 Hz), 6.31 (dd, 1H, J = 2.2 Hz , 2.2 Hz), 6.36 (dd, 1H, J = 8.2 Hz, 2.2 Hz), 6.71 (s, 2H), 7.09 (dd, 1H, J = 8.1 Hz, 8.1 Hz), 7.18-7.28 (m, 4H), 7.34 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.42 (s, 1H), 7.59 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz). 94

56% 1.72-1.92 (m, 4H), 2.10-2.23 (m, 2H), 2.92-3.60 (m, 2H), 3.59 (s, 2H), 3, 72 (s, 3H), 3.77-3.89 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.93 (s, 6H), 4.55 (s, 2H), 6.27 (dd, 1H, J = 8.0 Hz, 2.2 Hz), 6.31 (dd, 1H, J = 2.1 Hz, 2.1 Hz), 6, 36 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 6.70 (s, 2H), 6.75 (s, 2H), 7.09 (dd, 1H, J = 8.2 Hz, 8.2 Hz), 7.22 (d, 1H, J = 7.4 Hz), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.38 (d , 1H, J = 7.8 Hz), 7.40 (s, 1H), 7.77 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.69 (d , 1H, J = 1.8 Hz). 95

77% 1.66-1.89 (m, 4H), 2.08-2.18 (m, 2H), 2.95-3.05 (m, 2H), 3.58 (s, 2H), 3, 72 (s, 3H), 3.75-3.84 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.92 (s, 6H), 4.55 (s, 2H), 6.26 (dd, 1H, J = 8.0 Hz, 2.2 Hz), 6.30 (dd, 1H, 1 = 2.2 Hz , 2.2 Hz), 6.36 (dd, 1H, J = 8.3 Hz, 2.2 Hz), 6.70 (s, 2H), 6.76 (s, 2H), 7.08 ( dd, 1H, J = 8.3 Hz, 8.3 Hz), 7.22 (d, 1H, J = 7.3 Hz), 7.27-7.47 (m, 7H).

Production Example 122

Synthesis of 4- (o-anisidino) -1- (tert-butoxycarbonyl) piperidine

1- (tert-Butoxycarbonyl) -4-piperidone (4.78 g) was reacted with o- anisidine (2.96 g) according to the procedure similar to that described in Production Example 37 to afford the title compound.

Yield 2.61 g (36%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Production 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- Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 763 mg (68%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 7.6 Hz, 3.7 Hz), 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 = 7.6 Hz, 7.6 Hz , 1.2 Hz), 6.87 (dd, 1H, J = 8.5 Hz, 1.0 Hz), 7.00-7.06 (m, 2H), 7.14 (s, 2H), 7.20 (dd, 1H, J = 4.9 Hz, 1.0 Hz), 7.61 (s, 1H), 8.49 (d, 1H, J = 4.9 Hz).

Production 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 (763 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 701 mg (97%).

Production 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- Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example 9 to afford the title compound as a pale yellow amorphous substance.

Yield 353 mg (31%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 7.6 Hz, 7.6 Hz, 1.2 Hz), 6.84 (dd, 1H, J = 7.0 Hz, 1.2 Hz), 6.97-7.06 (m, 2H), 7.68 (dd, 1H, J = 1.3 Hz, 1.3 Hz), 8.49 (d, 1H, J = 2.0 Hz), 8.56 (d, 1H, J = 2.2 Hz).

Production 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 (353 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 312 mg (93%).

Production Example 127

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

4- ( o- Anisidino) -1- (tert-butoxycarbonyl) piperidine (613 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9, obtaining the specified in the title compound as a pale yellow amorphous substance.

Yield 1.12 g (100%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.1 Hz, 3.3 Hz), 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 = 7.3 Hz), 6.85 (d, 1H, J = 7.9 Hz), 6.96-7.03 (m, 2H), 7.24-7.34 (m, 3H), 7, 43 (s, 1H).

Production 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 (1.12 g) was treated in a similar manner to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 987 mg (99%).

Examples 96-101

These compounds are prepared by reacting the amines obtained in Production Examples 124, 126 and 128 with the chloride derivatives obtained in Production Examples 3 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 96

73% 1.62-1.74 (m, 2H), 1.82-1.90 (m, 2H), 1.98-2.08 (m, 2H), 2.86-2.94 (m, 2H) ), 3.13-3.22 (m, 1H), 3.52 (s, 2H), 3.85 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H) 3.94 (s, 6H), 3.96 (s, 6H), 4.40 (s, 2H), 6.80 (ddd, 1H, J = 7.6 Hz, 7.6 Hz, 1, 2 Hz), 6.86 (dd, 1H, J = 8.1 Hz, 1.2 Hz), 6.98-7.05 (m, 1H), 7.14 (s, 2H), 7.18 (dd, 1H, J = 4.9 Hz, 1.2 Hz), 7.20-7.24 (m, 1H), 7.22 (s, 2H), 7.58 (s, 1H), 7 62 (s, 1H), 8.49 (d, 1H, J = 4.9 Hz), 8.57 (d, 1H, J = 5.2 Hz). 97

55% 1.60-1.73 (m, 4H), 1.82-1.93 (m, 2H), 1.98-2.07 (m, 2H), 2.87-2.97 (m, 2H) ), 3.12-3.22 (m, 1H), 3.54 (s, 2H), 3.85 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H) 3.93 (s, 6H), 3.94 (s, 6H), 4.39 (s, 2H), 6.75 (s, 2H), 6.79 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 6.86 (d, 1H, J = 7.8 Hz), 6.97-7.05 (m, 2H), 7.13 (s, 2H), 7.20 ( d, 1H, J = 4.7 Hz), 7.61 (s, 1H), 7.75 (s, 1H), 8.46-8.50 (m, 2H), 8.68 (d, 1H , J = 2.0 Hz). 98

29% 1.64-1.82 (m, 2H), 1.84-1.97 (m, 2H), 2.00-2.15 (m, 2H), 2.84-3.01 (m, 2H) ), 3.13-3.27 (m, 1H), 3.56 (s, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H) 3.91 (s, 6H), 3.96 (s, 6H), 4.40 (s, 2H), 6.63 (s, 2H), 6.75-6.88 (m, 2H), 6.97-7.04 (m, 2H), 7.19 (d, 1H, J = 4.3 Hz), 7.25 (s, 2H), 7.58-7.73 (m, 2H) 8.50 (d, 1H, J = 1.6 Hz), 8.56 (d, 1H, J = 2.2 Hz), 8.58 (d, 1H, J = 4.9 Hz). 99

thirty% 1.62-1.75 (m, 2H), 1.83-1.94 (m, 2H), 1.95-2.11 (m, 2H), 2.84-3.01 (m, 2H) ), 3.12-3.23 (m, 1H), 3.55 (s, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H) 3.90 (s, 6H), 3.93 (s, 6H), 4.39 (s, 2H), 6.63 (s, 2H), 6.70-6.86 (m, 4H), 6.94-7.06 (m, 2H), 7.68 (s, 1H), 7.76 (s, 1H), 8.47 (d, 1H, J = 1.7 Hz), 8.49 (d, 1H, J = 1.7 Hz), 8.55 (d, 1H, J = 2.2 Hz), 8.69 (s, 1H). one hundred

67% 1.64-1.79 (m, 2H), 1.85-1.93 (m, 2H), 1.99-2.09 (m, 2H), 2.86-2.95 (m, 2H) ), 3.16-3.26 (m, 1H), 3.52 (s, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H) 3.96 (s, 6H), 4.40 (s, 2H), 6.67 (s, 2H), 6.78 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 6 85 (d, 1H, J = 8.2 Hz), 6.97 (dd, 1H, J = 7.8 Hz, 7.8 Hz), 7.02 (dd, 1H, J = 7.8, 1.6 Hz), 7.17-7.33 (m, 6H), 7.44 (s, 1H), 7.59 (s, 1H), 8.57 (d, 1H, J = 5.1 Hz). 101

55% 1.62-1.77 (m, 2H), 1.82-1.94 (m, 2H), 1.98-2.08 (m, 2H), 2.86-2.96 (m, 2H) ), 3.16-3.26 (m, 1H), 3.54 (s, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 3.90 (s, 9H) 3.93 (s, 6H), 4.39 (s, 2H), 6.66 (s, 2H), 6.73-6.80 (m, 3H), 6.84 (d, 1H, J = 7.8 Hz), 6.97 (dd, 1H, J = 7.8 Hz, 7.8 Hz), 7.01 (d, 1H, J = 7.8 Hz), 7.23-7, 32 (m, 3H), 7.43 (s, 1H), 7.77 (s, 1H), 8.47 (d, 1H, J = 1.4 Hz), 8.68 (d, 1H, J = 1.8 Hz).

Production Example 129

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

1- (tert-Butoxycarbonyl) -4-piperidinone (4.78 g) was reacted with 2,3-dimethoxyaniline (3.68 g) according to the method described in Production Example 37 to afford the title compound.

Yield 3.18 g (39%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29-1.42 (m, 2H), 1.45 (s, 9H), 1.97-2.03 (m, 2H), 2, 92 (dt, 2H, J = 13.5 Hz, 2.2 Hz), 3.38 (dt, 1H, J = 13.8 Hz, 4.1 Hz), 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 = 8.4 Hz).

Production 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 (673 mg) was reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to a procedure similar to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 613 mg (52%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.8 Hz, 3.6 Hz), 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 = 8.3 Hz), 7.14 (s, 2H), 7.17 (dd, 1H, J = 5.1 Hz, 1.2 Hz), 7.62 (s, 1H), 8 50 (d, 1H, J = 5.1 Hz).

Production Example 131

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

1- (tert-butoxycarbonyl) -4- [N- (2,3-dimethoxyphenyl) -N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (613 mg ) are processed according to a procedure similar to that described in Production Example 94, to give the title compound as a light yellow powder.

Yield 512 mg (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

4- [N- (2,3-Dimethoxyphenyl) -N - [[2- (3,4,5-trimethoxyphenyl) pyridin-4-yl] methyl] piperidine dihydrochloride (113 mg) is reacted with 4-chloromethyl-2 - (3,4,5-trimethoxyphenyl) pyridine (59 mg) according to the procedure similar to that described in example 2. After converting the product to hydrochloride, the title compound is obtained in the form of a light yellow powder.

Yield 21 mg (12%).

¹ H-NMR (400 MHz, defined 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 = 8.0 Hz), 6.62 (d, 1H, J = 8.2 Hz), 6.85 (dd, 1H, J = 8.4 Hz, 8.4 Hz), 7.11-7.29 (m, 6H), 7.59 (s, 1H), 7 63 (s, 1H), 8.50 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 4.9 Hz).

Production Example 132

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4- (fluoromethoxy) aniline (4.23 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as white powder.

Yield 5.22 g (60%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz).

Production 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 (721 mg) is reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) a procedure similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 543 mg (44%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz), 7.07 (d, 2H, J = 8.6 Hz), 7.12 ( dd, 1H, J = 5.2 Hz, 1.3 Hz), 7.15 (s, 2H), 7.52 (s, 1H), 8.58 (d, 1H, J = 5.2 Hz) .

Production 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 (543 mg) are treated according to a procedure similar to that described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 481 mg (93%).

Production 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 (721 mg) 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) is treated according to the procedure, similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 201 mg (16%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.4 Hz), 7.06 (d, 2H, J = 8 4 Hz), 7.64 (t, 1H, J = 2.1 Hz), 8.49 (d, 1H, J = 2.2 Hz), 8.68 (d, 1H, J = 2.1 Hz).

Production 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] benzyl] amino] piperidine (201 mg) are treated according to a procedure similar to that described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 185 mg (96%).

Production 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 (721 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to a procedure similar to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 1.06 g (86%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.3 Hz), 6.70 (s, 2H), 7.04 (d, 2H, J = 8 5 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.34-7.44 (m, 3H).

Production 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 (1.06 g) was processed according to the procedure similar to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 795 mg (84%).

Examples 103-110

These compounds are prepared by reacting the amines obtained in Production Examples 134, 136 and 138 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 103

70% 1.71-1.90 (m, 4H), 2.15-2.23 (m, 2H), 2.95-3.02 (m, 2H), 3.58 (s, 2H), 3, 76-3.85 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.96 (s, 6H), 4.54 (s, 2H), 6.66 (d, 2H, J = 9.3 Hz), 7.05 (d, 2H, J = 8.5 Hz), 7.13 (dd, 1H, J = 5, 1 Hz, 1.2 Hz), 7.14 (s, 2H), 7.20 (dd, 1H, J = 4.9 Hz, 1.2 Hz), 7.22 (s, 2H), 7, 53 (s, 1H), 7.59 (s, 1H), 8.57 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 5.2 Hz). 104

48% 1.68-1.92 (m, 4H), 2.13-2.25 (m, 2H), 2.95-3.06 (m, 2H), 3.60 (s, 2H), 3, 75-3.87 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.93 (s, 6H), 4.52 (s, 2H), 6.65 (d, 2H, J = 9.4 Hz), 6.75 (s, 2H), 7.05 (d, 2H, J = 9.2 Hz), 7.12 (d, 1H, J = 5.1 Hz), 7.14 (s, 2H), 7.52 (s, 1H), 7.76 (s, 1H), 8.51 (d, 1H, J = 1.8 Hz), 8.57 (d, 1H, J = 5.1 Hz), 8.70 (d, 1H, J = 2.1 Hz). 105

69% 1.70-1.89 (m, 4H), 2.10-2.19 (m, 2H), 2.98-3.08 (m, 2H), 3.59 (s, 2H), 3, 72-3.84 (m, 1H), 3.89 (s, 6H), 3.92 (s, 6H), 3.92 (s, 6H), 4.52 (s, 2H), 6.65 (d, 2H, J = 9.4 Hz), 6.76 (s, 2H), 7.04 (d, 2H, J = 8.6 Hz), 7.11 (d, 1H, J = 5, 1 Hz), 7.14 (s, 2H), 7.25-7.33 (m, 1H), 7.37 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.41 -7.48 (m, 2H), 7.51 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz). 106

41% 1.73-1.93 (m, 4H), 2.12-2.26 (m, 2H), 2.93-3.07 (m, 2H), 3.53-3.65 (m, 2H) ), 3.74-3.84 (m, 1H), 3.88 (s, 9H), 3.90 (s, 3H), 3.96 (s, 6H), 4.58 (s, 2H) 6.66 (s, 2H), 6.69 (d, 2H, J = 9.2 Hz), 7.05 (d, 2H, J = 8.8 Hz), 7.18-7.29 ( m, 3H), 7.59 (br, 1H), 7.64 (s, 1H), 8.49 (s, 1H), 8.60 (d, 1H, J = 5.3 Hz), 8, 67 (d, 1H, J = 2.0 Hz). 107

28% 1.72-1.91 (m, 4H), 2.12-2.28 (m, 2H), 2.94-3.06 (m, 2H), 3.60 (s, 2H), 3, 76-3.82 (m, 1H), 3.88 (s, 9H), 3.90 (s, 3H), 3.93 (s, 6H), 4.56 (s, 2H), 6.65 (s, 2H), 6.69 (d, 2H, J = 9.2 Hz), 6.75 (s, 2H), 7.05 (d, 2H, J = 8.8 Hz), 7.63 (s, 1H), 7.76 (s, 1H), 8.48 (d, 1H, J = 1.8 Hz), 8.51 (d, 1H, J = 1.8 Hz), 8.66 (d, 1H, J = 2.2 Hz), 8.70 (d, 1H, J = 2.2 Hz). 108

78% 1.76-1.91 (m, 4H), 2.14-2.23 (m, 2H), 2.94-3.03 (m, 2H), 3.57 (s, 2H), 3, 75-3.84 (m, 1H), 3.87 (s, 9H), 3.90 (s, 3H), 3.96 (s, 6H), 4.56 (s, 2H), 6.65 -6.72 (m, 4H), 7.03 (d, 2H, J = 8.8 Hz), 7.18-7.24 (m, 4H), 7.33-7.43 (m, 3H ), 7.59 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz). 109

5% 1.72-1.90 (m, 4H), 2.12-2.21 (m, 2H), 2.94-3.03 (m, 2H), 3.59 (s, 2H), 3, 73-3.86 (m, 1H), 3.87 (s, 9H), 3.90 (s, 3H), 3.93 (s, 6H), 4.54 (s, 2H), 6.66 -6.70 (m, 4H), 6.75 (s, 2H), 7.03 (d, 2H, J = 9.0 Hz), 7.21 (d, 1H, J = 7.2 Hz) 7.32-7.41 (m, 3H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.6 Hz), 8.69 (d, 1H, J = 1 , 6 Hz). 110

62% 1.72-1.89 (m, 4H), 2.08-2.20 (m, 2H), 2.97-3.07 (m, 2H), 3.59 (s, 2H), 3, 73-3.83 (m, 1H), 3.87 (s, 9H), 3.89 (s, 3H), 3.92 (s, 6H), 4.55 (s, 2H), 6.67 (d, 2H, J = 9.3 Hz), 6.69 (s, 2H), 6.76 (s, 2H), 7.02 (d, 2H, J = 8.6 Hz), 7.20 (d, 1H, J = 7.6 Hz); 7.25-7.47 (m, 7H).

Production Example 139

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4- (methylthio) aniline (3.33 g) according to the method described in Production Example 37 to afford the title compound as white powder.

Yield 3.80 g (49%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz), 7.21 (d, 2H, J = 8.8 Hz).

Production 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 (644 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure , similarly as described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 671 mg (58%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.0 Hz), 7.11-7.18 (m, 1H ), 7.16 (s, 2H), 7.22 (d, 2H, J = 6.6 Hz), 7.54 (s, 1H), 8.57 (d, 1H, J = 5.1 Hz )

Production 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-trimethoxyphenyl) pyridin-4-yl] methyl] amino] piperidine (671 mg) are treated according to a procedure similar to that described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 602 mg (94%).

Production 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 (645 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure , similarly as described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 312 mg (27%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.0 Hz), 7, 21 (d, 2H, J = 9.0 Hz), 7.64 (s, 1H), 8.48 (d, 1H, J = 2.2 Hz), 8.66 (d, 1H, J = 2 , 1 Hz).

Production 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 (312 mg) are treated according to a procedure similar to that described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 251 mg (84%).

Production 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 - [(4-methylthio) phenyl] amino] piperidine (645 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure, similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 1.10 g (95%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Production 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-trifluoromethoxyphenyl) benzyl] amino] piperidine (1.10 g) is processed according to the procedure similar to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 866 mg (89%).

Examples 111-118

These compounds are prepared by reacting the amines obtained in Production Examples 141, 143 and 145 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 111

40% 1.70-1.90 (m, 4H), 2.14-2.26 (m, 2H), 2.40 (s, 3H), 2.94-3.04 (m, 2H), 3, 58 (s, 2H), 3.76-3.88 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.53 (s, 2H), 6.66 (d, 2H, J = 9.0 Hz), 7.11-7.24 (m, 8H), 7.54 (s, 1H), 7.59 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz). 112

53% 1.66-1.90 (m, 4H), 2.12-2.24 (m, 2H), 2.40 (s, 3H), 2.94-3.05 (m, 2H), 3, 59 (s, 2H), 3.73-3.88 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.51 (s, 2H), 6.65 (d, 2H, J = 8.8 Hz), 6.75 (s, 2H), 7.12 (d, 1H, J = 4.9 Hz), 7.14 (s, 2H), 7.21 (d, 2H, J = 8.8 Hz), 7.53 (s, 1H), 7.76 (s, 1H), 8 50 (d, 1H, J = 1.9 Hz), 6.55 (d, 1H, J = 4.9 Hz), 8.69 (d, 1H, J = 1.4 Hz). 113

53% 1.68-1.89 (m, 4H), 2.10-2.20 (m, 2H), 2.39 (s, 3H), 2.98-3.07 (m, 2H), 3, 58 (s, 2H), 3.75-3.87 (m, 1H), 3.89 (s, 6H), 3.92 (s, 6H), 3.92 (s, 6H), 4.51 (s, 2H), 6.65 (d, 2H, J = 9.0 Hz), 6.76 (s, 2H), 7.11 (d, 1H, J = 5.1 Hz), 7.14 (s, 2H), 7.21 (d, 2H, J = 8.8 Hz), 7.29 (d, 1H, J = 7.4 Hz), 7.37 (dd, 1H, J = 7, 6 Hz, 7.6 Hz), 7.42-7.49 (m, 2H), 7.52 (s, 1H), 8.54 (d, 1H, J = 4.9 Hz). 114

fifty% 1.57-2.00 (m, 4H), 2.12-2.30 (m, 2H), 2.39 (s, 3H), 2.90-3.13 (m, 2H), 3, 50-3.74 (m, 2H), 3.75-3.86 (m, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s, 6H) 3.97 (s, 6H), 4.57 (s, 2H), 6.66 (s, 2H), 6.70 (d, 2H, J = 9.0 Hz), 7.17-7, 30 (m, 5H), 7.66 (br, 2H), 8.48 (s, 1H), 8.58-8.70 (m, 2H). 115

59% 1.68-1.92 (m, 4H), 2.12-2.27 (m, 2H), 2.39 (s, 3H), 2.94-3.08 (m, 2H), 3, 60 (s, 2H), 3.74-3.83 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.55 (s, 2H), 6.66 (s, 2H), 6.69 (d, 2H, J = 8.8 Hz), 6.73-6.80 (m, 2H), 7.20 (d, 2H, J = 8.8 Hz), 7.64 (s, 1H), 7.77 (br, 1H), 8.48 (s, 1H), 8.50 ( s, 1H), 8.65 (s, 1H), 8.71 (s, 1H). 116

85% 1.76-1.93 (m, 4H), 2.14-2.24 (m, 2H), 2.39 (s, 3H), 2.94-3.03 (m, 2H), 3, 57 (s, 2H), 3.76-3.86 (m, 1H), 3.88 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.55 (s, 2H), 6.67-6.73 (m, 4H), 7.18-7.29 (m, 6H), 7.34 (dd, 1H, J = 7.6 Hz, 7.6 Hz), 7.37-7.44 (m, 2H), 7.59 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz). 117

53% 1.72-1.90 (m, 4H), 2.12-2.22 (m, 2H), 2.39 (s, 3H), 2.95-3.05 (m, 2H), 3, 59 (s, 2H), 3.74-3.85 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.93 (s, 6H), 4.54 (s, 2H), 6.67-6.70 (m, 4H), 6.75 (s, 2H), 7.19-7.23 (m, 3H), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.36-7.40 (m, 2H), 7.76 (s, 1H), 8.50 (d, 1H , J = 1.8 Hz), 8.69 (s, 1H). 118

83% 1.72-1.90 (m, 4H), 2.09-2.20 (m, 2H), 2.38 (s, 3H), 2.97-3.06 (m, 2H), 3, 58 (s, 2H), 3.73-3.84 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.92 (s, 6H), 4.54 (s, 2H), 6.66-6.71 (m, 4H), 6.76 (s, 2H), 7.18-7.24 (m, 3H), 7.26-7.48 (m, 7H).

Production Example 146

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) and p-toluidine (2.56 g) were worked up as described in Production Example 37 to afford the title compound as a white powder.

Yield 5.79 g (83%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.4 Hz), 6.98 (d, 2H, J = 8.0 Hz).

Production 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 (581 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure, similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 1.00 g (91%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.6 Hz), 7.02 (d, 2H, J = 8 , 2 Hz), 7.13-7.16 (m, 3H), 7.55 (s, 1H), 8.55 (d, 1H, J = 8.1 Hz).

Production 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] benzyl] methyl] piperidine (1.00 g ) are processed according to a procedure similar to that described in Production Example 94, to give the title compound as a light yellow powder.

Yield 924 mg (97%).

Production 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 (581 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are treated in a similar manner to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 426 mg (39%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.6 Hz), 7, 01 (d, 2H, J = 8.2 Hz), 7.67 (dd, 1H, J = 2.1 Hz, 2.1 Hz), 8.50 (d, 1H, J = 2.0 Hz) 8.64 (d, 1H, J = 2.2 Hz).

Production 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 (426 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 400 mg (99%).

Production 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 (581 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9 obtaining the title compound as a pale yellow amorphous substance.

Yield 1.03 g (94%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.6 Hz), 6.71 (s, 2H), 7, 00 (d, 2H, J = 8.8 Hz), 7.23-7.27 (m, 1H), 7.32-7.44 (m, 3H).

Production Example 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 (1.03 g) was processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 882 mg (97%).

Examples 119-126

These compounds are prepared by reacting the amines obtained in Production Examples 148, 150 and 152 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 119

66% 1.70-1.82 (m, 2H), 1.83-1.91 (m, 2H), 2.13-2.25 (m, 2H), 2.23 (s, 3H), 2, 96-3.02 (m, 2H), 3.57 (s, 2H), 3.73-3.83 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H) 3.93 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.64 (d, 2H, J = 8.8 Hz), 7.01 (d, 2H, J = 8.5 Hz), 7.13-7.17 (m, 3H), 7.20 (d, 1H, J = 4.9 Hz), 7.22 (s, 2H), 7, 56 (s, 1H), 7.59 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 4.9 Hz). 120

41% 1.60-1.91 (m, 4H), 2.12-2.24 (m, 2H), 2.23 (s, 3H), 2.95-3.05 (m, 2H), 3, 59 (s, 2H), 3.73-3.83 (m, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.49 (s, 2H), 6.63 (d, 2H, J = 8.6 Hz), 6.75 (s, 2H), 7.00 (d, 2H, J = 8.6 Hz), 7.13-7.16 (m, 3H), 7.55 (s, 1H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.53 (d, 1H, J = 5.1 Hz), 8.70 (s, 1H). 121

69% 1.67-1.80 (m, 2H), 1.81-1.89 (m, 2H), 2.09-2.20 (m, 2H), 2.22 (s, 3H), 2, 98-3.06 (m, 2H), 3.58 (s, 2H), 3.72-3.81 (m, 1H), 3.88 (s, 3H), 3.89 (s, 3H) 3.92 (s, 6H), 3.92 (s, 6H), 4.49 (s, 2H), 6.63 (d, 2H, J = 8.4 Hz), 6.76 (s, 2H), 7.00 (d, 2H, J = 8.6 Hz), 7.12-7.15 (m, 3H), 7.26-7.32 (m, 1H), 7.37 (dd , 1H, J = 7.6 Hz, 7.6 Hz), 7.41-7.48 (m, 2H), 7.55 (s, 1H), 8.53 (d, 1H, J = 5, 0 Hz). 122

47% 1.55-2.00 (m, 4H), 2.12-2.31 (m, 2H), 2.22 (s, 3H), 2.93-3.10 (m, 2H), 3, 60 (broad, 2H), 3.69-3.80 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.53 (s, 2H), 6.66 (s, 2H), 6.69 (d, 2H, J = 8.6 Hz), 7.00 (d, 2H, J = 8.6 Hz), 7.19-7.27 (m, 4H), 7.68 (s, 1H), 8.50 (s, 1H), 8.60 (d, 1H, J = 4.9 Hz), 8.64 (d, 1H, J = 2.2 Hz). 123

34% 1.67-1.98 (m, 4H), 2.10-2.38 (m, 2H), 2.22 (s, 3H), 2.85-3.10 (m, 2H), 3, 53-3.67 (s, 2H), 3.67-3.79 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H) 3.93 (s, 6H), 4.51 (s, 2H), 6.66 (s, 2H), 6.68 (d, 2H, J = 8.8 Hz), 6.76 (s, 2H), 7.00 (d, 2H, J = 8.2 Hz), 7.67 (s, 1H), 7.77 (br, 1H), 8.47-8.53 (m, 2H), 8.63 (d, 1H, J = 2.0 Hz), 8.70 (s, 1H). 124

91% 1.73-1.92 (m, 4H), 2.12-2.26 (m, 2H), 2.21 (s, 3H), 2.92-3.02 (m, 2H), 3, 57 (s, 2H), 3.72-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.95 (s, 6H), 4.53 (s, 2H), 6.67 (d, 2H, J = 7.8 Hz), 6.70 (s, 2H), 6.99 (d, 2H, J = 8.0 Hz), 7.18-7.25 (m, 4H), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.38 (d, 1H, J = 7.2 Hz), 7.42 (s, 1H), 7.59 (s, 1H), 8.58 (d, 1H, J = 4.7 Hz). 125

74% 1.70-1.92 (m, 4H), 2.10-2.28 (m, 2H), 2.21 (s, 3H), 2.92-3.06 (m, 2H), 3, 58 (s, 2H), 3.72-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.93 (s, 6H), 4.51 (s, 2H), 6.66 (d, 2H, J = 8.6 Hz), 6.70 (s, 2H), 6.75 (s, 2H), 7 23 (d, 1H, J = 7.0 Hz), 7.32 (dd, 1H, J = 7.6 Hz, 7.6 Hz), 7.37 (d, 1H, J = 7.8 Hz ), 7.41 (s, 1H), 7.77 (s, 1H), 8.49 (s, 1H), 8.69 (s, 1H). 126

84% 1.71-1.88 (m, 4H), 2.08-2.18 (m, 2H), 2.21 (s, 3H), 2.96-3.04 (m, 2H), 3, 58 (s, 2H), 3.71-3.83 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.92 (s, 6H), 4.52 (s, 2H), 6.66 (d, 2H, J = 8.6 Hz), 6.70 (s, 2H), 6.76 (s, 2H), 6 98 (d, 2H, J = 8.3 Hz); 7.22-7.47 (m, 8H).

Production Example 153

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4- (trifluoro) aniline (3.85 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as white powder.

Yield 3.30 g (40%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.4 Hz); 7.39 (d, 2H, J = 8.4 Hz).

Production 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 (688 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are treated according to the procedure , similarly as described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 412 mg (34%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz), 7.09 (d, 1H, J = 3.7 Hz), 7.13 ( s, 2H), 7.44 (d, 2H, J = 8.8 Hz), 7.49 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz).

Production 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 (412 mg) are treated according to a procedure similar to that described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 359 mg (91%).

Production 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 (689 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to a procedure similar to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 522 mg (44%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz), 7.19 (s, 1H, J = 7 4 Hz), 7.33-7.44 (m, 5H).

Production Example 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 (522 mg) are treated according to the procedure, similar to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 460 mg (99%).

Examples 127-132

These compounds are prepared by reacting the amines obtained in Production Examples 155 and 157 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 127

72% 1.74-1.92 (m, 4H), 2.17-2.26 (m, 2H), 2.96-3.04 (m, 2H), 3.59 (s, 2H), 3, 89 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.60 (s, 2H), 6.72 (d, 2H) , J = 8.8 Hz), 7.10 (d, 1H, J = 4.9 Hz), 7.13 (s, 2H), 7.20 (d, 1H, J = 5.1 Hz), 7.43 (d, 2H, J = 8.8 Hz), 7.50 (s, 1H), 7.59 (s, 1H), 8.56 (d, 1H, J = 4.9 Hz), 8.58 (d, 1H, J = 5.1 Hz). 128

51% 1.70-1.90 (m, 4H), 2.14-2.28 (m, 2H), 2.96-3.08 (m, 2H), 3.61 (s, 2H), 3, 87-3.96 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.93 (s, 6H), 4.59 (s, 2H), 6.71 (d, 2H, J = 8.8 Hz), 6.75 (s, 2H), 7.07-7.15 (m, 3H), 7.43 (d, 2H, J = 8.8 Hz), 7.49 (s, 1H), 7.76 (s, 1H), 8.51 (d, 1H, J = 1.8 Hz), 8.57 (d, 1H, J = 5.1 Hz), 8.70 (s, 1H). 129

59% 1.72-1.88 (m, 4H), 2.11-2.24 (m, 2H), 2.98-3.10 (m, 2H), 3.59 (s, 2H), 3, 87-3.95 (m, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s, 6H), 3.92 (s, 6H), 4.59 (s, 2H), 6.71 (d, 2H, J = 9.0 Hz), 6.76 (s, 2H), 7.08 (d, 1H, J = 5.1 Hz), 7.12 (s, 2H), 7.29 (d, 1H, J = 7.4 Hz), 7.37 (dd, 1H, J = 7.6 Hz, 7.6 Hz), 7.40-7.52 (m, 5H), 8.56 (d, 1H, J = 5.1 Hz). 130

81% 1.78-1.94 (m, 4H), 2.15-2.27 (m, 2H), 2.94-3.08 (m, 2H), 3.58 (s, 2H) 3.86 (s, 6H), 3.87 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H), 4.63 (s, 2H), 6.67 (s, 2H) 6.74 (d, 2H, J = 8.8 Hz), 7.17-7.24 (m, 4H), 7.34-7.45 (m, 5H), 7.59 (s, 1H ), 8.59 (d, 1H, J = 5.1 Hz). 131

54% 1.75-1.90 (m, 4H), 2.14-2.24 (m, 2H), 2.95-3.04 (m, 2H), 3.60 (s, 2H), 3, 84-3.88 (m, 1H), 3.86 (m, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 4.61 (s, 2H), 6.67 (s, 2H), 6.72-6.77 (m, 4H), 7.18 (d, 1H, J = 7.4 Hz), 7.33-7, 43 (m, 5H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.9 Hz), 8.69 (d, 1H, J = 1.9 Hz). 132

67% 1.76-1.88 (m, 4H), 2.11-2.19 (m, 2H), 2.98-3.06 (m, 2H), 3.59 (s, 2H), 3, 86 (s, 6H), 3.87 (s, 3H), 3.89 (s, 3H), 3.92 (s, 6H), 4.61 (s, 2H), 6.67 (s, 2H) ), 6.73 (d, 2H, J = 8.8 Hz), 6.76 (s, 2H), 7.18 (d, 1H, J = 7.3 Hz), 7.29 (d, 1H , J = 7.6 Hz), 7.32-7.47 (m, 8H).

Production Example 158

Synthesis of 1- (tert-butoxycarbonyl) -4- (4-bromophenyl) aminopiperidine

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4-bromaniline (4.11 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a white powder.

Yield 3.09 g (36%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz); 7.24 (d, 2H, J = 9.0 Hz).

Production 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) aminopiperidine (711 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure similar to that described in example 9 obtaining the title compound as a pale yellow amorphous substance.

Yield 607 mg (50%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.1 Hz), 7.10 (d, 1H, J = 5.2 Hz), 7.14 ( s, 2H), 7.28 (d, 2H, J = 9.1 Hz), 7.50 (s, 1H), 8.57 (d, 1H, J = 5.0 Hz).

Production 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 (607 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 541 mg (93%).

Production Example 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) aminopiperidine (711 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to the procedure similar to that described in example 9, receiving the title compound as a pale yellow amorphous substance.

Yield 347 mg (28%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz), 6.65 (s, 2H), 7.28 (d, 2H, J = 9 4 Hz), 7.61 (s, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.67 (d, 1H, J = 2.2 Hz).

Production Example 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 (347 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 302 mg (91%).

Production 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) aminopiperidine (711 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9, to obtain the specified in the title compound as a pale yellow amorphous substance.

Yield 1.14 g (93%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz), 6.69 (s, 2H), 7.19 (d, 1H, J = 7 6 Hz), 7.25 (d, 2H, J = 5.5 Hz), 7.32-7.42 (m, 3H).

Production 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 (1.03 g) was processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 973 mg (84%).

Examples 133-140

These compounds are prepared by reacting the amines obtained in Production Examples 160, 162 and 164 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 133

52% 1.70-1.90 (m, 4H), 2.14-2.25 (m, 2H), 2.94-3.04 (m, 2H), 3.58 (s, 2H), 3, 73-3.84 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H), 6.57 (d, 2H, J = 8.8 Hz), 7.10 (d, 1H, J = 4.9 Hz), 7.14 (s, 2H), 7.20 (d, 1H, J = 4.9 Hz), 7.22 (s, 2H), 7.26 (d, 2H, J = 8.5 Hz), 7.51 (s, 1H), 7.59 (s, 1H), 8.56 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 4.9 Hz). 134

56% 1.68-1.88 (m, 4H), 2.12-2.24 (m, 2H), 2.95-3.04 (m, 2H), 3.59 (s, 2H), 3, 72-3.84 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.50 (s, 2H), 6.57 (d, 2H, J = 9.2 Hz), 6.74 (s, 2H), 7.09 (d, 1H, J = 3.9 Hz), 7.13 (s, 2H), 7.26 (d, 2H, J = 8.8 Hz), 7.50 (s, 1H), 7.75 (s, 1H), 8.50 (d, 1H, J = 2.0 Hz), 8.55 (d, 1H, J = 5.0 Hz), 8.69 (d, 1H, J = 2.0 Hz). 135

65% 1.70-1.86 (m, 4H), 2.10-2.20 (m, 2H), 2.97-3.08 (m, 2H), 3.59 (s, 2H), 3, 72-3.82 (m, 1H), 3.89 (s, 6H), 3.92 (s, 6H), 3.92 (s, 6H), 4.50 (s, 2H), 6.56 (d, 2H, J = 9.2 Hz), 6.76 (s, 2H), 7.09 (d, 1H, J = 5.1 Hz), 7.13 (s, 2H), 7.23 -7.33 (m, 3H), 7.37 (dd, 1H, J = 7.4 Hz), 7.41-7.48 (m, 2H), 7.49 (s, 1H), 8, 54 (d, 1H, J = 5.1 Hz). 136

49% 1.77-1.93 (m, 4H), 2.12-2.30 (m, 2H), 2.94-3.10 (m, 2H), 3.60 (s, 2H), 3, 73-3.83 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.55 (s, 2H), 6.61 (d, 2H, J = 9.2 Hz), 6.65 (s, 2H), 7.19-7.29 (m, 5H), 7.62 (broad, 2H), 8.47 (d, 1H, J = 1.6 Hz), 8.60 (d, 1H, J = 4.9 Hz), 8.66 (d, 1H, J = 2.0 Hz) . 137

fifty% 1.70-1.92 (m, 4H), 2.12-2.27 (m, 2H), 2.93-3.07 (m, 2H), 3.60 (s, 2H), 3, 67-4.08 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.54 (s, 2H), 6.60 (d, 2H, J = 9.0 Hz), 6.64 (s, 2H), 6.73-6.80 (m, 2H), 7.25 (s, 2H), 7.61 (s, 1H), 7.77 (br, 1H), 8.45 (d, 1H, J = 1.7 Hz), 8.50 (d, 1H, J = 1.7 Hz), 8.65 (d, 1H, J = 2.0 Hz). 138

81% 1.75-1.90 (m, 4H), 2.17-2.24 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H), 3, 72-3.83 (m, 1H), 3.88 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.95 (s, 6H), 4.54 (s, 2H), 6.60 (d, 2H, J = 9.2 Hz), 6.69 (s, 2H), 7.18-7.27 (m, 6H), 7.32-7, 42 (m, 3H), 7.60 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz). 139

80% 1.72-1.90 (m, 4H), 2.13-2.21 (m, 2H), 2.94-3.05 (m, 2H), 3.59 (s, 2H), 3, 72-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.93 (s, 6H), 4.53 (s, 2H), 6.60 (d, 2H, J = 9.0 Hz), 6.68 (s, 2H), 6.75 (s, 2H), 7.19 (d, 1H, J = 7.2 Hz), 7.24 (d, 2H, J = 9.0 Hz), 7.31-7.41 (m, 3H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.70 (s, 1H). 140

78% 1.72-1.88 (m, 4H), 2.08-2.18 (m, 2H), 2.97-3.06 (m, 2H), 3.58 (s, 2H), 3, 71-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.92 (s, 6H), 4.53 (s, 2H), 6.59 (d, 2H, J = 9.3 Hz), 6.68 (s, 2H), 6.76 (s, 2H), 7.18 (d, 1H, J = 7.3 Hz), 7.21-7.47 (m, 9H).

Production Example 165

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4-chloraniline (3.05 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a white powder.

Yield 3.80 g (49%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 (broad, 1H), 6.52 (d, 2H, J = 9.0 Hz), 7 11 (d, 2H, J = 9.0 Hz).

Production Example 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 (621 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are treated in a similar manner to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 789 mg (69%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.0 Hz), 7.14 (d, 1H, J = 5.3 Hz), 7.15 (d, 2H, J = 9.0 Hz), 7 51 (s, 2H); 8.57 (d, 2H, J = 5.1 Hz).

Production Example 167

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 (789 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 673 mg (90%).

Production 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 (621 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) according to a procedure similar to that described in Example 9 to afford the title compound as a pale yellow amorphous.

Yield 268 mg (24%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz), 7.15 (d, 2H, J = 9 , 0 Hz), 7.63 (s, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.66 (d, 1H, J = 2.0 Hz).

Production Example 169

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 (268 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 233 mg (91%).

Production 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 (622 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9, receiving the title compound as a pale yellow amorphous substance.

Yield 1.04 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz), 6.70 (s, 2H), 7.12 (d, 2H, J = 9 , 0 Hz), 7.20 (d, 2H, J = 7.3 Hz), 7.33-7.43 (m, 3H).

Production Example 171

Synthesis of 4- [N- (4-chlorophenyl) -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 (1.04 g) was processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 899 mg (97%).

Examples 141-148

These compounds are prepared by reacting the amines obtained in Production Examples 167, 169 and 171 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 141

66% 1.71-1.90 (m, 4H), 2.15-2.24 (m, 2H), 2.95-3.05 (m, 2H), 3.58 (s, 2H), 3, 73-3.84 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H), 6.62 (d, 2H, J = 9.0 Hz), 7.10-7.16 (m, 5H), 7.19-7.24 (m, 3H), 7, 52 (s, 1H), 7.59 (s, 1H), 8.56 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 4.9 Hz). 142

67% 1.69-1.90 (m, 1H), 2.12-2.25 (m, 2H), 2.93-3.06 (m, 2H), 3.59 (s, 2H), 3, 72-3.83 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.50 (s, 2H), 6.62 (d, 2H, J = 9.2 Hz), 6.75 (s, 2H), 7.10 (d, 1H, J = 5.3 Hz), 7.13 (s, 2H), 7.13 (d, 2H, J = 9.0 Hz), 7.50 (s, 1H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.55 (d, 1H, J = 5.1 Hz), 8.70 (d, 1H, J = 1.8 Hz). 143

70% 1.65-1.88 (m, 4H), 2.08-2.20 (m, 2H), 2.97-3.07 (m, 2H), 3.59 (s, 2H), 3, 71-3.82 (m, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90-3.93 (m, 3H), 4.50 (s, 2H) 6.61 (d, 2H, J = 8.2 Hz), 6.76 (s, 2H), 7.07-7.14 (m, 5H), 7.28 (d, 1H, J = 6 6 Hz), 7.37 (dd, 1H, J = 7.4 Hz), 7.40-7.47 (m, 2H), 7.50 (s, 1H), 8.54 (d, 1H , J = 5.1 Hz). 144

57% 1.56-1.93 (m, 4H), 2.12-2.30 (m, 2H), 2.92-3.10 (m, 2H), 3.53-3.68 (m, 2H) ), 3.70-3.82 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H) 4.56 (s, 2H), 6.64-6.70 (m, 4H), 7.13 (d, 2H, J = 9.0 Hz), 7.20-7.30 (m, 3H ), 7.63 (br, 2H), 8.48 (s, 1H), 8.60 (d, 1H, J = 5.1 Hz), 8.66 (d, 1H, J = 2.2 Hz ) 145

70% 1.71-1.92 (m, 4H), 2.12-2.27 (m, 2H), 2.94-3.07 (m, 2H), 3.59 (s, 2H), 3, 69-3.81 (s, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.54 (s, 2H), 6.63-6.68 (m, 4H), 6.75 (s, 2H), 7.13 (d, 2H, J = 9.0 Hz), 7.62 (s, 1H), 7.76 (s, 1H), 8.47 (d, 1H, J = 1.8 Hz), 8.50 (d, 1H, J = 1.8 Hz), 8.65 (d, 1H, J = 2.0 Hz), 8.70 (s, 1H). 146

78% 1.75-1.91 (m, 4H), 2.13-2.23 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H), 3, 73-3.82 (m, 1H), 3.88 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.55 (s, 2H), 6.65 (d, 2H, J = 9.0 Hz), 6.68 (s, 2H), 7.11 (d, 2H, J = 8.5 Hz), 7.18 -7.24 (m, 4H), 7.32-7.42 (m, 3H), 7.59 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz). 147

63% 1.72-1.89 (m, 4H), 2.12-2.21 (m, 2H), 2.94-3.03 (m, 2H), 3.59 (s, 2H), 3, 72-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.53 (s, 2H), 6.64 (d, 2H, J = 9.2 Hz), 6.68 (s, 2H), 6.75 (s, 2H), 7.11 (d, 2H), 7 19 (d, 1H, J = 7.6 Hz), 7.32-7.40 (m, 3H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.69 (d, 1H, J = 2.2 Hz). 148

68% 1.72-1.87 (m, 4H), 2.08-2.18 (m, 2H), 2.97-3.05 (m, 2H), 3.58 (s, 2H), 3, 71-3.82 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.92 (s, 6H), 4.53 (s, 2H), 6.64 (dt, 2H, J = 9.3 Hz, 2.9 Hz), 6.68 (s, 2H), 6.76 (s, 2H), 7.10 (dt , 2H, J = 9.0 Hz, 2.8 Hz), 7.19 (d, 1H, J = 7.6 Hz), 7.24-7.47 (m, 7H).

Production Example 172

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 3,4-difluoroaniline (3.09 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a white powder .

Yield 4.66 g (62%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 12.7 Hz, 6.6 Hz, 2.9 Hz), 6.94 (dd, 1H, J = 19 , 1 Hz, 9.0 Hz).

Production 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] piperidine (625 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 534 mg (47%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 13.6 Hz, 6.4 Hz, 3.1 Hz), 6.98 (dd, 1H, J = 19.1 Hz, 9.2 Hz), 7.11 (dd, 1H, J = 5.0 Hz, 1.3 Hz), 7.16 (s, 2H), 7.51 (s, 1H), 8.58 (d, 1H, J = 5.1 Hz).

Production 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 (534 mg ) are processed according to a procedure similar to that described in Production Example 94, to give the title compound as a light yellow powder.

Yield 442 mg (87%).

Production Example 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 (625 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure, similar to that described in example 9, obtaining specified in the title compound as a pale yellow amorphous substance.

Yield 350 mg (31%).

Production 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 (350 mg ) are processed according to a procedure similar to that described in Production Example 94, to give the title compound as a light yellow powder.

Yield 305 mg (92%).

Production 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 (625 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to a procedure similar to that described in Example 9 to afford the title compound as a pale yellow amorphous.

Yield 1.04 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.8 Hz, 3.8 Hz), 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 = 13.9 Hz, 6.8 Hz, 2.9 Hz), 6.71 (s, 2H), 6.95 (dd, 1H, J = 19.2 Hz, 9.2 Hz), 7.20 (d, 1H, J = 7.4 Hz), 7.36-7.43 (m, 3H).

Production 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 (980 mg) was processed according to the procedure similar to that described in the example obtain 94, getting mentioned in the title compound as a pale yellow powder.

Yield 819 mg (94%).

Examples 149-156

These compounds are prepared by reacting the amines obtained in Production Examples 174, 176 and 178 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 149

67% 1.70-1.90 (m, 4H), 2.16-2.23 (m, 2H), 2.95-3.03 (m, 2H), 3.58 (s, 2H), 3, 64-3.74 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.49 (s, 2H), 6.31-6.37 (m, 1H), 6.51 (ddd, 1H, J = 13.9 Hz, 6.6 Hz, 3.1 Hz), 6.96 (dd , 1H, J = 19.2 Hz, 9.8 Hz), 7.11 (d, 1H, J = 5.1 Hz), 7.15 (s, 2H), 7.20 (d, 1H, J = 5.1 Hz), 7.22 (s, 2H), 7.52 (s, 1H), 7.59 (s, 1H), 8.57 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 5.1 Hz). 150

47% 1.67-1.79 (m, 2H), 1.81-1.89 (m, 2H), 2.13-2.20 (m, 2H), 2.95-3.05 (m, 2H) ), 3.59 (s, 2H), 3.63-3.75 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 12H) 4.47 (s, 2H), 6.30-6.36 (m, 1H), 6.50 (ddd, 1H, J = 13.9 Hz, 6.6 Hz, 3.1 Hz), 6 75 (s, 2H), 6.96 (d, 1H, J = 19.0 Hz, 9.4 Hz), 7.10 (d, 1H, J = 4.1 Hz), 7.15 (s , 2H), 7.51 (s, 1H), 7.75 (s, 1H), 8.50 (d, 1H, J = 1.8 Hz), 8.56 (d, 1H, J = 5, 1 Hz), 8.70 (s, 1H). 151

53% 1.68-1.87 (m, 4H), 2.09-2.18 (m, 2H), 2.98-3.06 (m, 2H), 3.58 (s, 2H), 3, 63-3.72 (m, 1H), 3.89 (s, 3H), 3.89 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.47 (s, 2H), 6.33-6.35 (m, 1H), 6.50 (ddd, 1H, J = 13.9 Hz, 6.4 Hz, 2.9 Hz), 6.76 (s , 2H), 6.95 (dd, 1H, J = 19.2 Hz, 9.4 Hz), 7.09 (d, 1H, J = 5.1 Hz), 7.15 (s, 2H), 7.25-7.30 (m, 1H), 7.37 (dd, 1H, J = 7.3 Hz, 7.3 Hz), 7.42-7.46 (m, 2H), 7.50 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz). 152

fifty% 1.72-1.96 (m, 4H), 2.12-2.28 (m, 2H), 2.94-3.08 (m, 2H), 3.59 (s, 2H), 3, 62-3.72 (m, 1H), 3.89 (s, 3H), 3.90 (s, 9H), 3.96 (s, 6H), 4.52 (s, 2H), 6.36 -6.43 (m, 1H), 6.55 (ddd, 1H, J = 13.7 Hz, 6.6 Hz, 2.9 Hz), 6.67 (s, 2H), 6.96 (dd , 1H, J = 19.1 Hz, 9.2 Hz), 7.21 (dd, 1H, J = 5.1 Hz, 1.2 Hz), 7.24 (s, 2H), 7.61 ( broad, 1H), 7.64 (s, 1H), 8.47 (d, 1H, J = 2.0 Hz), 8.60 (d, 1H, J = 4.9 Hz), 8.67 ( d, 1H, J = 2.0 Hz). 153

61% 1.71-1.90 (m, 4H), 2.12-2.25 (m, 2H), 2.95-3.05 (m, 2H), 3.57-3.75 (m, 1H ), 3.59 (s, 2H), 3.88 (s, 3H), 3.90 (s, 9H), 3.93 (s, 6H), 4.50 (s, 2H), 6.32 -6.43 (m, 1H), 6.54 (ddd, 1H, J = 13.6 Hz, 6.4 Hz, 2.7 Hz), 6.67 (s, 2H), 6.73-6 78 (m, 3H), 6.96 (dd, 1H, J = 18.9 Hz, 9.6 Hz), 7.63 (s, 1H), 7.76 (s, 1H), 8.46 (s, 1H), 8.50 (d, 1H, J = 1.6 Hz), 8.66 (d, 1H, J = 1.8 Hz), 8.70 (d, 1H, J = 2, 0 Hz). 154

82% 1.74-1.90 (m, 4H), 2.13-2.22 (m, 2H), 2.95-3.01 (m, 2H), 3.57 (s, 2H), 3, 63-3.73 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.51 (s, 2H), 6.34-6.40 (m, 1H), 6.52 (ddd, 1H, J = 14.1 Hz, 6.6 Hz, 3.1 Hz), 6.70 (s , 2H), 6.94 (dd, 1H, J = 19.2 Hz, 9.4 Hz), 7.17-7.26 (m, 4H), 7.32-7.42 (m, 3H) 7.59 (s, 1H); 8.59 (d, 1H, J = 5.1 Hz). 155

75% 1.74-1.90 (m, 4H), 2.13-2.21 (m, 2H), 2.95-3.04 (m, 2H), 3.59 (s, 2H), 3, 63-3.72 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.89 (s, 3H), 3.93 (s, 6H), 4.49 (s, 2H), 6.33-6.39 (m, 1H), 6.52 (ddd, 1H, J = 14.3 Hz, 3.7 Hz, 2.9 Hz), 6.69 (s , 2H), 6.75 (s, 2H), 6.94 (dd, 1H, J = 19.1 Hz, 9.8 Hz), 7.19 (d, 1H, J = 7.8 Hz), 7.32-7.41 (m, 3H), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.5 Hz), 8.69 (s, 1H). 156

79% 1.72-1.88 (m, 4H), 2.08-2.18 (m, 2H), 2.98-3.05 (m, 2H), 3.58 (s, 2H), 3, 62-3.72 (m, 1H), 3.88 (s, 3H), 3.89 (s, 9H), 3.92 (s, 6H), 4.45 (s, 2H), 6.33 -6.39 (m, 1H), 6.51 (ddd, 1H, J = 13.9 Hz, 6.6 Hz, 3.0 Hz), 6.69 (s, 2H), 6.76 (s , 2H), 6.93 (dd, 1H, J = 19.3 Hz, 9.5 Hz), 7.19 (d, 1H, J = 7.6 Hz), 7.25-7.47 (m , 7H).

Production Example 179

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with 4-fluoroaniline (2.66 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a white powder.

Yield 4.99 g (71%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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).

Production 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 (589 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are treated in a similar manner to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 702 mg (64%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 9.2 Hz, 9.2 Hz), 7, 12-7.16 (m, 3H); 7.53 (s, 1H).

Production 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 (702 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 561 mg (84%).

Production 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 (589 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are treated in a similar manner to that described in Example 9, obtaining the title compound as a pale yellow amorphous substance.

Yield 190 mg (17%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.7 Hz, 3.1 Hz), 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 = 9.2 Hz, 8.2 Hz), 7.65 (s, 1H), 8.49 (d, 1H, J = 2.0 Hz), 8.65 (d, 1H, J = 2.0 Hz).

Production 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 (190 mg) is treated according to a similar manner to that described in Production Example 94, to give the title compound as a pale yellow powder.

Yield 165 mg (91%).

Production 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 (589 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to the procedure similar to that described in example 9 obtaining the title compound as a pale yellow amorphous substance.

Yield 1.01 g (92%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.7 Hz, 3.5 Hz), 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 = 9.2 Hz, 8.2 Hz), 7.21-7.25 (m, 1H), 7.32-7.41 (m, 3H).

Production 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 (1.01 g) was processed according to the procedure similar to that described in Production Example 94, affording the title compound as a light yellow powder.

Yield 790 mg (88%).

Examples 157-164

These compounds are prepared by reacting the amines obtained in Production Examples 181, 183 and 185 with the chloride derivatives obtained in Production Examples 3, 42 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 157

62% 1.60-1.82 (m, 2H), 1.83-1.91 (m, 2H), 2.13-2.23 (m, 2H), 2.95-3.03 (m, 2H) ), 3.57 (s, 2H), 3.64-3.75 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H) 3.96 (s, 6H), 4.48 (s, 2H), 6.65-6.70 (m, 2H), 6.90 (dd, 2H, J = 8.8 Hz, 8.8 Hz), 7.13-7.16 (m, 3H), 7.20 (d, 1H, J = 5.1 Hz), 7.22 (s, 2H), 7.54 (s, 1H), 7.59 (s, 1H), 8.55 (d, 1H, J = 5.1 Hz), 8.59 (d, 1H, J = 4.9 Hz). 158

53% 1.66-1.95 (m, 4H), 2.12-2.24 (m, 2H), 2.95-3.07 (m, 2H), 3.60 (s, 2H), 3, 64-3.76 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.47 (s, 2H), 6.63-6.70 (m, 1H), 6.75 (s, 2H), 6.90 (dd, 1H, J = 9.2 Hz, 9.2 Hz), 7 11-7.16 (m, 3H), 7.53 (s, 1H), 7.77 (s, 1H), 8.50 (d, 1H, J = 2.0 Hz), 8.55 ( d, 1H, J = 4.9 Hz), 8.70 (d, 1H, J = 5.9 Hz). 159

51% 1.64-1.90 (m, 4H), 2.07-2.20 (m, 4H), 2.97-3.08 (m, 2H), 3.59 (s, 2H), 3, 64-3.76 (m, 1H), 3.89 (s, 6H), 3.92 (s, 6H), 3.93 (s, 6H), 4.47 (s, 2H), 6.62 -6.70 (m, 2H), 6.77 (s, 2H), 6.86-6.93 (m, 2H), 7.11-7.16 (m, 3H), 7.25-7 , 31 (m, 3H), 7.37 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.42-7.49 (m, 2H), 7.53 (s, 1H) 8.54 (d, 1H, J = 5.1 Hz). 160

49% 1.74-1.98 (m, 4H), 2.10-2.30 (m, 2H), 2.90-3.12 (m, 2H), 3.53-3.73 (m, 3H ), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.50 (s, 2H), 6.66 (s, 2H), 6.70-6.76 (m, 2H), 6.90 (dd, 2H, J = 8.8 Hz, 8.8 Hz), 7.19-7.28 (m, 3H), 7.65 (br, 2H), 8.49 (d, 1H, J = 1.8 Hz), 8.60 (d, 1H, J = 4.9 Hz), 8.64 (d, 1H, J = 2.2 Hz). 161

26% 1.67-1.97 (m, 4H), 2.10-2.27 (m, 2H), 2.94-3.06 (m, 2H), 3.56-3.68 (m, 3H ), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.49 (s, 2H), 6.65 (s, 2H), 6.69-6.80 (m, 4H), 6.84-6.93 (m, 2H), 7.64 (s, 1H), 7.77 (br, 1H), 8.48 (d, 1H, J = 1.7 Hz), 8.50 (d, 1H, J = 1.7 Hz), 8.64 (d, 1H, J = 1.9 Hz), 8, 70 (s, 1H). 162

83% 1.72-1.92 (m, 4H), 2.12-2.21 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H), 3, 64-3.74 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.51 (s, 1H), 6.66-6.71 (m, 4H), 6.88 (dd, 2H, J = 8.6 Hz, 8.6 Hz), 7.18-7.27 (m, 4H), 7.34 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.39 (d, 2H, J = 5.4 Hz), 7.59 (s, 1H), 8 59 (d, 1H, J = 5.1 Hz). 163

68% 1.68-1.87 (m, 4H), 2.10-2.22 (m, 2H), 2.94-3.04 (m, 2H), 3.59 (s, 2H), 3, 65-3.74 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.49 (s, 2H), 6.66-6.70 (m, 6H), 6.88 (dd, 2H, J = 8.8 Hz, 8.8 Hz), 7.19-7.40 (m, 4H), 7.77 (s, 1H), 8.49 (d, 1H, J = 1.8 Hz), 8.70 (s, 1H). 164

74% 1.70-1.90 (m, 4H), 2.08-2.18 (m, 2H), 2.95-3.05 (m, 2H), 3.58 (s, 2H), 3, 63-3.73 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 3H), 3.92 (s, 6H), 4.50 (s, 2H), 6.65-6.72 (m, 2H), 6.69 (s, 2H), 6.76 (s, 2H), 6.87 (dd, 2H, J = 9.0 Hz, 9.0 Hz), 7.22 (d, 1H, J = 7.6 Hz), 7.25-7.48 (m, 9H).

Production Example 186

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

1- (tert-Butoxycarbonyl) -4-piperidone (5.00 g) was reacted with aniline (2.23 g) according to the procedure similar to that described in Production Example 37 to afford the title compound as a white powder.

Yield 3.77 g (57%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 6.2 Hz, 1.0 Hz), 7.17 (dd, 2H, J = 8.6 Hz, 7.2 Hz).

Production 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 (553 mg) and 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (588 mg) were processed according to the procedure similar to that described in example 9, to obtain the title compound in the form of a light yellow amorphous substance.

Yield 760 mg (71%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz, 7.4 Hz), 7.55 (s, 1H), 8.56 (d, 1H, J = 5.1 Hz).

Production 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 (760 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 652 mg (90%).

Production Example 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 (553 mg) and 5-chloromethyl-3- (3,4,5-trimethoxyphenyl) pyridine (588 mg) are processed according to the procedure similar to that described in example 9, obtaining the specified in the title compound as a pale yellow amorphous substance.

Yield 222 mg (21%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 8.8 Hz , 7.2 Hz), 7.67 (s, 1H), 8.50 (d, 1H, J = 5.3 Hz, 2.2 Hz), 8.66 (d, 1H, J = 2.1 Hz).

Production 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 (222 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound as a light yellow powder.

Yield 197 mg (94%).

Production Example 191

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

1- (tert-Butoxycarbonyl) -4-phenylaminopiperidine (553 mg) was reacted with 3- (3,4,5-trimethoxyphenyl) benzyl chloride (586 mg) according to a similar manner to that described in Example 9 to give the title compound as light yellow amorphous substance.

Yield 1.06 g (100%).

¹ H-NMR (400 MHz, CDCl ₃ ) 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 = 11.7 Hz, 3.3 Hz), 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).

Production 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 (1.06 g) was processed according to the procedure similar to that described in Production Example 94 yielding the title compound as a pale yellow powder.

Yield 909 mg (97%).

Examples 165-169

These compounds are prepared by reacting the amines obtained in Production Examples 188, 190 and 192 with the chloride derivatives obtained in Production Examples 3 and 48. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 165

53% 1.63-1.81 (m, 4H), 1.82-1.92 (m, 2H), 2.14-2.24 (m, 2H), 2.95-3.05 (m, 2H) ), 3.59 (s, 2H), 3.80-4.02 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H) 3.93 (s, 6H); 4.53 (s, 2H); 6.69-6.77 (m, 5H); 7.13-7.17 (m, 3H); 7.20 (dd , 2H, J = 7.6 Hz, 7.6 Hz), 7.55 (s, 1H), 7.76 (s, 1H), 8.51 (d, 1H, J = 1.8 Hz), 8.55 (d, 1H, J = 5.1 Hz), 8.70 (s, 1H). 166

fifty% 1.85-2.04 (m, 4H), 2.20-2.40 (m, 2H), 2.92-3.25 (m, 2H), 3.60-3.77 (m, 3H) ), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.97 (s, 6H), 4.59 (s, 2H), 6.67 (s, 2H), 6.72-6.81 (m, 4H), 7.17-7.30 (m, 4H), 7.68 (s, 1H), 8.50 (s, 1H), 8.62 (d, 1H, J = 4.9 Hz); 8.65 (d, 1H, J = 2.0 Hz). 167

43% 1.72-1.92 (m, 4H), 2.13-2.26 (m, 2H), 2.95-3.04 (m, 2H), 3.59 (s, 2H), 3, 78-4.01 (m, 1H), 3.88 (s, 9H), 3.90 (s, 3H), 3.93 (s, 6H), 4.56 (s, 2H), 6.66 (s, 2H), 6.70-6.78 (m, 5H), 7.19 (dd, 2H, J = 8.2 Hz, 8.2 Hz), 7.66 (s, 1H), 7 77 (s, 1H), 8.50 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 2.2 Hz), 8.65 (d, 1H, J = 1.9 Hz), 8.70 (d, 1H, J = 2.2 Hz). 168

82% 1.75-1.92 (m, 4H), 2.14-2.23 (m, 2H), 2.94-3.01 (m, 2H), 3.57 (s, 2H), 3, 80-3.94 (m, 1H), 3.87 (s, 3H), 3.88 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.57 (s, 2H), 6.67-6.77 (m, 5H), 7.15-7.27 (m, 5H), 7.34 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.39 (d, 1H, 7.6 Hz), 7.42 (s, 1H), 7.59 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz) . 169

65% 1.72-1.91 (m, 4H), 2.13-2.22 (m, 2H), 2.95-3.03 (m, 2H), 3.59 (s, 2H), 3, 79-4.00 (m, 1H), 3.87 (s, 3H), 3.87 (s, 6H), 3.90 (s, 3H), 3.93 (s, 6H), 4.56 (s, 2H), 6.66-6.77 (m, 7H), 7.18 (dd, 2H, J = 7.4 Hz, 7.4 Hz), 7.24 (d, 1H, J = 7.4 Hz), 7.33 (dd, 1H, J = 7.4 Hz, 7.4 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.41 (s, 1H ), 7.76 (s, 1H), 8.50 (d, 1H, J = 1.6 Hz), 8.69 (d, 1H, J = 2.2 Hz)

Examples of obtaining 193-203

These compounds are prepared using the procedure described in Production Examples 1-3. The structures and NMR data are listed below.

Production Example Structure NMR data (400 MHz, CDCl ₃ ) δ 193

4.61 (s, 2H), 7.25 (d, 1H, J = 1.2 Hz), 7.41-7.52 (m, 3H), 7.75 (d, 1H, J = 0, 8 Hz), 7.98-8.02 (m, 2H), 8.69 (d, 1H, J = 4.9 Hz). 194

3.87 (s, 3H), 4.60 (s, 2H), 7.01 (d, 1H, J = 8.4 Hz), 7.08 (t, 1H, J = 7.4 Hz), 7.24 (dd, 1H, J = 5.1 Hz, 1.4 Hz), 7.38 (dt, 1H, J = 7.4 Hz, 1.8 Hz), 7.77 (dd, 1H, J = 7.6 Hz, 1.8 Hz), 7.84 (s, 1H), 8.69 (d, 1H, J = 5.1 Hz). 195

3.90 (s, 3H), 4.60 (s, 2H), 6.87-7.03 (1H, m), 7.39 (t, 1H, 7.8 Hz), 7.50-7 66 (m, 2H), 7.73 (s, 1H), 8.68 (d, 1H, J = 5.1 Hz) 196

1.45 (t, 3H, J = 7.0 Hz), 4.12 (q, 2H, J = 7.0 Hz), 4.59 (s, 2H), 6.99 (d, 2H, J = 8.8 Hz), 7.18 (d, 1H, J = 5.1 Hz), 7.20-7.29 (m, 1H), 7.68 (s, 1H), 7.95 (d , 2H, J = 8.8 Hz), 8.63 (d, 1H, J = 5.1 Hz). 197

3.95 (s, 3H), 4.00 (s, 3H), 4.60 (s, 2H), 6.96 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H , J = 4.1 Hz), 7.53 (dd, 1H, J = 8.4 Hz, 2.0 Hz), 7.67 (d, 1H, J = 2.0 Hz), 7.70 ( s, 1H), 8.65 (d, 1H, J = 5.1 Hz). 198

4.61 (s, 2H), 7.14-7.21 (m, 1H), 7.21-7.23 (m, 2H), 7.35-7.42 (m, 1H), 7, 80 (s, 1H), 7.98 (1H, dt, J = 8.0 Hz, 2.0 Hz), 8.73 (d, 1H, J = 5.1 Hz). 199

4.61 (s, 2H), 7.13 (1H, dt, J = 8.4 Hz, 2.8 Hz), 7.28 (1H, d, J = 5.0 Hz), 7.40- 7.79 (m, 1H), 7.70-7.79 (m, 3H), 8.69 (d, 1H, J = 5.0 Hz). 200

4.60 (s, 2H), 7.13-7.20 (m, 2H), 7.25 (1H, d, J = 5.1 Hz), 7.70 (s, 1H), 7.95 -8.03 (m, 2H); 8.66 (d, 1H, J = 5.1 Hz). 201

4.61 (s, 2H), 7.21-7.30 (m, 2H), 7.69 (s, 1H), 7.73-7.76 (m, 1H), 7.85-7, 92 (m, 1H), 8.76 (d, 1H, J = 4.9 Hz). 202

4.61 (s, 2H), 6.86-6.91 (m, 1H), 7.31 (1H, d, J = 5.1 Hz), 7.51-7.59 (m, 2H) 7.71 (s, 1H); 8.69 (d, 1H, J = 5.1 Hz). 203

4.61 (s, 2H), 7.26 (d, 1H, J = 4.9 Hz), 7.45 (d, 2H, J = 8.4 Hz), 7.72 (s, 1H), 7.95 (d, 2H, J = 8.4 Hz), 8.68 (s, 1H, J = 4.9 Hz).

Production Example 204

Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N - [(2-phenylpyridin-4-yl) methyl] amino] piperidine

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (612 mg) was reacted with 4-chloromethyl-2-phenylpyridine (204 mg) according to the procedure similar to that described in Example 9 to give the title compound.

Yield 407 mg (43%).

Production 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 (407 mg) was processed according to the procedure similar to that described in Production Example 94 receiving the title compound.

Yield 365 mg (95%).

Production Example 206

Synthesis of 1- (tert-butoxycarbonyl) -4- [N- (4-methoxyphenyl) -N - [[2- (2-methoxyphenyl) pyridin-4-yl] methyl] amino] piperidine

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (2-methoxyphenyl) pyridine (234 mg) according to the procedure similar to that described in example 9, obtaining the specified in the connection header.

Yield 237 mg (72%).

Production 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 (360 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 365 mg (65%).

Production Example 208

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (234 mg) and then condensed according to the procedure similar to that described in example 9 receiving the title compound.

Yield 550 mg (theoretical yield).

Production 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 (550 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 436 g (85%).

Production Example 210

Synthesis of 1- (tert-butoxycarbonyl) -4- [N - [[2- (4-ethoxyphenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (4-ethoxyphenyl) pyridine (248 mg) according to the procedure similar to that described in example 9, obtaining the specified in the connection header.

Yield 515 mg (99%).

Production 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 (515 mg) is processed according to the procedure similar to that described in Production Example 94 to afford the title compound.

Yield 418 mg (80%).

Production Example 212

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (264 mg) according to the procedure similar to that described in example 9, receiving the title compound.

Yield 600 mg (theoretical yield).

Production 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 (600 mg) is processed according to the method similar to that described in Production Example 94 to afford the title compound.

Yield 416 mg (77%).

Production Example 214

Synthesis of 1- (tert-butoxycarbonyl) -4- [N - [[2- (2-fluorophenyl) pyridin-4-yl] methyl] - [N- (4-methoxyphenyl) amino] piperidine

4- (p-Anisidino) - (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (2-fluorophenyl) pyridine (222 mg) according to the procedure similar to that described in example 9, to obtain the title compound.

Yield 530 mg (theoretical yield).

Production Example 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 (530 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 423 mg (85%).

Production Example 216

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (153 mg) was reacted with 4-chloromethyl-2- (3-fluorophenyl) pyridine (111 mg) according to the procedure similar to that described in example 9, obtaining the specified in the connection header.

Yield 270 mg (theoretical yield).

Production Example 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 (270 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 193 mg (70%).

Production Example 218

Synthesis of 1- (tert-butoxycarbonyl) -4- [N - [[2- (4-fluorophenyl) pyridin-4-yl] methyl] -N- (4-methoxyphenyl) amino] piperidine

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (4-fluorophenyl) pyridine (222 mg) according to the procedure similar to that described in example 9, obtaining the specified in the connection header.

Yield 550 mg (theoretical yield).

Production 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] -N- (4-methoxyphenyl) amino] piperidine (550 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 439 mg (88%).

Production Example 220

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (3,4-difluorophenyl) pyridine (240 mg) according to the procedure similar to that described in example 9, receiving the title compound.

Yield 590 mg (theoretical yield).

Production 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 (590 mg) is processed according to the method similar to that described in Production Example 94 to afford the title compound.

Yield 483 mg (93%).

Production Example 222

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

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (3,5-difluorophenyl) pyridine (240 mg) according to the procedure similar to that described in example 9, receiving the title compound.

Yield 530 mg (theoretical yield).

Production 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 (530 mg) is treated according to the procedure similar to that described in Production Example 94 to afford the title compound.

Yield 418 mg (81%).

Production Example 224

Synthesis of 1- (tert-butoxycarbonyl) -4- [N - [[2- (4-chlorophenyl) pyridin-4-yl] methyl] - [N- (4-methoxyphenyl) amino] piperidine

4- (p-Anisidino) -1- (tert-butoxycarbonyl) piperidine (306 mg) was reacted with 4-chloromethyl-2- (4-chlorophenyl) pyridine (238 mg) according to the procedure similar to that described in example 9, obtaining the specified in the connection header.

Yield 600 mg (theoretical yield).

Production 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 (600 mg) is treated in a similar manner to described in Production Example 94 to afford the title compound.

Yield 447 mg (86%).

Examples 170-202

These compounds are prepared by reacting amines obtained in Production Examples 96, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, and 225, with chloride derivatives obtained in Production Examples 3, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202 and 203. The resulting free bases are then converted to the corresponding hydrochlorides. The yields and NMR data of their free bases are indicated below.

Example Structure Exit NMR data (400 MHz, defined as free bases, CDCl ₃ ) δ 170

47% 1.67-1.80 (m, 2H), 1.83-1.91 (m, 2H), 2.10-2.19 (m, 2H), 2.93-3.00 (m, 2H) ), 3.54-3.65 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.45 (s, 3H), 6.73 (d, 2H, J = 9.4 Hz), 6.78 (d, 2H, J = 9.4 Hz), 7.14-7.21 ( m, 2H), 7.15 (s, 2H), 7.38-7.49 (m, 3H), 7.57 (s, 1H), 7.68 (s, 1H), 7.97 (d , 1H, J = 1.0 Hz), 7.99 (d, 1H, J = 1.6 Hz), 8.54 (d, 1H, J = 5.1 Hz), 8.61 (d, 1H , J = 5.1 Hz). 171

55% 1.62-1.80 (m, 2H), 1.84-1.93 (m, 2H), 2.10-2.20 (m, 2H), 2.93-3.02 (m, 2H) ), 3.53-3.66 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.44 (s, 2H), 6.65-6.83 (m, 4H), 7.14-7.30 (m, 4H), 7.36-7.50 (m, 3H), 7 59 (s, 1H), 7.67 (s, 1H), 7.93 (d, 2H, J = 7.0 Hz), 8.54-8.61 (m, 2H). 172

54% 1.67-1.92 (m, 4H), 2.08-2.20 (m, 2H), 2.92-3.01 (m, 2H), 3.52-3.65 (m, 1H ), 3.55 (s, 2H), 3.72 (s, 3H), 4.38 (s, 2H), 6.72 (d, 2H, J = 9.2 Hz), 6.78 (d , 2H, J = 9.0 Hz), 7.18 (dd, 2H, J = 4.9 Hz, 4.9 Hz), 7.36-7.50 (m, 6H), 7.67 (s , 1H), 7.68 (s, 1H), 7.93 (dd, 2H, J = 8.4 Hz, 1.2 Hz), 7.98 (dd, 2H, J = 8.6 Hz, 1 4 Hz), 8.57 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.1 Hz). 173

one hundred% 1.66-1.79 (m, 2H), 1.82-1.91 (m, 2H), 2.09-2.20 (m, 2H), 2.93-3.03 (m, 2H) ), 3.56 (s, 2H), 3.56-3.59 (m, 1H), 3.73 (s, 3H), 3.80 (s, 3H), 3.89 (s, 3H) 3.93 (s, 6H), 4.45 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz) 6.98 (d, 1H, J = 8.5 Hz), 7.07 (t, 1H, J = 7.6 Hz), 7.15 (s, 2H), 7.15-7.19 ( m, 2H), 7.33-7.38 (m, 1H), 7.57 (s, 1H), 7.66-7.74 (m, 2H), 8.53 (d, 1H, J = 5.1 Hz), 8.61 (d, 1H, J = 4.9 Hz). 174

94% 1.70-1.80 (m, 2H), 1.83-1.91 (m, 2H), 2.11-2.18 (m, 2H), 2.92-3.01 (m, 2H) ), 3.56 (s, 2H), 3.57-3.65 (m, 1H), 3.73 (s, 3H), 3.74 (s, 3H), 3.90 (s, 3H) 3.96 (s, 6H), 4.44 (s, 2H), 6.71 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz) 6.96 (d, 1H, J = 8.3 Hz), 7.05 (dt, 1H, J = 7.3 Hz, 1.0 Hz), 7.14 (d, 1H, J = 5, 2 Hz), 7.20 (d, 1H, J = 5.2 Hz), 7.22 (2H, s), 7.32-7.37 (m, 1H), 7.59 (s, 1H) 7.71-7.75 (m, 2H); 8.56-8.60 (m, 2H). 175

98% 1.67-1.80 (m, 2H), 1.83-1.90 (m, 2H), 2.10-2.19 (m, 2H), 2.94-3.03 (m, 2H) ), 3.50-3.67 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H) 4.44 (s, 2H), 6.70 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 6.96 (d, 1H, J = 8.3 Hz), 6.98 (d, 1H, J = 8.8 Hz), 7.04 (dd, 1H, J = 7.6 Hz, 1.0 Hz), 7.07 (dd , 1H, 7.6, J = 1.0 Hz), 7.12-7.19 (m, 2H), 7.32-7.39 (m, 2H), 7.70-7.75 (m , 4H), 8.58 (d, 1H, J = 5.1 Hz), 8.61 (d, 1H, J = 4.9 Hz). 176

one hundred% 1.68-1.79 (m, 2H), 1.82-1.90 (m, 2H), 2.10-2.19 (m, 2H), 2.90-3.01 (m, 2H) ), 3.56 (s, 2H), 3.56-3.58 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H) 3.93 (s, 6H), 4.45 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz) 6.93-6.99 (m, 1H), 7.15 (s, 2H), 7.16-7.20 (m, 2H), 7.37 (t, 1H, J = 7.8 Hz ), 7.52-7.59 (m, 3H), 7.67 (s, 1H), 8.54 (d, 1H, J = 5.1 Hz), 8.60 (d, 1H, J = 5.1 Hz). 177

one hundred% 1.68-1.79 (m, 2H), 1.83-1.92 (m, 2H), 2.11-2.16 (m, 2H), 2.91-3.02 (m, 2H) ), 3.56 (s, 2H), 3.55-3.65 (m, 1H), 3.73 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H) 3.96 (s, 6H), 4.43 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz) 6.95 (dd, 1H, J = 8.3 Hz, 2.7 Hz), 7.16-7.21 (m, 2H), 7.22 (s, 2H), 7.35 (t, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.53 (t, 1H, J = 2.7 Hz), 7.59 (s, 1H) 7.65 (s, 1H); 8.55-8.60 (m, 2H). 178

one hundred% 1.65-1.79 (m, 2H), 1.82-1.90 (m, 2H), 2.09-2.19 (m, 2H), 2.92-3.00 (m, 2H) ), 3.50-3.66 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 3.73 (s, 3H), 3.88 (s, 3H) , 3.89 (s, 3H), 4.44 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz) 6.92-6.98 (m, 2H), 7.16-7.21 (m, 2H), 7.34 (d, 1H, J = 7.8 Hz), 7.38 (d, 1H , J = 8.5 Hz), 7.46-7.59 (m, 4H), 7.65 (s, 1H), 7.67 (s, 1H), 8.57 (dd, 1H, J = 5.1 Hz, 0.7 Hz), 8.60 (d, 1H, J = 5.1 Hz). 179

76% 1.44 (t, 3H, J = 7.1 Hz), 1.70-1.80 (m, 2H), 1.82-1.91 (m, 2H), 2.10-2.19 ( m, 2H), 2.90-3.02 (m, 2H), 3.54 (s, 2H), 3.73-3.78 (m, 1H), 3.73 (s, 3H), 3 88 (s, 3H), 3.93 (s, 6H), 4.09 (q, 2H, J = 7.1 Hz), 4.45 (s, 2H), 6.73 (d, 2H, J = 9.2 Hz), 6.78 (d, 2H, J = 9.2 Hz), 6.97 (d, 2H, J = 8.8 Hz), 7.10-7.18 (m, 2H), 7.15 (s, 2H), 7.57 (s, 1H), 7.61 (s, 1H), 7.92 (d, 2H, J = 8.8 Hz), 8.52- 8.58 (m, 2H). 180

93% 1.43 (t, 3H, J = 6.8 Hz), 1.68-1.80 (m, 2H), 1.82-1.92 (m, 2H), 2.10-2.19 ( m, 2H), 2.90-3.01 (m, 2H), 3.56 (s, 2H), 3.57-3.64 (m, 1H), 3.73 (s, 3H), 3 90 (s, 3H), 3.96 (s, 6H), 4.08 (q, 2H, J = 6.8 Hz), 4.42 (s, 2H), 6.72 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.3 Hz), 6.95 (d, 2H, J = 8.8 Hz), 7.11 (d, 1H, J = 5.1 Hz), 7.20 (d, 1H, J = 5.1 Hz), 7.22 (s, 2H), 7.58-7.62 (m, 2H), 7.87 (d, 2H, J = 8.8 Hz), 8.52 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 5.1 Hz). 181

one hundred% 1.43 (t, 3H, J = 7.1 Hz), 1.44 (t, 3H, J = 7.1 Hz), 1.67-1.78 (m, 2H), 1.82-1 90 (m, 2H), 2.09-2.18 (m, 2H), 2.92-3.00 (m, 2H), 3.54 (s, 2H), 3.55-3.65 (m, 1H), 3.73 (s, 3H), 4.08 (q, 2H, J = 7.1 Hz), 4.09 (q, 2H, J = 6.8 Hz), 4.42 (s, 2H), 6.71 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 6.93-7.00 (m, 4H) 7.10-7.14 (m, 2H), 7.60 (s, 2H), 7.88 (s, 2H), 7.88 (d, 2H, J = 8.8 Hz), 7, 93 (d, 2H, J = 8.8 Hz), 8.52 (d, 1H, J = 5.1 Hz), 8.56 (d, 1H, J = 4.9 Hz). 182

one hundred% 1.68-1.79 (m, 2H), 1.82-1.90 (m, 2H), 2.10-2.19 (m, 2H), 2.90-3.01 (m, 2H) ), 3.55 (s, 2H), 3.56-3.59 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 3.94 (s, 3H), 3.99 (s, 3H), 4.45 (s, 2H), 6.76 (d, 2H, J = 9.5 Hz), 6.78 (d, 2H, J = 9.5 Hz), 6.94 (d, 1H, J = 8.3 Hz), 7.15 (s, 2H), 7.16-7.19 (m, 2H), 7, 49-7.66 (m, 4H), 8.54 (d, 1H, J = 4.9 Hz), 8.57 (d, 1H, J = 5.1 Hz). 183

one hundred% 1.68-1.78 (m, 2H), 1.82-1.91 (m, 2H), 2.10-2.18 (m, 2H), 2.93-3.00 (m, 2H) ), 3.56 (s, 2H), 3.56-3.62 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H) 3.96 (s, 6H), 3.97 (s, 3H), 4.43 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 6.92 (d, 1H, J = 8.3 Hz), 7.12 (d, 1H, J = 5.1 Hz), 7.20 (d, 1H, J = 5.1 Hz), 7.22 (s, 2H), 7.42 (d, 1H, J = 8.5 Hz, 2.2 Hz), 7.58-7.63 (m, 3H) 8.53 (d, 1H, J = 4.9 Hz); 8.58 (d, 1H, J = 5.1 Hz). 184

89% 1.67-1.79 (m, 2H), 1.84-1.90 (m, 2H), 2.10-2.19 (m, 2H), 2.93-3.01 (m, 2H) ), 3.50-3.65 (m, 1H), 3.55 (s, 2H), 3.73 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H) 3.99 (s, 3H), 4.43 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz) 6.92 (d, 1H, J = 8.6 Hz), 6.94 (d, 1H, J = 8.3 Hz), 7.14 (d, 1H, J = 5.6 Hz), 7 15 (d, 1H, J = 6.4 Hz), 7.43 (dd, 1H, J = 8.6 Hz, 2.0 Hz), 7.50 (dd, 1H, J = 8.3 Hz , 1.9 Hz), 7.60-7.63 (m, 3H), 7.66 (d, 1H, J = 2.2 Hz), 8.53 (d, 1H, J = 5.1 Hz ), 8.57 (d, 1H, J = 4.9 Hz). 185

one hundred% 1.68-1.79 (m, 2H), 1.82-1.90 (m, 2H), 2.10-2.20 (m, 2H), 2.93-3.01 (m, 2H) ), 3.57 (s, 2H), 3.57-3.65 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.46 (s, 2H), 6.73 (d, 2H, J = 7.3 Hz), 6.78 (d, 2H, J = 7.3 Hz), 7.11-7.19 ( m, 2H), 7.15 (s, 2H), 7.22-7.29 (m, 2H), 7.34-7.40 (m, 1H), 7.58 (s, 1H), 7 73 (s, 1H), 7.94 (t, 1H, J = 8.3 Hz), 8.54 (d, 1H, J = 5.1 Hz), 8.64 (d, 1H, J = 4.9 Hz). 186

88% 1.68-1.79 (m, 2H), 1.83-1.92 (m, 2H), 2.09-2.16 (m, 2H), 2.93-3.01 (m, 2H) ), 3.56 (s, 2H), 3.56-3.62 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.44 (s, 2H), 6.71 (d, 2H, J = 9.3 Hz), 6.77 (d, 2H, J = 9.3 Hz), 7.10-7.16 ( m, 1H), 7.17-7.26 (m, 3H), 7.22 (s, 2H), 7.32-7.38 (m, 1H), 7.59 (s, 1H), 7 73 (s, 1H), 7.92 (dt, 1H, J = 8.0 Hz, 2.0 Hz), 8.57-8.61 (m, 2H). 187

one hundred% 1.66-1.80 (m, 2H), 1.83-1.93 (m, 2H), 2.10-2.20 (m, 2H), 2.92-3.02 (m, 2H) ), 3.53-3.65 (m, 1H), 3.57 (s, 2H), 3.73 (s, 3H), 4.44 (s, 2H), 6.71 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.10-7.18 (m, 2H), 7.19-7.29 (m, 4H), 7.32-7.40 (m, 2H), 7.73 (s, 2H), 7.91 (dd, 1H, J = 8.1 Hz, 1.4 Hz), 7.95 (dd, 1H , J = 7.6 Hz, 1.5 Hz), 8.60 (d, 1H, J = 4.9 Hz), 8.64 (d, 1H, J = 5.1 Hz). 188 F

96% 1.67-1.80 (m, 2H), 1.82-1.92 (m, 2H), 2.10-2.20 (m, 2H), 2.91-3.01 (m, 2H) ), 3.56 (s, 2H), 3.56-3.61 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.46 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.06-7.19 ( m, 2H), 7.15 (s, 2H), 7.20-7.26 (m, 1H), 7.38-7.45 (m, 1H), 7.56 (s, 1H), 766 -7.78 (m, 3H), 8.54 (d, 1H, J = 5.1 Hz), 8.61 (d, 1H, J = 4.9 Hz). 189

92% 1.65-1.78 (m, 2H), 1.79-1.92 (m, 2H), 2.21-2.26 (m, 2H), 2.90-3.01 (m, 2H) ), 3.56 (s, 2H), 3.56-3.63 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.44 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.08 (dt, 1H, J = 8.3 Hz, 1.7 Hz), 7.18-7.40 (m, 2H), 7.22 (s, 2H), 7.37-7.43 (m, 1H), 7, 56-7.72 (m, 4H); 8.55-8.60 (m, 2H). 190

55% 1.66-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.10-2.20 (m, 2H), 2.88-3.01 (m, 2H) ), 3.50-3.66 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 4.45 (s, 2H), 6.72 (d, 2H, J = 8.5 Hz), 6.79 (d, 2H, J = 9.0 Hz), 7.04-7.13 (m, 2H), 7.19-7.25 (m, 2H), 7.35-7.46 (m, 2H), 7.62-7.79 (m, 6H), 8.57 (d, 1H, J = 5.1 Hz), 8.61 (d, 1H, J = 4.9 Hz). 191

one hundred% 1.68-1.79 (m, 2H), 1.82-1.91 (m, 2H), 2.10-2.19 (m, 2H), 2.92-3.00 (m, 2H) ), 3.55 (s, 2H), 3.56-3.63 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.45 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.11-7.19 ( m, 4H), 7.15 (s, 2H), 7.57 (s, 1H), 7.63 (s, 1H), 7.92-8.01 (m, 2H), 8.54 (d , 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 5.1 Hz). 192

one hundred% 1.68-1.79 (m, 2H), 1.83-1.92 (m, 2H), 2.11-2.19 (m, 2H), 2.93-3.01 (m, 2H) ), 3.56 (s, 2H), 3.57-3.62 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.43, (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.10-7.22 (m, 4H), 7.22 (s, 2H), 7.54-7.66 (m, 2H), 7.88-7.94 (m, 2H), 8.55 (d, 1H, J = 4.9 Hz), 8.58 (d, 1H, J = 4.9 Hz). 193

90% 1.66-1.80 (m, 2H), 1.83-1.91 (m, 2H), 2.10-2.19 (m, 2H), 2.92-3.00 (m, 2H) ), 3.50-3.66 (m, 1H), 3.55 (s, 2H), 3.73 (s, 3H), 4.44 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 7.78 (d, 2H, J = 9.3 Hz), 7.09-7.20 (m, 6H), 7.62 (s, 1H), 7.63 ( s, 1H), 7.89-8.00 (m, 4H), 8.55 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 4.9 Hz). 194

36% 1.68-1.80 (m, 2H), 1.82-1.90 (m, 2H), 2.11-2.19 (m, 2H), 2.91-2.99 (m, 2H) ), 3.55 (s, 2H), 3.56-3.62 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.45 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.15 (s, 2H) 7.16-7.26 (m, 3H), 7.57 (s, 1H), 7.62 (s, 1H), 7.71 (br, 1H), 7.80-7.90 (m , 1H), 8.54 (d, 1H, J = 5.1 Hz), 8.58 (d, 1H, J = 4.9 Hz). 195

one hundred% 1.60-1.80 (m, 2H), 1.82-1.91 (m, 2H), 2.12-2.19 (m, 2H), 2.91-3.00 (m, 2H) ), 3.56 (s, 2H), 3.56-3.64 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.45 (s, 2H), 6.72 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 7.17-7.24 ( m, 4H), 7.25-7.27 (m, 1H), 7.60 (s, 2H), 7.65 (br, 1H), 7.77-7.84 (m, 1H), 8 53-8.61 (m, 2H). 196

one hundred% 1.66-1.79 (m, 2H), 1.82-1.91 (m, 2H), 2.09-2.20 (m, 2H), 2.90-3.00 (m, 2H) ), 3.50-3.65 (m, 1H), 3.55 (s, 2H), 3.73 (s, 3H), 4.44 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.79 (d, 2H, J = 9.3 Hz), 7.18-7.28 (m, 4H), 7.60 (s, 1H), 7.62 ( s, 1H), 7.63-7.68 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.89 (m, 2H), 8.55 (d, 1H, J = 4.9 Hz), 8.58 (d, 1H, J = 5.1 Hz). 197

one hundred% 1.68-1.80 (m, 2H), 1.82-1.90 (m, 2H), 2.10-2.21 (m, 2H), 2.90-3.00 (m, 2H) ), 3.56 (s, 2H), 3.56-3.63 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.56 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 6.81-6.87 ( m, 1H), 7.15 (s, 2H), 7.18 (d, 1H, J = 4.2 Hz), 7.22-7.26 (m, 1H), 7.51-7.59 (m, 3H), 7.65 (s, 1H), 8.54 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 5.1 Hz) 198

one hundred% 1.65-1.79 (m, 2H), 1.80-1.94 (m, 2H), 2.22-2.25 (m, 2H), 2.90-3.05 (m, 2H) ), 3.56 (s, 2H), 3.56-3.65 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.44 (s, 2H), 6.72 (d, 2H, J = 9.2 Hz), 6.78 (d, 2H, J = 9.2 Hz), 6.80-6.94 ( m, 2H), 7.22 (s, 2H), 7.19-7.28 (m, 1H), 7.45-7.51 (m, 2H), 7.59 (s, 1H), 7 62 (s, 1H), 8.56 (d, 1H, J = 4.9 Hz), 8.59 (d, 1H, J = 5.1 Hz). 199

one hundred% 1.67-1.79 (m, 2H), 1.82-1.92 (m, 2H), 2.12-2.20 (m, 2H), 2.92-2.99 (m, 2H) ), 3.50-3.65 (m, 1H), 3.56 (s, 2H), 3.73 (s, 3H), 4.45 (s, 2H), 6.72 (d, 2H, J = 9.0 Hz), 6.79 (d, 2H, J = 9.3 Hz), 6.80-6.88 (m, 2H), 7.23-7.27 (m, 2H), 7.48 (dd, 2H, J = 8.8 Hz, 2.2 Hz), 7.55 (dd, 2H, J = 8.8 Hz, 2.2 Hz), 7.63 (s, 1H) 7.65 (s, 1H); 8.57 (d, 1H; J = 4.9 Hz); 8.60 (d, 1H; J = 4.9 Hz). 200

84% 1.68-1, 80 (m, 2H), 1.83-1.92 (m, 2H), 2.10-2.21 (m, 2H), 2.91-3.00 (m, 2H) ), 3.56 (s, 2H), 3.57-3.62 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.93 (s, 6H) 4.45 (s, 2H), 6.73 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.15 (s, 2H) 7.17 (d, 1H, J = 4.9 Hz), 7.20 (d, 1H, J = 5.1 Hz), 7.43 (d, 2H, J = 8.3 Hz), 7 , 57 (s, 1H), 7.65 (s, 1H), 7.93 (d, 2H, J = 8.3 Hz), 8.54 (d, 1H, J = 4.9 Hz), 8 59 (d, 1H, J = 5.1 Hz). 201

72% 1.65-1.78 (m, 2H), 1.82-1.91 (m, 2H), 2.10-2.16 (m, 2H), 2.91-3.02 (m, 2H) ), 3.56 (s, 2H), 3.56-3.64 (m, 1H), 3.73 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H) 4.43 (s, 2H), 6.72 (d, 2H, J = 9.3 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.17-7.21 ( m, 1H), 7.22 (2H, s), 7.41 (d, 2H, J = 8.7 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.59 ( s, 1H), 7.63 (s, 1H) 7.87 (d, 2H, J = 8.7 Hz), 8.56 (d, 1H, J = 4.9 Hz), 8.58 (d , 1H, J = 5.1 Hz). 202

94% 1.67-1.88 (m, 2H), 1.83-1.90 (m, 2H), 2.10-2.17 (m, 2H), 2.92-2.99 (m, 2H) ), 3.50-3.65 (m, 1H), 3.55 (s, 2H), 3.73 (s, 3H), 4.44 (s, 2H), 6.72 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.3 Hz), 7.17-7.22 (m, 2H), 7.39-7.45 (m, 4H), 7.63 (s, 1H), 7.65 (s, 1H), 7.88 (d, 2H, J = 8.6 Hz), 7.93 (d, 2H, J = 8.5 Hz), 8.56 (d, 1H, J = 4.9 Hz); 8.59 (d, 1H, J = 4.9 Hz).

Production 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 (52 mg, obtained in Production Example 145) was dissolved in dichloromethane (1 ml ) and 3-chloroperbenzoic acid (69 mg) is added to the resulting solution at 0 ° C. After the mixture was allowed to warm to room temperature and stirring for 3 hours, saturated sodium bicarbonate solution was added. After separation of the organic layer, the aqueous layer was extracted with chloroform. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting pale yellow oil was used in the next step 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) pyridine synthesis -4-yl] methyl] piperidine

The crude 4- [N- [3- (3,4,5-trimethoxyphenyl) benzyl] -N- [4- (methylsulfonyl) phenyl] amino] piperidine obtained in Production Example 226 is reacted with 4-chloromethyl-2- (3,4,5-trimethoxyphenyl) pyridine (29 mg) according to a similar manner to that described in Example 2. After the obtained free base was converted to the corresponding dihydrochloride, the title compound was obtained as a pale yellow powder.

Yield 23 mg (26% in two stages).

¹ H-NMR (400 MHz, defined 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 = 9.3 Hz), 7.19-7.30 (m, 7H), 7.39 (dd, 1H, J = 7.6 Hz, 7.6 Hz) 7.60 (s, 1H); 7.68 (d, 2H; J = 9.0 Hz); 8.60 (d, 1H; J = 4.9 Hz).

Example 204

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

4- [N- (4-methoxyphenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (139 mg, see Production Example 98) is reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70 mg, see Production Example 195) according to the procedure similar to that described in Example 2, to obtain the title compound as trihydrochloride.

Yield 131 mg (66%).

¹ H-NMR (400 MHz, defined 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 = 8.3 Hz), 7.21 (br, 1H), 7.38 (t, 1H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.59 (s, 1H), 7.63-7.75 (m, 2H), 8, 50 (s, 1H); 8.62 (broad, 1H).

Example 205

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

4- [N- (4-methoxyphenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (139 mg, see Production Example 98) is reacted with 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (80 mg, see Production Example 197) according to the procedure similar to that described in Example 2, to obtain the title compound as trihydrochloride.

Yield 139 mg (67%).

¹ H-NMR (400 MHz, defined 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 = 8.3 Hz), 7.15 (br, 1H), 7.52 (br, 1H), 7.58-7.71 (m, 3H), 8.50 (s, 1H ), 8.57 (d, 1H, J = 5.2 Hz), 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) trihydrochloride pyridin-4-yl] methyl] piperidine

4- [N- (4-fluorophenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (135 mg, see Production Example 183) is reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (70 mg, see Production Example 195) according to the procedure similar to that described in Example 2, to obtain the title compound as trihydrochloride.

Yield 178 mg (92%).

¹ H-NMR (400 MHz, defined 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 (broad, 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 = 8.3 Hz), 6.96 (d, 1H, J = 8.3 Hz), 7.21 (br, 1H), 7.38 (t, 1H, J = 8.0 Hz), 7.54 (d, 1H, J = 7.8 Hz), 7.58 (s, 1H), 7.65 (s, 1H), 7.74 (br, 1H), 8.50 (s, 1H), 8.61 (d, 1H, J = 5.1 Hz), 8 65 (broad, 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

4- [N- (4-fluorophenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (135 mg, see Production Example 183) is reacted with 4-chloromethyl-2- (3,4-dimethoxyphenyl) pyridine (80 mg, see Production Example 197) according to the procedure similar to that described in Example 2, to obtain the title compound as trihydrochloride.

Yield 195 mg (96%).

¹ H-NMR (400 MHz, defined as free base, CDCl ₃ ) 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 (broad, 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 = 4.9 Hz), 7.51 (d, 1H, J = 8.5 Hz), 7.60-7.70 (m, 3H), 8.50 (s, 1H), 8.58 (d, 1H, J = 4.9 Hz), 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

4- [N- (3,4-difluorophenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (160 mg, see Production Example 176) reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (80 mg, see Production Example 195) according to the procedure similar to that described in Example 2, to obtain the title compound as trihydrochloride.

Yield 130 mg (57%).

¹ H-NMR (400 MHz, defined 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 (broad, 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 = 7.8 Hz), 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 = 2.0 Hz).

Example 209

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

4- [N- (4-methylthiophenyl) -N - [[3- (3,4,5-trimethoxyphenyl) pyridin-5-yl] methyl] amino] piperidine dihydrochloride (121 mg, see Production Example 143) is reacted with 4-chloromethyl-2- (3-methoxyphenyl) pyridine (55 mg, see Production Example 195) according to the procedure similar to that described in Example 2, to obtain the title compound.

Yield 71 mg (44%).

¹ H-NMR (400 MHz, defined 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 = 10.8 Hz), 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 = 7.8 Hz, 1.9 Hz ), 7.17-7.26 (m, 4H), 7.35 (t, 1H, J = 7.8 Hz), 7.51-7.66 (m, 4H), 8.47 (s, 1H), 8.59 (d, 1H, J = 4.6 Hz), 8.63 (s, 1H).

Test Example 1

(inhibitory effect on cell adhesion)

The test is carried out according to a method similar to that described by Ross et al. (J. Biol. Chem., 267 , 8537-8543 (1992)). More specifically, after culturing in a 48-well plate of human umbilical vein endothelial cells (HUVEC), TNFα is added to confluent growth. 5 hours after this addition, U937, a monocytic / histocytic leukocyte fluorescently labeled with PKH2 (product of Sigma-Aldrich Co., Ltd.), was added in an amount of 1 × 10 ⁶ cells per well. After the tablet is at rest at room temperature for an hour, non-adherent U937 is washed and lysed in 1% Triton X-100 to measure the remaining fluorescence intensity (excitation wavelength 480 nm; measurement wavelength 530 nm). HUVEC and U937 were cultured in EGM-2 (product Sanko Junyaku KK) and RPMI1640 containing 10% FCS (fetal calf serum), respectively. Each test agent is added to HUVEC after the addition of TNFα and to U937 24 hours before the start of the cell adhesion test. The degree of inhibition is determined in accordance with the equation (AC) / (AB) × 100 (%), where A is the number of U937 cells adhering to HUVEC stimulated by TNF without adding the test agent, B is equal to the number of U937 cells adhering to HUVEC not stimulated with TNFα without the addition of the test agent, and C is equal to the number of U937 cells adhering to HUVEC stimulated with TNFα with the addition of the test agent. The results are presented in the table. As control compounds, the test compound 1, described in Japanese Patent Laid-open Application No. 9-143075, and the diazep described in Japanese Patent Laid-open Application No. 11-92382, were simultaneously evaluated.

Example IC ₅₀ (μm) 3 0.3 5 0.2 7 0.3 10 0.04 13 0,03 16 0.3 19 0.3 23 0,03 29th 0,03 36 0.2 40 0.2 42 0,07 67 0.09 88 0,07 89 0.09 111 0.08 157 0.09 Test compound 1 10 Dilazep > 10

As indicated above, the compound of the present invention is characterized in that the cyclic amine contains phenylpyridyl or biphenyl groups at both ends of the molecule.

The inhibitory effect on cell adhesion of a cyclic amine compound containing pyridyl groups at its both ends, obtained in Production Example 91, was determined in accordance with the above procedure. As a result, this compound did not exhibit an inhibitory effect on cell adhesion even at a concentration as high as 10 μM.

The following are examples of specific compositions.

Formulation Example 1 (capsule preparation) The compound obtained in example 13 30 mg Microcrystalline cellulose 30 mg Lactose 57 mg Magnesium stearate 3 mg Total amount 120 mg

The above ingredients are mixed according to the method known in the art per se, and then placed in gelatin capsules to obtain capsule preparations.

Formulation Example 2 (tablet preparation) The compound obtained in example 13 30 mg Starch 44 mg Starch (for bonding) 5.6 mg Magnesium stearate 0.4 mg Calcium Carboxymethyl Cellulose 20 mg Total amount 100 mg

The above ingredients are mixed according to a method known in the art per se to formulate tablets.

Formulation Example 3 (injection)

The compound obtained in Example 13 (100 mg) and sodium chloride (900 mg) are dissolved in distilled water (about 80 ml) for injection, and distilled water is added to the resulting solution to a total amount of 100 ml. The resulting diluted solution is sterilized by filtration and then divided into doses and placed in 10 ampoules, after which the ampoules are sealed, receiving preparations for injection.

Industrial applicability

As indicated above, the compounds (1) in accordance with the present invention exhibit an inhibitory effect both against cell adhesion and cell infiltration, and can be useful as drugs for the prevention or treatment of allergies, asthma, rheumatism, arteriosclerosis, inflammatory diseases, syndrome Sjogren etc.

Claims (10)

1. The cyclic amine compound represented by the following general formula (1):

where each of R ¹ , R ² and R ³ independently represents a hydrogen atom, a halogen atom, a hydroxy group, a C ₁ -C ₈ alkoxy group; each of W ¹ and W ² independently represents N or CH; X represents O, NR ⁴ , CONR ⁴ or NR ⁴ CO; R ⁴ represents a hydrogen atom, C ₁ -C ₈ alkyl, C ₃ -C ₆ alkynyl, unsubstituted or substituted phenyl, unsubstituted benzyl, unsubstituted indanyl, where phenyl substituent (s) are 1-3 groups or atoms, selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxy, substituted with 1-3 halogen atoms, C ₁ -C ₈ alkylthio group, C ₁ -C ₈ alkylsulfonyl, halogen atom, trifluoromethyl group and C ₁ -C ₃ alkylenedioxy groups; and each of l, m and n represents the number 0 or 1, its pharmaceutically acceptable salt or hydrate. 2. The compound according to claim 1, where W ² represents N. 3. A medicament having an inhibitory effect on cell adhesion and / or cell infiltration, containing, as an active ingredient, a compound according to any one of claims 1 and 2. 4. The drug according to claim 3 for the treatment of a disease selected from allergies, asthma, inflammation, rheumatic disease, arteriosclerosis and Sjogren's syndrome. 5. A pharmaceutical composition having an inhibitory effect on cell adhesion and / or cell infiltration, comprising a compound according to any one of claims 1 and 2, and a pharmaceutically acceptable carrier. 6. The pharmaceutical composition according to claim 5 for the treatment of a disease selected from allergy, asthma, inflammation, rheumatic disease, arteriosclerosis and Sjogren's syndrome. Priority on points and signs: 08/30/2001 according to claims 1-6, variations in the definitions of the radicals R ¹ , R ² and R ³ , W ¹ and W ² , R ⁴ , l, m and n; 10.26.2001 according to claims 1-6, variations of the definitions of the radicals R ¹ , R ² and R ³ , W ¹ and W ² , R ⁴ , l, m and n; 03/28/2002 according to claims 1-6, variations of the definitions of the radicals R ¹ , R ² and R ³ , W ¹ and W ² , R ⁴ , l, m and n; 07/10/2002 according to claims 1-6, variations of the definitions of the radicals R ¹ , R ² and R ³ , W ¹ and W ² , R ⁴ , l, m and n.